OA17311A - Aminocyclobutane derivatives, their preparation process and their use as medicaments. - Google Patents

Abstract

The present invention relates to aminocyclobutane derivatives, in particular as NMDA receptor antagonists, their application in human therapy, and their preparation process. These compounds correspond to the general formula (1) <img file="OA17311A_A0001.tif"/> wherein: X1 represents a hydrogen atom or a fluorine atom; X2 is a hydrogen atom or a fluorine atom or a chlorine atom; R1 represents a hydrogen atom or a fluorine atom or a chlorine atom or a methyl group or a methoxy group or a cyano group; R2 represents, together or separately, a methyl group or an ethyl group.

Description

Aminocyclobutane derivatives, their preparation process and their use as medicaments

The present invention relates to aminocyclobutane derivatives, as well as to a process for their preparation and their use in human therapy.

Glutamate receptors of the NMDA (N-methyl-D-aspartic acid) subtype are ionotropic receptors, primarily permeable to Ca ⁺⁺ ions. Physiologically, their activation triggers the opening of an ion channel and the production of an inward current that inactivates only slowly. Stimulation of this receptor requires the simultaneous presence of glutamate (endogenous agonist) and glycine or D-serine (endogenous co-agonists) as well as depolarization of the plasma membrane initiated by non-NMDA currents. NMDA receptors are abundant in the central nervous system and are also present in the periphery. They are found in neurons, astrocytes, and oligodendrocytes (Karadottir et al., 2005, Nature, 438, 1162-1166). At the neuronal level, they are located mainly at the postsynaptic level, but also in extrasynaptic regions along axons. NMDA receptors play a key role in neuronal communication and plasticity, as well as in exitotoxicity.

Physiological activity of NMDA receptors is essential for normal neuronal function (Chen et

Lipton, 2006, J. Neurochem., 97, 1611-1626). On the other hand, over-activation of these receptors is involved in acute neuronal damage, for example stroke or head trauma.

λ in chronic stress conditions, for example neurodegenerative diseases. It is also one of the main causes of hyperexcitability that leads to epileptic seizures. The pathologies considered to be associated with hyperactivity of NMDA receptors, and therefore potentially sensitive to NMDA antagonists, are numerous. Examples include: epilepsy, neurodegenerative diseases such as Huntington's disease, Parkinson's disease, Alzheimer's disease, stroke, amyotrophic lateral sclerosis or multiple sclerosis, AIDS dementia, anxiety, depression and pain syndromes.

In the present invention, the Applicant is particularly interested in the antidepressant and analgesic properties of the NMDA receptor antagonists of formula (1).

The term chronic pain, as used in this patent application, covers pain syndromes that last for more than three months, but whose intensity may vary over time. On the other hand, the term acute pain refers to pain that lasts for less than three months.

For the purposes of the present invention, pain is defined as an abnormal, unpleasant, or even distressing sensory and emotional experience that is perceived and integrated at the highest level of the cerebral cortex, giving it its emotional and affective tone. Analgesia means a reduction in the intensity of pain felt in response to a painful stimulus. Analgesic drugs (or painkillers) mean drugs that relieve or eliminate pain without

" "cause loss of sensation or consciousness.

Pain of different etiologies requires different therapeutic strategies. Generally, several types of pain are distinguished, classified according to the mechanisms involved:

- pain due to excess nociception results from lesions or excitations (for example inflammation) of peripheral or visceral tissues;

neuropathic (or neurogenic) pain is linked to a lesion or dysfunction or disturbance of the somatosensory system; it is distinguished from nociceptive pain by a different semiology;

- Psychogenic (or idiopathic) pain is pain that exists in the absence of lesions. The physiological mechanisms of this pain are not clearly defined. It is generally resistant to analgesics.

Some pains, however, have characteristics common to several types of pain. This is the case, for example, of lower back pain or cancer pain, which presents as pain due to excess nociception or neuropathic pain, or most often a combination of pain.

Depression is defined in psychiatry as a mood disorder. It is characterized by a loss of motivation, with or without associated symptoms, such as a loss of hope, self-esteem, anxiety, anguish, and, in some extreme cases, hallucinations. It is often multifactorial and its causes are generally multiple.

»

It is reported that approximately 7% of Europeans are affected by it and that a third of them are resistant to clinically used antidepressants. The cost of depression to society in 15-44 year olds is among the highest of all known pathologies. One objective of the present invention is precisely to describe new NMDA antagonists that exhibit advantageous properties in this indication for which existing treatments are not entirely satisfactory.

Chronic administration of antidepressants with different mechanisms of action: monoamine oxidase inhibitors, tricyclics, serotonin uptake inhibitors (SSRIs), or mixed serotonin and norepinephrine inhibitors (SNRIs), has been shown in mice to modify the distribution and density of NMDA receptors. In rats, acute intraperitoneal administration of ketamine, an NMDA receptor antagonist, reduces immobility time in the forced swim test, a preclinical model recognized for demonstrating the antidepressant activity of molecules. In addition, recent studies indicate that ketamine has antidepressant properties in humans. Thus, the administration of a single sub-anesthetic dose of ketamine intravenously in patients with resistant depression significantly improves their condition, just 2 hours after injection. The antidepressant effects obtained are, moreover, maintained for more than a week (Zarate et al., 2006, Arch. Gen. Psychiatry, 63, 856-864). This rapidity of action contrasts with the delay in action observed with classics, i.e. first-generation tricyclic antidepressants, SSRI or SNRI, which require several weeks of treatment before showing any possible benefit. It therefore appears that NMDA receptor antagonists, and in particular ketamine, are effective in the treatment of depression and in particular in the treatment of depression resistant to existing medications.

The therapeutic needs in the treatment of pain are considerable. Indeed, an incalculable number of individuals suffer from acute pain, and more than one in five adults, in Europe as in the United States, suffer from chronic pain (Johannes et al., 2010, J. Pain, 11, 1230-1239). The object of the present invention is to describe the advantageous analgesic properties possessed by the compounds of formula (1) and the therapeutic perspectives that they open up in the field of the treatment of acute and chronic pain.

Numerous animal and human studies have shown that NMDA receptor antagonists such as ketamine can relieve pain of multiple etiologies, such as neuropathic, postoperative, or cancer pain (Cohen et al., 2011, Adv. Psychosom. Med., 30, 139-161). For example, intravenous ketamine reduces neuropathic pain in patients resistant to conventional antidepressant treatment. It also improves allodynia and hyperalgesia in patients with CRPS (complex regional pain syndrome) (Finch et al., 2009, Pain, 146, 1825). As an adjuvant, ketamine administered at low doses perioperatively reduces analgesic consumption and limits acute tolerance to morphine in the postoperative period (Elia and Tramer, 2005, Pain, 113, 61-70).

As a preventive treatment, ketamine and dextromethorphan (another NMDA antagonist) improve postoperative pain management (Muir, 2006, Current Opinion in Pharmacology, 6, 53-60). Ketamine also appears to prevent the occurrence of chronic postsurgical pain (Wilder-Smith et al., 2002, Pain, 97, 189194). However, results obtained with other NMDA antagonists such as amantadine or MK-801 in neuropathic pain have not been conclusive (Muir, 2006, already cited).

The opening of NMDA channels causes an increase in intracellular calcium which activates, among others, NO synthetase and type II cyclooxygenase, which are responsible for the synthesis of prostaglandins (PGs). NMDA antagonists, through the inhibition of PGs, particularly PGE2, therefore have a direct action on the regulation of the inflammatory state (Beloeil et al., 2009, Anesth. Analg., 109, 943-950). This complementary anti-inflammatory activity of NMDA antagonists may be advantageous for the treatment of acute or chronic pain of inflammatory origin. Similarly, NMDA receptors are expressed in chondrocytes and participate in the mechanical function of these cells (Salter et al., 2004, Biorheology, 41, 273281). They appear to be particularly involved in their proliferation and in the inflammation leading to the destruction of articular cartilage (Piepoli et al., 2009, Osteoarthritis and Cartilage, 17, 1076-1083). As the latter does not regenerate in adults, the use of an NMDA antagonist therefore seems particularly advantageous in preventing or slowing down the destruction of articular cartilage occurring in pathologies such as,

example, inflammatory monoarthritis, rheumatoid arthritis, septic arthritis, osteoarthritis, rheumatoid polyarthritis, gout, spondylarthritis, acute abarticular rheumatism.

However, the usefulness of NMDA antagonists in human clinical practice is limited by their adverse effects, particularly at the central nervous system level and especially during repeated treatments. Examples of side effects of NMDA antagonists include: hallucinations, confusion, personality disorders, nightmares, agitation, impaired concentration, mood changes, seizures, sedation, drowsiness, nausea (Aarts and Tymianski, 2003, Biochem. Pharmacol., 66, 877-886). These side effects result from the fact that NMDA antagonists not only block excessive activation of the glutamate/NMDA system, but also disrupt its normal physiological function. In practice, it therefore appears essential to improve the benefit/risk ratio of clinically available NMDA antagonists.

When the type of pain to be treated lends itself to it, as for example in the case of arthritis, the benefit/risk ratio of the NMDA antagonist can be improved by limiting its action on the central nervous system, for example by means of a topical application. The concentration of the compound at the target tissue level is then much higher than its concentration in the blood, thus reducing the risks of toxicity. Several NMDA antagonists have thus been studied by epidural or topical route. Thus, ketamine in local application has shown efficacy in the treatment of neuropathic pain not relieved by conventional medications. Different combinations between an NMDA antagonist and one or more other analgesic agents have also been studied in local application. For example, ketamine or other NMDA antagonists have been combined with antidepressants or antihypertensives (US 6,387,957); antiepileptics (WO 03/061656, WO 98/07447, WO 99/12537, US 20040204366, WO 2010036937); adrenergic agonists (US 20040101582); or opioids (WO 2000003716).

Given the essential role played by receptors

NMDA in many psychiatric and neurological pathologies, they have been the subject of intensive research and a multitude of antagonists/blockers/modulators have been described.

Schematically, they can be classified into three main families according to their site of action on the NMDA receptor. We thus distinguish:

1) competitive antagonists that target either glutamate binding sites, e.g., selfotel, perzinfotel and prodrugs (WO 2009029618); or glycine binding sites, e.g., gavestinel, GV-196771 (Wallace et al., 2002, Neurology, 59, 1694-1700) and quinolines reported in patent application WO 2010037533. This category includes partial agonists of the 25 glycine site such as D-cycloserine (US 2011160260).

2) non-competitive (or allosteric) antagonists which act at the level of the numerous modulatory sites of receptor regulation, such as for example polyamines, belonging to this group studied in clinical practice.

phenylethanolamines family are currently

The sites of the most One of the leaders is ifenprodil^ • · (23210-56-2) and derivatives more selective than the latter for the NMDA receptor are under clinical evaluation, such as traxodopril, RGH-896, MK-0657, EVT-101 and EVT-103 (Mony et al., 2009, Br. J. Pharmacol., 157, 1301-1317).

3) non-competitive antagonists, blockers of the canal pore. This is the family that has had the most clinical success since the anesthetic/analgesic), the cough suppressant), memantine ketamine (Ketalar®), dextromethorphan (Atuxane®, (Ebixa®, anti-Alzheimer),

amantadine (Mantadix®, antiviral then antiparkinsonian).

felbamate (Taloxa®, anticonvulsant) are marketed. Phencyclidine (Sernyl®) developed as an anesthetic has been withdrawn from the market and dizocilpine (MK

801) is not marketed as a medicine.

The compounds of the invention belong to this latter family of non-competitive antagonists, blockers of the NMDA receptor channel. A major advantage of compounds of this type lies in the fact that they only block the channel when the latter is open, and are therefore all the more effective when the activity of the NMDA receptor is excessive. It is also easy to understand that the biophysical characteristics of the blocker/antagonist, which will condition the frequency and duration of opening of the channel, will play a determining role in its pharmacological activity and its benefit/risk ratio. Several compounds of this type are in clinical studies such as, for example, CNS-5161 (160754-76-7), neramexane (21981059-0), dimiracetam (126100-97-8), V-3381 (1104525-45-2),

NEU-2000 (640290-67-1). Others are in the preclinical stage, including, for example, oxazolidines^ « «

IO claimed in patent application WO 2009092324, indanes (WO 2009069610), diarylethylamines (WO 2010074647), arylcyclohexylamines (WO 2010142890), ketamine and phencyclidine analogues (Zarantonello et al., 2011, Bioorg. Med, Chem. Lett. _f 21, 2059-2063).

The present invention relates to the derivatives represented by the general formula (1):

in which:

- 11th represents an atom hydrogen or an atom of fluorine • r - X ₂ is an atom hydrogen or a fluorine atom or A atom of chlorine; - RI represents an atom hydrogen or an atom of fluorine Or a chlorine atom or a methyl group or A

methoxy group or a cyano group;

R2 represents together or separately a methyl group or an ethyl group.

Preferably, the compounds of general formula (1) according to the invention are those in which:

- Xi represents a hydrogen atom or a fluorine atom;

- X ₂ is a hydrogen atom or a fluorine atom or a chlorine atom;

- RI represents a hydrogen atom or a fluorine atom or a chlorine atom or a methyl group or a methoxy group or a cyano group;

- R2 is an ethyl group.

The compounds of the invention may occur as pure diastereoisomers or mixtures of diastereoisomers. More specifically, the invention relates to pure diastereoisomers in which the 1-carboxamide group and the 3-amino group occupy opposite faces of the plane defined by cyclobutane. This stereochemical relationship between said substituents is referred to as 'trans' in the present invention. The invention therefore relates to pure trans diastereoisomers of the following products:

- trans-3-amino-N,N-diethyl-1phenylcyclobutanecarboxamide,

- trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide

- trans-3-amino-N,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide,

- trans-3-amino-N,W-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide,

- trans-3-amino-AT,N-diethyl-l- (3-fluorophenyl) cyclobutanecarboxamide,

- trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide,

- trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide,

- trans-3-amino-N, N-diethyl-1-(3-cyanophenyl)cyclobutanecarboxamide,

- trans-3-amino-N, W-diethyl-1-(2-fluoro-3chlorophenyl)-cyclobutanecarboxamide,

- trans-3-amino-JV, W-diethyl-l-(2,5-difluorophenyl)cyclobutanecarboxamide,

- trans-3-amino-N, N-diethyl-1-(3,5-difluorophenyl)cyclobutanecarboxamide,

- trans-3-amino-W, N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide and their pharmaceutically acceptable salts.

By pure diastereoisomers it is understood that the 'trans' diastereoisomer of the compound of general formula (1) contains less than 5% of the 'cis' diastereoisomer, i.e. the one in which the 1-carboxamide group and the 3-amino group occupy the same half-space of the plane defined by cyclobutane.

For the purposes of the present invention, diastereoisomers are understood to mean stereoisomers which are not mirror images of each other.

For the purposes of the present invention, the term "stereoisomers" means isomers of identical constitution but which differ in the arrangement of their atoms in space.

The closest state of the art is represented by the derivatives described in patent application WO 2003063797 and corresponding to the following formula:

in which:

m and p are independently equal to 0, 1, 2 or 3;

the dotted bond possibly represents a double bond when the Ria group is absent

RI can be a group NR ₆ Rî with Rê and R? possibly representing a hydrogen atom;

Ria can be a hydrogen atom;

R2 may be a substituted or unsubstituted aryl group;

J can be a liaison;

R3 may be a -C(Zi)-Rs group with Rs optionally representing an NReaR?a group;

R ₆ a and R?a optionally represent a substituted or unsubstituted alkyl group and Zi optionally representing a carbonyl group (C=O);

Rx can be one or more substituted or unsubstituted groups attached to all available ring carbon atoms but also a hydrogen atom.

This patent application therefore covers a considerable number of compounds, including a large number of cyclobutane-type derivatives (m = O and p = 1). Of these, only four are exemplified in the said patent. These are compounds with the following formula:

/

in which G is a group NH ₂ or N(CH3) ₂ or NH(CH ₂ CH3) or NH (CH ₂ CHCH ₂ ) The compounds of this patent application are claimed to be inhibitors of the current produced by voltage-dependent potassium channels of the Kvl type and in

particularly that produced by the Kvl.5 isoform.

They are presented as useful in a wide range of indications that do not include the treatment of depression and pain.

It is important to mention that the compounds of the present invention do not interact with potassium channels and in particular with those of the Kvl.5 type. In addition, the NMDA antagonist activity of the compounds of the invention proves to be very sensitive to structural modifications of the compounds of formula (1). Thus, the NMDA antagonist activity is abolished when:

1) the 1-carboxamide function is reduced to a 1-aminomethyl function, such as that of the cyclobutane compounds of patent WO 2003/063797;

2) the amino group at position 3 on cyclobutane is different from a primary amine group (NH ₂ ). In patent application WO 2003063797, the 3-amino group is substituted by a C(G)=NCN group;

3) cis stereochemistry between the 1-aryl and 3-amino groups is not respected. Indeed, when the 1-aryl and 3-amino groups are of trans stereochemistry, the corresponding compounds have no affinity for the NMDA receptor.

The state of the art is also represented by the derivatives described in patent application WO 99/52848 and corresponding to the following formula:

R3

X in which:

X is different from a hydrogen atom;

A can be an NR ₇ group with R? other than a hydrogen atom;

R3 may be a group CfOJNRgRio in which Rg and Rio may be C1- _C4 alkyl chains. Said compounds are claimed to be selective inhibitors of type 4 phosphodiesterases, useful for treating inflammatory and autoimmune diseases. The compounds of the present invention are therefore distinguished from those described in WO 99/52848 both by their chemical structure and their pharmacological activity.

The state of the art is also represented by the derivatives described in patent application WO 2010/112597 and having the general formula:

R1 in which:

a may be a simple bond;

Ar represents a substituted or unsubstituted phenyl group, or a pyridin-3-yl ring substituted by one or more halogen atoms or alkyl groups or alkoxide groups or by a cyano group;

RI and R2 may together or independently represent a C1-C6 alkyl group.

Unlike the compounds of patent application WO 2010/112597, those of the present invention do not have affinity for serotonin reuptake sites and

of norepinephrine. compounds of formula (D se therefore differ from those described In the request WO 2010/112597 no only at the level of their structure chemical but also at level of their activity pharmacological. The state of the technical is finally represented by THE

compounds described in patent application WO 2000/051607 and having the general formula:

in which R12 and R13 represent a C1-C6 alkyl group, or a C2-6 alkenyl group or a C2-6 alkynyl group, substituted or not.

Said derivatives are chemokine modulators useful in the prevention or treatment of certain inflammatory or immune system diseases. Here again, the compounds of the present invention are therefore distinguished from those described in application WO 2000/051607, both by their chemical structure and their pharmacological activity.

The present invention also extends to salts of the derivatives of general formula (1) with pharmaceutically acceptable organic or mineral acids. In the present invention, the term pharmaceutically acceptable refers to molecular entities and compositions which do not produce any adverse, allergic or other undesirable effects when administered to a human. When used herein, the term pharmaceutically acceptable excipient includes any diluent, adjuvant or excipient, such as preservatives, fillers, disintegrating, wetting, emulsifying, dispersing, antibacterial or antifungal agents, or agents which would make it possible to delay intestinal and digestive absorption and resorption. The use of these media or vectors is well known to those skilled in the art. Pharmaceutically acceptable salts of a compound are those salts defined herein and which possess the pharmacological activity of the parent compound. Such salts include: acid addition salts formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-Ltartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like.A

Pharmaceutically acceptable salts also include solvent addition (solvated) forms or crystalline (polymorphic) forms, as defined herein, of the same acid addition salt.

The present invention also relates to the compounds of formula (1) as well as their pharmaceutically acceptable salts for their use as a medicament.

The present invention relates to the compounds of formula (1) as well as their pharmaceutically acceptable salts for their use as NMDA receptor antagonists.

The present invention also relates to the compounds of formula (1) as well as their pharmaceutically acceptable salts for their use as medicaments intended for the treatment and/or prevention of depression.

The present invention also relates to the compounds of formula (1) as well as their pharmaceutically acceptable salts for their use as medicaments intended for the treatment of pain, in particular pain due to excess nociception, neuropathic pain and mixed pain.

Among the pains potentially sensitive to the action of compounds of general formula (1), we can cite more particularly, as illustrative but non-limiting examples:

- pain from peripheral or central neuropathies resulting from nerve damage of traumatic origin (e.g. stroke), metabolic origin (e.g. diabetes), infectious origin (e.g. HIV, shingles, herpes), trigeminal neuralgia,

* pain due to chemotherapy and/or radiotherapy;

- inflammatory pain, for example rheumatoid arthritis, septic arthritis, osteoarthritis, polyarthritis, gout, spondylarthritis, acute abarticular rheumatism, visceral pain, for example irritable bowel syndrome, Crohn's disease;

- pain due to excess nociception, such as post-traumatic pain, post-operative pain, burns, torsion/distension, renal or hepatic colic attacks, joint pain, osteoarthritis, spondyloarthropathies;

- mixed pain, such as cancer pain, back and lower back pain, or other pain that is difficult to classify such as headaches, fibromyalgia, pain associated with vascular/ischemic problems such as angina, Reynaud's disease.

The present invention also relates to the compounds of formula (1) as well as their pharmaceutically acceptable salts for their use as a medicament intended for the treatment and/or prevention of inflammation in the joints. Among the inflammations potentially sensitive to the action of the compounds of general formula (1), there may be mentioned more particularly, by way of illustrative but non-limiting examples: inflammatory monoarthritis, rheumatoid arthritis, septic arthritis, osteoarthritis, rheumatoid polyarthritis, gout, spondylarthritis, acute abarticular rheumatism.

F

The present invention further relates to a pharmaceutical composition characterized in that it contains as active ingredient at least one compound of general formula (1) or one of its pharmaceutically acceptable salts.

The invention also extends to a pharmaceutical composition characterized in that it comprises at least one compound of general formula (1) or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient.

The invention also extends to a pharmaceutical composition for its use as a medicament intended for the treatment and/or prevention of depression.

The invention also extends to a pharmaceutical composition for its use as a medicament intended for the treatment of pain, in particular pain due to excess nociception, neuropathic and mixed pain.

The pharmaceutical compositions according to the present invention may be formulated for administration to humans. These compositions are made so as to be suitable for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration. In this case, the active ingredient may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to humans. Suitable unit dosage forms include oral forms, such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, subcutaneous, topical, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

Advantageously, the pharmaceutical composition according to the present invention is formulated for oral or topical administration. Topical administration is the preferred route for the treatment of certain types of pain, such as, for example, joint pain.

Topical administration means local administration to the skin or mucous membrane.

Suitable formulations for the chosen administration form are known to those skilled in the art and described, for example, in Remington, The Science and Practice of Pharmacy, ^19th Edition, 1995, Mack Publishing Company.

When preparing a solid composition in tablet form, the principal active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, silica or the like. The tablets may be coated with sucrose or other suitable materials, or may be treated so that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable coloring agent.

Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with flavor correctors or sweeteners.

For rectal administration, suppositories are used, which are prepared with binders that melt at rectal temperature, for example, cocoa butter or polyethylene glycols.

For parenteral (intravenous, intramuscular, intradermal, subcutaneous), intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile, injectable solutions containing pharmacologically compatible dispersing agents and/or wetting agents are used.

The active ingredient can also be formulated in the form of microcapsules, possibly with one or more additive carriers.

Topical administration of the pharmaceutical composition may be accomplished by applying a solution, suspension, gel, lotion, milk, ointment, salve, cream, eye drops, or other vehicle used for topical application well known to those skilled in the art. One possible means is the administration of the pharmaceutical composition by an aerosol spray making it possible to vaporize a liquid in fine droplets for distribution over the entire surface to be treated or, on the contrary, to precisely limit a particular area to be treated or in solid form, in the form of a stick. Another exemplary embodiment is the patch or stamp which provides a continuous release of the topical composition. The patch may have a reservoir and a porous membrane or a solid matrix which are well known to those skilled in the art. Other modes of administration, such as iontophoresis or electroporation, are also usable.

The compositions described herein may comprise in addition to the ingredients or components usually mixed in such topical preparations, for example the compositions may also include additional ingredients, such as carriers, moisturizers, oils, fats, waxes, surfactants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, colorants, humectants, emollients, dispersants, sunscreens with radiation blocking compounds and particularly UV blockers, antibacterials, antifungals, disinfectants, vitamins, antibiotics or other anti-acne agents, as well as other suitable substances which do not have adverse adverse effects on the activity of the topical composition. For example, additional ingredients may be used, such as sodium acid phosphate, witch hazel extract, glycerin, apricot kernel oil, corn oil. In addition to the components described above, the compositions of the present invention may optionally contain other ingredients. For example, triethanolamine may be added as a crosslinking agent. A preservative such as butylated hydroxytoluene may also be added.

Other irritation reducing agents may also be added; in this regard, glycerol may be mentioned but is not limited to. For topical administration, the compositions may contain conventional emollients and emulsifiers including alginates, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propylparaben, butylparaben, sorbitols, ethoxylated anhydrosorbitol monostearate (TWEEN), white petrolatum (VASELINE), triethanolamine, emu oil, aloe vera extracts, lanolin, cocoa butter and others.

The compositions described can be applied to the patient's skin area to be treated. The frequency of application will depend on the circumstances and the patient. For example, the compositions can be applied daily, twice a day, or even more frequently.

The dosages of a compound of general formula (1) or one of its pharmaceutically acceptable salts in the compositions of the invention may be adjusted in order to obtain an amount of substance which is effective in obtaining the desired therapeutic response for a particular composition and method of administration. The effective dose of the compound of the invention varies depending on many parameters, such as, for example, the chosen route of administration, the weight, age, sex, nature of the pathology, sensitivity of the individual to be treated. Accordingly, the optimal dosage should be determined by the person skilled in the art depending on the parameters he deems relevant. Although effective doses may vary widely, daily doses could range from 1 mg to 100 mg.

1000 mg per 24 hours for an adult with an average weight of 70 kg, in one or more doses.

The invention finally includes the method of synthesizing products of compounds of general formula (1) as well as those of the synthesis intermediates of formulas (C) and (D).

The compounds of general formula (1) can be obtained by the process described in the reaction scheme illustrated below.^

Reaction scheme

The preparation of the compounds of the invention uses as raw material the derivatives of benzeneacetic acid, of formula (A), commercially available as: benzeneacetic acid (RN 103-82-2); 2-fluorobenzeneacetic acid (RN 451-82-1); 3-fluorobenzeneacetic acid (RN 331-25-9); 3-chlorobenzeneacetic acid (RN 1878-655); 3-methylbenzeneacetic acid (RN 621-36-3);

3-cyanobenzeneacetic acid (RN 1878-71-3);

3-methoxybenzeneacetic acid (RN 1798-09-0);

2,5-difluorobenzeneacetic acid (RN 85068-27-5);

3,5-difluorobenzeneacetic acid (RN 105184-38-1) 3,5-dichlorobenzeneacetic acid (RN 51719-65-4) 2-fluoro3-chlorobenzeneacetic acid (RN 261762-96-3). The derivatives of formula (A) are condensed with epichlorohydrin according to a method adapted from that described in patent application WO 2007/038452 to give the derivatives of formula (B) in which the alcohol and carboxylic acid functions are of 'cis' stereochemistry. Said patent does not describe the intermediates of formula (B). The lactones of formula (C) are then formed from the derivatives of formula (B) using a conventional method of activating the acid function, such as, for example, by means of an alkyl chloroformate, as described in application WO 2008/092955. The opening of the lactone of formula (C) is then advantageously carried out by means of the magnesium salt of the appropriate secondary amine according to Williams et al. (Tetrahedron Lett., 1995, 36, 5461-5464) to lead to the corresponding carboxamide of formula (D). The introduction of the primary amine function in the 3-position of cyclobutane with inversion of the stereochemistry can be carried out via the azide of formula (E) according to Soltani Rad et al. (Tetrahedron Lett., 2007, 48, 3445-3449). The reduction of the azido function to the corresponding primary amine is then accomplished either by catalytic hydrogenation or by a Staudinger reaction.

Alternatively, the conversion of the compound of formula (D) to the amine of formula (1) can be carried out via the phthalimide of formula (F) according to the classical method of Gabriel (e.g., application WO 2006081179).

The following examples illustrate the invention but do not limit it in any way. In the following examples:

(i) different crystalline forms may give different melting points; the melting points reported in this application are those of the products prepared according to the method described and are not corrected;

(ii) the structure of the products obtained according to the invention is confirmed by nuclear magnetic resonance (NMR) spectra and mass spectrometry; the purity of the final products is verified by TLC and centesimal analysis;

(iii) NMR spectra are recorded in the indicated solvent; chemical shifts (δ) are expressed in parts per million (ppm) relative to tetramethylsilane; signal multiplicity is indicated by: s, singlet; d, doublet; t, triplet; q, quadruplet; qu, quintuplet, m, multiplet; 1, large;

(iv) the various unit symbols have their usual meaning: pg (microgram); mg (milligram); g (gram); mL (milliliter); mV (millivolt); *C (degree Celsius); mmole (millimole); nmole (nanomole); cm (centimeter); nm (nanometer); min (minute); ms (millisecond), Hz (hertz);

(v) the abbreviations have the following meanings: F (melting point); Eb (boiling point) (vi) by room temperature.

we mean a temperature between 20°C and 25 ^° C.

Example 1: trans-3-amino-N,N-diethyl-1-phenylcyclobutanecarboxamide (1al)

Step 1: cis-l-phenyl-3-hydroxycyclobutanecarboxylic acid (Bl)

In a three-necked flask, introduce 2.2 eq of isopropylmagnesium chloride and cool the reaction medium

0 ^e C. Add 1 eq of phenylacetic acid diluted in THF, the temperature must be maintained between 40 and 50*C. Cool the medium to 20*C and add 1.8 eq of epichlorohydrin; the temperature must be maintained between 20 and 25*C, and leave stirring at this temperature for 45 min. Then add 2 eq of isopropylmagnesium chloride (2M in THF) dropwise and leave stirring at room temperature for 2 h. Then heat the reaction medium to 60 ^e C for 19 h.

Allow the medium to cool and acidify it with HCl solution (1N) to pH 1. Add dichloromethane (DCM) and extract. Decant, dry the organic phase over MgSO1, then evaporate the DCM under reduced pressure. Purify the residue by flash chromatography using DCM, then DCM/methanol 70:30 as eluent. The title product is obtained in the form of a pale yellow solid (yield = 70%).

C11H12O3 (molecular weight = 192).

^X H-RMN (DMSO D ₆ , 400 MHz) Δ (ppm): 2.50 (m, 2h), 2.74 (T, 2h, J = 9.4 Hz), 3.32 (S, IH), 3.85 (Qu, IH, J-7.2 Hz), 7.22-7.38 (m, 5h), 12.21 (S, IH).

SM-ESI: 193.1 (MH ⁺ ).

Step 2: 4-phenyl-2-oxabicyclo[2.1.1]hexane-3-one (Cl)

In a round-bottomed flask, introduce 1 eq of compound (Bl), diluted in THF, and 1.03 eq of triethylamine. Stir at room temperature until dissolved, then cool the reaction mixture to 0°C. Add 1.03 eq of ethyl chloroformate and stir at this temperature for 1 h, then return to room temperature and stir for 20 h. Evaporate the THF under reduced pressure, take up the residue obtained with water and extract with ethyl acetate (AcOEt). Decant, dry the acetate over MgSO ₄ then evaporate it under reduced pressure. Purify the residue by flash chromatography using as eluent: heptane, then heptane/AcOEt 60:40. The title product is obtained in the form of a colorless oil (yield = 87%).

CuH _I0 O ₂ (PM = 174).

^-NMR (CDCla, 400 MHz) δ (ppm): 2.71 (m, 2H), 2.89 (m,

2H), 4.97 (s, IH), 7.31-7.42 (m, 5H).

SM-ESI î 175 (MH*) .

Step 3: cïs-3-hydroxy-N,N-diethyl-1phenylcyclobutanecarboxamide (Dla)

In a three-necked flask under a nitrogen atmosphere, introduce 1 eq of the compound (Cl), 2 eq of diethylamine and THF. Cool the reaction medium to -20”C, then add dropwise the 3 eq of isopropylmagnesium chloride (2M in THF) while maintaining the temperature below -5 ^e C. Leave the mixture stirring for 2 h at a temperature between -10 and -20 ^e C. Hydrolyze the reaction medium with a saturated NaCl solution, then add a HCl solution (1N) and extract with AcOEt. Dry the organic phase on MgSO ₄ , filter and concentrate.!

Purify the residue by flash chromatography using a mixture of DCM/methanol 85:15 as eluent. The title product

is obtained under the (yield = 99%). shape of a solid YELLOW pale 5 C15H21NO2 (PM - 247) . ^X H-NMR (CDCl3, 400 MHz) δ (ppm): 0.63 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz) , 2.72 (m, 2H) . 2.82 (m, 2H), 2.90 (q, 2H, J - 7.2 Hz), 3.21 (q, 2H, J = 7 ,2 Hz), 4.36 (which, IH,

J = 7.4 Hz), 7.21-7.36 (m, 5H). The signal corresponding to the H of OH is not visible on the spectrum.

SM-ESI: 248 (MH*).

Step 4: trans-3-azido-N, N-diethyl-1phenylcyclobutanecarboxamide (Ela)

In a flask, introduce 1 eq of the compound (Dla),

1.5 eq of N-(p-toluenesulfonyl)imidazole, 2 eq of triethylamine, 0.025 eq of tetrabutylammonium iodide, 3 eq of sodium azide and DMF. Stir and heat the reaction mixture at 160”C for 4 h. Pour the reaction mixture onto ice-cold water and extract with ethyl ether. Dry the organic phase over MgSO ₄ , filter and concentrate.

Purify the residue by flash chromatography using a heptane/AcOEt 70:30 mixture as eluent. The title product is obtained in the form of a colorless oil (yield = 65%).

C15H20N4O (PM = 272).

'H-NMR (CDCI3, 400 MHz) δ (ppm): 0.52 (t, 3H, J = 7.2 Hz),

1.11 (t, 3H, J = 7.2 Hz), 2.47 (m, 2H), 2.89 (q, 2H, J = 7.2 Hz), 3.14 (m, 2H), 3.34 (q, 2H, J - 7.2 Hz), 3.96 (qu, IH, J = 7.8 Hz), 7.23 (m, 3H), 7.35 (m, 2H).

SM-ESI: 273 (M+H*) .

Step 5: trans-3-amino-N, W-diethyl-1phenylcyclobutanecarboxamide (lal)

In a flask, dissolve 1 eq of compound (Ela) in methanol. Degas the solution for 30 min with nitrogen, then add Pd/C (20% by mass). Purge the system (vacuum/H ₂ gas cycle) and hydrogenate the reaction medium for 3 h at room temperature with stirring. Filter the catalyst and evaporate the solvent. Purify the residue obtained by flash chromatography with a mixture as eluent: DCM/methanol/NHiOH: 90:9:1.

product of the title East got in the form of an oil colorless (yield = 70%). Ci ₅ H ₂₂ N ₂ O (PM = 246) • ^-NMR (DMSO d ₆ . 400 MHz) δ (ppm): 0.50 (t, 3H, J = 7.2 Hz), 1.10 (t. 3H, J = 7.2 Hz), 2.11 (m, 2H), 2.92 (q, 2H, J = 6.8 Hz), 3.12 (m, 2H), 3.32 (q, 2H, J = 6.8 Hz), 3.46 (qu, IH, J = 8, 0 Hz), 7, .18-7.35 (m, 5H) . The signal corresponding to the H of the NH ₂ is not not visible on the spectrum. SM-ESI: 247 (MH ⁺ ) •

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 185’C.

¹ H-NMR (DMSO of. 400 MHz) δ (ppm): 0.42 (t, 3H, J = 7.0 Hz), 1.02 (t, 3H, J = 7.0 Hz), 2.56 (m, , 2H), 2, 85- 2.96 i (m, 4H), 3.25 (Qr 2H, J = 6.8 Hz), 3.54 (that, IH, J = 8.4 Hz), 6.03 (s, 2H) , 7.26 (m, 3H), 7.39 (t, 2 hours, J = 7.6 Hz), 8.00 (s, 2H) . The corresponding signal to H of the NH ₂

is not visible on the spectrum.

¹³ C-NMR (DMSO of, 100 MHz) δ (ppm): 12.02, 12.15, 36.93, ^

39.19, 40.07, 41.19, 46.61, 124.87, 126.51, 128.71, 136.02, 142.69, 167.19, 171.10.

Theoretical %: C 62.97, H 7.23, N 7.73.

% Found: C 63.00, H 7.17, N 7.78.

Example 2: trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide (la2) Step 3: cis-3-hydroxy-N,N-dimethyl-1-phenylcyclobutanecarboxamide (Dlb)

Same as step 3 described in Example 1, using dimethylamine instead of diethylamine. The title product is obtained as a colorless oil (yield = 89%).

¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm) î 2.65 (m, 2H), 2.55 (s, 3H), 2.95 (s, 3H), 2.80 (m, 2H), 4.27 (qu, 1H, J = 7.8 Hz), 7.19-7.35 (m, 5H). The signal corresponding to 1Ή of OH is not visible on the spectrum.

Step 4: trans-3-azido-N, N-dimethyl-1phenylcyclobutanecarboxamide (Elb)

Same as step 4 of example 1. The title product is obtained as a beige solid (yield = 95%).

'H-NMR (CDClj, 400 MHz) δ (ppm): 2.50 (m, 2H), 2.54 (s, 3H), 2.96 (s, 3H), 3.18 (m, 2H), 3.97 (qu, IH, J = 7.8 Hz), 7.24 (m, 3H), 7.36 (m, 2H) .

Step 5: trans-3-amino-N,N-dimethyl-1-phenylcyclobutanecarboxamide (la2)

Same as step 5 described in example 1. The title product is obtained in the form of a colorless oil (yield = 84%).

C ₁₃ Hi ₈ N ₂ 0 (PM = 218) ¹ H-NMR (CDC1 ₃ , 400 MHz) δ (ppm): 2.13 (m, 2H), 2.55 (s, 3H), 2.95 (s, 3H), 3.15 (m, 2H), 3.47 (qu, 1H, J - 7.8 Hz), 7.19-7.35 (m, 5H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

SM-ESI: 219 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 163*C.

¹ H-NMR (DMSO _d e, 400 MHz) δ (ppm): 2.51 (m, 5H), 2.86 (s, 3H), 2.98 (m, 2H), 3.36 (s, IH), 3.53 (qu, IH, J = 8.4 Hz), 6.03 (s, 2H), 7.26 (m, 3H), 7.39 (t, 2H, J = 7.6 Hz), 8.05 (s, 3H).

¹³ C-NMR (DMSO of, 100 MHz) δ (ppm): 35.80, 37.20, 37.34,

39.91, 46.54, 124.94, 126.59, 128.72, 136.00, 142.43,

167.15, 171.68.

Theoretical %: C 61.07, H 6.63, N 8.38.

% Found: C 60.73, H 6.43, N 8.15.

Example 3: trans-3-amino-W,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide (lb)

Step 1: cis-3-hydroxy-l-(2-fluorophenyl)cyclobutanecarboxylic acid (B2)

Same as step 1 described in Example 1, using 2-fluorophenylacetic acid as starting material. The title product is obtained as a white solid (yield = 49%).

CuHnFOa (PM = 210).

¹ H-NMR (CDCI3, 400 MHz) δ (ppm): 2.80 (m, 2H), 2.97 (m,

2H), 4.29 (qu, 1H, J= 6.4 Hz), 7.04-7.23 (m, 4H). The signals corresponding to the H of the OH of the alcohol and the acid are not visible on the spectrum.

SM-ESI: 211 (MH ⁺ ).

Step 2: 4-(2-fluorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C2)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield = 81%).

C11H9FO2 (PM = 192).

^X H-RMN (CDCI3, 400 MHz) Δ (ppm) î 2.75 (m, 2h), 2.99 (m,

2H), 5.01 (s, IH), 7.07-7.42 (m, 4H).

SM-ESI: = 193 (MH ⁺ ) .

Step 3: cis-3-hydroxy-N,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide (D2a)

Same as step 3 of example 1. The title product is obtained as a white solid (yield = 85%).

C15H20NO2F (PM = 265).

’H-NMR (CDCl3, 400 MHz) δ (ppm): 0.47 (t, 3H, J = 6.8 Hz), 1.10 (t, 3H, J = 6.8 Hz), 2.77-2.89 (m, 4H), 2.95 (m, 2H), 3.31 (m, 2H), 4.32 (qu, 1H, J = 6.8 Hz), 7.04 (t, 1H, J = 7.8 Hz), 7.15 (t, 1H, J = 7.8 Hz), 7.26 (m, 1H), 7.37 (t, 1H, J = 7.8 Hz). The signal corresponding to the H of OH is not visible on the spectrum.

SM-ESI: 266 (MH ⁺ ).

Step 4: trans-3-azido-N,N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide (E2a)

Same as step 4 described in example 1. The title product is obtained in the form of a colorless oil (yield = 75%).

Ci ₅ Hi ₉ N ₄ OF (PM = 290).X

^X H-NMR (CDCl3, 400 MHz) δ (ppm): 0, 42 (t, 3H, J = 7.0 Hz), 1.10 (t, 3H, J = 7.0 Hz) , 2.55 (m, , 2H), 2.98 (q, 2H, J = 7.0 Hz), 3.19 (m, 2H), 3, 31 (q, 2 hours, J = 7.0 Hz), 4.02 (that,

1H, J = 8.0 Hz), 7.03 (m, 1H), 7.14-7.29 (m, 3H).

SM-ESI: 291 (MH ⁺ ).

Step 5: trans-3-amino-N, N-diethyl-1-(2-fluorophenyl)cyclobutanecarboxamide (lb)

Same as step 5 described in example 1. The title product is obtained in the form of a colorless oil (yield = 90%).

Ci ₅ H ₂ iN ₂ OF (PM = 264).

^X H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 0.42 (t, 3H, J = 6.8 Hz), 1.10 (t, 3H, J = 6.8 Hz), 2.19 (m, 2H), 3.00 (q, 2H, J = 6.8 Hz), 3.17 (m, 2H), 3.31 (q, 2H, J = 6.8 Hz), 3.53 (qu, 1H, J = 8.0 Hz), 7.00 (m, 1H), 7.11-7.31 (m, 3H). Signals corresponding to H of NH ₂ are not visible on the spectrum.

SM-ESI: 265 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 193 ^e C.

^H -NMR (DMSO of. 400 MHz) δ (ppm): 0.01 (t, 3H, J = 6.8 Hz), 0.77 (t. 3H, J = 6, 8 Hz), 2.36 (m. 2H), 2.72 (m, 4H), 2.97 (q. 2 hours, J = 6.8 Hz), 3.22 (s, IH), 3.38 (q. IH, J = 8.0 Hz), 5.81 (s, 2H), 64 94 (m, IH), 7.04 -7.14 (m, 2H), 7.33 (m, 1H), 7.75 (s. 3H) . ¹³ C-NMR (DMSO dg, 100 MHz) δ (ppm): 12 ,00, 12, 20, 36 ,14,

39, 97, 40, 60, 41.19, 43.60, 115.71 {d, ² J _c -f = 21 Hz), 124.64 (d, ⁴ J _C _ _F = 4 Hz),

128.00 (d, ³ J _c -f = 5 Hz),

128.80 (d, ³ J _c -f =

Hz), 130.07 (d, ² J _c -f = 13 Hz), 136.04, 158.52, 160.96,

167.14, 169.93.

Theoretical %: C 59.99, H 6.62, N 7.36.

% Found: C 60.15, H 6.48, N 7.20.

Example 4: trans-3-amino-N,N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide (Ie)

Step 1: cís-3-hydroxy-l-(3-fluorophenyl)cyclobutanecarboxylic acid (B3)

Same as step 1 of Example 1 using 3-fluorophenylacetic acid as the starting acid. The title product is obtained as a white solid (yield - 52%).

CnH _n FO ₃ (PM = 210).

¹ H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 2.50 (m, 2H), 2.75 (m, 2H), 3.86 (qu, IH, J = 7.2 Hz), 5.18 (s, IH), 7.07-7.21 (m, 3H), 7.40 (m, IH), 12.40 (s, IH).

SM-ESI: 211 (MH ⁺ ).

Step 2: 4-(3-fluorophenyl)-2-oxabicyclo[2.l.l]hexane-3-one (C3)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield = 91%).

C11H5O2F (PM = 192).

^X H-RMN (DMSO D _E , 400 MHz) Δ (ppm): 2.83 (S, 4h), 5.09 (S, IH), 7.15-7,22 (M, 3h), 7.38-7,47 (M, IH).

SM-ESI: 193 (MH*).

Step 3: cïs-3-hydroxy-N, ΛΓ-diethyl-l-(3-fluorophenyl) cyclobutanecarboxamide (D3a)

Identical to step 1, the title is obtained in the form of a white solid (yield = 92%).

Ci ₅ H ₂ o N0 ₂ F (PM = 265)

5 ¹ H-NMR (DMSO dg, 400 MHz) δ (ppm): 0.62 (t, 3H, I 7.2 Hz), 0.97 (t. 3H, J = 7.2 Hz), 2.50 (m, 2H), 2.66 (m 2H), 2.86 (q. 2 hours, J = 7.2 Hz) , 3.19 (q, 2H, J = 7.2 Hz) 4.05 (m, IH), 5.12 (d, IH, J = 6.8 Hz), 7.04- -7.15 (m, 3H) 7.39 (m, 1H). 10 SM-ESI: 266 (MH ⁺ ) .

/ f

f

Step 4: trans-3-azido-lV, N-diethyl-1-(3-fluorophenyl)cyclobutanecarboxamide (E3a)

Same as step 4 described in example 1. The

product of the title is obtained below the shape of an hour uil< colorless (yield = 72%). *H-NMR (DMSO d ₆ , 400 MHz) δ (ppm) : 0.59 (t. 3H, I 7.2 Hz), 1.00 (t, 3H, J = 7.2 Hz), : 2.40 (m. 2H), 2.86 (q 2H, J = 7.2 Hz), 3.04 (m, 2H) , 3.24 (q, 2H, J = 7.2 Hz), 4.07 (m, HI), 7.04-7.15 (m, 3H) , 7.39 (m, IH).

r t

: trans-3-amino-W, N-diethyl-1-(3-fluorophenyl)Step 5 cyclobutanecarboxamide (le)

Same as step 5 described in example 1. The title product is obtained in the form of a colorless oil (yield = 93%).

C15H21N2OF (PM = 264).

SM-ESI: 265 (MH ^f ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the compound of title 30 in the form of a white powder.

F: 174-C.^

^X H-NMR (DMSO ds, 400 MHz) δ (ppm): 0.49 (t, 3H, J = 7.0 Hz), 1.02 (t. 3H, J = 7.0 Hz), 2.56 (m, 2H), 2.91 (m. 4H), 3.26 (q, 2 hours, J = 7.0 Hz), 3.35 (s, IH), 3.53 (which, IH, J = 8.4 Hz), 6.03 (s. 2H), 7.01 (d. IH, J = 8.0 Hz), 7, 09- 7.20 (m, 2H), 7.42 (m, IH), 7.99 (s, 3H) . ¹³ C-NMR (DMSO d ₆ . 100 MHz) S (ppm) : 12.10, 36, 93, 39, 23,

39.91, 41.18, 46.40, 111.03 (d, ² JC-F = 22 Hz), 113.39 (d, ^Z JC- _F = 21 Hz), 121.11 (d, ⁴ Jc-f = 2 Hz), 130.77 (d, ³ JC-f =

Hz), 136.02, 145.55 (d, ³ J _C . _F = 7 Hz), 161.21, 163.64,

167.14, 170.60.

Theoretical %: C 59.99, H 6.62, N 7.36.

% Found: C 59.11, H 6.40, N 7.07.

Example 5: trans-3-amino-W,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide (ld)

Step 1: cis-3-hydroxy-l-(3-methoxyphenyl)cyclobutanecarboxylic acid (B4)

Same as step 1 of Example 1 using 3-methoxyphenylacetic acid instead of phenylacetic acid. The title product is obtained as a white solid (yield = 50%).

Ci ₂ HnO ₄ (PM = 222).

¹ H-NMR (DMSO d _e , 400 MHz) δ (ppm): 2.50 (m, 2H), 2.73 (m,

2H), 3.75 (s, 3H), 3.86 (qu, IH, J - 7.2 Hz), 5.14 (s, IH), 6.82 (dd, IH, J = 8.0 Hz and J = 2.0 Hz), 6.87 (s, IH), 6.93 (d, IH, J = 8.0 Hz), 7.26 (t, 1H, J = 8.0 Hz), 12.23 (s, 1H).

SM-ESI: 222.

Step 2: 4-(3-methoxyphenyl)-2-oxabicyclo[2.l.l]hexane-3one (C4)

Same as step 2 described in example 1. The

product of the title is obtained below there in the form of an oil colorless (yield = 85%). Ci ₂ Hi ₂ O ₂ (PM = 188). ¹ H-NMR (DMSO of, 400 MHz) δ (ppm): 2.80 (m. 4H), 3.76 (s, 3H), 5.06 (s, 1H), 6.87-6.91 (m, 3H), 7.30 (t, IH, J =

8.0 Hz).

SM-ESI: 189 (MH*).

Step 3: ci s-3-hydroxy-W, W-diethyl-l-(3-methoxyphenyl)cyclobutanecarboxamide (D4a)

Same as step 3 described For the example 1. The product of the title is obtained under the shape of a solid white (yield = 92%). C16H23NO3 (PM - 277) . *H NMR (DMSO, 400 MHz) δ (ppm): 0.62 (t, 3H, J = 6.8

Hz), 0.97 (t, 3H, J = 6.8 Hz), 2.50 (m, 2H), 2.64 (m, 2H),

2.86 (q, 2H, J = 6.8 Hz), 3.19 (q, 2H, J = 6.8 Hz), 3.73 (s, 3H), 4.06 (se, IH, J = 7.6 Hz), 5.08 (d, IH, J - 7.2 Hz), 6.81 (m, 2H), 6.89 (d, 1H, J = 7.6 Hz), 7.27 (m, 1H).

SM-ESI: 278 (MH*).

Step 4: trans-3-azido-N,N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide (E4a)

Same as step 4 described for example 1. The title product is obtained in the form of a colorless oil (yield = 82%).

CieH ₂ 2N ₄ O2 (PM - 302) .

’H-NMR (DMSO of, 400 MHz) δ (ppm): 0.59 (t, 3H, J = 6.8 Hz), 1.00 (t, 3H, J = 6.8 Hz), 2.40 (m, 2H), 2.86 (9/ 2H, J = 6.8 Hz), 3.05 (m, 2H), 3.24 (q, 2 hours, J = 6.8 Hz), 3.74 (s, 3H), 3.95 (qu, IH, J = 7.6 Hz), 6.76 (m. IH), 6.83

(m, 2H), 7.30 (m, 1H).

SM-ESI: 303 (MH*)

Step 5: trans-3-amino-N, N-diethyl-1-(3-methoxyphenyl)cyclobutanecarboxamide (ld)

Same as step 5 described for example 1. The

product of the title is got under the shape of an oil colorless (yield = 88%). C16H24N2O2 (PM = 276). H-NMR (DMSO d _s , 400 MHz) δ (ppm): 0.50 (t, 3H, J = 7.0 Hz), 1.00 (t, 3H, J = 7.0 Hz), 2.02 (m, 2H), 2.83 (m,

4H), 3.10 (qu, IH, J - 8.0 Hz), 3.23 (q, 2H, J = 7.2 Hz), 10 3.33 (s, 2H), 3.73 (s, 3H), 6.73-6.79 {m, 3H), 7.25 (t, IH, J = 8.0 Hz).

SM-ESI: 277 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 156’C.

'H-NMR (DMSO of, 400 MHz) δ (ppm): 0.47 (t, 3H, J = 6.8 Hz), 1.02 (t. 3H, J = 6.8 Hz), 2.55 (m, 2H), 2.89 (m, 4H), 3.26 (q, 2 hours, J = 6.8 Hz), 3.35 (s, IH), 3.52 (that, IH, J = 8.4 Hz), 3.75 (s, 3H), 6.03 (s, 2H), 6.78 -6.86 (m, 3H),

7.31 (t, 1H, J = 8.0 Hz), 7.98 (s, 3H).

¹³ c-rmn (DMSO of. 100 MHz) δ (ppm): 12.11, 36.98, 39.23, 39.99, 41.23, 46, 57, 55.03, 111.05, 111.54, 117.12, 129.89,

136.03, 144.22, 159.54, 167.12, 171.02.

Theoretical %: C 61.21, H 7.19, N 7.14.

% Found: C 61.38, H 7.09, N 6.98./f

Example 6: trans-3-amino-N,N-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide (Ie)

Step 1: cis-3-hydroxy-l-(3-chlorophenyl)cyclobutanecarboxylic acid (B5)

Same as step 1 described in Example 1 using 3-chlorophenylacetic acid as the starting acid. The title compound is obtained as a white solid (yield = 52%).

C11H11O3CI (PM = 226.5) .

¹ H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 2.50 (m, 2H), 2.75 (m, 2H), 3.86 (qu, IH, J = 7.2 Hz), 5.19 (s, IH), 7.31-7.40 (m, 4H), 12.44 (s, IH).

Step 2: 4-(3-chlorophenyl)-2-oxabicyclo[2.1.1]hexane-3-one (C5)

Same as step 2 described in the example 1. The The title product is obtained under the shape of a oil colorless (yield = 78%). C11H9O2CI (PM - 208) . ^: H-NMR (DMSO d _s , 400 MHz) δ (ppm): 2.84 (m, 4H), 5, 09 (s,

IH), 7.29-7.45 (m, 4H).

SM-ESI: 209 (MH*).

Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide (D5a)

Same as step 3 described in Example 1. The title compound is obtained as a white solid (yield = 99%).

C15H20NO2CI (PM = 281.5). 'H-NMR (DMSO d _e , 400 MHz) δ (ppm): 0.63 (t, 3H, J - 6.8 Hz), 0.96 (t, 3H, J = 6.8 Hz), 2.51 (m, 2H), 2.66 (m, 2H), 2.86 (q, 2H, J = 6.8 Hz), 3.19 (q, 2H, J = 6.8 Hz), 4.05 (qu, IH, J = 7.6 Hz), 5.13 (s, IH), 7.29-7.41 (m, 4H).

SM-ESI: 282.1 (MH ⁺ ).

Step 4: trans-3-(dioxoisoindoline-2-yl)-N,N-diethyl-1-(3chlorophenyl)-cyclobutanecarboxamide (F5a).

In a flask under nitrogen atmosphere, introduce 1 eq of compound (D5a), 1.1 eq of triphenylphosphine, 1.05 eq of phthalimide and THF. Then add dropwise 1.2 eq of diisopropyldiazodicarboxylate (DIAD) and leave stirring at room temperature for 16 h. Add water and extract with DCM. Dry the organic phase on Na ₂ SO4, filter and concentrate. Purify the residue by flash chromatography with a mixture as eluent: heptane/AcOEt: 80:20. The title product is obtained with a yield of 77%.

C23H23N2O3CI {PM = 410.5).

'H-NMR (CDCI3, 400 MHz) 6 (ppm): 0.67 (t, 3H, J = 7.2 Hz), 1.18 (t, 3H, J = 7.2 Hz), 2.91 (q, 2H, J = 7.2 Hz), 3.11 (m, 2H), 3.35 (m, 2H), 3.42 (q, 2H, J = 7.2 Hz), 4.79 (qu, IH, J = 8.8 Hz), 7.23 {m, IH), 7.32 (m, 2H), 7.41 (s, IH), 7.73 (m, 2H), 7.83 (m, 2H).

SM-ESI: 411.1 (MH ⁺ ).

Step 5: trans-3-amino-N,W-diethyl-1-(3-chlorophenyl)cyclobutanecarboxamide (le)

Place the derivative (F5a) dissolved in ethanolamine in a flask. Heat the reaction medium at 60°C for 1 h 30 min. Add a mixture of ice and water, stir for 15 min and extract with AcOEt. Wash the organic phase with saturated NaCl solution and decant. Dry the organic phase over MgSCh, filter and concentrate. Purify the residue by flash chromatography using a mixture of: DCM/methanol/NH40H: 90:9:1 as eluent. The title product is obtained with a yield of 40%-rl

C15H21N2OCI (PM = 280.5).

¹ H-NMR (CDCl3, 400 MHz) δ (ppm): 0.58 (t, 3H, J = 7.2 Hz), 1.10 (t, 3H, J = 7.2 Hz), 2.08 (m, 2H), 2.91 (q, 2H, J = 7.2 Hz), 3.11 (m, 2H), 3.34 (q, 2H, J = 7.2 Hz), 3.46 (qu, 1H, J = 8.0 Hz), 7.12 (dd, 1H, J = 7.6 Hz and J = 1.2 Hz), 7.19 (m, 2H), 7.26 (m, 1H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

SM-ESI: 281.1 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 167C.

¹ H-NMR (DMSO d _s , 400 MHz) δ (ppm): 0.50 (t, 3H, J = 6.8 Hz) , 1.02 (t, 3H, J = 6.8 Hz), 2.56 (m, 2H), 2.86-2.95 (m, 4H) , 3.26 (m, 2H), 3.34 (s, 1H), 3.54 (qu, IH, J = 8.0 Hz) , 6.03 (s, 2H), 7.15 (d, 1H, J = 7.6 Hz), 7.34-7.44 (m, 3H) , 8.00 (s, 3H). ¹³ c-rmn (DMSO d ₆ , 100 MHz) δ (ppm): 12.09, 12.12, 36.88, 39.19, 39.90, 41.14, 46.37, 123.76, 124, 94, 126, 61, 130, 65, 133.51, 136.00 , 145.09, 167.14, 170.54.

% Theoretical: C 57.50, H 6.35, N 7.06. % Found: C 57.36, H 6.26, N 6.68.

Example 7: trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide (lf)

Step 1: cis-3-hydroxy-1-(3-methylphenyl)cyclobutanecarboxylic acid (B6)

Same as step 1 of Example 1 using 3-methylphenylacetic acid instead of phenylacetic acid. The title product is obtained as a white solid (yield = 40%).

Ci ₂ HuO ₃ (PM = 206).

'H-NMR (CDClj, 400 MHz) 5 (ppm): 2.35 (s, 3H), 2.73 (m, 2H), 2.94 (m, 2H), 4.21 (qu, 1H, J = 6.4 Hz), 7.08 (d, 1H, J = 7.6 Hz), 7.16 (s, 2H), 7.24 (m, 1H). The signals corresponding to the H of the OH of the alcohol and the acid are not visible on the spectrum.

SM-ESI: 205.

Step 2: 4-(3-methylphenyl)-2-oxabicyclo[2.1.1]hexane-3-one <C6)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield - 74%).

C12H12O2 (PM = 188).

'H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 2.37 (s, 3H), 2.70 (m, 2H), 2.87 (m, 2H), 4.96 (s, 1H), 7.09-7.30 (m, 4H).

SM-ESI: 189 (MH ⁺ ).

Step 3: cis-3-hydroxy-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide (D6a)

Same as step 3 described in Example 1. The title product is obtained in 77% yield. 'H-NMR (CDClj, 400 MHz) δ (ppm): 0.65 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz), 2.69 (s, 3H), 2.73 (m, 2H), 2.81 (m, 2H), 2.90 (q, 2H, J - 7.2 Hz), 3.31 (q, 2H, J = 7.2 Hz), 4.35 (qu, 1H, J = 7.4 Hz), 7.04 (m, 1H), 7.11 (m, 2H), 7.23 (m, 1H). The signal corresponding to the H of the OH is not visible on the spectrum.

Step 4: trans-3-azido-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide (E6a)

Same as step 4 described in Example 1. The title product is obtained with a yield of 70 ¹ H-NMR (CDClA, 400 MHz) δ (ppm): 0.54 (t, 3H, J = 7.2 Hz), 1.11 (t, 3H, J = 7.2 Hz), 2.34 (s, 3H), 2.47 (m, 2H), 2.89 (q, 2H, J = 7.2 Hz), 3.12 (m, 2H), 3.34 (q, 2H, J = 7.2 Hz), 3.95 (qu, 1H, J = 7.8 Hz), 7.04 (m, 3H), 7.23 (m, 1H).

Step 5: trans-3-amino-N,N-diethyl-1-(3-methylphenyl)cyclobutanecarboxamide (lf)

Same as step 5 described in example 1. The title product is obtained with a yield of 57%. Ci ₆ H ₂₄ N ₂ O (PM =260).

¹ H-NMR (CDCla, 400 MHz) δ (ppm): 0.52 (t, 3H, J = 7.2 Hz), 1.10 (t, 3H, J = 7.2 Hz), 2.11 (m, 2H), 2.33 (s, 3H), 2.92 (q, 2H, J = 7.2 Hz), 3.10 (m, 2H), 3.33 (q, 2H, J = 7.2 Hz), 3.44 (qu, 1H, J= 8.0 Hz), 7.03 (m, 3H), 7.21 (m, 1H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

SM-ESI: 261 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 173*C.

¹ H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 0.45 (t, 3H,J =

6.8 Hz), 1.02 (t, 3H, J = 6.8 Hz), 2.31 (s, 3H), 2.52(m,

2H), 2.89 (m, 4H), 3.25 (q, 2H, J = 6.8 Hz), 3.52 (qu,IH,

J = 8.4 Hz), 6.02 (s, 2H), 7.05 (m, 3H), 7.27 (t, 1H, J = 7.6 Hz), 8.00 (s, 2H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

¹³ C-NMR (DMSO d ₆ , 100 MHz) δ (ppm): 12.07, 12.13, 21.05, 36.97, 39.15, 40.09, 41.18, 46.56, 48.53, 121.99, 125.43, 127.15, 128.63, 136.07, 137.88, 142.66, 167.21, 171.19.^ « « % Theoretical: C 63.81, H 7.50, N 7.44.

% Found: C 63.93, H 7.45, N 7.27.

Example 8: trans-3-amino-N, N-diethyl-1-(2-fluoro-3chlorophenyl)-cyclobutanecarboxamide (lg)

Step 1: cis-3-hydroxy-l-(2-fluoro-3-chlorophenyl)cyclobutanecarboxylic acid (B7)

Same as step 1 of Example 1 using 2-fluoro-3-chlorophenylacetic acid instead of phenylacetic acid. The title product is obtained as a white solid (yield = 30%).

CuHioFClOa (PM = 244.5).

^X H-RMN (DMSO D ₆ , 400 MHz) Δ (ppm): 2.58 (m, 2h), 2.75 (m, 2h), 3.93 (Qu, IH, J = 7.6 Hz), 5.33 (S, IH), 7.22 (M, IH), 7.52 (M, 2h), 12.56 (M, IH).

SM-ESI: 243.0.

Step 2: 4-(2-fluoro-3-chlorophenyl)-2oxabicyclo[2.1.1]hexane-3-one (C7)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield = 66%).

CnHsOaClF (PM = 226.5).

^X H-RMN (DMSO D ₆ , 400 MHz) Δ (ppm): 2.89 (S, 4h), 5.16 (S, IH), 7.22-7,29 (M, 2h), 7.61 (M, IH).

SM-ESI: 227 (MH ⁺ ).

Step 3: cïs-3-hydroxy-N, ΛΓ-diethyl-l-(2-fluoro-3chlorophenyl)-cyclobutanecarboxamide (D7a)

Same as step 3 described in example 1. The title product is obtained with a yield of 87%. Ci ₅ H ₁₉ NO ₂ C1F (PM - 299.5).

^X H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 0.35 (t, 3H, J =

7.0 Hz), 0.96 (t, 3H, J = 7.0 Hz), 2.57 (m, 2H), 2.67 (m 2H), 2.87 (9/ 2H, J = 7.0 Hz), 3.16 (q, 2 hours, J = 7.0 Hz) 4.00 (se. IH, J = 8.0 Hz), , 5.02 (d, IH, J = 7.2 Hz), 7.2' (t, IH, J - 8, 0 Hz), 7.50 (t, IH, J = 8.0 Hz) , 7.65 (t, IH

J = 8.0 Hz).

SM-ESI: 300 (MH ⁺ ).

Step 4: trans-3-(dioxoisoindoline-2-yl)-N,l\T-diethyl-l-(2fluoro-3-chlorophenyl)-cyclobutanecarboxamide (F7a)

Same as step 4 described for example 6. The 10 product of the title is obtained with a yield of 45%.

C ₂₃ H ₂₂ FC1N ₂ O ₃ (PM = 428.5).

¹ H-NMR (CDC1 ₃ , 400 MHz) δ (ppm): 0.29 (t, 3H, J = 6.8 Hz),

1.04 (t, 3H, J - 6.8 Hz), 2.94-3.04 (m, 4H), 3.22-3.28 (m, 4H), 4.61 (qu, IH, J = 8.8 Hz), 7.35 (t, IH, J = 8.0 Hz), 15 7.54 (t, IH, J = 8.4 Hz), 7.62 (t, IH, J = 7.2 Hz), 7.83 (s,

4H) .

SM-ESI: 429 (MH ⁺ ).

Step 5: trans-3-amino-N,N-diethyl-1-(2-fluoro-3chlorophenyl)-cyclobutanecarboxamide (lg)

Same as step 5 described for example 6. The title product is obtained with a yield of 93%.

C ₁₅ H ₂₀ FClN ₂ O (MW = 298.5).

^l H-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 0.27 (t, 3H, J =

6.8 Hz), 0.97 (t, 3H, J = 6.8 Hz), 2.08 (m, 2H), 2.88-2.94 25 (m, 4H), 3.17-3.25 (m, 3H), 7.26 (t, 1H, J = 8.0 Hz), 7.447.49 (m, 2H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

SM-ESI: 299 (MH*).

Maleate of the title compound &

Salification of the preceding compound by means of acid

maleic acid allows us to obtain the maleate of the compound of title in the form of a white powder. F: 179°C. ¹ H-NMR (DMSO of, 400 MHz) δ (ppm): 0.26 (t, 3H, J = 6.8 Hz), 0.99 (t. 3H, J = 6.8 Hz), 2.60 (m, 2H), 2.91 -3.00 (m, 4H), 3.20 (q/ 2H, J = 6.8 Hz), 3.34 (s, IH), 3.61 (that, 1H, J = 8.4 ' Hz), 6.02 (s, 2H), 7.32 (t, IH, J - 8.0 Hz), 7.52-7.57 (m, 2H), 7.97 (s, 3H).

ⁿ C-NMR (DMSO d ₆ , 100 MHz) 5 (ppm) î 12.15, 12.21, 36.19, 40.08, 40.56, 41.16, 43.81, 120.16, 125.59, 127, 11, 129, 12, 132.00, 136.11, 153.74, 156.22, 167.19, 169.48.

Theoretical %: C 55.01, H 5.83, N 6.75.

% Found: C 54.73, H 5.98, N 6.46.

Example 9; trans-3-amino-N,2V-diethyl-l-(2,5-difluorophenyl)-cyclobutanecarboxamide (lh) Step 1: cis-3-hydroxy-l-(2,5-difluorophenyl)cyclobutanecarboxylic acid (B8)

Same as step 1 described in Example 1 using 2,5-difluorophenylacetic acid as starting acid. The title product is obtained as a white solid (yield - 69%).

'H-NMR (DMSO d ₆ , 400 MHz) 5 (ppm): 2.55 (m, 2H), 2.71 (m,

2H), 3.94 (qu, IH, J = 7.2 Hz), 5.32 (s, IH), 7.12-7.23 (m, 2H), 7.41 (m, IH), 12.48 (s, IH).

Step 2: 4-(2,5-difluophenyl)-2-oxabicyclo[2.1.1]hexane-3one (C8)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield = 91%).

C _n H ₀ F ₂ O ₂ (PM - 210) .

¹ H-NMR (CDC1 ₃ , 400 MHz) δ (ppm): 2.77 (m, 2Η), 2.98 (m,

2H), 5.01 (s, IH), 6.93-7.08 (m, 3H).

SM-ESI: 228 (M+NH4*) .

Step 3: cis-3-hydroxy-N,N-diethyl-l-(2,5-difluorophenyl)cyclobutanecarboxamide (D8a)

Same as step 3 of example 1. The title product is obtained as a white solid (yield = 100%).

Ci5Hi ₉ NO ₂ F ₂ (PM = 283) .

'H-NMR (CDCI3, 400 MHz) δ (ppm): 0.56 (t, 3H, J = 6.8 Hz), 1.09 (t, 3H, J = 6.8 Hz), 2.82 (m, 5H), 2.95 (q, 2H, J = 6.8 Hz), 3.31 (q, 2H, J = 6.8 Hz), 4.32 (qu, IH, J = 7.2 Hz), 6.91-7.11 (m, 3H).

SM-ESI: 284 (MH ⁺ ).

Step 4: trans-3-azido-N,N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide (E8a)

Same as step 4 described in example 1. The title product is obtained in the form of a colorless oil (yield = 76%).

Ci ₅ HibN ₄ OF ₂ (PM = 308) . 'H-NMR (CDC1 _3/ 400 MHz) δ (ppm): 0.51 (t, 3H, J = 7.2 Hz) 1.10 (t, 3H, J = 7.2 Hz) , 2.51 (m, 2H), 2.98 (q, 2H, I 7.2 Hz), 3.19 (m, 2H), 3, 32 (q, 2H, J = 7.2 Hz), 4.02 (that

IH, J - 8.0 Hz), 6.90-7.04 (m, 3H).

SM-ESI: 309 (MH ⁺ ).

Step 5: trans-3-amino-N, N-diethyl-1-(2,5-difluorophenyl)cyclobutanecarboxamide (lh)

Introduce 1 eq of compound (E8a) into a flask and dissolve it in 20 volumes of THF. Place under stirring and under a nitrogen atmosphere, then add 1 volume of water and KÎ

1.5 eq of triphenylphosphine. Leave stirring overnight. Evaporate the THF under reduced pressure and take up the residue obtained with water and extract twice with DCM. Dry the organic phases over MgSO ₄ , filter then evaporate the solvent under reduced pressure. The oil obtained is purified by flash chromatography with the mixture DCM/methanol/NHiOH 95:4.5:0.5 as eluent.

The title product is obtained as a colorless oil with a 97% yield. Ci _S H ₂₀ N ₂ OF ₂ (PM = 282). 'H-NMR (CDCl1, 400 MHz) δ (ppm): 0.51 (t, 3H, J = 6.8 Hz) , 1.10 (t, 3H, J = 6.8 Hz) 9 2.15 (m, 2H), 2.99 (q, 2H, J = 6.8 Hz), 3.16 (m, 2H), 3, 32 (q, 2H, J = 6.8 Hz), 3.52 (qu.

IH, J = 8.0 Hz), 6.85-7.02 (m, 3H). The signal corresponding to the H of NH ₂ is not visible on the spectrum.

SM-ESI: 283 (MH ⁺ ).

Maleate of the title compound

Salification of the preceding compound using maleic acid gives the maleate of the title compound in the form of a white powder.

F: 184*C.

h-NMR (DMSO d ₆ , 400 MHz) δ (ppm): 0.31 (t, 3H, J = 6.8 Hz), 0.99 (t, 3H, J = 6.8 Hz), 2.58 (m, 2H), 2, 93-2.97 (m, 4H), 3.20 (q, 2H, J = 6.8 Hz), 3.34 (s, IH), 3, 59 (qu. IH, J = 8.4 Hz), 6.02 (s, 2H), 7.13-7.30 (m. 2H), 7, 49-7.53 (m. IH), 7.97 (s, 3H). 13 _C _ NMR (DMSO of, 100 MHz) δ (ppm): 12 ,04, 12.15, 36.08, 40, 00, 40,61, 41.20, 43.48, 114.90, 117 ,2, 124.37, 132.1, 136 , 00, 154, 6, 157.05, 157.13, 159.51, 167.12, 169.41 Theoretical %: C 57.28, H 6.07, N 7.03. % Found C: 57.21, H 6.01, N ( 5, 66.fd

Example 10: trans-3-amino-N,N-diethyl-l-(3,5-dichlorophenyl)-cyclobutanecarboxamide ( li ) Step 1: cis-3-hydroxy-l-(3,5-dichlorophenyl)cyclobutanecarboxylic acid (B9)

Identical to step 1 described in example 1 by first synthesizing 3,5-dichlorophenylacetic acid, which is then used as the starting acid. The title product is obtained in the form of a white solid (yield = 50%).

C11H10CI2O3 (PM = 261).

^X H-RMN (DMSO D ₆ , 400 MHz) Δ (ppm): 2.53 (m, 2h), 2.77 (m, 2h), 3.87 (qu, IH, J = 7.4 Hz), 5.23 (S, IH), 7.38 (M, 2h), 7.51 (M, IH), 12.62 (S, IH).

SM-ESI: 259.

Step 2: 4-(3,5-dichlorophenyl)-2-oxabicyclo[2.1.ljhexane3-one (C9)

Same as step 2 described in example 1. The title product is obtained in the form of a colorless oil (yield = 87%).

C11H8CI2O2 (PM = 243).

^l H-NMR (CDCI3, 400 MHz) δ (ppm): 2.72 {m, 2H), 2.88 (m, 2H), 4.99 (s, 1H), 7.21 (m, 2H), 7.34 (m, 1H).

SM-ESI: 244 (MH ⁺ ).

Step 3: cis-3-hydroxy-N,N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide (D9a)

Same as step 3 of example 1. The title product is obtained as a white solid (yield = 100%).

Ci5Hi ₉ Cl ₂ O ₂ N (PM = 316).

¹ H-NMR (CDCI3, 400 MHz) δ (ppm): 0.77 (t, 3H, J = 7.2 Hz), 1.09 (t, 3H, J = 7.2 Hz), 2.58 (s, 1H), 2.75 (m, 4H), 2.88, ·

(q, 2H, J = 7.2 Hz), 3.32 (q, 2H, J = 7.2 Hz), 4.34 (qu, IH, J = 7.6 Hz), 7.20-7.27 (m, 3H).

SM-ESI î 316.

Step 4: trans-3-azido-N, N-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide (E9a)

Same as step 4 described in example 1. The title product is obtained in the form of a colorless oil (yield = 79%).

CisH _ie N ₄ OCl ₂ (PM = 341).

^X H-RMN (CDCLG, 400 MHz) Δ (ppm): 0.67 (T, 3h, J = 7.2 Hz), 1.12 (T, 3h, J = 7.2 Hz), 2.40 (m, 2h), 2.87 (Q, 2h, J = 7.2 Hz), 3.15 (M, 2h), 3.36 (q, 2H, J = 7.2 Hz), 3.99 (qu, 1H, J = 7.6 Hz), 7.13 (m, 2H), 7.25 (m, 1H).

SM-ESI: 341.

Step 5: trans-3-amino-W,AT-diethyl-1-(3,5-dichlorophenyl)cyclobutanecarboxamide (li)

Same as step 5 of Example 9. The title product is obtained as a colorless oil with a yield of 78%.

Ci5H ₂ qN ₂ OC1F (PM = 283) .

¹ H-NMR (DMSO of, 400 MHz) δ (ppm): 0.58 (t, 3H, J = 7.2 Hz), 1.00 (t, 3H, J = 7 ,2 Hz), 1.90 (s. 2H), 2.07 (m, 2H), 2.85 (m, 4H), 3.11 (qu. 1H, J = 8.0 Hz), 3.25 (q. 2 hours,

J = 7.2 Hz), 7.23 (m, 2H), 7.48 (m, 1H).

SM-ESI: 283.

Maleate of the title compound

Salification of the preceding compound using maleic acid allows the maleate of the title compound to be obtained in the form of a white powder.

F: 180’C.

^X H-RMN (DMSO D ₆ , 400 MHz) Δ (ppm): 0.57 (T, 3h, J = 6.8 Hz), 1.02 (T, 3h, J = 6.8 Hz), 2.58 (m, 2h), 2.85-2.96 (M, 4h), 3.28 (Q, 2h, J = 6.8 Hz), 3.54 (qu, IH, J 8.4 Hz), 6.02 (s, 2H), 7.28 (s, 2H), 7.56 (s, IH), 7.99 (s, 3H).

¹³ C-NMR (DMSO d ₆ , 100 MHz) δ (ppm): 11.96, 12.19, 36.83,

39.20, 41.10, 46.2, 124.03, 126.38, 134.50, 136.02, 146.66, 167.12, 170.04.

Theoretical %: C 52.91, H 5.61, N 6.50.

% Found: C 53.01, H 5.53, N 6.11.

The following examples provide a better understanding of the invention without limiting its scope.

The compounds of general formula (1) and their pharmaceutically acceptable salts exhibit remarkable pharmacological properties: they are generally more potent than ketamine as an NMDA channel blocker while exhibiting fewer adverse effects on the central nervous system than ketamine.

We examined the effects of the compounds of the invention on NMDA current inhibition in Xenopus (Xenopus iaevis) oocytes expressing recombinant human NMDA receptors constructed from the NR1 and NR2B subunits. The currents produced by stimulation of these receptors with endogenous agonists were studied using the two-electrode voltage-clamp technique reported by Planells-Cases et al., 2002, J. Pharmacol. Exp. Ther., 302, 163-173.dji

Protocol: Oocytes were surgically collected from adult Xenopus, enzymatically defolliculated and stored at 17°C in a solution containing: 96 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2 and 5 mM HEPES at pH 7.5 (NaOH) and 50 mg/L gentamicin (Heusler et al., 2005, Neuropharmacology, 49, 963-976). Complementary DNA (cDNA) encoding the NR1 subunit was cloned by PCR using primers targeted to the start and end codons of the published sequence (GenBank accession number M_007327). The cDNA encoding the NR2B subunit was synthesized by Eurogentec (Seraing, Belgium) according to the published sequence (GenBank accession number NM_000834). The NR1 and NR2B cDNAs were then subcloned into the high-expression vector pGEMHE for in vitro cDNA transcription. The cRNAs encoding NR1 and NR2B were prepared according to the method described by Heusler et al. (already cited). Aliquots of the cRNA solution were injected into the oocytes (20-500 pg/oocyte for NR1 and 40-1000 pg/oocyte for NR2B). Each oocyte was injected with 100 nL of a solution containing: 4 mM Na ⁺ BAPTA (pH 7.2) to block all residual chlorine currents. After stabilization, NMDA currents are activated by superfusion of glutamate and glycine each at a concentration of 10 μM. The test compounds are then superfused in Ringer Ba ⁺⁺ solution at increasing concentrations in the presence of glutamate and glycine (4 to 5 concentrations are tested per oocyte). The concentration-response curves obtained are analyzed for each oocyte by non-linear regression and a pCI ₅ o value calculated. By pCI 5 o is meant the negative logarithm of the concentration of the test compound necessary to decrease the amplitude of the NMDA current of Table 1

Results :

pCI ₅ o for some of the compound springs

NMDA of that, (lal), in half.

Below are the values of the compounds of the invention. It is under the conditions of the test, the powerful clinical.

(lb), (le), (ld) and (le) block concentration-dependent manner and that ketamine, an NMDA antagonist the current are more used in

Table 1.

Compound Inhibition of NMDA current pCIso lal 6.3 lb 6.3 THE 6.8 ld 6.4 THE 7.1 ketamine 6.1

Given the low oral bioavailability of ketamine, we chose the intraperitoneal (ip) route as the sole route of administration in in vivo experiments. The analgesic activity of compounds of formula (1) and ketamine, chosen as a reference compound, was determined in a classical acute inflammatory pain model, the intradermal injection of formaldehyde (Bardin et al., 2001, Eur. J. Pharmacol., 421, 109-114).

Protocol: Male rats (Sprague-Dawley Iffa Credo, France) were placed in Plexiglas observation boxes above an inclined mirror to facilitate observation of their hind paws. After 30 min of acclimatization, the animals received an injection of 2.5% diluted formaldehyde on the plantar surface of the right hind paw. The formaldehyde injection produced behavioral responses that appeared in two phases:

- an early phase, from 0 to 5 min after the injection of formaldehyde, corresponding to the stimulation of receptors specialized in the transmission of nociceptive stimuli;

- a late phase that occurs between 20 and 30 min after the injection. This phase corresponds to the stimulation of receptors by inflammatory mediators and/or the hyperexcitability of neurons in the dorsal horn of the spinal cord. This later phase therefore involves central sensitization of the pain neurotransmission system, in which the glutamate/NMDA system plays a predominant role. As a result, the pain present during this second phase is more representative of neuropathic pain than that which occurs during the first phase. For this reason, only the results obtained in this late phase are taken into consideration in the present application.

We selected the licking of the injected paw as a behavioral parameter for quantifying pain and chose as observation periods the one corresponding to the late phase (i.e., 22.527.5 min post-formaldehyde injection). During this 5-min phase, the animals are observed every 30 s to note whether the animal licks the injected paw or not; thus, the maximum score is 10. The products of the invention or the vehicle are administered ip • « min before the formaldehyde injection.

Results: In this test, the compounds of formulae (lal) and (le), representative of the compounds of the invention, exert a remarkable analgesic activity (Table 2). Thus, the minimal significant dose (MSD, dose necessary to significantly reduce licking of the injected paw) obtained with the compounds of formulae (lal) and (le) is lower than that obtained with ketamine. Another advantage of the compounds of formulae (lal) and (le) compared to ketamine is also at the level of the amplitude of the analgesic effect. Indeed, we note that at the dose of 40 mg/kg, licking of the paw is completely inhibited with compounds (lal) and (le) while it only reaches a 75% reduction with ketamine. Compounds (lal) and (le) are therefore more powerful and more effective than ketamine.

Table 2.

Compound Licking the paw DMS (mg/kg) % reduction at 40 mg/kg lal 10 100 THE 10 100 ketamine 40 75

In summary, the analgesic activity of compounds (lal) and (le), representative of the compounds of formula (1), surpasses that of ketamine in a rat model of acute inflammatory pain.

We also demonstrate that the compounds of the invention have antidepressant activity in vivo.

The antidepressant activity of compounds of formula (1) and ketamine was determined in the forced swimming rat model, a widely used model predictive of antidepressant activity in humans.

Protocol: Male rats (Sprague-Dawley Iffa Credo, France) are placed in a cylinder (45 cm high and 20 cm in diameter) filled with water at 25°C ± 0.5°C up to a height of 17 cm. This height allows the rats to swim or float without their paws touching the bottom of the cylinder. Twenty-four hours before the test day, the rats are placed in the cylinder for 15 min, after which they no longer attempt to escape and remain motionless at the surface. On the test day, the test compound or vehicle is injected (ip) into the animal, which is placed in the cylinder 30 min later. The duration of immobility (defined as the rat allowing itself to float and making only small movements to maintain its surface) is measured with an accuracy of 0.1 s for 5 min.

Results: In the forced swimming test, compounds of formulae (le) and (le), representative of the series, significantly reduced the animal's immobility time. When comparing the ED ₅ q, i.e. the doses that reduced the immobility time by half compared to control animals, they were found to be lower than that of ketamine for compounds (le) and (le), see Table 3. Similarly, the magnitude of the antiimmobility effect observed at the dose of 20 mg/kg was greater with compounds (le) and (le) than that obtained with ketamine.fÎ

"

Table 3.

Compound Time of immobility DEso (mg/kg) % reduction at 20 mg/kg THE 13 83 THE 15 77 ketamine 20 50 In summary, the compounds (the) and the), representative of the

compounds of formula (1), are more potent and more effective than ketamine in a predictive test of antidepressant activity.

We have already emphasized the importance of normalizing the function of the NMDA receptor, i.e., blocking its excessive activity without interfering or with the least possible interference with its normal physiological functioning. As a marker of interaction of the products of the invention with the normal functioning of the NMDA receptor, we have chosen the pre-pulse inhibition of the startle reflex (PPI) test. This test represents a measure of the body's ability to filter non-essential information. Non-competitive and competitive antagonists as well as channel blockers decrease this PPI phenomenon in rats (Depoortere et al., 1999, Behav. Pharmacol., 10, 51-62), such a decrease being considered predictive of the psychotomimetic effects of NMDA antagonists in humans.

Protocol: Male rats (Sprague-Dawley Iffa Credo, Les Oncins, France) were placed in 18.4 cm long, 8.8 cm diameter cylinders resting on a base below which was fixed a piezoelectric accelerometer used to detect the startle response. The whole was enclosed in a box with a loudspeaker * <* fc fixed to the ceiling to deliver the sound pulses and pre-pulses, and acoustically isolated (SR LAB, San Diego Instruments, San Diego, USA). All events were controlled using dedicated software. The animals were first subjected to a 13-min pre-test intended to habituate them to the procedure and to eliminate those not meeting a series of minimal response criteria. Three types of sound stimuli (white noise) were delivered: 1) a 118 dB pulse (P, duration 40 msec); 2) a 78 dB prepulse (duration 20 msec), followed by a 118 dB pulse (pP); and 3) no prepulse or pulse (NP). The interval between the onset of the prepulse and the onset of the pulse is 100 msec, with a background noise of 70 dB. The startle response is recorded for 100 ms, 100 ms after the onset of the stimulus (pP or NP) by a 12-bit digital/analog acquisition card. The session starts with a 5-min stimulus-free period, after which the animals are exposed to 10 Ps (separated on average by 15 s and intended to stabilize the startle response). Responses recorded with these 10 Ps are not used for calculations. Subsequently, 10 P, 10 pP, and 3 NP are delivered in a pseudo-random order spaced on average 15 s apart. At the end of this pre-test, the rats are injected ip with the test compounds or saline as a control, and are returned to their housing box. The actual test session (in all respects similar to the pre-test) is carried out 60 min later. The percentage of pre-pulse inhibition is calculated using the data from this test session, according to the formula:

(median amplitude P - median amplitude pP) x 100/(median amplitude P).

"b" *

Results: From the attached Figure 1, it appears that compound (lal) only disrupts pre-pulse-induced startle reflex inhibition (PPI) from a dose of 20 mg/kg. However, surprisingly, the decrease in PPI is significantly less marked than that observed with ketamine. Indeed, at a dose of 20 mg/kg ip, ketamine induces a total disappearance of PPI while compound (lal) only causes a decrease of around 30%. The reduction in PPI remains modest even at a dose of 40 mg/kg. Therefore, compound (lal) has a significantly less marked tendency than ketamine to cause centrally-mediated side effects.

In summary, the compounds of the invention possess analgesic and antidepressant activity superior to that of ketamine in the animal models described above. Surprisingly, the compounds of the invention cause only very moderate central effects. It therefore emerges from these experiments that the benefit/risk ratio of the compounds of the invention is clearly more favorable than that of ketamine. Therefore, the compounds of the present invention as well as the pharmaceutical compositions containing as active ingredient a compound of general formula (1) or one of its pharmaceutically acceptable salts are potentially useful as medicaments, in particular in the treatment of certain pathologies such as, for example, depression and pain, in particular acute and chronic pain, areas for which therapeutic needs are not entirely satisfied and for which the discovery of new treatments is therefore highly desirable.

Claims (15)

1. Compound of the following general formula (1): (D or a salt or this, for Xi fluor; - X ₂ atom of which the pharmaceutically acceptable solvate represents is a chlorine atom; RI fluorine or a hydrogen atom or a hydrogen atom or a fluorine atom or a hydrogen atom or an atom a chlorine atom or represents a methyl group or one of a methoxy group or a cyano group R2 represents methyl together or an ethyl group. 2. Composed according to whether: Xi represents or separately a fluorine group; - X ₂ is a chlorine atom; claim 1, characterized in that a hydrogen atom or a hydrogen atom or a fluorine atom or a hydrogen atom or an atom - RI represents fluorine or a chlorine atom or a methyl group or methoxy group or a cyano group of one of a r · * - R2 is an ethyl group. 3. Compound according to any one of claims 1 or 2, characterized in that it is chosen from the following compounds: - trans-3-amino-N, N-diethyl-1-phenylcyclobutanecarboxamide, - trans-3-amino-N, N-dimethyl-1phenylcyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (2-fluorophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3-methoxyphenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3-fluorophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3-chlorophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3-methylphenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3-cyanophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (2-fluoro-3chlorophenyl) -cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (2,5-difluorophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3,5-difluorophenyl) cyclobutanecarboxamide, - trans-3-amino-N, N-diethyl-1- (3,5-dichlorophenyl) cyclobutanecarboxamide. 4. A compound according to any one of claims 1 to 3, for its use as a medicament. 5. A compound according to any one of claims 1 to 3, for its use as a medicament for the treatment of depression. 6. A compound according to any one of claims 1 to 3, for its use as a medicament for the treatment of pain, in particular pain due to excess nociception, neuropathic pain and mixed pain. 7. Pharmaceutical composition comprising at least one compound of general formula (1) according to any one of claims 1 to 3, and at least one pharmaceutically acceptable excipient. 8. A pharmaceutical composition according to claim 7 for its use as a medicament for the treatment and / or prevention of depression. 9. Pharmaceutical composition according to claim 7, for its use as a medicament for the treatment of pain, in particular pain due to excess nociception, neuropathic and mixed pain. 10. Pharmaceutical composition according to any one of claims 7 to 9, characterized in that it is formulated for oral administration. 11. Pharmaceutical composition according to any one of claims 7 to 9, characterized in that it is formulated for topical administration. 12. Pharmaceutical composition according to any one of claims 8 to 11, characterized in that it is presented in the form of a daily dosage unit of a compound of general formula (1) of between 1 and 1000 mg. 13. A process for preparing compounds of general formula (1) as defined in one of claims 1 to 3, characterized in that a secondary amine of formula (R2> 2NH is reacted with a compound of formula ( VS) R1 (C) to give the compound of formula (D) RI OH (D) the compound of formula (D) is formula (1), the radicals RI, reactants above being then converted into the amine of R2, Xi and X2 present in as defined in claim 14. Synthesis intermediates of formula (D) in which RI, R2, Xi and X ₂ are as defined in claim 1, used for the preparation of compounds of general formula (1) as defined in one of claims 1 to 3. 15. Synthetic intermediate of formula (C) (C) in which RI, Xi and X ₂ are as defined in claim 1, used for the preparation of compounds of general formula (D) as defined in claim