BG113103A - Nmda-receptor antagonist with antimicrobial activity - Google Patents

Abstract

The invention relates to a compound of general formula (I), a method for its preparation and its application as an NMDA-receptor antagonist for the prevention and treatment of Alzheimer's disease, as well as a means of preventing and treating diseases caused by clinically significant , conditionally pathogenic bacteria and fungi.

Description

NMDA- RECEPTOR ANTAGONIST WITH ANTIMICROBIAL ACTIVITY

Field of the invention

The invention relates to an M-methyl-O-aspartate (NMDA) receptor antagonist with antimicrobial activity applicable to Alzheimer's disease patients with bacterial and fungal infections caused by clinically relevant, conditionally pathogenic bacterial species and fungi.

Antecedent condition

Many neurodegenerative diseases result from progressive loss of neuronal structure or function, including neuronal death. These are difficult-to-treat diseases that lead to progressive degeneration and/or loss of nerve cells. The progressive deterioration of cognitive abilities labeled as Alzheimer's disease is currently considered to be an incurable, degenerative and terminal disease. Treatment is usually symptomatic - antidepressants, anxiolytics, neuroleptics, cholinesterase inhibitors and other symptomatic drugs are used. However, since the disease is the result of impaired signaling in the brain, in which the so-called M-methyl-O-aspartate (NMDA)-receptors play an important role, recently means have been used to bind to the NMDA receptors on brain cells and block them. the activity of the neurotransmitter glutamate. One such agent is memantine, which is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of Alzheimer's disease (AD) [1]. This is the reason, according to patent application US2019336509 A1, for the inclusion of memantine as an NMDA-receptor antagonist together with a histamine-3 receptor inverse agonist and an acetylcholinesterase inhibitor in a composition for the treatment of cognitive disorders.

Regardless of the proven therapeutic effect in moderate and acute conditions of BA and dementia, however, memantine manifests some negative manifestations that limit its use, namely - too high a degree of solubility in water, which represents a challenge for obtaining the medicinal forms, as well as some adverse side effects of its use such as confusion, dizziness, drowsiness, headache, insomnia, nausea and hallucinations.

On the other hand, according to Pisa, D. et al. (2017) [2], infections of different types may underlie the neurodegenerative disease BA, and a study by Yu, J. Y. et al. 2015 [3], designed to identify unknown antimicrobial properties of known drugs, showed for the first time that memantine could effectively block bacteremia and meningitis caused by E. coli in a mouse model. The results of the studies found that memantine has the potential to treat meningococcal infection, but it targets the host rather than the bacterial pathogen because it does not show antimicrobial activity in vitro.

The task of the invention is to propose a compound representing an antagonist of Nmethyl-O-aspartate (NMDA) receptors and a method for its preparation, applicable both as a means of prevention and treatment of the chronic neurodegenerative disease Alzheimer's disease, and as a means against clinically significant, conditionally pathogenic bacterial species and fungi.

Nature of the invention

The invention relates to a compound of general formula (I), _z R NH

(I) where R represents an amino acid or a peptidomimetic selected from the group consisting of: aminoethanoic acid, 2-amino-3-methylbutanoic acid, 2-aminopropanoic acid, 3-aminopropanoic acid, 2-amino-3-phenylpropanoic acid, 2-amino-3 -(4hydroxyphenyl)propanoic acid, 2-amino-3-(4-fluorophenyl)propanoic acid, 2(aminomethyl)-1,3-thiazole-4-carboxylic acid and 2-(aminomethyl)-1',3'-thiazolyl -4'-2-(1,3thiazole)-4-carboxylic acid.

The chemical compound of general formula (I) is obtained in the following sequence of operations:

The parent compound comprising a protecting group M-(tert-butoxycarbonyl) (BOC) amino acid or a peptidomimetic selected from the group consisting of Ν-(τρβτbutoxycarbonyl)-aminoethanoic acid, M-(tert-butoxycarbonyl)-2-amino-3methylbutanoic acid , M-(tert-butoxycarbonyl)-2-aminopropanoic acid, Ν-(τρβτbutoxycarbonyl)-3-aminopropanoic acid, M-(tert-butoxycarbonyl)-2-amino-3-(4fluorophenyl)propanoic acid, M-(tert- butoxycarbonyl)-2-amino-3-phenylpropanoic acid, N-(τpeτ-быτoκciκapbonyl)-2-amino-3-(4-xidpoκciφenyl)πpoπanoic acid, Ν(tert-butoxycarbonyl)-2-(aminomethyl)-1,3 -thiazole-4-carboxylic acid and Ν-(τρβτbutoxycarbonyl)-2-(aminomethyl)-1',3'-thiazolyl-4'-2-(1,3-thiazole)-4-carboxylic acid), was dissolved in dimethylformamide, adding triethylamine (TEA) and dicyclohexylcarbodiimide (DCC) with continuous stirring [4].

Memantine hydrochloride was dissolved in dimethylformamide and added after twenty minutes. The progress of the reaction was monitored by thin layer chromatography (TLC). After the completion of the reaction, a double wash with a 5% NaHCO3 solution, a 5% NaHSCU solution and a single wash with water are carried out. The organic layer was dried with anhydrous Na2SO«. After evaporation of the solvent, an intermediate compound is obtained which, in accordance with the starting compound, is (M-(tert-butoxycarbonyl)-aminoethaneM-(3,5-dimethyladamantane)-amide; M-(tert-butoxycarbonyl)-2-amino- 3-methylbutane-N-(3,5dimethyladamantane)-amide;N-(tert-butoxycarbonyl)-2-aminopropane-N-(3,5dimethyladamantane)-amide;N-(tert-butoxycarbonyl)-3-aminopropane-M- (3,5dimethyladamantane)-amide; N-(τpeτ-быτoκciκapcarbonyl)-2-amino-3-(4-φlyopoφenyl)πpoπan-N(3,5-dimethyladamantane)-amide; M-(tert-butoxycarbonyl)-2- amino-3-phenylpropane-N-(3,5-dimethyladamantane)-amide; N-(tert-butoxycarbonyl)-2-amino-3-(4-hydroxyphenyl)propane-N-(3,5-dimethyladamantane)-amide; M- (tert-butoxycarbonyl)-2-(aminomethyl)-1,3-thiazole-4carboxy-N-(3',5'-dimethyladamantane)-amide and N-(tert-butoxycarbonyl)-2-(aminomethyl)-1' ,3-thiazolyl-4'-2-(1,3-thiazole)-4-carboxy-N-(3,5"-dimethyladamantane)-amide) as an oil.

To the intermediate cooled to 0°C and dissolved in dichloromethane, an equivalent volume of trifluoroacetic acid (TFA) was added dropwise to deblock the BOC protecting group. The solution is stirred at 0°C and the process is monitored chromatographically until the BOC group is unblocked.

After evaporation of the solvents, diethyl ether was added several times, which was evaporated accordingly. To the obtained oily product, depending on the solubility, mixtures of ethyl acetate/hexane or methanol/diethyl ether are added, as a result of which crystals of trifluoroacetates of chemical compounds are obtained, which, in accordance with the starting compounds, represent memantine derivatives as follows:

1. aminoethane-N-(3,5-dimethyladamantane)-amide

2. 2-amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide

3. 2-amino-propane-N-(3',5'-dimethyladamantane)-amide

4. 3-Amino-propane-N-(3',5'-dimethyladamantane)-amide

5. 2-Amino-3-(4-fluorophenyl)propane-N-(3”,5-dimethyladamantane)-amide

6. 2-amino-3-phenylpropane-N-(3',5'-dimethyladamantane)-amide

7. 2-amino-3-(4-hydroxyphenyl)propane-N-(3”,5”-dimethyladamantane)-amide

8. 2-(Aminomethyl)-1,3-thiazole-4-carboxy-N-(3',5'-dimethyladamantane)-amide

9. 2-(Aminomethyl)-1',3'-thiazolyl-4'-2-(1,3-thiazole)-4-carboxy-N-(3,5"-dimethyladamantane)amide.)

The solvents were evaporated and water, methanol and/or acetonitrile were added to the crystals and the pH of the solution was adjusted to 7.5-8.0 using 25% ammonia solution. This was followed by a double extraction with ethyl acetate, evaporation of the solvent and chromatographic purification of the obtained crystals.

The yield of the various memantine derivatives varies from 28% to 45%.

1. aminoethane-H-(3,5-dimethyladamantane)-amide ^1H (DMSO-d6) δ (ppm): 0.82 (s, 6H, 2xCH3), 1.12 (m, 2H), 1.26 (d, 2H, J =12.6 Hz), 1.32 (dd, 2H, J=2.8 Hz, J=12.5 Hz), 1.55 (d, 2H, J=11.9 Hz), 1.60 (d, 2H, J=11.6 Hz), 1.77 (d, 2H, J=2Hz) 2.09 (m, 1H), 3.45 (s, 2H), 7.9 (brs, 1H, NH-amide), 7.95 (brs, 2H, NH2-amine). ¹³ C (DMSO-d6) δ (ppm): 29.9 (CH), 30.5 (CH3), 32.3 (Cquat), 39.81 (CH2), 40.8 (CH2), 44.6 (CH2), 47.4 (CH2), 50.5 (CH2 ), 53.3 (Cquat), 165.2 (CO). ESI-MS: m/z: 237, [M+HJ+

2. 2-amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide ¹ H (DMSO-d6) δ (ppm): 0.82 (s, 6H, 2xCH3), 0.91 (d, 3H, J=6.9 Hz, CH3), 0.92 (d, 3H, J=6.9 Hz, CH3), 1.12 (m, 2H), 1.26 (d, 2H, J=12.6 Hz), 1.32 (dd. 2H, J=2.8 Hz, J=12.5 Hz), 1.55 (d, 2H, J=11.9 Hz), 1.62 (d, 2H, J=11.6 Hz), 1.78 (m, 2H), 2.00 (m, 1H), 2.09 (m, 1H), 3.48 (d, 1H, J=6 Hz), 7.91 (brs, 1H, NH-amide), 8.02 (brs, 2H, NH2-amine). ¹³ C (DMSO-d6) δ (ppm): 18.1 (CH3), 18.8 (CH3), 29.9 (CH), 30.3 (CH), 30.4 (CH3), 32.3 (Cquat), 39.7 (CH2), 42.6 (CH2 ), 47.3 (CH2), 47.3 (CH2), 50.5 (CH2), 53.2 (Cquat), 58.0 (CH), 167.3 (CO).ESI-MS: m/z: 279, [M+H]+

3. 2-amino-propane-M-(3',5'-dimethyladamantane)-amide ¹ H (DMSO-d6) δ (ppm): 0.82 (s, 6H, 2xCH3), 0.91 (d, 3H, J= 6.9 Hz, CH3), 0.92 (d, 3H, J=6.9 Hz, CH3), 1.12 (m, 2H), 1.26 (d, 2H, J=12.6 Hz), 1.32 (dd, 2H, J=2.8 Hz, J=12.5 Hz), 1.55 (d, 2H, J=11.9 Hz), 1.62 (d, 2H, J=11.6 Hz), 1.78 (m, 2H), 2.00 (m, 1H), 2.09 (m, 1H) , 3.48 (d, 1H, J=6 Hz), 7.91 (brs, 1H, NH-amide), 8.02 (brs, 2H, NH2amine).

¹³ C (DMSO-d6) δ (ppm): 18.1 (CH3), 29.9 (CH), 30.5 (CH3), 32.3 (Cquat), 39.7 (CH2), 42.6 (CH2), 47.3 (CH2), 47.3 (CH2 ), 48.8 (CH), 50.5 (CH2), 53.2 (Cquat), 169.0 (CO). ESI-MS: m/z: 251, [M+H] +

4. 3-amino-propane-M-(3',5'-dimethyladamantane)-amide ¹ H (DMSO-d6) δ (ppm): 0.81 (s, 6H, 2xCH3), 1.10 (m, 2H), 1.25 (d, 2H, J=12.6 Hz), 1.30 (d, 2H, J=12.5 Hz), 1.58 (m, 4H). 1.75 (d, 2H, J=2.8 Hz), 2.07 (m, 1H), 2.39 (t, 2H, J=7.0 Hz), 2.92 (t, 2H, J=7.0 Hz), 7.64 (brs, 1H, NH - amide), 7.73 (brs, 2H, NH2-amine). ¹³ C (DMSO-d6) δ (ppm): 29.9 (CH), 30.5 (CH3), 32.3 (Cquat), 32.8 (CH2), 35.8 (CH2), 39.9 (CH2), 42.7 (CH2), 47.4 (CH2 ), 50.6 (CH2), 52.9 (CH2), 52.9 (Cquat), 169.3 (CO). ESI-MS: m/z: 251, [M+H] + .

5. 2-amino-3-(4-fluorophenyl)propane-N-(3”,5”-dimethyladamantane)-amide ¹ H (DMSO-d6) δ (ppm): 0.80 (s, 6H, 2xCH3), 1.07 (d, 2H, J=12.5 Hz), 1.10 (d, 2H, J=12.5 Hz), 1.24 (d, 2H, J=12.4

Hz), 1.28 (d, 2H, J=12.5 Hz), 1.44 (m, 2H). 1.5 (d, 2H, J=12.0 Hz), 1.68 (m, 2H), 2.06 (m, 1H), 2.95 (d, 2H, J=7.0 Hz), 3.88 (m, 1H), 7.16, (br, 2H, Ar), 7.26 (m, 2H, Ar), 7.82 (brs, 1H, NH-amide), 8.14 (brs, 2H, NH2-amine). ¹³ C (DMSO-d6) δ (ppm): 29.8 (CH), 30.4 (CH3), 32.3 (Cquat), 36.9 (CH2), 39.6 (CH2), 42.6 (CH2), 47.2 (CH2), 50.5 (CH2 ), 53.3 (Cquat), 54.0 (CH), 115.6 (CHAr, 3JCF=22.0 Hz), 131.6 (Cquat-Ar), 132.0 (CH-Ar, 4JCF=8.3 Hz), 162.8 (Cquat, 1JCF=243 Hz) , 167.1 (CO). ESIMS: m/z: 345, [M+H] +

6. 2-amino-3-phenylpropane-N-(3',5'-dimethyladamantane)-amide ¹ H (DMSO-d6) δ (ppm): 0.78(br, 3H, H-2'), 1.33 (m , 3H, H-2a), 1.41 (m, 3H, H-2b), 1.426 (s, 9H, tBu), 1.560 (m, 3H, H-4b), 1.66 (m, 3H, H-4a), 2.99 (dd, 1H, ³ J=9.6, ² J=13.5, CH2, PheAla), 3.11 (dd, 1H, ³ J=6.2, ² J=13.8, CH2, PheAla), 3.59 (m, 1H, H- 3'), 4.24 (br q, 1H, CH, PheAla), 5.20 (br, 1H, NH), 5.41 (br, 1H, NH), 7.23 (m, 3H), 7.30 (t, 2H). ¹³ C (DMSO-d6) δ (ppm): 14.2 (CH ₃ , C-2'), 28.2 (Mem C-3), 36.9 (CH ₂ , C-4), 38.1 (CH ₂ , C-2) , 38.2 (Mem-CH ₂ , C-2), 38.2 (PheAla-CH ₂ ), 53.0 (CH, C-l'), 56.2 (Mem-CH), 126.9 (Ph), 128.7 (Ph), 129.4 ( Ph), 170.2 (CO). ESI-MS: m/z: 326, [M+H] +

7. 2-Amino-3-(4-hydroxyphenyl)propane-1-(3”,5”-dimethyladamantane)-amide ¹ H-NMR: (DMSO-d6) δ (ppm): 0.75. (d, J=6.7 Hz, 3H, H-2', D2), 0.93 (d, J=6.7 Hz, 3H, H-2'), 1.49 (3H, H-4b), 1.57 ( 3H, H-4a'), 1.84 (br, 3H, H-3, D1), 2.87 (m, 2H, CH2, D1+D2), 3.44 (D1+D2) 3.93 (m, 1H, CH, D2) , 6.69 (m, 2H, Ar, D1), 6.70 (m, 2H, Ar), 7.04 (m, 2H, Ar), 7.01 (m, 2H, Ar), 7.78 (d, 1H, J=9.4 Hz, NH - amide), 7.89 (d, 2H, J=9.4 Hz, NH - amide), 8.12 (br., 1H, NH2); ¹³ C-NMR: (DMSO-d6) δ (ppm): 13.6 (CH3, D2), 13.9 (CH3), 27.5 (CH) 27.6 (CH), 37.5 (C-4), 37.6 (C-4), 37.5 (C-2), 37.6 (C-2), 52.7 (CH), 53.6 (CH), 53.5 (CH), 115 (CH-Ar), 130.4 (CH-Ar) 130.2 (CH-Ar), 156.5 (Cquat), 167.1 (CO); ESI-MS: m/z: 343, [M+HJ+

8. 2-(Aminomethyl)-1,3-thiazole-4-carboxy-N-(3',5'-dimethyladamantane)-amide ¹ H-NMR (CDCl3) δ (ppm): 1.12 (m, 2H), 1.26 (d, 2H, J = 12.6 Hz), 1.32 (dd, 2H, J = 2.8 Hz, J = 12.5 Hz), 1.55 (d, 2H, J = 11.9 Hz), 1.60 (d, 2H, J = 11.6 Hz), 1.77 (d, 2H, J = 2 Hz) 2.09 (m, 1H), 3.45 (s, 2H), 4.39 (d, 2H, CH2), 7.25 (s, 1H, NH), 8.04 (br t , 1H, NH), 8.95 (s, 1H, CHThz). ¹³ C (DMSO-d6) d (ppm): 171.9 (COamide), 156.2 (C-Thz), 150.6 (C-Thz), 123.6 (CH-Thz), 79.9 (C), 50.6 (CH2), 47.4 ( CH 2 ), 42.7 (CH 2 ), 42.4 (CH 2 ), 29.6 (CH 2 ), 35.7 (CH 2 ), 38.1 (CH 2 ), 29.6 (CH 2 ). ESI-MS: m/z: 320, [Μ+Η]+

9. 2-(Aminomethyl)-N,3'-thiazolyl-4'-2-(1,3-thiazole)-4-carboxy-N-(3",5"-dimethyladamantane)-amide ¹ H-NMR ( CDCI3) δ (ppm): 0.79 (s, 6H, CH3), 1.18 (m, 2H), 1.31 (d, 2H, J = 13.2 Hz), 1.39 (d, 2H, J = 12.9 Hz), 1.81 (m , d, 2H, J = 12.2 Hz), 1.71 (m, d, 2H, J = 10.6 Hz), 1.99 (m, 2H), 2.16 (m, 1H), 4.26 (t, 1H, J = 6.5 Hz) , 4.42 (d, 2H, J = 6.2 Hz), 4.53 (d, 2H. J = 6.7 Hz), 7.34 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.45 (s, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.91 (d, J = 7.7 Hz, 2H), 8.26 (s, 1H), 8.37 (s, 1H). ¹³ C NMR (DMSO-d6) δ (ppm): 15.2 (CH3, C-2', D1), 15.4 (CH3, C-2', D2), 28.4 (Mem C-3, D2), 28.6 (Mem C-3, D1), 28.1 (C(CH3)3, D2), D1), 37.1 (CH2, C-4, D2), 37.9 (CH2,

C-4, D1), 38.1 (CH2, D2), 38.2 (Mem-CH2, C-2, D1), 53.3 (CH, C-1', D1), 53.5 (CH, C-1', D2) , 56.4 (Mem-CH, D2+D1), 132.5 (C5 Thz), 147.9 (C4 Thz), 163.1 (C2 Thz). ESI-MS: m/z: 366, [M+HJ+

The steps of the synthesis of the compound of formula (I), according to the invention, are summarized in Scheme I below:

i) DCCTE A: i) TFA

Scheme I

Where:

BOC is M-(tert-butoxycarbonyl);

R is the starting compound selected from the group indicated above and representing an amino acid or a peptidomimetic;

BOC-R is a Boc-protected amino acid or peptidomimetic

The thus achieved chemical modification of the existing anti-Alzheimer drug memantine with the natural amino acids aminoethanoic acid, 2-amino-3-methylbutanoic acid, 2-aminopropanoic acid, 3-aminopropanoic acid, 2-amino-3-phenylpropanoic acid, 2 -amino-3-(4hydroxyphenyl)propanoic acid, the unnatural amino acid 2-amino-3-(4fluorophenyl)propanoic acid and the peptidomimetics 2-(aminomethyl)-1,3-thiazole-4carboxylic acid and 2-(aminomethyl)-1', 3'-thiazolyl-4'-2-(1,3-thiazole)-4-carboxylic acid leads to the production of a new compound, which under the conditions of the body is hydrolyzed and separated into the two participating components: component 1 - memantine and component 2 - the corresponding amino acid or peptidomimetic. In this way, conditions are created in the body for the newly synthesized compound to act both as an NMDA-receptor antagonist and as a transport molecule facilitating the passage of memantine across the cell membrane when the second component is an amino acid or an antimicrobial agent, as well as when the second component is a modified amino acid or a peptidomimetic. Thus, the compound according to the present invention is simultaneously effective both in overcoming an emerging infection caused by clinically significant, opportunistic bacterial species and fungi, and in the treatment of Alzheimer's Disease.

The invention is illustrated by the following exemplary embodiments without limiting its scope.

Example 1. Preparation of 2-amino-3-(4-fluorophenyl)propane-N-(3",5''-dimethyladamantane)amide, according to the invention.

To obtain the compound 2-amino-3-(4-fluorophenyl)propane-M-(3”,5”dimethyladamantane)-amide, 10 mmol of M-(tert-butoxycarbonyl)-2-amino-3-(4fluorophenyl)propane acid were dissolved in 3 mL of dimethylformamide at room temperature with continuous stirring. To this solution was added 10 mmol of triethylamine (TEA) and 14 mmol of the coupling reagent dicyclohexylcarbodiimide (DCC). In a separate vessel, 11 mmol of memantine hydrochloride was dissolved in 2 mL of dimethylformamide and twenty minutes after the preparation of the first solution, the solutions were mixed. The progress of the reaction is monitored chromatographically. The duration of the reaction is about 7 hours. After its completion, a double wash with a solution of 5% NaHCO3, a solution of 5% NaHSCU and a single wash with water is carried out. The organic layer was dried with anhydrous magnesium sulfate, then filtered and the solvent was evaporated. The product (N-(tert-butoxycarbonyl)-2-amino-3-(4fluorophenyl)propane-N-(3",5-dimethyladamantane)-amide) was isolated.

Trifluoroacetic acid was added dropwise to the obtained and isolated N-(τpeτ-бyτoκciκapbonyl)-2-amino-3-(4-φlyopoφenyl)πpoπan-N(3”,5”-dimethyladamantane)-amide, cooled to 0°C . The solution was stirred at 0 °C until the (tert-butoxycarbonyl) protecting group was completely removed. The process is monitored chromatographically. The solvents were evaporated, then 30 mL of diethyl ether were added three times with subsequent evaporation. A few drops of ethyl acetate and about 10-20 mL of diethyl ether are added to the resulting oily product. As a result of the workup, crystals of the trifluoroacetate salt of 2-amino-3-(4-fluorophenyl)propane-N-(3'',5''-dimethyladamantane)-amide were obtained. The solvents were evaporated and 3 mL of water, 1 mL of methanol, and 1 mL of acetonitrile were added to the crystals. 25% ammonia is added to the resulting solution until pH 7.5-8 is reached. This is followed by repeated extraction with ethyl acetate, drying of the organic layer with anhydrous Na2SO4, filtration and evaporation of the solvent. The resulting crystals were purified by column chromatography.

The product obtained is 2-amino-3-(4-fluorophenyl)propane-N-(3,5"-dimethyladamantane)-amide - free base. Yield 2002.5 mg (45%).

The resulting compound has the IUPAC name: 2-amino-3-(4-fluorophenyl)propane-H(3,5-dimethyladamantane)-amide.

¹ H (DMSO-d6) δ (ppm): 0.80 (s, 6H, 2xCH3), 1.07 (d, 2H, J=12.5 Hz), 1.10 (d, 2H, J=12.5 Hz), 1.24 (d, 2H , J=12.4 Hz), 1.28 (d, 2H, J=12.5 Hz), 1.44 (m, 2H). 1.5 (d, 2H, J=12.0 Hz), 1.68 (m,2H), 2.06 (m, 1H), 2.95 (d, 2H, J=7.0 Hz), 3.88 (m, 1H), 7.16, (br, 2H, Ar), 7.26 (m, 2H, Ar), 7.82 (brs, 1H, NHamide), 8.14 (brs, 2H, NH2-amine). ¹³ C (DMS0-d6) δ (ppm): 29.8 (CH), 30.4 (CH3), 32.3 (Cquat), 36.9 (CH2), 39.6 (CH2), 42.6 (CH2), 47.2 (CH2), 50.5 (CH2 ), 53.3 (Cquat), 54.0 (CH), 115.6 (CHAr, 3JCF=22.0 Hz), 131.6 (Cquat-Ar), 132.0 (CH-Ar, 4JCF=8.3 Hz), 162.8 (Cquat, 1JCF=243 Hz) , 167.1 (CO). ESI-MS: m/z: 345, [M+H] +

Example 2: Neuroprotective effect of memantine derivatives according to the invention

Biological studies in vitro

The results of the in vitro studies show that the studied derivatives have a favorable neuroprotective effect. They maintain neuronal cell viability despite beta amyloid-induced cytotoxicity. Compared to the control group of cells treated with memantine, 2-amino-3-(4-fluorophenyl)propane-N-(3”,5”dimethyladamantane)-amide demonstrated a relatively equivalent neuroprotective effect at nanomolar concentrations, whereas 2-amino- 3-Phenylpropane-H-(3,5-dimethyladamantane)amide and 2-amino-3-(4-hydroxyphenyl)propane-M-(3'',5"-dimethyladamantane)-amide showed a much better neuroprotective effect. It is evident from Table 1 below that among the compounds tested, the aromatic amino acid analogs have an equivalent, and in some cases even better, neuroprotective effect to the control, compared to that of the aliphatic amino acids.

Table 1: Neuroprotective effect of memantine derivatives

Compounds Cu ² *-ECso (μΜ) CoCh-ECso (μΜ) LPS(TNF-a)-IC50 (μΜ) LPS(IL-6)-IC50 (μΜ) Memantine 8.34x10 ³ ± 0.51 x10' ³ 0.1141 ± 0.047 0.0804 ±0.017 0.1436 ± 0.0117 aminoethane-N-(3,5dimethyladamantane)-amide 22.87 ± 1.89 0.7434 ±0.1288 21.75 ±3.88 26.10 ±0.68 2-Amino-3-methylbutane-N(3',5'-dimethyladamantane)amide 44.87 ± 9.30 0.2308 ± 0.068 53.23 ± 3.18 58.77 ± 0.66 2-Amino-propane-Ν-(3',5'dimethyladamantane)-amide 41.09 ±3.19 58.92 ± 7.44 32.17 ±2.96 39.22 ±5.19 3-Amino-propane-Ν-(3',5'dimethyladamantane)-amide 33.17 ± 9.54 0.1192 ±0.047 40.12 ± 1.29 42.39 ± 4.82 2-amino-3-(4fluorophenyl)propane-N(3",5-dimethyladamantane)amide 1.26x10' ² ± 0.86x10' ² 0.4141 ± 0.055 0.0234 ± 0.016 0.2570 ± 0.0274 2-Amino-3-phenylpropaneN-(3',5'-imethyladamantane)-amide 4.28x10-± 1.24*10- 0.6546 ± 0.0465 0.0594 ± 0.0131 0.1878 ±0.0153 2-amino-3-(4- hydroxyphenyl)propane-N-(3,5-dimethyladamantane)amide 2.18*10-± 1.29*10- 0.5604 ±0.0189 0.0916 ±0.0144 0.9708 ±0.0150

C ² '-EC _I denotes the effective concentration of the test compound in beta amyloid (Αβ)-induced cytotoxicity stimulated by copper ions.

CoCb-ECu denotes the effective concentration of the test compound in beta amyloid (Αβ)-induced cytotoxicity stimulated by cobalt dichloride.

LPS(TNF-α)-IC50 denotes the inhibitory concentration of the test compound on tumor necrosis factor alpha (TNF-α)-induced liposaccharide-stimulated cytotoxicity.

LPS(IL-6)-IC50 denotes the inhibitory concentration of the test compound on interleukin-6 (IL-6)-induced liposaccharide-stimulated cytotoxicity.

Example 3: In Vitro Antimicrobial Activity Testing of Memantine Derivatives

The following memantine derivatives, numbered as follows, were tested:

1. aminoethane-N-(3,5-dimethyladamantane)-amide;

2. 2-amino-3-(4-fluorophenyl)propane-N-(3",5-dimethyladamantane)-amide;

3. 2-amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide;

4. 3-amino-propane-N-(3',5'-dimethyladamantane)-amide;

5. 2-(Aminomethyl)-1,3-thiazole-4-carboxy-N-(3',5'-dimethyladamantane)-amide

Test cultures.

The model test cultures are from the NBPMKK and the collection of the Faculty of Biology at SU "St. Kliment Ohridski".

• Bacteria: Gram-positive and Gram-negative clinically significant conditionally pathogenic bacteria Escherichia coli NBPMKK 3397, Salmonella enterica NBPMKK 8691, Staphylococcus aureus NBPMKK 6538 and Bacillus megaterium BF 145 were used for the experiments. The test cultures were prepared by sowing in meat-peptone broth medium (MPB) with composition (g/L): 5 peptone, 3 beef extract, 5. NaCl, pH 7.0 and cultured for 16 hours at T = 37°C. Cultures with density ODses = 0.5 McF (McFerland optical density standard) were used.

• Yeast microorganisms: The test cultures Rhodotorula sp. BF 16-25 and Candida lusitniae BF 744 were prepared by inoculation in YPD liquid nutrient medium with composition (g/L): 20 glucose, 10 peptone, 5 yeast extract and culturing on a shaker apparatus at 220 rpm for 16 h, at T = 28°С. Working cultures with density ODses = 0.8 McF were used.

Methods: Qualitative analysis of antimicrobial activity - agar diffusion method

Bacterial and yeast test cultures were prepared as described above.

Bacterial cultures are inoculated deeply, and yeast - superficially in the respective agarized nutrient media at a concentration of 1 ml of test culture for bacteria and 0.1 ml for yeast per 15 ml of a suitable nutrient medium. After seeding, wells with a diameter of 9 mm are made in the nutrient media, in which 50 μΙ of the studied samples are placed. After incubation for 1.5 hours at 4'C to diffuse the sample, culturing for 24 - 48 h at 28/37'C is carried out.

The efficacy of the test compounds at concentrations of 10 mM was determined by measuring the zone of inhibition (in mm) and compared with that of controls DMSO, memantine and commercial preparations tetracycline and nystatin (30 pg/disk) and nemdatin (memantine-HCl, 10 mg/tablet).

Quantitative analysis of antimicrobial activity: determination of the minimum inhibitory concentration (MIC)

Test cultures were prepared as described above. A series of solutions of 2-fold decreasing concentrations were prepared from 10 mM memantine conjugates. Aliquots (20 μΙ) of these solutions are dropped onto Petri dishes with test cultures and incubated for 24/48 hours at the temperature optimal for the microbial species. The zones of inhibition were read and the MIC was determined.

Influence of the cell density of the bacterial cultures on the inhibitory effect of the studied MEM-conjugates

Test cultures were prepared as described above with an initial concentration of 0.1, 0.3 and 0.5 McF. 0.5 ml of a 1 mM solution of the tested conjugates was added to each culture. Samples were incubated at 37°C. Measurements of ODses were performed at 2, 3, 4, 5, 6, and 7 h of incubation.

The test results according to the present example are presented in Tables 2, 3 and 4 below. Of all the tested substances, substances No. 1 - 5 exhibit an inhibitory effect on individual test microorganisms. Substance No. 3 is more effective against Gram-negative bacteria, and against Gram-positive bacteria, it affects the growth of only B. megaterium BF 145. Compound No. 4 has an effect only on the growth of S. enterica NBPMKK 8691, and No. 5 has more good inhibitory effect against Gram-positive bacteria. Species specificity was observed in the effect of the different memantine derivatives, with the exception of conjugate #2, which was effective against all strains tested. Its inhibitory effect is comparable to that of the positive controls, commercial preparations tetracycline and nystatin.

The evaluation of the effect of the cell density of the model bacterial cultures on the inhibitory effect of the investigated MEM-conjugates allows to derive a model of the survival of the strains, presented in Table 3. The physiological indicator of survival increases in direct proportion with an increase in the initial concentration of the bacterial inoculum. Over a period of 5 hours, when the untreated culture entered stationary phase, growth inhibition was observed in the samples to varying extents. It is specific both with respect to the test substances and with respect to the species affiliation of the test cultures. The most sensitive is S. enterica NBPMKK 8691 to substance No. 2, where the lowest culture survival values were recorded.

Table 2: Antimicrobial activity of memantine derivatives

Gram-negative bacteria Gram-positive bacteria Yeast microorganisms Compound* Ns (10 mM) S. enterica NBPMKK 8691 E. coli NBPMKK 3397 li St aureus NBPMKK 6538 B. megaterium BF 145 Rhodotorula sp. BF 16-25 Candida lustiniae BF 74-4 1 no no no no no no 2 20 22 21 22 26 23 3 11 11 no 16 no no 4 16 no no no no no 5 no 13 10 16 no no MEM-HCl no no no no no no MEM no no no no no no 2-Amino-3-(4fluorophenyl)propanoic acid no no no no no no DMSO no no no no no no Tetracycline 26 26 28 34 - - Nystatin - - - - 26 24

*Compounds numbered 1 to 5 correspond to:

1. aminoethane-N-(3,5-dimethyladamantane)-amide;

2. 2-amino-3-(4-fluorophenyl)propane-N-(3",5-dimethyladamantane)-amide;

3. 2-amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide;

4. 3-amino-propane-N-(3',5'-dimethyladamantane)-amide;

5. 2-(Aminomethyl)-1,3-thiazole-4-carboxy-N-(3',5'-dimethyladamantane)-amide.

The zones of inhibition of the growth of the test microorganisms are presented in mm and include the sample well; "no" - no zone of inhibition is observed.

Table 3: Minimum inhibitory concentration (MIC) of memantine derivatives

Gram-negative bacteria Gram-positive bacteria Yeast microorganisms Co-ordinator No. (tM) S. enterica NBPMKK 8691 E. coli NBPMKK 3397 P St aureus NBPMKK 6538 B. megaterium BF 145 Rhodotorula sp. BF 16-25 Candida lustiniae BF 74-4 1 1.25 0 0 1.25 0 0.3125 2 0.156 1.25 1.25 0.625 0.078 0.078 3 1.25 5 10 2.5 0 0.3125 4 0 10 0 0 0 0.078 5 5 5 10 10 1.25 0.3125

- no zone of inhibition;

The MIC of the compounds is presented in mM.

Table 4: Model of the survival of conditionally pathogenic bacteria against the investigated substances; cultivation - 5 h.

Connect. ODsss Survival (%) E. coli NBPMKK 3397 S. enterica NBPMKK 8691 St aureus NBPMKK 6538 B. megaterium BF 145 1 0.1 0.3 0.5 5.88 19.05 38.46 16.67 1.67 17.65 86.36 20.00 25 25 85 0 2 0.1 0.3 0.5 0 0 0 0 0 0 0 0 0 0 5 0 3 0.1 0.3 0.5 5.26 0 15.38 16.67 26.67 11.76 31.82 0 53.33 6.25 40 0 4 0.1 0.3 0.5 21.05 9.52 19.23 0 20 11.76 54.55 33.33 40 31.25 25 0 5 0.1 0.3 0.5 21.05 0 15.38 16.67 33.33 5.88 36.36 0 46.67 6.25 35 80

Example 4. In vitro antimicrobial activity testing of 2-amino-3-(4-fluorophenyl)propane-N(3”,5”-dimethyladamantane)-amide

Test cultures.

The model bacterial and yeast test cultures and their preparation are as in Example 3. Test cultures of the filamentous fungi Fusarium graminearum - NBPMKK 2294 and Penicillium claviforme BT 136 were prepared by sowing on potato-glucose agar (KGA) nutrient medium with a composition (g/L ): 200 potatoes, 10 glucose, 15 agar and cultivation for 5 days at T = 28°C.

Methods:

The qualitative assay for antibacterial and antiyeast activity of 2-amino-3-(4fluorophenyl)propane-N-(3,5”-dimethyladamantane)-amide at concentrations of 0.1 mM, 1 mM and 10 mM was performed as described in Example 3. For a qualitative evaluation of the activity against filamentous fungi, spore suspensions of five day cultures on ΚΓΑ were prepared at a concentration of 1 x 10 ⁵ spores/ml, determined by a Burger counting chamber. The antifungal effect was evaluated by inoculating fresh ΚΓΑ medium (15 ml) in a petri dish with 3 μΙ of the respective spore suspension and culturing for 5 days at 28°C. Inhibition of the radial growth rate (Kg) of the fungal cultures, measured as the increase in the diameter of the fungal colony (mm) per unit time (h), was calculated as a percentage of that of the untreated control. Positive control is the commercial fungicide preparation topsin.

Determination of minimum bactericidal concentration (MBC)

The minimum bactericidal concentration was evaluated according to the following scheme: in MPB containing different concentrations of 2-amino-3-(4-fluorophenyl)propane-N-(3,5''-dimethyladamantane)amide (10 gmM, 1 mM, 0.5 mM , 0.1 tM, 0.01 tM) are inoculated with 10 μΙ of the investigated test culture with OD585 = 0.5 McF. The samples were incubated for 24 hours at the optimal temperature for the microbial species. After incubation, the tubes were examined for growth. Dilutions of 1:1 and 1:10, 1:100 and 1:1000 are prepared from the last tube with no visible growth. The latter were incubated under the same conditions for 24 hours. 10 μΙ of each tube was then plated on MPA, incubated for 24 hours and checked for presence/absence of growth to determine minimal bactericidal concentration.

"Time-kill" test for evaluation of bacteriostatic/bactericidal effect.

Test cultures were prepared as described in Example 3 with an initial concentration of 0.1, 0.3 and 0.5 McF. 0.5 ml of a 1 mM solution of 2-amino-3-(4fluorophenyl)propane-N-(3",5-dimethyladamantane)-amide was added to each culture. Samples were incubated at 37°C. Measurements of ODsas were performed at 2, 3, 4, 5, 6 and 7 h of incubation. The samples were determined for CFU/ml (xi) and compared to the control (no inhibitor) data from the same hour (hq). The results are interpreted according to the following scheme: when xi > xk - the compound stimulates the growth of microorganisms; at xi = xk - the compound has no effect; at xi = CFU/ml before incubation - the effect of the compound is bacteriostatic; when xi < xk - the effect of the compound is bactericidal.

The results of the test according to the present example are presented in Tables 5 and 6 below and are illustrated by the attached Figure 1 representing the growth dynamics of S. enterica NBPMKK 8691 in the presence of 1 mM 2-amino-3-(4- fluorophenyl)propane-N-(3”,5”dimethyladamantane)-amide. At 0.1 mM 2-amino-3-(4-fluorophenyl)propane-N-(3,5”dimethyladamantane)-amide, an inhibitory effect on bacterial growth was not observed, at 1 mM such an inhibitory effect was registered against St. aureus NBPMKK 6538 and B. megaterium BF 145, and at 10tM the growth of all tested bacterial species is inhibited. The MIC determination in Example 3 shows that the most sensitive species is S. enterica NBPMKK 8691 (MIC = 0.156 tM), followed by B. megaterium BF 145 (MIC = 0.625 tM). For S. enterica NBPMKK 8691 MBK = 0.3 tM.

"The time-kill test of 2-amino-3-(4-fluorophenyl)propane-M-(3",5"-dimethyladamantane)-amide, conducted with the most sensitive bacterial species - Salmonella enterica NBPMKK 8691 showed a bactericidal effect and 100 % inhibition of bacterial growth after 7 hours of cultivation in the presence of the test substance. Over the same period, the control reached a cell density above 6 x 10 ⁸ CFU/ml.

Table 5: Antimicrobial activity of 2-amino-3-(4-fluorophenyl)propane-N-(3”,5”dimethyladamantane)-amide

Gram-negative bacteria Gram-positive bacteria Yeast microorganisms phenylalanyl(4-P)-M-(3,5dimethyl-adamantane)-amide (mM) S. enterica NBPMKK 8691 E. coli NBPMKK 3397 N St. aureus NBPMKK 6538 c. megaterium BF 145 Rhodotor ula sp. BF 16-25 Candida lustiniae BF74-4 0.1 no no no no no no 1 no no 5 12 no no 10 20 22 21 22 26 23 MEM-HCl no no no no no no MEM no no no no no no 2-Amino-3-(4fluorophenyl)propanoic acid no no no no no no DMSO no no no no no no

The zones of inhibition of the growth of the test microorganisms are presented in mm and include the sample well; "no" means that no zone of inhibition is observed.

Table 6 below shows a highly pronounced inhibitory effect of 2-amino-3-(4fluorophenyl)propane-N-(3",5"-dimethyladamantane)-amide on the growth of filamentous fungi. It is in the range of 9.5% for Penicillium chaviforme BT136 and 39.4% for Fusarium graminearum NBPMKK 2294.

Table 6: Inhibition of radial growth rate of filamentous fungi by 2-amino-3(4-fluorophenyl)propane-N-(3,5”-dimethyladamantane)-amide

Hour (h) Penicillium chaviforme d (mm) Fusarium graminearum d (mm) K Topsin DMSO N2 K Topsin DMSO N2 0 0 0 0 0 0 0 0 0 24 5.5 0/0 8.5 6.5 8.5 15.0 21.0 7.0 48 11.5 0/0 13.5 10.5 26.0 39.0 39.0 35.0 72 16.0 0/0 13.5 14.5 50.5 44.0 66.0 46.0 96 21.0 0/0 23.0 19.5 70.0 47.0 82.5 48.0 120 25.0 0/0 27.0 23.0 85.0 50.0 85.0 52.0 kg (mm/h) 0.21 0 0.22 0.19 0.71 0.42 0.71 0.43

Physico-chemical characteristics

X-ray structural analysis

Currently, X-ray structural analysis is the leading method providing unambiguous information on the structure of substances in the solid state. The method requires a source of monochromatic radiation, a single crystal or polycrystal (powder), a goniometric system and an X-ray detector. The radiation is directed at the crystals, thereby producing bundles of reflected rays that are registered by the detector. The combination of diffraction intensity and its position (reflex) generates a set of reflexes that are specific to each crystalline material. The X-ray structural analysis used to prove the crystal structure of the substances was carried out on a Supernovadual, Oxford diffraction or D2Phasr Bruker apparatus, at room temperature of the samples with Mo or Si radiation.

Differential thermal analysis (DTA)

DTA is used to measure endothermic or exothermic effects associated with transitions (phase, etc.) as a function of temperature. Transitions include crystallization, amorphization, desorption, melting, and sublimation. The experiment is conducted in a controlled atmosphere (air). It is based on reading the difference between the temperature of the tested substance and that of a standard. DTA can be used to determine the melting point of organic molecules.

Thermogravimetric analysis (TGA)

TGA measures the change in weight of substances as a function of temperature and/or time. Most often, this method is used to determine weight changes related to decomposition, oxidation or moisture absorption, etc. Differential thermal analysis (DTA) and thermogravimetric analysis (TG) were carried out on a Stanton STA (Simultaneous thermal analyzer) Redcroft 1500. Experimental conditions: heating from room temperature to 250 °C, with a temperature rise rate of - 5 °C.min ^-1 ; blowing gas - air.

The DTA curve of 3-amino-propane-N-(3',5'-dimethyladamantane)-amide presented in Fig. 2a, shows two effects at 160°C and in the region 200-250°C. These endo effects correspond respectively to melting (phase transition) of the crystal structure and subsequent destruction. In TGA, a sharp drop in sample weight (-80%) was observed starting at about 215 °C. During cooling, no effects related to crystallization were registered. The DTA and TGA curves of 2amino-3-(4-φlyopoφhenyl)πpoπan-N-(3”,5”-dimethyladamantan)-amide presented in Fig. 2b, again show two endo effects related to melting (-150 °) and destruction (~210 °C) accompanied by weight losses.

The powder X-ray diffraction analysis of the substances presented in FIG. For and 3b, shows the unambiguous presence of one phase for 3-amino-propane-N-(3',5'-dimethyladamantane)amide, and 2-amino-3-(4-fluorophenyl)propane-N-(3,5 ”-dimethyladamantane)-amide. Upon dissolution and subsequent evaporation of the solvent, the crystalline phase is preserved and the degree of crystallinity increases, while the amorphous halo practically disappears.

Data from thermal and powder X-ray phase analysis revealed the stability of the substances, absence of phase transitions as a function of temperature (thermal stability) and absence of phase transitions after dissolution (absence of polymorphism).

The crystal structures of 3-amino-propane-M-(3',5'-dimethyladamantane)-amide and 2amino-3-(4-fluorophenyl)propane-M-(3'',5-dimethyladamantane)-amide have also been solved . Table 7 below presents the basic crystal structure data of the memantine analogs. While the compound 3-amino-propane-M-(3',5'-dimethyladamantane)-amide crystallizes in a centrosymmetric space group (P2Fc, No 14), 2-amino-3-(4fluorophenyl)propane-H-(3, 5-dimethyladamantane)-amide crystallizes in a non-centrosymmetric space group (P2i2i2i, No. 19). It is the presence and absence of a racemic mixture that can explain the differences in the observed antimicrobial activities.

Table 7: Crystal structure data of memantine derivatives

Substance 3-Amino-propane-H-(3',5'dimethyladamantane)-amide 2-amino-3-(4-fluorophenyl)propane-L(3",5-dimethyladamantane)-amide Temperature/K 290(2) 290(2) Crystal system monoclinic orthorhombic Spatial group P2,/C P2,2,2i a/A 15.6374(10) 6.9402(6) b/a 11.9090(8) 10.4856(7) with/A 10.9889(8) 35.454(3) a/° 90 90 β/° 110.208(8) 90 u/ 90 90 Volume/A ³ 1920.4(2) 2580.0(4) Z 4 4 ^Pcacg /cm3 1,260 1.227 μ/mm ^-1 0.105 0.102 F(000) 776.0 1008.0 Crystal size/mm ³ 0.3 x 0.15 x 0.15 0.3 x 0.2 x 0.15 Radiation MoΚα (λ = 0.71073) MoΚα (A = 0.71073) 2Θ range for data collection/“ 6.522 to 50.046 5.982 to 57.36 Collected reflexes 9411 9244 Independent reflexes 3370 [R,„, = 0.0634] 5265 [Rw = 0.0588] Data/restraints/parameters 3370/0/229 5265/37/331 Goodness-of-fit on F ² 1.039 0.957 Final R indices [/>=2σ (1)] R, = 0.0893, wR ₂ = 0.2410 Ri = 0.0855, wR ₂ = 0.2062 Final R indexes [all data] Ri = 0.1688, wR ₂ = 0.2960 R, = 0.2168, wR ₂ = 0.2762 Largest diff, peak/hole / e A ^-3 0.32/-0.30 0.79/-0.19

The data from the studies above show that the compound according to the present invention is stable in the conditions of the gastrointestinal tract (pH 1.0 and pH 7.4), as the best antibacterial efficiency against both Gram-negative and Gram-positive bacteria shows compound 2- amino-3-(4-fluorophenyl)propane-N-(3,5-dimethyladamantane)-amide. Its inhibitory effect is comparable to that of the positive control commercial preparation tetracycline. The antibacterial activity of compounds 2amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide and 2-(aminomethyl)-1,3-thiazole-4carboxy-N-(3',5'-dimethyladamantane)- amide is comparable but lower and varies between 10 and 16 mm zone of inhibition. The compound 3-amino-propane-N-(3',5'-dimethyladamantane)-amide demonstrated an effect only against S. enterica NBPMKK 8691, while the compound 2-(aminomethyl)1',3'-thiazolyl-4'-2 -(1,3-thiazole)-4-capbocy-N-(3”,5”-dimethyladamantan)-amide inhibitory effect was not observed. All test substances were dissolved in DMSO. This solvent, 2-amino-3-(4-fluorophenyl)propanoic acid, memantine and memantine hydrochloride (MEM-HCI) were set as experimental controls.

The comparative analysis of the antimicrobial activity in relation to the Gram-status of the test bacteria shows that the substance 2-amino-3-methylbutane-N-(3',5'-dimethyladamantane)-amide is more effective against the Gram-negative bacteria, and to Gram-positives, affects the growth of Bacillus megaterium BF 145. Compound 3-amino-propane-N-(3',5'dimethyladamantane)-amide has an effect on the growth of S. enterica NBPMKK 8691, and 2-(aminomethyl) -1,3-thiazole-4-carboxy-N-(3',5'-dimethyladamantane)-amide has a better inhibitory effect against Gram-positive bacteria. Species specificity was observed in the effect of the different memantine derivatives, with the exception of the conjugate 2-amino-3-(4-fluorophenyl)propane-M-(3”,5”-dimethyladamantane)amide, which was effective against all tested strains.

When testing a 1 mM concentration of memantine conjugates, the substance 2-amino-3-(4-fluorophenyl)propane-H-(3”,5dimethyladamantane)-amide exhibited an inhibitory effect on bacterial growth against Gram-positive St. aureus NBPMKK 6538 and B. megaterium BF 145.

The compound 2-amino-3-(4-fluorophenyl)propane-M-(3",5-dimethyladamantane)-amide exhibits an antifungal effect. Quantitatively, it is comparable to that of the positive control commercial preparation Nystatin.

Experimental data show that memantine derivatives: aminoethane-M-(3,5dimethyladamantane)-amide, 2-amino-3-methylbutane-M-(3',5'-dimethyladamantane)-amide, 3-aminopropane-N-(3 ', 5'-dimethyladamantane)-amide, 2-amino-3-(4-fluorophenyl)propane-N-(3,5”dimethyladamantane)-amide and 2-(aminomethyl)-1,3-thiazole-4-carboxy -N-(3',5'dimethyladamantane)-amide exhibited a certain antimicrobial effect against both the model prokaryotic species and the eukaryotic cultures studied.

LITERATURE:

1. Aracava, Y., Pereira, E. E, Maelicke, A., & Albuquerque, E. X. (2005). Memantine blocks α7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. Journal of Pharmacology and Experimental Therapeutics, 312(3), 1195-1205. DOI: httos://doi. oro/10.1124/ioet. 104.077172.

2. Pisa, D., Alonso, R., Fernandez-Fernandez, A. M., Rabano, A., & Carrasco, L. (2017). Polymicrobial infections in brain tissue from Alzheimer's disease patients. Scientific reports, 7(1), 1-14.DOI: https://doi.org/10.103B/S41598-017-05903У-

3. Yu, J.Y., Zhang, B., Peng, L., Wu, C.H., Cao, H., Zhong, J.F. et al. (2015). Repositioning of memantine as a potential novel therapeutic agent against meningitic E. Coli-induced pathogenicities through disease-associated Alpha7 cholinergic pathway and RNA sequencing-based transcriptome analysis of host inflammatory responses. PloS one, 10(5). DOI: 10.1371/joumal.pone.0121911

4. Knorr, R., Trzeciak, A., Bannwarth, W., & Gillessen, D. (1989). New coupling reagents in peptide chemistry. Tetrahedron Letters. 30(15), 1927-1930. DOI: httos://doi.oro/10,1016/30040-4039(00)99616-3

5. US2019336509 A1

6. Patent application BG112806

Claims (4)

1. A compound of general formula (I), _z R NH (I) wherein R represents an amino acid or a peptidomimetic selected from the group consisting of aminoethanoic acid, 2-amino-3-methylbutanoic acid, 2-aminopropanoic acid, 3-aminopropanoic acid, 2-amino-3-phenylpropanoic acid, 2-amino-3- (4-hydroxyphenyl)propanoic acid, 2-amino-3-(4-fluorophenyl)propanoic acid, 2(aminomethyl)-1,3-thiazole-4-carboxylic acid and 2-(aminomethyl)-N,3'-thiazolyl-4 '-2-(1,3thiazole)-4-carboxylic acid. 2. Method for preparing a compound of formula (I) according to claim 1, characterized in that protected by the protective group M-(tert-butoxycarbonyl) starting compound selected from the group including M-(tert-butoxycarbonyl)-aminoethane acid, Ν-(τρβτbutoxycarbonyl)-2-amino-3-methylbutanoic acid, M-(tert-butoxycarbonyl)-2aminopropanoic acid, M-(tert-butoxycarbonyl)-3-aminopropanoic acid, Ν-(τρβτbutoxycarbonyl)-2-amino -3-(4-fluorophenyl)propanoic acid, Ν-(τρβτ- butoxycarbonyl)-2-amino-3-phenylpropanoic acid, M-(tert-butoxycarbonyl)-2-amino3-(4-hydroxyphenyl)propanoic acid, M- (tert-butoxycarbonyl)-2-(aminomethyl)-1,3thiazole-4-carboxylic acid and N-(tert-butoxycarbonyl)-2-(aminomethyl)-1',3'-thiazolyl-4'2-(1, 3-thiazole)-4-carboxylic acid) was dissolved in dimethylformamide by adding triethylamine and dicyclohexylcarbodiimide with continuous stirring, followed by the addition of memantine hydrochloride predissolved in dichloromethane under sonication and triethylamine and after the completion of the reaction washing with 5% solution of NaHSO3, 5% solution of NaHSO4 and water is carried out; the organic layer was dried with anhydrous NazSOi, the solvent was evaporated, and to the resulting intermediate, cooled to 0°C and dissolved in dichloromethane, an equivalent volume of trifluoroacetic acid was added dropwise, the solution was stirred at 0°C until unblocking of N(tert- butoxycarbonyl) group and after evaporation of the solvent, diethyl ether is added several times, which evaporates accordingly, and a mixture of ethyl acetate/hexane or methanol/diethyl ether is added to the resulting oily product, the pH of the solution is brought to 7.5-8.0 and a double extraction with ethyl acetate, evaporation of the solvent and chromatographic purification of the obtained crystals. 3. A compound according to claims 1 and 2, useful as an NMDA-receptor antagonist for the prevention and treatment of Alzheimer's disease. 4. A compound according to claims 1-3, applicable as a means for the prevention and treatment of diseases caused by clinically significant, conditionally pathogenic bacterial species and fungi.