RU2700595C1 - 3,6,9-triazatricyclotetradecane derivative and use thereof for treating depression - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a novel negative modulator of kainate receptors – 6-[4-methoxy-3-(pyrrolidin-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1^3,11]tetradecane-4,8,12-trion, the structure below or its pharmaceutically acceptable salt. Invention also relates to use of the compound of the given formula and to a pharmaceutical composition based thereon.

EFFECT: obtaining a novel heterocyclic compound which is a high-efficiency negative modulator of kainate receptors useful for treating psychic diseases, depressive disorders, anxiety disorders and stress-related disorders.

14 cl, 6 dwg, 1 ex

Description

Technical field

The invention relates to the field of medicine, pharmacology and psychiatry, namely to negative modulators of kainate receptors and can be used, in particular, for the treatment of depression.

State of the art

Kainate receptors (KARs) consist of a class of ionotropic glutamate receptors that perform a variety of pre- and postsynaptic functions through complex signaling that regulates the activity of nerve chains. Kainate receptors are highly expressed in the central nervous system (CNS). Molecular cloning revealed 5 subtypes: GluK1, GluK2, GluK3, GluK4 and GluK5, which are assembled in various combinations to form functional receptors.

Kainate receptors are present in both neuronal and glial cells and astrocytes. They modulate the functional state of the central nervous system through fine-tuning of synaptic transmission, the balance between the activity of glutamate and GABAergic systems, the rhythmic activity of the neuronal network, the functioning of astroglia and the interaction of neurons and glia (Popov AV, et al / Kainate receptors are the key to understanding synaptic plasticity, learning and memory (review) // Modern Tehnologies in Medicine. 2017; 9 (4): 228-238, https://doi.org/10.17691/stm2017.9.4.28). Excessive activation of kainate receptors by kainic acid in the experiment leads to limbic seizures similar to human temporal lobe epilepsy, causing mitochondrial dysfunction and degeneration of individual neuron populations due to excitotoxicity. In contrast, Kainate receptor antagonists have been shown to have beneficial effects in certain neurological disorders such as chronic pain, migraine and epilepsy (Jane DE et al / Kainate receptors: pharmacology, function and therapeutic potential // Neuropharmacology. 2009. 56 (1): 90-113. doi: 10.1016 / j.neuropharm.2008.08.023).

It is known that the inconsistency of excitable and inhibitory signals during neurotransmission, as well as a decrease in neuronal plasticity, leads to disruption of functional connections in vast areas of the brain. It is assumed that these mechanisms underlie both monopolar and bipolar depression. An additional argument in favor of this hypothesis is the rapid antidepressant effect of ketamine, an agent that affects, among other things, the neurochemical balance between the functional activity of glutamate and hamkergic systems (Lener MS et al / Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depressionand Antidepressant Response to Ketamine.// Biol Psychiatry. 2017.15; 81 (10): 886-897. Doi: 10.1016 / j.biopsych.2016.05.05.005).

Some researchers have hypothesized that kainate receptor dysfunction (Larsen AM et al / Sex differences in glutamate receptor gene expression in major depression and suicide // ACS Chem Neurosci. 2011. 16; 2 (2): 60-74. Doi: 10.1021 / cn1001039; Gray AL et al / Medicinal chemistry of competitive kainate receptor antagonists // Mol Psychiatry. 2015.20 (9): 1057-68. Doi: 10.1038 / mp.2015.91; Milanesi E et al / The role of GRIK4 gene in treatment-resistant depression // Genet Res (Camb). 2015.3; 97: 14. Doi: 10.1017 / S0016672315000142) the regulation of which can be a target for creating fast antidepressants.

It can be assumed that the effect on kainate receptors in depressed patients will lead to an improvement in their condition due to their effect on various pathogenetic mechanisms, including extrasynaptic disorders, such as dysfunction of astroglia.

Of particular interest in the pathophysiology of depressive disorders is one of the subunits of the Kluin receptors GluK4, which are mainly expressed in the pyramidal neurons of the hippocampal region CA3, dentate gyrus, neocortex and Purkinje cells. In the experiment, it was shown that overexpression of these receptors in the forebrain leads to a violation of social behavior, increased anxiety and depressive disorders. (Aller MI et al / Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features // J Neurosci. 2015.7; 35 (40): 13619-28. Doi: 10.1523 / JNEUROSCI.2217 -15.2015).

Other studies have found that GluK4 variability affects the therapeutic response to antidepressants. It turned out that some variants of these receptors lead to therapeutic resistance and an increased risk of psychotic symptoms at the height of a depressive episode (Milanesi E et al / The role of GRIK4 gene in treatment-resistant depression. Genet Res (Camb). 2015. 3; 97: e14. doi: 10.1017 / S0016672315000142). Koromina et al (2018) found in a twin cohort study that deletion of the GLUK4 gene reduces the risk of developing bipolar disorder and improves the quality of cognitive functioning. (Koromina M et al / A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the Twins UK cohort // World J Biol Psychiatry. 2018. 11: 1-9. Doi: 10.1080 / 15622975.2017. .1417637).

Thus, kainate receptors are a promising therapeutic target, including for the treatment of depression. Improving the treatment of depressive disorders is one of the leading tasks of modern psychiatry.

Disclosure of invention

The present invention is to develop a new effective negative modulator of kainate recipes, which is promising for use in clinical practice as a medicine for the treatment of mental diseases and / or disorders of the central nervous system, including depressive disorders.

The technical result consists in the development of a new highly effective negative modulator of kainate receptors, which is promising for the treatment of mental diseases and / or disorders, including for the treatment of depressive disorders, in particular as a rapid antidepressant, and is also promising for the treatment of anxiety disorders, disorders associated with stressful.

The specified technical result is achieved by obtaining a new compound 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3,11 ] tetradecane- 4,8,12-trion of the following structure:

or pharmaceutically acceptable salts thereof, which are negative kainate receptor modulators.

The achievement of the specified technical result is also achieved as a result of the use of the compounds of the invention for the treatment and / or prevention of a mental illness or disorder, and / or for the preparation of a pharmaceutical composition for the treatment and / or prevention of a mental illness or disorder.

In particular embodiments, the disorder is a depressive disorder, anxiety disorder, and / or a stress disorder.

In particular embodiments, a depressive disorder is a depressive episode, an adaptive reaction disorder, a recurrent depressive disorder, and / or a depressive episode associated with a behavior disorder.

In particular embodiments, the anxiety disorder is anxiety-phobic disorder.

In particular embodiments, the anxiety-phobic disorder is agoraphobia, social phobia and / or isolated phobia.

In particular embodiments of the invention, anxiety disorder is panic disorder, generalized anxiety disorder, mixed anxiety-depressive disorder.

In particular embodiments, the disorder is a condition associated with persistent pain.

The achievement of the specified technical result is also achieved by creating a pharmaceutical composition for the treatment and / or prevention of mental illness or disorder, characterized in that it contains an effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.

In particular embodiments, the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent.

In particular embodiments, the disorder is a depressive disorder, anxiety disorder, and / or stress related disorder.

In particular embodiments, a depressive disorder is a depressive episode, an adaptive reaction disorder, a recurrent depressive disorder, and / or a depressive episode associated with a behavior disorder.

In particular embodiments, the anxiety disorder is anxiety-phobic disorder.

In particular embodiments, the anxiety-phobic disorder is agoraphobia, social phobia and / or isolated phobia.

In particular embodiments of the invention, anxiety disorder is panic disorder, generalized anxiety disorder, mixed anxiety-depressive disorder.

In particular embodiments, the disorder is a condition associated with persistent pain.

The invention also includes the preparation of the compound 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3,11 ] tetradecane-4.8 , 12-trion and its pharmaceutically acceptable salts.

As a result of the studies, the compound 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3,11 ] tetradecan- 4,8,12-trion of the following structure:

The experiments showed that the obtained compound is a highly effective negative modulator of kainate receptors, and the claimed compound has significantly higher efficiency compared to compounds characterized by a similar structure. So, in particular, as a result of an experiment on the study of antidepressant activity in the test "hanging by the tail" of the claimed compound and its structural analogues, it was unexpectedly shown that a comparable level of effectiveness for the compounds of the invention is observed at a dose hundreds of times lower than for the nearest structural analogues.

Along with this, as a result of a study of antidepressant activity in the test "forced swimming" of the claimed compound also demonstrated efficacy in a dose hundreds of times lower than structural analogues.

In addition, the antidepressant activity of a compound of the invention was tested in a novelty suppression test of eating behavior. The results of a study on a model of suppression of eating behavior in mice caused by novelty demonstrated the high effectiveness of ketamine, which manifested itself in the form of a reduction in the latent period of the approach to food in an unfamiliar environment. This action of ketamine manifested itself in a single dose of 20 mg / kg. The compound of the invention also reduced the duration of the latent period, and this effect was manifested in a dose range of 0.025-2.5 mg / kg. Based on the data obtained, it can be concluded that the ketamine and the compound according to the invention exhibit the properties of high-speed antidepressants in a model of suppressing eating behavior caused by novelty.

Additionally, a study was conducted of the antidepressant activity of the compounds of the invention in a model of a depression-like state caused by the administration of bacterial lipopolysaccharide (LPS) in experiments in mice. The results of the experiments show that the introduction of LPS causes a depressive state in mice, which is expressed in an increase in the immobility time in the tail suspension test. In this test, a statistically significant reduction in immobility time was detected under the influence of ketamine at a dose of 20 mg / kg, as well as the test compound (0.25-2.5 mg / kg). Based on the data obtained, it can be concluded that the test compound have an antidepressant effect.

Detailed Disclosure of Invention

Definitions and Terms

For a better understanding of the present invention, the following are some of the terms used in the present description of the invention. In addition, unless otherwise indicated, all occurrences of functional groups are selected independently, two occurrences can be the same or different.

In the description of the present invention, the terms “includes” and “including” are interpreted as meaning “includes, inter alia,”. These terms are not intended to be construed as “consists of only”.

The term “patient” or “subject” encompasses all types of mammals, preferably humans.

The compound of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which, within the framework of a medical opinion, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable balance of benefits and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be prepared in situ during the isolation or purification of the compounds of the invention, and can also be prepared separately by reacting the free base of the compound of the invention with a suitable acid. An example of pharmaceutically acceptable, non-toxic acid salts is the amino group formed by inorganic acids such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained by other methods used in this field, for example, by ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, heptofluorosulfonate, glucose gluconate, formate glucose phosphate heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, perspec ulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecane, valerate and the like.

The compounds of the invention may exist in a radioisotope-labeled form, i.e. these compounds may contain one or more atoms, whose atomic mass or mass number differs from the atomic mass or mass number of the most common natural isotopes. The radioisotopes of hydrogen, carbon, phosphorus, chlorine include 3H, 14C, 32P, 35S, and 36Cl, respectively. Compounds of the present invention that contain such radioisotopes and / or other radioisotopes of other atoms are within the scope of the present invention. Tritium, i.e. 3H and carbon, i.e. 14C, radioisotopes are particularly preferred due to the ease of preparation and detection.

The compounds of the present invention labeled with radioactive isotopes can be prepared using methods well known to those skilled in the art. Labeled compounds can be prepared using the procedures described herein by simply replacing unlabelled reagents with the corresponding labeled reagents.

The term “depression” (including “depressive disorders” or “depressive symptoms”) as used herein includes central nervous system disorders characterized by a combination of signs and symptoms, which may include feelings of hopelessness, guilt, futility and / or sadness decreased concentration along with changes in sleep and / or food intake.

The term “anxiety disorders” as used herein refers to a group of mental disorders characterized by significant feelings of anxiety and fear.

In this document, “phobic disorders” are characterized by a strong and irrational fear of certain situations or objects, often accompanied by avoiding the cause of fear. There are two types: general and specific. Common phobias include agoraphobia and sociophobia. Agoraphobia is the fear of being trapped in a situation or place without the possibility of salvation or help; for example, a person may be afraid to be in a movie or ride a bus. Sociophobia is an anxiety provoked by certain social situations. Individuals with such a phobia are often afraid that there will be indecision or humiliation if they do not behave accordingly, and that the symptoms of anxiety are sweating, redness, trembling voice, etc. - become noticeable, lead to further indecision and humiliation.

For specific phobias, the source of anxiety is a specific object, such as animals (zoophobia), thunderstorms (astrophobia and brontophobia), or blood (hemophobia); or the source is a specific situation, such as being at a height (acrophobia) or being in a confined space (claustrophobia).

In this document, "stress disorders" are generally divided into types: acute stress disorder and post-traumatic stress disorder. Acute stress disorder occurs after a person has witnessed or experienced a traumatic event; symptoms, among others, include recurrent event memories, increased arousal, unemotionality, and / or amnesia. Acute stress disorder does not last long, usually four or less weeks. A longer duration of symptoms often indicates post-traumatic stress disorder. Post-traumatic stress disorder is characterized by recurring frequent, unwanted recollections of the traumatic event, nightmares, feelings of depression or guilt, as well as unemotionality.

By “negative kainate receptor modulator” is meant herein a modulator that decreases receptor sensitivity to endogenous ligand.

The term "fast antidepressant" in this document refers to a tool, as a result of which, in the treatment of depression (depressive disorder), the therapeutic response (effect) occurs within a few hours, in contrast to traditional antidepressants, the response to the therapy of which is observed within a few days / weeks.

Brief Description of the Drawings

Figure 1. Modulation of ionic currents induced by the use of kainic acid under the influence of a compound of the invention and cyclothiazide (CTZ). The upper and lower halves of the 95% confidence interval of the average response are highlighted in color.

Figure 2. The effect of intraperitoneal administration of substances on the duration of complete immobilization in a 6-minute tail suspension test in mice. Test compounds were administered in 15 minutes. # - p <0.05, significant effect compared with the control group (t-test, two tail).

Figure 3. The effect of intraperitoneal administration of the compound of the invention and compound 2 (structural analogue) on the duration of active behavior in the 5-minute test "forced swimming (Porsolt test)" in rats 1, 4 and 24 hours after administration. * p <0.05, ** p <0.01, significant effect compared to the control group (t-test, two tail).

Figure 4. The effect of intraperitoneal administration of the compound of the invention on the duration of the latent period in the new medium in the test for suppressing eating behavior caused by novelty in mice 1 hour after administration. * p <0.05; ** p <0.01; *** p <0.001 (Dunnet test for multiple comparisons).

Figure 5. The effect of intraperitoneal administration of a compound of the invention on the duration of the latent period in a familiar medium in a test of suppressing eating behavior caused by novelty in mice 1 hour after administration.

Figure 6. The effect of intraperitoneal administration of substances on the duration of complete immobilization in a 6-minute tail suspension test in mice. ** p <0.01 compared with the control, + p <0.05; ++ p <0.01, +++ p <0.0001 compared with the group receiving LPS (Dunnet test for multiple comparisons).

The use of compounds for medical reasons

The compounds described in this invention can be used to treat mental illness or disorder, including depressive disorder, anxiety disorder and / or stress related disorder.

Method for the therapeutic use of compounds

The subject of this invention also includes the administration to a subject in need of appropriate treatment of a therapeutically effective amount of a compound of general formula (I).

By a therapeutically effective amount is meant an amount of a compound administered or delivered to a patient in which the patient is most likely to exhibit the desired response to treatment (prophylaxis). The exact amount required can vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

The compound of the invention or a pharmaceutical composition comprising the compound can be administered to the patient in any amount and by any route of administration effective for treating or preventing a disease.

After mixing the drug with a specific suitable pharmaceutically acceptable carrier in the desired dosage, the compositions constituting the essence of the invention can be administered orally, parenterally, nasally, etc. to the human body or other animals.

In the case where the compound of the invention is used as part of a combination therapy regimen, a dose of each of the components of the combination therapy is administered during the required treatment period. The compounds that make up the combination therapy can be administered into the patient's body both at a time, in the form of a dosage containing all the components, and in the form of individual dosages of the components.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions that contain a compound of general formula (I) (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and / or excipients, such as may be introduced into the patient’s body together with the compound that is the essence of the present invention, and which do not destroy the pharmacological activity of this compound, and are non-toxic administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

The subject of this invention is also dosage forms — a class of pharmaceutical compositions whose composition is optimized for a particular route of administration into the body in a therapeutically effective dose, for example, for administration to the body orally, nasally, for example, as an inhalation spray, or intravascularly, intranasally, subcutaneously , intramuscularly, as well as by infusion, in recommended dosages.

Dosage forms of the present invention may contain formulations prepared using liposome methods, microencapsulation methods, methods for preparing nanoforms of the preparation, or other methods known in the pharmaceutical art.

In preparing the composition, for example, in tablet form, the active principle is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.

Tablets may be coated with sucrose, a cellulosic derivative, or other suitable coating materials. Tablets can be prepared in various ways, such as direct compression, dry or wet granulation, or hot fusion.

A pharmaceutical composition in the form of a gelatin capsule can be prepared by mixing the active principle with a solvent and filling the mixture with soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used that contain pharmacologically compatible agents, for example propylene glycol or butylene glycol.

Preparation of Compounds of the Invention

The compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

Example 1. 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3,11 ] tetradecane-4,8,12 Trion.

In a 100 ml one-neck flask with reflux condenser and a calcium chloride tube, 10.28 g of 3,7-bis (chloroacetyl) -1,5-dimethyl-3,7-diazabicyclo [3.3.1] nonan-9-one ( 0.032 mol, mol. Weight = 321.2, C ₁₃ H ₁₈ Cl ₂ N ₂ O ₃ ) and 13.15 g of K ₂ CO ₃ (0.095 mol, mol. Weight = 138) in 150 ml of absolute DMF, 7 g of 4 were added with stirring -methoxy-3- (pyrrolidin-1-ylmethyl) benzylamine (0.032 mol, mol. weight = 220.31, C ₁₃ H ₂₀ N ₂ O). The reaction mixture was heated on a magnetic stirrer to 80 ° C and stirring was continued for 4 hours until the starting compounds completely disappeared. After cooling to room temperature, the mixture was filtered using a 250 ml Schott filter, 750 ml of water was added and the mixture was extracted with 3 × 60 ml chloroform. The combined organic extracts were dried over sodium sulfate. Then sodium sulfate was filtered off, the solvent was distilled off in vacuo (60 ° С at 10 mmHg) on a rotary evaporator. The solid residue after distillation of the solvent was applied to a silica gel chromatography column. Chloroform (1000 ml) was used as an eluent, then it was eluted with the CHCl ₃ / EtOH system (50: 1) (mixture volume 1500 ml) and then with the CHCl ₃ / EtOH system (20: 1) (mixture volume 2500 ml). A fraction with Rf 0.42 in the CHCl ₃ -EtOH system (20: 1) was selected. The solvent was distilled off in vacuo (60 ° C at 10 mm Hg) on a rotary evaporator and a light yellow clear oil was obtained, which was dissolved in 50 ml of Et ₂ O, 10 ml of hexane was slowly added and 8/10 of the solvent was slowly distilled off on a rotary vaporizer. White amorphous crystals fell out. Received 13.4 g (90% of theory) of 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3.11 ] tetradecane-4,8,12-trion (mol. weight = 468.59, C2 ₆ H ₃₆ N ₄ O ₄ ). Mp = 115-117 ° C.

1 H NMR (CDCl ₃ ): 1.00 (s, 3 H); 1.12 (s, 3 H); 1.45-1.53 (m, 4 H); 2.47 (broad s, 4 H); 2.73 (d, J 13.3, 2 H); 3.04 (d, J 13.3, 2 H); 3.24 (d, J 14.1, 2 H); 3.53 (s, 2 H); 3.58 (s, 2 H); 3.75 (d, J 14.1, 2 H); 3.92 (s, 3 H); 4.94 (m, 4 H); 6.93 (d, J 8.4, 1 H); 7.26 (d, J 8.4, 1 H); 7.42 (s, 1 H).

The biological activity of the compounds of the invention

1. Electrophysiological experiments on Purkinje neurons

The authors of the present invention investigated the effect of the compounds of the invention on Purkinje neurons of rat cerebellum. In the experiment, the compound of the invention and the positive control, cyclothiazide, a well-known positive allosteric modulator of AMPA receptors, are known.

The results obtained (see figure 1) are consistent with the literature on the known value of EC ₅₀ for cyclothiazide. It was completely unexpected in an experiment that the compound of the invention was a negative allosteric regulator of glutamate receptors.

Thus, it was shown that the compound of the invention is capable of modulating ionic currents induced by kainic acid in Purkinje neurons of rat cerebellum.

2. Tests of the specific activity of drug compounds in in vivo models.

The study of antidepressant activity in the test "hanging by the tail"

The model of “hanging mice by the tail” is one of the most commonly used experimental models for studying the possible antidepressant effect of new substances. This test simulates behavioral despair. The test places the experimental animal in an uncomfortable situation for him, after which the time during which it fights with it is measured. Antidepressants usually increase fight time.

The research results are presented in figure 2.

Intraperitoneal administration of the compounds of the invention at a dose of 0.0025 mg / kg showed the presence of high efficacy (Figure 2) as an antidepressant. Along with the claimed compound, its closest structural analogues were tested:

1. compound 1, characterized by the following structural formula:

2. Compound 2, characterized by the following structural formula:

Moreover, the indicated structural analogues showed comparable activity only at a dose of 0.25 mg / kg, while the indicated dose was 100 times higher than the effective dose for the compound of the invention. Thus, the claimed compounds are characterized by activity hundreds of times higher than the closest analogues, and the experimental results in the model of "hanging by the tail" confirmed the activity of the developed drug candidate.

The study of antidepressant activity in the test "forced swimming".

The “forced swimming test, Porsolt test” in rats along with the test “hanging mice by the tail” is one of the most commonly used experimental models for studying the possible antidepressant effect of substances. The test is based on the fact that rats, being placed in a transparent cylinder filled with water from which it is impossible to get out, quickly stop trying to get out of it and simply freeze in anticipation. This behavior is interpreted as a passive stress management strategy - “behavioral despair”. Antidepressants increase the time that rats make active attempts to get out.

In the first experiment, the effect of the compound of the invention at a dose of 0.002 mg / kg and compound 2 (structural analogue of the claimed compound) at a dose of 0.1 mg / kg with intraperitoneal administration 1 and 24 hours before the test was studied. The comparison drug was imipramine, which was administered intraperitoneally at a dose of 15 mg / kg. The procedure consisted of a “classic” forced swimming test protocol. On the first day (the stage of development of the state of "behavioral despair"), the rats were placed in cylinders with water for 15 minutes, after which the animals were removed, wiped with a towel and placed in a cage with clean bedding and paper towels. 24 hours after the stage of developing the state of “behavioral despair”, the test substances and the reference drug were introduced. 1 hour after a single injection of the studied drugs, the experimental animals were again placed in glass cylinders with water for 5 minutes to assess the acute effect of the tested drugs. 24 hours after a single injection, the corresponding experimental groups were tested. The following indicators of the structure of rat behavior were evaluated:

- Avoiding aversive conditions (climbing the wall, diving);

- orientation in space (rowing with two hind limbs);

- indicators of discomfort (number of shakes);

- passivity (duration of drift);

- index of emotionality (level of bowel movement).

The results of the study are presented in figure 3.

As a result of the study, it was shown that the test compound according to the invention with a single intraperitoneal administration to a large extent influenced the structure of the behavior of experimental animals in the Porsolt test 1 hour after administration than its closest analogue, compound 2 (see figure 3). Changes in the structure of behavior can be considered as a manifestation of a pronounced antidepressant effect, which was characterized by an increase in the duration of active and a decrease in passive behavior of rats compared with the control group. 24 hours after the administration of the manifestation of the antidepressant effect, they were not statistically significant. However, there was a tendency to actively get rid of aversive environmental conditions and thereby reduce the manifestation of “behavioral despair” (antidepressant effect) in response to the administration of the tested substances.

The observed change in the structure of behavior after administration of the test compound according to the invention remained unchanged for 24 hours after administration, in contrast to the reference drug imipramine, whose antidepressant effect was less pronounced after 24 hours compared with the groups receiving the test compound according to the invention, and did not differ from indicators in the control group. This observation indicates the prolonged action of the compounds of the invention.

The study of antidepressant activity in the test of suppression of eating behavior caused by novelty.

Novely suppressed feeding (NSF) is a conflicting test based on two competing motivations: the desire for food and the fear of getting into the center of a brightly lit arena. The duration of the latent period before eating is used as an indicator of anxiety. An increase in the duration of the latent period is considered an indicator of a depressive-like state in animals (Santarelli L., et al., Science, 2003, 301, 805-809).

As previous studies have shown, well-known tricyclic antidepressants and selective serotonin reuptake inhibitors shorten the latent period of food intake without affecting the amount of food consumed. A feature of the action of antidepressants in this test is that their effect is observed only with repeated administration, and their single administration does not affect the duration of the latent period. It is believed that this test is a more adequate test for the detection of antidepressant action, because corresponds to the clinical features of the antidepressant effect in patients (Dulawa S., Hen R., Neurosci. Biobehav. Rev., 2005, 29, 771-783). Some studies have shown that the antidepressant effect of ketamine in this test appears after a single dose of 5-10 mg / kg (Li, N., et al., Science, 2010, 329, 959-964). The authors of the present invention believe that when studying fast-acting antidepressants, their effects should be manifested already with a single administration.

For the experiment, male mice of the C57BL / 6 line were used. 24 hours before the experiments, the animals were removed food, leaving only water. Food deprivation was necessary to create persistent nutritional motivation. After 24 hours, the test substances were injected into the animal and after 60 minutes one animal was placed in a new medium, which was a box 50 × 50 × 20 cm in size, in the center of which was a feeder with a food pellet. The bottom of the box was covered with sawdust and the box was lit with 600 lux lamps. In preliminary experiments, the light intensity was set so that the latent period of approach to food in an individual animal was no more than 5 minutes. Each animal was placed in the corner of the box and measured the duration of the latent period in seconds of the animal's approach to the feeder and the start of food intake. The maximum follow-up was 5 minutes. Immediately after the test in a new environment, the animal was placed in a home cage with the same light source, in the center of which there was a food pellet feeder, and the latent period of the approach to the feeder was measured again for 5 minutes. Additionally, the animal was given free access to food and the amount of food in grams that the animal consumed for 5 minutes was measured. During the behavior analysis, the following parameters were measured:

- the duration of the latent period in seconds in the new environment;

- the duration of the latent period in seconds in the home environment;

- the amount of food consumed in grams.

In the experiment, the effect of the compound of the invention in doses of 0.0025-2.5 mg / kg, as well as ketamine in a dose of 20 mg / kg, was investigated. Substances were administered intraperitoneally to mice.

The effect of substances on the duration of the latent period in the new environment is presented in figure 4, on the duration of the latent period in the home environment - in figure 5. The results of a study on a model of suppression of eating behavior in mice caused by novelty demonstrated high efficacy of ketamine, which manifested itself as a reduction in the latent period approach to food in an unfamiliar environment. This action of ketamine manifested itself in a single dose of 20 mg / kg. The compound of the invention also reduced the duration of the latent period, and this effect was manifested in a dose range of 0.025-2.5 mg / kg.

The decrease in the duration of the latent period under the influence of ketamine and the compounds of the invention was not associated with a possible increase in food motivation, since these substances did not affect the duration of the latent period and the amount of food consumed in a familiar environment.

Based on the data obtained, it can be concluded that the ketamine and the compound according to the invention exhibit the properties of high-speed antidepressants in a model of suppressing eating behavior caused by novelty.

The study of antidepressant activity on a model of a depressive-like state caused by the introduction of bacterial lipopolysaccharide in experiments in mice.

Numerous data accumulated over recent years indicate that the immune system is involved in the etiology and pathogenesis of depression.

Bacterial lipopolysacchapride (LPS) is the main component of the outer membrane of gram-negative bacteria. Systemic administration of LPS in high doses causes a state of septic shock and leads to death. In small doses, the systemic administration of LPS causes the activation of the immune system with the release of cytokines and damage to the blood-brain barrier. Penetrated into the brain cytokines and, first of all, tumor neurosis factor (TNF) activate the local immune system. At the behavioral level, this is manifested in the development of the so-called "painful behavior". A characteristic sign of this behavior is depressive-like symptoms, which manifests itself in the form of anhedonia, a reduced ability to cope with stress, impaired learning and memory, anxiety reactions.

In connection with the foregoing, it was interesting to study the effect of ketamine and drug candidates on depressive-like behavior caused by LPS administration in mice. As a behavioral test reflecting a depressive-like state after LPS administration, a tail suspension test was widely used to evaluate the effect of antidepressants in mice.

In the experiment, male mice of the C52BL / 6 line were used. 6 hours before the start of the experiments, the animals were injected intraperitoneally with an LPS solution (0.5 mg / kg) and then, 2 hours before the start of the test, the test substances were administered. Mice were hung by the tail from a wooden bar using adhesive tape 1 cm from the end of the tail. Animals were suspended for 6 minutes. During the behavior analysis, the following parameters were measured:

- total duration of immobility for 6 minutes;

- the number of episodes of immobility;

- latent period until the first episode of immobility.

In the experiment, the effect of the compound of the invention in doses of 0.25 - 2.5 mg / kg, as well as ketamine in a dose of 20 mg / kg, was investigated. Substances were administered intraperitoneally to mice. The results of the experiment are presented in figure 6.

The results of the experiments show that the introduction of LPS causes a depressive state in mice, which is expressed in an increase in the immobility time in the tail suspension test. In this test, a statistically significant reduction in immobility time was detected under the influence of ketamine at a dose of 20 mg / kg, as well as the test compound (0.25-2.5 mg / kg). Based on the data obtained, it can be concluded that the test compound have an antidepressant effect.

Thus, studies have shown that the claimed compound of the invention are highly effective negative modulators of kainate receptors. The specified compound is promising for use in the treatment of mental diseases of the central nervous system, including for the treatment of depression, in particular as fast antidepressants.

Although the invention has been described with reference to the disclosed embodiments, it will be apparent to those skilled in the art that the specific experiments described in detail are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. It should be understood that various modifications are possible without departing from the gist of the present invention.

Claims (16)

1. The compound 6- [4-methoxy-3- (pyrrolidin-1-ylmethyl) benzyl] -1,11-dimethyl-3,6,9-triazatricyclo [7.3.1.1 ^3,11 ] tetradecane-4,8,12 trion of the following structure:

or a pharmaceutically acceptable salt thereof. 2. The use of a compound according to claim 1 for the treatment and / or prevention of a mental illness or disorder, and / or for the preparation of a pharmaceutical composition for the treatment and / or prevention of a mental illness or disorder in which the disease and / or disorder is a depressive disorder, anxiety a disorder and / or a stress disorder. 3. The use of claim 2, wherein the depressive disorder is a depressive episode, a disorder of adaptive reactions, a recurrent depressive disorder, and / or a depressive episode associated with a behavior disorder. 4. The use according to claim 2, in which the anxiety disorder is an anxiety-phobic disorder. 5. The use according to claim 4, in which the anxiety-phobic disorder is agoraphobia, social phobia and / or isolated phobia. 6. The use according to claim 2, in which the anxiety disorder is a panic disorder, generalized anxiety disorder, mixed anxiety-depressive disorder. 7. The use according to claim 2, in which the disorder is a condition associated with persistent pain. 8. A pharmaceutical composition for treating and / or preventing a mental illness or disorder, which is a depressive disorder, anxiety disorder and / or stress related disorder, the pharmaceutical composition comprising an effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable adjuvant substance. 9. The pharmaceutical composition of claim 8, in which the pharmaceutically acceptable excipient is a carrier, excipient and / or solvent. 10. The pharmaceutical composition of claim 8, wherein the depressive disorder is a depressive episode, an adaptive reaction disorder, a recurrent depressive disorder, and / or a depressive episode associated with a behavior disorder. 11. The pharmaceutical composition of claim 8, in which the anxiety disorder is an anxiety-phobic disorder. 12. The pharmaceutical composition according to claim 11, in which the anxiety-phobic disorder is agoraphobia, social phobia and / or isolated phobia. 13. The pharmaceutical composition of claim 8, in which the anxiety disorder is a panic disorder, generalized anxiety disorder, mixed anxiety-depressive disorder. 14. The pharmaceutical composition of claim 8, wherein the disorder is a condition associated with persistent pain.

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