OA19594A - Use of a glutarimide derivative to treat diseases related to the aberrant activity of cytokines - Google Patents

Abstract

The invention relates to medicine and concerns the treatment of diseases related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), preferably the treatment of pain, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis, psoriasis and other diseases, using the compound 1-(2-(1H-imidazol4-yl)ethyl)piperidine-2,6-dione of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to pharmaceutical compositions that contain a therapeutically effective amount of the claimed compound. The present compound and pharmaceutically acceptable salts thereof are highly effective in inhibiting the activity of the glutaminyl cyclase enzyme, which is involved in particular in processes of post-translational modification of the above-mentioned cytokines.

Description

USE OF A GLUTARIMIDE DERIVATIVE TO TREAT DISEASES RELATED TO THE ABERRANT ACTIVITY OF CYTOKINES

Field of the invention

The invention relates to medicine and concems the treatment of diseases related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), preferably the treatment of pain, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis, psoriasis and also other diseases, using the compound that is effective in inhibiting an enzyme - glutaminyl cyclase, which is involved in particular in processes of posttranslational modification of the abovementioned cytokines.

Background of the invention

Cytokines are a group of hormone-like proteins and peptides which are secreted by immune system cells and other types of cells and are involved in the control of the development and homeostasis of the immune system, the control of the growth and différentiation of blood cells (hemopoiesis system) and in nonspecific protective reactions of organism. The cytokines also take part in the régulation of growth, différentiation and life time of the cells, and in the control of apoptosis.

The cytokine production by mammalian cells is a complex and multi-stage process. Most cytokines (e.g., fractalkine and monocyte chemoattractant proteins) are expressed in the form of an inactive precursor, from which in the process of detachment of a signal peptide and the posttranslational modification of individual amino acid residues of the protein an active form of the cytokine forms. One of the most important post-translational modifications is the cytokine Nterminal pyroglutamation. The pyroglutamation significantly increases the stability of hormones and chemokines containing the N-terminal residue of glutamine or glutamic acid. The pyroglutamation of the N-terminal residue is catalyzed by the enzyme - glutaminyl cyclase (QPCT or QC) [J Biol Chem 2003 Dec 12; 278 (50): 49773-9; J Mol Biol. 2008 Jun 20; 379 (5): 966-80]. Glutaminyl cyclase has the broad substrate specificity and is involved in the posttranslational modification of a variety of peptide molécules. In particular, the well-studied substrates of glutaminyl cyclase are monocyte chemoattractant proteins (CCL2), CCL7, CCCL8, CCL13) [EMBO Mol Med. 2011 Sep; 3 (9): 545-58] and fractalkine [Biosci Rep. 2017 Aug 23; 37 (4)]. It has been shown in studies of the substrate specificity of glutaminyl cyclase that the enzyme can catalyze the pyroglutamation of different substrates, regardless of the length of the polypeptide chain [FEBS Lett. 2004 Apr 9; 563 (1-3): 191-6, J Biol Chem 2011 Apr 8; 286 (14): 12439-49],

Since the pyroglutamation of the N-terminal residue mediated by glutaminyl cyclase significantly increases the stability of fractalkine and monocyte chemoattractant proteins, the strategy directed to the inhibition of glutaminyl cyclase is a possible approach to modulate the aberrant activity of these cytokines. Thus, glutaminyl cyclase inhibitors can obviously be used for the therapy of a wide range of diseases and, in particular, lower respiratory tract diseases such as pneumonia, bronchitis and bronchiolitis. The pathogenesis of these diseases is related to excessive biosynthesis of cytokines and, in particular, monocyte chemoattractant proteins CCCL2 and CCL7 [Am J Respir Cell Mol Biol. 2014 Jan;50(l): 144-57] and fractalkine [Expert Opin Ther Targets. 2010 Feb;14(2):207-19.], which are glutaminyl cyclase substrates [Biosci Rep. 2017 Aug 23;37(4). pii: BSR20170712; EMBO Mol Med. 2011 Sep;3(9):545-58], It has been shown that the neutralization of CCL2 and CCL7 with the use of antibodies significantly reduces the influx of leukocytes, in particular neutrophils, to the lower respiratory tracts of experimental animais [Am J Respir Cell Mol Biol. 2014 Jan;50(l):144-57], The action of bacterial lipopolysaccharides, lipoteichoic acid or other stimuli on the mucous membrane of respiratory organs leads to the increase in sécrétion of monocyte chemoattractant protein CCL2 by cells of bronchial smooth muscles [Am J Physiol Lung Cell Mol Physiol. 2012 Apr 15;302(8):L785-92] and the increase in CCL2 concentration in bronchoalveolar lavage [Mol Immunol. 2011 Jul;48(12-13):1468-76]. The increase in the CCL2 concentration, in turn, causes the migration of cells of the immune system (predominantly neutrophils and basophils) and the development of the aberrant response related to the release of a greater quantity of chemokines (TNFa, IL-1, IL-6) and active forms of oxygen which damage surrounding cells of respiratory organs, in particular, bronchi [Immunobiology. 2016 Feb;221(2):182-7; Int J Biol Sci. 2012;8(9): 1281 -90; Mol Immunol. 2013 Nov;56(l-2):57-63]. The damage of the lower divisions of respiratory tracts results in the development and maintenance of the increased activity of cells of the immune system and the further destruction of tissues of respiratory organs.

It is important to note that the CC2-mediated development of neutrophil inflammation and the development of the aberrant response related to the release of pyrogenic cytokines (IL-1, TNFa, IL-6) results in the increase in température and development of fever [J Infect Dis. 1999 Mar; 179 Suppl 2:S294-304; Front Biosci. 2004 May 1;9:1433-49.]. Thus, the inhibition of the activity of glutaminyl cyclase may resuit in the decrease in the CCL2 concentration, the decrease in the intensity of the aberrant immune response and the réduction of the intensity of fever and the normalization of température.

In addition to fever and elevated température, pain syndrome is also the extremely common symptom of various diseases. It is obvious that the réduction of the intensity of the aberrant response reiated to the release of the increased number of active forms of oxygen which damage surrounding tissues should in itself resuit in the decrease in the intensity of the pain syndrome. In recent work, the key rôle of fractalkine in the pathogenesis of chronic pain has been shown [J Neurochem. 2017 May; 141(4):520-531]. Glutaminyl cyclase inhibitors can be used for the therapy of various autoimmune diseases, in particular rheumatoid arthritis and psoriasis. Fractalkine is one of the key proinflammatory mediators involved in the development of autoimmune diseases. The interaction between fractalkine and its unique receptor (CX3CR1) induces the cell adhesion, chemotaxis and cell survival [Mol Interv. 2010 Oct;10(5):263-70]. The fractalkine level is increased in patients with rheumatoid arthritis (PA) [Mod Rheumatol. 2017 May;27(3):392-397], psoriasis [Ann Clin Lab Sci. 2015 Fall;45(5):556-61] and correlates with the severity of disease. Fractalkine is expressed on fibroblast-like synoviocytes and endothélial cells in synovial tissue of patients with rheumatoid arthritis. In case of psoriasis, high levels of fractalkine production are observed in dermal papillae and antigen-presenting cells [Br J Dermatol. 2001 Jun;144(6):l 105-13], The expression of fractalkine is enhanced by the tumor necrosis factor-α and interferon-γ, and in case of rheumatoid arthritis, promûtes the migration of monocytes, T-cells and osteoclast precursors to the synovial tissue [Mod Rheumatol. 2017 May;27(3):392-397], The increased expression of fractalkine in dermal papillae explains the migration and accumulation of T-cells at these sites in case of psoriasis [Br J Dermatol. 2001 Jun;144(6):l 105-13], Fractalkine also induces the formation of inflammatory mediators by macrophages, T-cells and fibroblast-like synoviocytes. Moreover, fractalkine promûtes angiogenesis and osteoclastogenesis.

Thus, based on the literature data, it is possible to conclude that the strategy directed to the inhibition of glutaminyl cyclase is the possible approach to the treatment of pain syndrome, fever and a whole number of diseases such as pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis.

However, so far there is no drug acting as the glutaminyl cyclase inhibitor, which would be used in the therapy of diseases reiated to the aberrant activity of fractalkine and monocyte chemoattractant proteins, therefore there remains a need for the development and the practical application of new effective drugs based on glutaminyl cyclase inhibitors.

The présent invention relates to the use of a novel Chemical compound which is the glutaminyl cyclase inhibitor and is effective in suppressing the aberrant activity of fractalkine and monocyte chemoattractant proteins, for the therapy of pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis, as well as other diseases.

Disclosure of the invention

It is an object of the présent invention to provide a novel médicament effective for the prévention and/or treatment of diseases related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), preferably, the therapy of pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis, as well as other diseases.

The technical resuit of the invention is the development and production of an effective glutaminyl cyclase inhibitor having a high inhibitory activity, which makes it possible to use the inhibitor for the therapy of pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis, as well as other diseases related to the aberrant activity of fractalkine and/or monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13). Said therapeutic effect is achieved by the inhibition of the activity of the enzyme - glutaminyl cyclase, which may resuit in the suppression of the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), as well as the réduction of the concentration of the abovementioned cytokines in the pathological process development zone.

The indicated technical resuit is achieved by using the compound 1-(2-(1 H-imidazol-4yl)ethyl)piperidine-2,6-dione (Compound 1)

or a sait or solvaté thereof as the compound suppressing the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4.

The indicated technical resuit is also achieved by using the compound 1 -(2-( IH-imidazol4-yl)ethyl)piperidine-2,6-dione or a sait or solvaté thereof for preparing a médicinal agent for the prévention and/or treatment of a disorder related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13).

The invention also includes a method of preventing and/or treating disorders related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13) in the body, comprising administering to body an effective amount of l-(2-(lHimidazol-4-yl)ethyl)piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof. Such a disorder related to the activity of cytokines that are substrates of the enzyme glutaminyl cyclase, in some non-limiting embodiments of the invention, is pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis. In particular embodiments of the invention, the body is a body of a human or an animal.

Compound 1-(2-( lH-imidazol-4-yl)ethyl)piperidine-2,6-dione is described in the invention application WO 2014/168522.

In particular, the invention relates to a médicament for the prévention and/or treatment of a disease or condition related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), comprising as an active component 1 -(2-( 1 H-imidazol-4-yl) ethyl)piperidine-2,6-dione:

or a pharmaceutically acceptable sait or solvaté thereof.

The disease to the treatment of which the médicament is directed is selected from the group consisting of pneumonia, bronchitis, bronchiolitis, alveolitis or autoimmune disease, in particular psoriasis or rheumatoid arthritis, as well as pain syndrome.

The condition to the treatment of which the médicament is directed is selected from the group consisting of fever and elevated température.

The active ingrédient or a pharmaceutically acceptable sait or solvaté thereof are présent in an effective amount for the prévention and/or treatment of a disease or condition associate with the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13). An amount of said active component in the médicament provides a dose thereof from 0.01 to 0.2 g for a patient per day.

Preferably, the amount of the active component in the médicament provides a dose thereof of 0.1 to 0.2 g for a patient per day.

Further, the invention comprises a method for preventing and/or treating a disease or condition related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1 4 (CCL2, CCL7, CCL8, CCL13) in a body, comprising administering to said body an effective amount of 1-(2-(l-imidazol-4-yl)ethyl)piperidine-2,6-dione:

or a pharmaceutically acceptable sait or solvaté thereof.

The disease to the treatment of which said method is directed is selected from the group consisting of pneumonia, bronchitis, bronchiolitis, alveolitis, autoimmune disease, in particular psoriasis or rheumatoid arthritis, and also pain syndrome.

The condition to the treatment of which the médicament is directed is selected from the group consisting of fever and elevated température.

A dose of 1-(2-(1 H-imidazol-4-yl)ethyl)piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof, used in the method according to the invention, is from 0.01 to 0.2 g for a patient per day.

Preferably, the dose of 1 -(2-( lH-imidazol-4-yl)ethyl)piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof, used in the method according to the invention, is from 0.1 to 0.2 g for a patient per day.

Further, the invention comprises the use of l-(2-(lH-imidazol-4-yl)ethyl)piperidine-2,6-

or a pharmaceutically acceptable sait or solvaté thereof, in the manufacture of a médicament for the prévention and/or treatment of a disease or condition related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13).

At the same time, the disease to the prévention and/or treatment of which the claimed invention is directed is selected from the group comprising pneumonia, bronchitis, bronchiolitis, alveolitis, autoimmune disease, in particular psoriasis or rheumatoid arthritis, and also pain syndrome.

The condition to the prévention and/or treatment of which the claimed invention is directed is selected from the group consisting of fever and elevated température.

An amount of 1 -(2-( lH-imidazol-4-yl)ethyl))piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof in the médicament provides a dose thereof from 0.01 to 0.2 g for a patient per day.

Preferably, the amount of 1-(2-( lH-imidazol-4-yl)ethyl)piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof in said médicament provides a dose thereof from 0.1 to 0.2 g for a patient per day.

DETAILED DESCRIPTION OF THE INVENTION

The préparation of Compound 1 that is the object of the présent invention is described in the patent application publication WO 2014/168522.

Studies of Compound 1 that is the object of the présent invention in models of various diseases hâve allowed to establish that the use of Compound 1 significantly reduces the cytokine-mediated influx of immune system cells. Thus, it has been shown that Compound 1 affects the aberrant activity of various cytokines. The réduction of the aberrant activity of cytokines and the influx of immune System cells can be used in the therapy of a variety of diseases, in particular, lung and respiratory tract diseases such as pneumonia, acute and chronic bronchitis, bronchiolitis, alveolitis. The search of possible therapeutic targets using methods of computational chemistry, molecular modeling and in vitro tests on the enzyme préparation has allowed to reveal that the observed therapeutic effect of Compound 1 is related to the ability of the compound to suppress the glutaminyl cyclase activity.

Thus, Compound 1 has the previously unknown pharmacological activity related to the inhibition of the action of the enzyme - glutaminyl cyclase and the mediated influence on the biosynthesis and the activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8, CCL13), which indicates the applicability of Compound 1 for the therapy of pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis, psoriasis and other diseases.

Terms and définitions

The term aberrant activity of cytokine herein means the activity that is significantly different from a base level of the activity of the cytokine in the body in the absence of pathology. The aberrant activity may be caused by excessive cytokine production, the abnormality of processes related to cytokine dégradation, and also other factors.

The term Compound 1 refers to compound 1 -(2-(lH-imidazol-4-yl)ethyl)piperidine2,6-dione, that is also represented by the structural formula:

The term pharmaceutically acceptable salts or sait includes salts of active compounds which are prepared with the aid of relatively non-toxic acids. Examples of pharmaceutically acceptable non-toxic salts include salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, succinic acid, citric acid or malonic acid, or obtained by other methods used in the field of art. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycérophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, hemi-fumarate, stéarate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate), undecanoate, valerate and the like.

The term solvaté is used to describe a molecular complex containing the compound according to the invention and one or more molécules of a pharmaceutically acceptable solvent, e.g. éthanol.

The term glutaminyl cyclase means an enzyme - aminoacyl transferase involved in the conversion of N-terminal glutamine to pyroglutamine in various peptide substrates. The formation of the N-terminal pyroglutamate protects the biologically active peptides, hormones and chemokines from dégradation by exopeptidases and in some cases may increase the affmity of ligands to their receptors.

Terms treatment, therapy encompass the treatment of pathological conditions in mammals, preferably in human, and include: a) reducing, b) blocking (suspending) of the disease course, b) alleviating the severity of the disease, i. e. inducing the régression of the disease, d) reversing the disease or condition, to which the term is applied, or one or more symptoms of the disease or condition.

The term prophyiaxis, prévention encompasses the élimination of risk factors, as well as the prophylactic treatment of sub-clinical stages of the disease in mammals, preferably, in human, directed to reducing the likelihood of origin of clinical stages of the disease. Patients for the prophylactic therapy are selected based on factors which, on the basis on known data, involve the increase in the risk of origin of clinical stages of the disease as compared with the total population. The prophylactic therapy includes a) primary prophylaxis and b) secondary prophylaxis. The primary prophylaxis is defined as the prophylactic treatment in patients who hâve not yet reached the clinical stage of the disease. The secondary prophylaxis is the prévention of the repeated onset of the same or close clinical State of the disease.

Compound 1, which is the object of the présent invention, is promising for the treatment of pain syndrome, fever, pneumonia, bronchitis, bronchiolitis, alveolitis, rheumatoid arthritis and psoriasis. In some embodiments of the invention, the compound of the invention can be used to prevent or reduce the expression of fever, to normalize the température, and alleviate pain.

Method of therapeutical use of compounds

The object of the présent invention further comprises administering to a subject in need thereof a therapeutically effective amount of the compound of the invention. The therapeutically effective amount means such an amount of a compound administered or delivered to a patient, upon which the patient is most likely to develop the desired response to the treatment (prophylaxis). The précisé required amount may vary from subject to subject depending on the âge, body weight and general patient's condition, the severity of disease, the procedure of administration of the préparation, the combined treatment with other préparations and the like.

The compound according to the invention or a pharmaceutical composition comprising the compound can be introduced into the patient's body in any amount and by any way of administration under the condition that such a dose and such a way of the administration are effective for the treatment or prévention of the abovementioned diseases. The oral way of the administration is préférable. Preferably, the daily dose of the active ingrédient (the compound according to the invention) is from 0.01 to 0.2 g for a patient per day, the most preferably the daily dose is from 100 to 200 mg/day.

After mixing the required amount of the compound according to the invention (to provide the required dosage) with a pharmaceutically acceptable carrier, médicaments (pharmaceutical compositions) according to the invention can be administered to the body of humans or other animais orally, parenterally, topically, and the like.

The administration may take place both once and several times a day, a week (or at any other time interval), or time from time, as needed. Besides, the médicament (pharmaceutical composition) according to the invention can be administered to the patient's body daily for a certain period of time (that is, e.g., 5-90 days) followed by a period without the administration of the médicament (pharmaceutical composition) according to the invention (that is, e.g., 1-30 days).

When the médicament containing the compound according to the invention is used as the part of combination therapy regimen, the dose of each of components of the combination therapy is administered during the required treatment period. The compounds constituting the combination therapy can be administered to the patient's body both at a time, in the dosage form containing ail the components, and in the form of individual dosages of the components.

Use of Compound 1 in the combination therapy

Although Compound 1 of the présent invention can be administered as an individual active pharmaceutical agent, it can also be used in combination with one or more other agents, in particular, the other agent may be a non-steroidal anti-inflammatory préparation, a glucocorticosteroid, a monoclonal antibody, etc. In case of the combination intake, therapeutic agents may be different dosage forms, which are administered simultaneously or sequentially at different times, or the therapeutic agents can be combined in a single dosage form.

The phrase combination therapy in respect to the compound of the présent invention in combination with other pharmaceutical agents is the simultaneous or sequential administration of ail agents that would otherwise provide bénéficiai effect of the combination of médicaments. The co-administration implies, in particular, co-delivery, e.g. in one tablet, capsule, injection or other form, having a fixed ratio of active agents, as well as the simultaneous delivery in several separate dosage forms for each compound, respectively.

Thus, the administration of the compound of the présent invention may be carried out in combination with additional methods of treatment, known to those skilled in the field of the prophylaxis and treatment of corresponding diseases, comprising the use of antibacterial and cytostatic préparations for the suppression of symptoms or side effects of one of médicaments.

If the dosage form is a fixed dose, the combination uses compounds of the présent invention in a suitable dosage range. Compound 1 according to the présent invention can also be administered to a patient's body in sériés with other agents, when the combination of these préparations is impossible. The invention is not limited to the sequence of administration; the compound of the invention may be administered to the patient's body together, before or after the administration of the other préparation.

Examples

The préparation of the compound according to the invention

The préparation of Compound 1 that is the object of the présent invention is described in the invention application WO 2014/168522.

Study of the effect of Compound 1 on the enzymatic activity of human glutaminyl cyclase in vitro.

During studies of the effect of Compound 1 that is the object of the présent invention on the enzymatic activity of glutaminyl cyclase in vitro, the direct inhibitory effect of Compound 1 on recombinant intracellular human glutaminyl cyclase was first discovered.

The activity of glutaminyl cyclase at various concentrations of Compound 1 was studied at 25°C using the fluorescent substrate L-glutaminyl 2-naphthylamide (Gln-bNA) (Anal Biochem. 2002 Apr 1 ;303(l):49-56). The 100 μΐ reaction mixture contained 50 μΜ of a fluorogenic substrate; ~ 0.2 units of human pyroglutaminyl aminopeptidase (1 unit is defined as the amount that hydrolyzes 1 micromole of pGlu-bNA per minute) and an aliquot of recombinant intracellular human glutaminyl cyclase (gQC) in 50 mM of tris-aminomethane-HCl and 5% glycerol, pH is 8.0. The reaction was initiated by adding to the reaction mixture an aliquot of glutaminyl cyclase incubated with Compound 1 for 5 minutes. The further reaction proceeding was monitored spectrophotometrically (the length of the excitation and émission wave was 320 and 410 nm). The enzymatic activity was determined by the amount of the released 2naphthylamide (bNA) calculated according to a calibration curve. IC50 values were calculated by a nonlinear régression of the inhibitor concentration- enzyme activity curve. As a comparative substance, the known glutaminyl cyclase inhibitor - Compound PBD150 (J Med Chem. 2006 Jan 26;49(2):664-77) was used.

As a resuit of the experiment, it has been established that Compound 1 inhibits the activity of intracellular glutaminyl cyclase with 1C50 = 50.9 μΜ.

Study of the activity of Compound 1 on a mouse model of psoriasis.

The induction of psoriasis in mice was carried out according to the standard procedure [European Journal of Pharmacology. 2015. V. 756. P. 43-51]. Aldar cream (5% imiquimod) was applied to female Balb/c mice on the inner side of the right ear once daily by 30 mg/mouse for 7 days (0-6^th day). Vaseline was applied to the intact animais. Compound 1 and the reference préparation (neotigason) were administered to animais in an intragastrical way, daily, once per day for 7 days (0-6^th day). Euthanasia was carried out 24 hours later (7^th day) after the last application of the Aldar cream. Daily on the 0, 2^nd, 3^rd, 4^th, 5^th, 6^th day, the thickness of the right ear was measured in the morning before the next application of the Aldar cream and before the euthanasia. After the euthanasia, blood was collected from the heart cavities, sérum was isolated.

The content of MCP1 was determined in blood sérum by an enzyme-linked immunosorbent assay method, using test Systems Mouse CCL2 (MCP-1) Uncoated ELIS A Kit (Invitrogen).

The évaluation of the clinical signs of psoriasis was carried out according to the point scale presented in table 1 [Pharmacology. 2011. V. 88(1-2). P. 100-113],

Table 1

The system for assessing clinical signs of psoriasis development in mice

Score	Percentage of the ear exposed to the change
Erythema (reddening)	Flakes	Thickening
0	None	None	None
1	0-25	0-25	0-25
2	25-50	25-50	25-50
3	50-75	50-75	50-75
4	75-100	75-100	75-100

The results of the study showed that on the psoriasis model the intragastric administration of Compound 1 to mice significantly reduces the gain of the ear thickness, clinical signs of psoriasis - the formation of erythema, the thickening of the skin and the formation of flakes on 10 the skin, as well as the MCP-1 level in the blood sérum (Tables 2-4).

These results show the therapeutic effect of Compound 1 in case of psoriasis. The therapeutic effect starts already on the 2^nd day of the application of Compound 1 and, by the intensity of action, corresponds to or exceeds that of neotigason.

Table 2

The gain of the thickness of the affected ear at the determined day of study to day 0 in the mouse model of psoriasis, % (M±m, n=20)

Group	A dose of compound, mg/kg	The gain of the ear thickness at the determined day of study to day 0, %
Day 2	Day 3	Day 4	Day 5	Day 6
Intact	-	6.0±1.5	7.5±2.5	12.3±2.1	13.4±1.7	16.5±2.0
Control	-	27.6±1.1*	35.3±1.1*	65.3±1.3*	76.4±2.9*	95.1±3.1*
Compound 1	30	7.8±1.4&	11.2±1.9&	33.8±1.6&	46.9±1.6*&	55.8±0.8*&
Neotigason	5	14.2±1.9*&	27.5±1.8*&	45.9±2.5*&	68.9±1.8*	83.1±1.4*

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05 & - the distinction from the control group according to Student's t-test at p<0.05

Table 3

Evaluation of the clinical signs of psoriasis on the mouse model, points (M±m, n=20)

Group	A dose of compound, mg/kg	Day 4	Day 6
Erythema	Flakes	Thickening	Erythema	Flakes	Thickening

Intact	-	0.0±0.0	0.0±0.0	0.0±0.0	0±0	0±0	0±0
Control	-	3.0±0.2*	l.l±0.2*	2.5±0.2*	3.3±0.2*	1.7±0.2*	2.6±0.2*
Compound 1	30	1.5±0.1*&	0.0±0.0&	0.9±0.1*&	1.3±0.1*&	0.H0.1&	1.3±0.1*&
Neotigason	5	1.2±0.1*&	0.0±0.0&	1.4±0.1*&	1.6±0.1*&	0±0&	1.3±0.1*&

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05 & - the distinction from the control group according to Student's t-test at p<0.05

Table 4

The MCP-1 level in blood sérum of mice on the psoriasis model, pg/ml (M±m, n=10)

Group	A dose of compound, mg/kg	MCP-1, pg/ml
Intact	-	104.6±7.8
Control	-	172.5±18.5*
Compound 1	30	113.7±8.3 &

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05 & - the distinction from the control group according to Student's t-test at p<0.05

The study of the activity of Compound 1 on the macrophage and neutrophil chemotaxis model in the site of inflammation (carrageenan pouch) in mice

The induction of macrophages and neutrophils chemotaxis to the site of inflammation (carrageenan pouch) in mice was tested according to the standard procedure [Curr Protoc Pharmacol. 2012. V. 5. P. 5-6], Female Balb/c mice, six days before induction of inflammation, were placed in the CO₂ chamber until anesthésia was reached for 30 seconds, then 5 ml of air was injected subcutaneously to animais into the intracapsular area of the back by a stérile syringe filled with air. After 3 days to maintain the integrity of the air pouch without increasing the wound, 2.5 ml of air was introduced at the same site. On day 6 under CO₂ anesthésia to induce inflammation, 1 ml of 1% carrageenan solution prepared in physiological saline was administered directly into the pouch. The test compound was administered intragastrically 1 hour before the administration of carrageenan and then every 10-12 hours in the volume of 0.1 ml. The last administration is 12 hours before the slaughter. Euthanasia by the inhalation of CO₂ was performed 48 hours after the carrageenan injection. Immediately after the euthanasia, 1 ml of physiological saline containing 5.4 mM of EDTA of room température was introduced into the pouch with a stérile syringe. After gentle massage of the région of the air pouch, a sagittal incision was made across the pouch and exudate was collected by a dispenser. After the centrifugation of the exudate from the cell pellet, smears were prepared, which were then fixed in methanol and were stained by Romanowsky-Giemsa. A quantity of macrophages and neutrophils was then determined on the smears under a microscope. The cell calculation was made up to 100 pcs.

The results of the study showed that the introduction of carrageenan into the cavity of the air pouch caused the influx of neutrophils and macrophages to the inflammation site (Table 5). Thus, the chemotaxis model of neutrophils and macrophages is formed.

The intragastric administration of Compound 1 to animais reduced the quantity of neutrophils and macrophages in the pouch cavity to the level of intact animais. Thus, the results obtained provide grounds to conclude that Compound 1 prevents chemotaxis of neutrophils and macrophages (Table 5).

Table 5

A quantity of inflammation cells in the exudate from the carrageenan pouch on the neutrophil and macrophage chemotaxis model to the site of inflammation (carrageenan pouch) in mice, xl0⁹/l (M±m, n=10)

Group	A dose of compound, mg/kg	Neutrophils, xl09/l	Macrophages, xl09/l
Intact	-	0.3±0.1	0.6±0.1
Control	-	2.2±0.4*	7.7±1.5*
Compound 1	30	0.6±0.1 &	0.6±0.2 &

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05;

& - the distinction from the control group according to Student's t-test at p<0.05.

Study of the activity of Compound 1 on a mouse model of the macrophage chemotaxis to the site of inflammation (thioglycolate peritonitis)

The induction of macrophage chemotaxis to the site of inflammation (thioglycolate peritonitis) in mice were performed according to the standard procedure [J Leukoc Biol. 2009. V. 86.(2). P. 361-370], Male Balb/c mice were intraperitoneally administered with 2 ml of 3% thioglycolic medium stored for 1 month. The préparation of thioglycolic medium was carried out as follows: 15 g of dry thioglycolic medium was stirred in 500 ml of distilled water, was boiled at 100°C for 2 minutes, was filtered through a paper filter, was poured out by 50 ml in stérile tubes and was sterilized by autoclaving at 121°C for 15 minutes.

The intact animais were intraperitoneally administered with 2 ml of physiological saline. The test compound was intragastrically administered 1 hour before the administration of thioglycolate, 24 and 48 hours after the administration of thioglycolate.

After 72 hours, the animais were euthanized in a CO2-chamber and the peritoneum area was wetted with 70% alcohol, the skin on the abdominal cavity was carefully eut off, and 5 ml of a cold phosphate-saline buffer containing 0.1% of ethylenediamine tetraacetic acid was injected intraperitoneally with a syringe. After gentle massage of the abdominal cavity, the exudate was collected by a syringe into tubes, and the volume of the collected exudate was determined.

Smears were prepared from the cell pellet, which smears were further fixed in methanol (5 minutes) and stained by Romanowsky-Giemsa (40 min at 20-22°C). On the smears, under the microscope Olympus bx51 (at magnification 100) the quantity of monocytes/macrophages was counted by the routine method. The cell calculation was made up to 100 pcs.

The results of the study hâve showed that intraperitoneal administration of the thioglycolic medium hâve caused the apparent increase in the quantity of macrophages in the peritoneal exudate of mice (Table 6). Thus, the macrophage chemotaxis model is formed.

The intragastric administration of Compound 1 to animais reduced the quantity of macrophages in the peritoneal exudate of mice to the level of intact animais. Thus, the obtained results provide groups to conclude that Compound 1 prevents the chemotaxis of macrophages to the site of inflammation (Table 6).

Table 6

The quantity of macrophages in peritoneal exudate on the macrophage chemotaxis model to the site of inflammation (thioglycolate peritonitis) in mice.

Group	A dose of compound, mg/kg	Macrophages, x 109/l
Intact	-	0.84±0.16
Control	-	2.81±0.21*
Compound 1	30	0.84±0.16&

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05;

& - the distinction from the control group according to Student's t-test at p<0.05.

The study of the activity of Compound 1 on the model of non-infections pneumonia induced by cigarette smoke extract

The induction of non-infectious pneumonia in mice was carried out according to the standard procedure [Zhang Yl, Cao J, Chen Y, Chen P, Peng H, Cai S, Luo H, Wu SJ. Intraperitoneal injection of cigarette smoke extract induced emphysema, and injury of cardiac and skeletal muscles in BALB/C mice. Exp Lung Res. 2013 Feb;39(l): 18-31.] Male Balb/c mice were intraperitoneally administered with cigarette smoke extract (CSE, 0.45 ml/20 mg) at 0, 1 l^th, 15^th, 17^th, 19^th and 22^nd day. The CSE was prepared as follows: 5 cigarettes were bumt, using a vacuum pump, the smoke was filtered to remove particles and collected in a vessel containing a phosphate saline buffer. Compound 1 was administered intragastrically, daily, once a day from 7^th to 27^th day. Euthanasia was carried out on the 28^th day. The right lung lobe was fixed in 10% neutral formalin solution, passed through the alcohols of ascending concentrations to xylene, and embedded in paraffin by standard procedures. Deparaffinated 5-micron shears were stained with hematoxylin-eosin and the histological analysis was carried out.

Each lésion was evaluated according to a 5-point scale: 1 point - the inflammatory infiltrate occupies 0-20% of the area of the histological préparation under study, 2 point -the inflammatory infiltrate occupies 21-40% of the area of the histological préparation under study, 3 5 points - the inflammatory infiltrate occupies 41-60% of the area of the histological préparation under study, 4 points - the inflammatory infiltrate occupies 61-80% ofthe area ofthe histological préparation under study, 5 points - the inflammatory infiltrate occupies 81-100% of the area of the histological préparation under study. Alveolar destruction index (DI) as the percentage of the damaged alveoli relative to the total number of alveoli was also calculated.

The results of the study showed that multiple intraperitoneal administration of the cigarette smoke extract to mice induces the formation of perivasculitis, peribronchitis, alveolitis and interstitial pneumonia (Table 7).

The intragastric administration of Compound I significantly reduced the development of perivasculitis, peribronchitis, alveolitis and interstitial pneumonia (Table 7). The obtained results 15 make it possible to conclude that Compound I will hâve the therapeutic effect in case of bronchitis, bronchiolitis, alveolitis and interstitial pneumonia.

Table 7

Results of the histological study on the model of non-infectious pneumonia induced by cigarette smoke extract (M±m, n-12)

Group	A dose of compound, mg/kg	Perivasculitis, points	Peribronchitis, points	Alveolitis (DI, %)	Interstitial pneumonia, points
Intact	-	0.71±0.20	0.5H0.19	11.5±1.2	0.99±0.20
Control	-	1.50±0.24*	1.29±0.18	30.9±2.3*	1.8U0.27*
Compound I	30	1.03±0.11&	0.13±0.07 &	20.5±2.5*&	1.08±0.16&

Notes:

* - the distinction from the intact group according to Studenfs t-test at p < 0.05;

& - the distinction from the control group according to Studenfs t-test at p<0.05.

The study of the activity of Compound 1 on a non-infections pneumonia model induced by intranasal administration of poly I:C to mice

The induction of pneumonia in mice was carried out according to the standard procedure [Eur Respir J. 2013 V. 41(5). P. 1147-1156]. Female Balb/c mice were intranasally administered with 8 pg/kg of polyinosine-polycytidylic acid (poly EC) in 30 μΐ of PBS on days 1, 2, 3 and 4. Then at days 15, 16, 17 and 18, in the same volume 2 pg/kg of poly I:C were administered to the animais. Compound 1 was administered intragastrically, daily, once a day from day 6 to day 19. Ail mice were sacrificed on the 19^th day of the study. The bronchus from the right lung was pinched by the ligature, the left lung was washed 3 times with 0.8 ml of the stérile PBS. After each administration of PBS into the lung, the gentle massage of the lung was carried out, PBS was drained by gravity. Finally, the final volume of the resulting bronchoalveolar lavage (BAL) was considered and written. A number of neutrophils was evaluated in the BAL (using the DiffQuik staining). For histological study, the right lung lobe was fixed in 10% neutral formalin solution and embedded in paraffin by the standard procedure. Deparaffinated 5-micron shears were stained with hematoxylin-eosin. Each lésion was evaluated according to a 5-point scale: 1 point - the inflammatory infiltrate occupies 0-20% of the area of the histological préparation under study, 2 point - the inflammatory infiltrate occupies 21-40% of the area of the histological préparation under study, 3 points - the inflammatory infiltrate occupies 41-60% of the area of the histological préparation under study, 4 points - the inflammatory infiltrate occupies 61-80% of the area of the histological préparation under study, 5 points - the inflammatory infiltrate occupies 81-100% of the area of the histological préparation under study. Alveolar destruction index (DI) as the percentage of the damaged alveoli relative to the total number of alveoli was also calculated.

The results of the study hâve shown that the multiple nasal administration of poly I:C to mice induces the influx of neutrophils into the bronchoalveolar space, the formation of perivasculitis, peribronchitis, alveolitis and interstitial pneumonia formation (Tables 8-9).

The intragastric administration of Compound 1 has completely abolished the influx of neutrophils into the bronchoalveolar space, has significantly reduced the development of perivasculitis, peribronchitis, alveolitis and interstitial pneumonia (Tables 8-9).

Table 8

The quantity of neutrophils in the bronchoalveolar lavage on the model of non-infectious pneumonia induced by intranasal administration of poly I:C to mice (M±m, n=7)

Group	A dose of compound, mg/kg	Neutrophils in 1 μΐ Score
Intact	-	0.0±0.0
Control	-	39.8±36.0*
Compound 1	30	0.0±0.0&

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05;

& - the distinction from the control group according to Student's t-test at p<0.05.

Table 9

Results of histological study of the lung tissue on a model of non-infectious pneumonia induced by intranasal administration of poly I:C to mice (M±m, n=7)

Group	A dose of compound, mg/kg	Perivasculitis	Peribronchitis	Alveolitis (DI, %)	Interstitial pneumonia
Intact	-	0.36+0.18	0.43+0.20	10.3+1.7	0.57+0.20
Control	-	1.57+0.37*	1.71+0.29*	21.5+2.6*	1.43+0.3*
Compound 1	30	0.80+0.31&	0.73+0.32&	11.5+1.5&	0.76+0.1&

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05;

& - the distinction from the control group according to Student's t-test at p<0.05.

The obtained results provide grounds to conclude that Compound 1 has the therapeutic effect in case of bronchitis, bronchiolitis, alveolitis and interstitial pneumonia.

The study of the activity of Compound 1 on the model of fever in rats

The fever model was realized according to the standard procedure [Tomazzeti J., A' vila D.S., Ferreira A.P.O., Martins J.S., Souza F.R., Royer C. Baker’s yeast-induced fever in young rats: characterization and validation of an animal model for antipyretics screening // J Neurosci Methods. 2005. V. 147. P. 29-35], Wistar rats were injected subcutaneously with 20% Baker’s yeast (12 ml/kg). The test compound was administered twice, intragastrically, 2 hours and 14 hours after the yeast administration. The rectal température was measured by the electrothermometer before the administration of pyrogen and at the highest point of the development of the thermal response - after 18 hours after it.

The results of the study showed that the intragastric administration of Compound 1 has reduced the body rectal température gain of rats (Table 10). The obtained data allow to conclude that Compound 1 has the anti-pyrogenic effect.

Table 10

The body rectal température gain after 18 hours after the subcutaneous administration of yeast to rats, °C (M±m, n=10)

Group	A dose of compound, mg/kg	The body rectal température gain, °C
Intact	-	0.06±0.04
Control	-	1.67±0.14*
Compound 1	18	1.15±0.12*&

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05;

& - the distinction from the control group according to Student's t-test at p<0.05.

Study of the activity of Compound 1 on a model of spécifie pain reaction by the method of Chemical stimulation of peritoneum (abdominal constriction test.)

The model of the spécifie pain reaction by the method of Chemical stimulation of peritoneum (abdominal constriction test) was carried out according to the standard procedure. To conduct the abdominal constriction test, Balb/c mice were intraperitoneally administered with 1 % acetic acid in a volume of 10 ml per kg of the animal body weight. The test compound was administered intragastrically, once, 1 or 2 hour(s) before the administration of acetic acid. A quantity of constrictions (convulsive twitching of the abdominal muscles accompanied with stretching hind quarters and arching) was evaluated 15 minutes after the administration of acetic acid.

The results of the study hâve shown that the intragastric administration of Compound 1 has significantly reduced the quantity of constrictions in mice, caused by intraperitoneal administration of acetic acid (Table 11). The obtained data allow to conclude that Compound 1 has the pronounced analgésie effect.

Table 11

The quantity of acetic constrictions on the model of the spécifie pain reaction by the method of Chemical stimulation of peritoneum (abdominal constrictions test) (M±m, n=12)

Group	A dose of compound, mg/kg	The administration of préparations	Quantity of constrictions for 15 minutes
control	-	1 hour before the administration of acetic acid	36.3±2.1
Compound 1	30	23.8±3.7*
30	2 hour before the administration of acetic acid	22.7±2.6*

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05.

Study of the activity of Compound 1 on the model of thermal pain irritation hot plate

The model of thermal pain irritation hot plate was carried out according to the standard procedure [Valdman A.V., Ignatov Y.D. Central mechanisms of pain. L.: Nauka, 1976], The test compound was administered to Balb/c mice intragastrically, once. After 1, 4, 6, 12, 24 hours after the administration of the préparation, the hot plate test was carried out. To conduct the hot plate test, the mice were placed on the hot plate, the température (+55±1°C) of which is constant. The time of first manifestations of the pain response in mice (paw licking, jumping) was registered and the mean latent time of the threshold of pain sensitivity (TPS, sec) in each group was calculated.

The results of the study hâve shown that the intragastric administration of Compound 1 by 2 times has increased the threshold of pain sensitivity of mice in the hot plate test. The pharmacological effect of Compound 1 lasted for at least 24 hours (Table 12). The obtained data allow to conclude that Compound 1 has the pronounced analgésie effect of prolonged action.

Table 12

The threshold of pain sensitivity (TPS) of the model of thermal pain irritation hot plate, % to the values before the administration of the préparation (M±m, n=12)

Group	A dose of compound, mg/kg	TPS, % to the values before the administration of the préparation
After 1 hours after the administration of the préparation	After 4 hours after the administration of the préparation	After 6 hours after the administration of the préparation	After 12 hours after the administration of the préparation	After 24 hours after the administration of the préparation
Control	-	111.5±6.9	116.3±3.8	105.6±6.7	109.7±8.8	108.4±6.0
Compound 1	30	192.6±12.7*	205.2±20.3*	194.2±12.0*	191.4±19.4*	234.7±26.1*
Ketorol	15	146.4±16.6	195.9±30.0*	176.6±34.0	166.5±25.3	159.7±22.4

Notes:

* - the distinction from the intact group according to Student's t-test at p < 0.05.

The préparation of dosage forms of 1-(2-( lH-imidazol-4-yl)ethyl)piperidine -2,6-dione (Compound 1)

The dosage forms of Compound 1 or a pharmaceutically acceptable sait thereof for use in accordance with the présent invention are prepared by standard procedures, such as, for example, 5 mixing, granulation, dragee formation, dissolution.

Tableted form

The tableted form is prepared using the following ingrédients:

Compound 1 or a pharmaceutically acceptable

1-100 mg sait thereof

Potato starch 20-50 mg

Magnésium stéarate 3 mg

Aerosil 1 mg

Lactose up to 300 mg

The components are mixed and pressed to form tablets each of which weighs 300 mg.

Gelatin capsules

Compound 1 or a pharmaceutically acceptable sait thereof - 100 mg,

Lactose (milk sugar), potato starch, colloïdal Silicon dioxide (aerosil), magnésium stéarate - till the obtainment of a capsule content of 250 mg. The abovementioned ingrédients are mixed, granulated; the granules are fïlled into solid gelatin capsules in an amount of 250 mg

Suppositories

Suppository formulation example:

Compound 1 or a pharmaceutically acceptable

1-100 mg sait thereof

Cocoa butter An amount necessary for suppository production

It is possible, if necessary, to manufacture rectal, vaginal and uréthral suppositories with corresponding excipients.

Powder for preparing the solution for injections

Example 1 of the formulation:

Compound 1 or a pharmaceutically acceptable

10-100 mg sait thereof

As a solvent, 0.9% sodium chloride solution, distilled water, novocaine solution may be used in the préparation of the solution for injections. The drug form - ampoules, vials, syringe-tubes, insert.

Claims (22)

1. A médicament for the prévention and/or treatment of a disease or condition related to the aberrant activity of fractalkine and monocyte chemoattractant proteins (CCL2, CCL7, CCL8, CCL13), comprising as an active compound 1-(2-( lH-imidazol-4-yl)ethyI)piperidine-2,6-dione:

or a pharmaceutically acceptable sait or solvaté thereof.

2. The médicament according to claim 1, wherein the disease is pneumonia.

3. The médicament according to claim 1, wherein the disease is bronchitis.

4. The médicament according to claim 1, wherein the disease is bronchiolitis.

5. The médicament according to claim 1, wherein the disease is alveolitis.

6. The médicament according to claim 1, wherein the disease is an autoimmune disease, in particular psoriasis or rheumatoid arthritis.

7. The médicament according to claim 1, wherein the disease is pain syndrome.

8. The médicament according to claim 1, wherein the condition is fever.

9. The médicament according to claim 1, wherein the condition is an elevated température.

10. The médicament according to any one of claims 1-9, wherein the amount of said active component provides its dose from 0.01 to 0.2 g for a patient per day.

11. The médicament according to claim 10, wherein the amount of said active component provides a dose of 0.1 to 0.2 g for a patient per day.

12. Use of 1-(2-(lH-imidazol-4-yl)ethyl)piperidine-2,6-dione:

or a pharmaceutically acceptable sait or solvaté thereof, for the manufacture of a médicament for the prévention and/or treatment of a disease or condition related to the aberrant activity of fractalkine and monocyte chemoattractant proteins 1-4 (CCL2, CCL7, CCL8,

CCL13).

13. The use according to claim 12, wherein the disease is pneumonia.

14. The use of claim 12, wherein the disease is bronchitis.

15. The use according to claim 12, wherein the disease is bronchiolitis.

16. The use of claim 12, wherein the disease is alveolitis.

17. The use according to claim 12, wherein the disease is an autoimmune disease, in particular psoriasis or rheumatoid arthritis.

18. The use according to claim 12, wherein the disease is pain syndrome.

19. The use according to claim 12, wherein the condition is fever.

20. The use according to claim 12 wherein the condition is an elevated température.

21. The use according to any one of claims 12 to 20, wherein the amount of 1 -(2-( 1Himidazol-4-yl)ethyl)piperidine-2,6-dione or a pharmaceutically acceptable sait or solvaté thereof in the médicament provides its dose from 0.01 to 0.2 g for patient per day.

22. The use of claim 21, wherein the amount of 1 -(2-(lH-imidazol-4-yl)ethyl)piperidine2,6-dione or a pharmaceutically acceptable sait or solvaté thereof in the médicament provides its dose from 0.1 to 0.2 g for patient per day.