PL213730B1 - New derivatives of imidazol, application of new derivatives of imidazol and their production method - Google Patents

Abstract

Novel derivatives of imidazole, a method of manufacturing them as well as their use as the active substance in medicinal products for use in human and veterinary medicine have been disclosed.

Description

The present invention relates to imidazole derivatives, their preparation and their use as an active ingredient in human and / or veterinary medicaments.

The imidazole derivatives according to the invention are the compounds of the general formula I,

wherein:

2 1 2

- R ¹ is Br when R ² is nitro or R ¹ is nitro when R ² is Br;

₃

- when n takes a value from 1 to 4 then R ³ is 2-halogenophenyl, 3-halogenophenyl,

2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2,4-dimethylphenyl, ₃

2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,3-dimethylphenyl; or R ³ is 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl ₃ in which both halo substituents are equal; or R ³ is 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4-acetophenyl ₃

- when n takes a value from 2 to 4 then R ³ is phenyl, 4-halogenophenyl or 4-methylphenyl.

₃

Similar compounds in which R ³ is phenyl, 4-halogenophenyl or 4-methylphenyl and n is 1 are known from Sobiak S .; Polish J. Chem., 1998, 72, pp. 78-83.

Unexpectedly, it turned out that the new compounds exhibit biological activity and can be used as active substances in drugs.

Unexpectedly, it turned out that the modification of the substituent in the N1 position of the imidazole, consisting in the introduction of new substituents in the phenyl ring in different positions than in the previously known compounds, enables obtaining new unknown substances with some favorable biological properties that make them useful in the intended use. for humans and / or in veterinary medicine, in particular in the treatment of neoplastic diseases.

Biological activity as a pharmacophore is shown, in particular, by the imidazole member, while the structure and properties of the substituent at the N1 position of the imidazole are important for the bioavailability of the compound molecule as an active substance.

5-nitroimidazole and 4-nitroimidazole derivatives are used as anticancer, bactericidal and bacteriostatic drugs. Additional bromine substitution at the 4 or 5 position, respectively, brings about an increase in the antitumor activity of the compound and a change in pharmacokinetic parameters.

The novel compounds of the invention exhibit a wide range of biological activities, including antitumor, bactericidal, antifungal and antiprotozoal activities.

The novel compounds according to the invention are characterized by a high cytostatic activity, especially against leukemia cancer cells, colorectal tumors, myeloma, estrogen-dependent and estrogen-dependent breast cancer.

Moreover, the compounds according to the invention, due to the catalysis of the reaction of the formation of active oxygen species under the influence of ionizing radiation, can be used for the production of a radiosensitizing agent used in radiotherapy of tumors.

The biological activity of the compounds according to the invention is two-fold depending on the oxygen partial pressure in the cell. In the case of the hypoxic state, it consists in the selective accumulation of the compounds being the subject of the invention inside the cell, then the reduction of the nitro group of these compounds under the influence of the reductases present there to the toxic derivatives of nitroso-, hydroxyl and aminoimidazole responsible for their activity against cancer cells and anaerobic bacteria.

PL 213 730 B1

In the normoxic state, the compounds according to the invention catalyze the formation of active oxygen species responsible for the biological action against protozoa and the bactericidal action against aerobic bacteria.

Any pharmacologically acceptable salts of the compounds according to the invention can also exhibit biological activity.

The invention also relates to a method for the preparation of new 4 (5) -bromo-221 derivatives

-methyl-5 (4) -nitroimidazole of general formula 1, in which R, R ² and R ¹ and n are as defined above, consisting in the reaction between a suitable ω-haloacyl benzene derivative of general formula 2,

ABOUT

₃ wherein X is a halogen and R ³ and n are as defined above, and 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole in organic solvents at temperatures of from -30 to 150 ° C.

The order of introducing the reactants into the reaction mixture is not essential for the course of the reaction, but it is preferable to synthesize the new compounds disclosed in the invention according to the following scheme: dissolving 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole in solvent, adding the alkalizing agent and the water-absorbing or binding agent, mixing the included reagents and auxiliaries, and then adding the appropriate ω-haloacyl benzene derivative, and stirring the reaction mixture for a period necessary to complete the reaction followed by purification of the product obtained.

The method according to the invention consists in the synthesis in an organic solvent or a mixture of solvents selected from the group: polychlorinated hydrocarbons containing more than 1 chlorine atom, aliphatic mono and polyhydroxyl alcohols containing -C1-C20 alkyl, aromatic mono and polyhydroxy alcohols containing from 6 to 20 carbon atoms, monocyclic and polycyclic aromatic hydrocarbons and their homologues containing from 6 to 20 carbon atoms; cyclic aliphatic, acyclic, aromatic and aromatic-aliphatic ketones containing from 3 to 50 carbon atoms; cyclic aliphatic, acyclic, aromatic and aromatic-aliphatic ethers containing from 2 to 50; esters of aliphatic and aromatic carboxylic acids and aliphatic and aromatic alcohols containing from 2 to 50 carbon atoms; 1st, 2nd and 3rd order amides containing from 1 to 20 carbon atoms, aliphatic and aromatic nitriles containing from 2 to 20 carbon atoms.

It is preferable to carry out the synthesis in a solvent or a mixture of solvents selected from the group: chloroform, dichloromethane, aliphatic alcohols containing -C1-C5 alkyl, benzene, toluene, o-xylene, m-xylene, p-xylene, acyclic aromatic ketones containing from 3 to 6 carbon atoms, tertiary amides containing from 3 to 7 carbon atoms, N, N-dimethylformamide, nitriles containing from 2 to 7 carbon atoms

In particular, it is preferable to use N, N-dimethylformamide as the solvent.

The synthesis according to the invention takes place in an alkaline, neutral or slightly acidic environment.

It is preferable to carry out the process in a slightly basic environment, for this purpose an alkalizing agent is added to the mixture, it is preferable to add it before introducing the ω-haloacyl benzene derivative.

In order to obtain a basic environment, the following are used: inorganic salts, hydro-salts and hydroxysols, preferably carbonates and bicarbonates of metals of groups I and II; metal hydroxides, preferably Group I and II; ammonia and its aqueous solutions; tertiary amines, preferably tertiary aliphatic amines; aromatic and non-aromatic heterocyclic bases having in their structure a tertiary nitrogen atom in the sp2 or sp3 configuration, preferably imidazole, pyridine.

It is particularly advantageous to use compounds selected from the group K2CO3, Cs2CO3, KOH, NaOH, triethylamine.

The process for the preparation of the compounds according to the invention can also take place in a neutral environment, and it is preferred to use a significant excess of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole. It is particularly preferred to use at least a twofold excess of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole.

PL 213 730 B1

The synthesis is carried out at temperatures from -30 ° C to 150 ° C depending on the type of solvent used and the properties of the substrates. It is preferable to carry out the reaction at temperatures of 25-35 ° C. At lower temperatures the reaction proceeds very slowly, while at higher temperatures the reaction products are heavily contaminated with by-products and decomposition products.

The sonication of the reaction mixture has a beneficial effect on the reaction efficiency and its selectivity. In the initial phase of the reaction, the reaction mixture is sonicated for 0.25 to 10 hours, preferably 2-4 hours. Sonication is used for the ultrasonic generator is powered to ₃ senile from 0.5 to 100 W per 1 dm ³ of the reaction mixture with a frequency of 16 to 90 kHz. preferably 21.5 to 40 kHz.

The presence of water has an adverse effect on the yield of the reaction according to the invention. In order to increase the efficiency of the process, it is preferable to use agents which absorb or bind the water formed during the reaction. In particular, it is preferable to use desiccants selected from the group of CaCl2, CaSO4, CuSO4, MgSO4, Na2SO4, K2SO4, K2CO3, silica gel from 6-16 Mesh and molecular sieves 3 A, 4 A and 5 A.

The reaction time depends on the activity of the reactants and may be from 15 minutes to 7 days, preferably about 48 hours.

The preparation of the compounds of the present invention and their use are illustrated in the following examples. The structure of the compounds obtained was confirmed by nuclear magnetic resonance (NMR) spectroscopy.

P r z k ł a d 1

The method of obtaining 4 (5) -bromo-1-phenacyl-2-methyl-5 (4) -nitroimidazole used in comparative biological studies.

30 ml of DMF was dispensed into a 50 ml round bottom flask equipped with a tube with anhydrous calcium chloride. Then 2.14 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 0.87 g of sodium bicarbonate were added.

The reaction mixture was stirred at room temperature for 15 minutes until the evolution of carbon dioxide ceased. Then 2.07 g of α-bromoacetophenone was added. The mixture was stirred at room temperature for 48 hours. Then the contents of the flask were poured into 150 ml of distilled water and left at 5 ° C for 3 h. The precipitate was filtered off and dried. A mixture of 4-bromo-1-phenacyl-2-methyl-5-nitroimidazole and 5-bromo-1-phenacyl 2-methyl-4-nitroimidazole was obtained. The isomer mixture was separated on a silicon gel column chromatography using EtOAC as the mobile phase. There were obtained 4-bromo-1-phenacyl-2-methyl-5-nitroimidazole in a yield of 6% and 5-bromo-1-1-phenacyl-2-methyl-4-nitioimidazole in a yield of 42%.

P r z k ł a d 2

30 ml of DMF was dispensed into a 50 ml round bottom flask equipped with an anhydrous calcium chloride tube and 2 g of MgSO4 was added as a water binding agent. Then 2.32 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 0.95 g of sodium bicarbonate were added.

The reaction mixture was stirred at room temperature for 15 minutes until the evolution of carbon dioxide ceased. Then 2.4 g of α-bromo-2-methylacetophenone was added. The mixture was stirred at room temperature for 48 hours. Then the contents of the flask were poured into 150 ml of distilled water and left at 5 ° C for 3 h. The precipitate was filtered off and dried. A mixture of 4-bromo-2-methyl-1- (2-methylphenacyl) -5-nitroimidazole and 5-bromo-2-methyl-1- (2-methylphenacyl) -4-nitroimidazole was obtained. The isomer mixture was separated on a silicon gel column chromatography using EtOAC as the mobile phase. There was obtained 5-bromo-2-methyl-1- (2-methylphenacyl) -4-nitroimidazole in 50% yield, t.t = 203-205 ° C;

¹ H NMR 5 [ppm] 8.15-7.39 (4H, m, Ph); 5.89 (2H. S, _CH2); 2.45 (3H, s, PhCHa); 2.42 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 194.09 (C = O); 146.48 (C2-imi); 143.22 (C4-imi); 138.75 (Ph); 133.60 (Ph);

133.03 (Ph); 132.14 (Ph); 129.67 (Ph); 126.20 (Ph); 107.63 (C5-imi); (CH2) 53.91,

21.03 (PhCH3); 13.50 (CH3-imi).

as well as 4-bromo-2-methyl-1- (2-methylphenacyl) -5-nitroimidazole at an efficiency of 6%, t.t = 161-162 ° C;

¹ H NMR 5 [ppm]: 8,05-7,40 (4H, m, Ph); 5.77 (2H, s, _CH2); 2.45 (3H, s, PhCHa), 2.39 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 194.53 (C = O); 150.69 (C2-imi); 143.28 (C5-imi); 138.63 (Ph); 133.89 (Ph); 132.77 (Ph); 132.09 (Ph); 129.37 (Ph); 126.16 (Ph); 119.69 (C4-imi); 55.06 (CH2); 20.83 (PhCH3); 13.52 (CH3-imi).

PL 213 730 B1

P r z k ł a d 3

In the same conditions as in example 2, a reaction between 1.76 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 2.00 g of α-bromo-2-chloroacetophenone was carried out in the presence of 0, 72 g of NaHCO ₃ .

There was obtained 5-bromo-1- (2-chlorophenacyl) -2-methyl-4-nitroimidazole in 40% yield, mp = 165-168 ° C; ¹ H NMR 5 [ppm]: 8,01-7,56 (4H, m, Ph); 5.79 (2H, s, _CH2), 2.40 (3H, s, CHs-imi).

¹³ C NMR? [Ppm]: 191.95 (C = O); 147.41 (C2-imi); 143.28 (C4-imi); 134.14 (Ph); 133.97 (Ph);

131.13 (Ph); 130.86 (Ph); 130.37 (Ph); 127.59 (Ph), 107.63 (C5-imi); 54.46 (CH2); 13.47 (CH3-imi).

as well as 4-bromo-1- (2-chlorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 4%, t.t = 190-192 ° C;

¹ H NMR 5 [ppm]: 8,06-7,56 (4H, m, Ph); 5.91 (2H, s, _CH2); 2.46 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 192.87 (C = O); 150.63 (C2-imi); 134.92 (Ph); 134.05 (Ph); 133.90 (Ph); 131.19 (Ph); 130.40 (Ph); 127.58 (Ph); 119.72 (C5-imi); 55.46 (CH2); 13.47 (CH3-imi).

P r z k ł a d 4

In the same conditions as in example 2, 1.79 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole were reacted with 2.40 g of α-bromo-2-bromoacetophenone in the presence of 0, 72 g of NaHCO ₃ .

There was obtained 5-bromo-1- (2-bromophenacyl) -2-methyl-4-nitroimidazole in a yield of 62%, mp = 170-171 ° C; ¹ H NMR 5 [ppm]: 8,04-7,55 (4H, m, Ph), 5.79 (2H, s, _CH2), 2.50 (3H, s, CH ₃ -imidazo).

¹³ C NMR? [Ppm]: 193.85 (C = O); 146.36 (C2-imi); 143.29 (C4-imi); 136.08 (Ph); 134.35 (Ph);

133.83 (Ph); 130.15 (Ph); 128.00 (Ph); 119.03 (Ph); 107.63 (C5-imi); 54.21 (CH2); 13.53 (CH3-imi). as well as 4-bromo-1- (2-bromophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 8%, mp = 160-163 ° C; ¹ H NMR 5 [ppm]:]: 8,03-7,54 (4H, m, Ph); 5.90 (2H, s, _CH2); 2.46 (3H, s, CH ₃ -im) ¹³ C NMR? [Ppm]: 193.85 (C = O), 150.36 (C2-imi); 135.91 (Ph); 134.46 (Ph): 133.84 (Ph); 130.15 (Ph); 128.02 (Ph); 119.03 (Ph); 119.03 (C5-imi), 55.20 (CH2); 13.50 (CH3-imi).

P r z k ł a d 5

In the same conditions as in example 2, a reaction between 1.61 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.70 g of a-bromo-2-fluoroacetophenone was carried out in the presence of 0, 66 g of NaHCO ₃ .

There was obtained 5-bromo-1- (2-fluorophenacyl) -2-methyl-4-nitroimidazole in 48% yield, mp = 152-154 ° C; ¹ H NMR 5 [ppm]: 8,04-7,98 (1H, m, 6-Ph), 7,85-7,78 (1H, m, 4-Ph); 7.53-7.42 (2H, m, 3.5-Ph); 5.68 (2H, s, CH2); 2.39 (3H, s, CH3-imi).

¹⁹ F NMR? [Ppm]: -31.40.

¹³ C NMR? [Ppm]: 189.21 (d, ³ Jc-f = 4 Hz, C = O); 161.74 (d, ¹ JC-f = 255.4 Hz, C2-Ph); 136.81 (d, ³ JC-f = 10Hz, C4-Ph); 146.55 (C2-imi); 143.22 (C4-imi); 130.52 (d, ³ JC-F = 2 Hz, C6-Ph); 125.22 (d, ⁴ JC-F = 3Hz C5-Ph); 122.18 (d, ² JC-F = 13 Hz, C1-Ph); 117.12 (d, ² JC-F = 23 Hz, C3-Ph); 107.68 (C5-imi); 53.62 (d, ⁴ JC-F = = 12 Hz, CH2); 13.48 (CH3-imi).

P r z k ł a d 6

Under the conditions of example 2, a reaction between 1.83 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.90 g of α-bromo-3-methylacetophenone was carried out in the presence of 0, 72 g of NaHCO ₃ . There was obtained 5-bromo-1- (3-methylphenacyl) -2-methyl-4-nitroimidazole in 54% yield, mp = 159-163 ° C; ¹ H NMR 5 [ppm]: 7,96-7,50 (4H, m, Ph); 5.89 (2H, s, _CH2); 2.43 (3H, s, PhCH3); 2.37 (3Hs CH3). ¹³ C NMR? [Ppm]: 191.50 (C = O); 146.49 (C2-imi); 143.23 (C4-imi); 138.55 (Ph); 135.22 (Ph);

133.71 (Ph); 128.92 (Ph); 128.78 (Ph); 125.62 (Ph), 107.74 (C5-imi); 52.53 (CH2); 20.79 (PhCH3);

13.47 (CH3-imi).

as well as 4-bromo-1- (3-methylphenacyl) -2-methyl-5-nitroimidazole at an efficiency of 7%, mp = 131-134 ° C; ¹ H NMR 5 [ppm]: 7,87-7,49 (4H, m, Ph); 6.00 (2H, s, _CH2); 2.47 (3H, s, PhCH3); 2.42 (3H, s,

CH3-imi) ¹³ C NMR? [Ppm]: 191.92 (C = O); 150.64 (C2-imi); 143.99 (C4-imi); 138.49 (Ph); 133.92 (Ph);

128.90 (Ph); 128.61 (Ph); 128.78 (Ph); 125.47 (Ph); 119.64 (C5-imi); 53.65 (CH2); 20.81 (PhCH3);

13.47 (CH3-imi).

P r z k ł a d 7

In the same conditions as in example 2, a reaction between 1.68 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.90 g of α-bromo-3-chloroacetophenone was carried out in the presence of 0, 68 g of NaHCO ₃ .

There was obtained 5-bromo-1- (3-chlorophenacyl) -2-methyl-4-nitroimidazole in 48% yield, mp = 197-199 ° C; ¹ H NMR 5 [ppm]: 8.21 (1H, s, 2-Ph); 8.08-7.66 (3H, m, Ph); 5.96 (2H, s, _CH2); 2.37 (3H, s, CH3- imi). ¹³ C NMR? [Ppm]: 191.26 (C = O); 147.00 (C2-imi); 143.76 (C4-imi); 135.93 (Ph); 134.78 (Ph);

134.31 (Ph); 131.51 (Ph); 128.83 (Ph); 127.46 (Ph); 108.28 (C5-imi); 53.12 (CH2); 13.97 (CH3-imi).

as well as 4-bromo-1- (3-chlorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 6%, t.t = 132-135 ° C;

¹ H NMR 5 [ppm]: 8,12-7,63 (4H, m, Ph); 5.96 (2H, s, _CH2); 2.37 (3H, s, CHs-imi).

GB 213 730 B1 5 ¹³ C NMR? [Ppm]: 191.15 (C = O); 150.71 (C2-imi); 135.70 (Ph); 134.06 (Ph); 133.91 (Ph); 131.04 (Ph); 128.032 (Ph); 126.86 (Ph); 119.78 (C5-imi); 53.12 (CH2); 13.97 (CH3-imi).

P r z k ł a d 8

Under the conditions of example 2, a reaction between 1.11 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 2.40 g of α-bromo-3-bromoacetophenone was carried out in the presence of 0.11 g. 45 g NaHCO ₃ .

There was obtained 5-bromo-1- (3-bromophenacyl) -2-methyl-4-nitroimidazole in a yield of 58%, t.t = 203-205 ° C;

¹ H NMR 5 [ppm]: 8.33 (1H, s, 2-Ph); 8,33-7,58 (3H, m, Ph), 5.95 (2H, s, _CH2); 3.16 (3H, s, CH3).

¹³ C NMR? [Ppm]: 190.70 (C = O); 146.50 (C2-imi); 143.27 (C4-imi); 137.17 (Ph); 135.68 (Ph); 131.21 (Ph); 131.17 (Ph); 127.29 (Ph); 122.32 (Ph), 107.72 (C5-imi); 52.60 (CH2); 13.46 (CH3-imi).

as well as 4-bromo-1- (3-bromophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 5%, t.t = 150-154 ° C;

¹ H NMR 5 [ppm]: 8.24 (1H, s, 2-Ph); 8,06-7,57 (3H, m, Ph), 6.04 (2H, s, _CH2); 2.44 (3H, s, CH _3- th).

¹³ C NMR? [Ppm]: 191.08 (C = O); 150.69 (C2-imi); 137.17 (C4-imi); 136.94 (Ph); 135.90 (Ph); 131.24 (Ph); 130.88 (Ph); 127.19 (Ph); 122.30 (Ph); 119.77 (C5-imi); 53.67 (CH2); 13.47 (CH3-imi).

P r z k ł a d 9

In the same conditions as in example 2, a reaction between 1.52 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.60 g of a-bromo-3-fluoroacetophenone was carried out in the presence of 0, 62 g NaHCO ₃ .

There was obtained 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole in an efficiency of 30%, mp = 183-186 ° C; ¹ H NMR 5 [ppm]: 7,94-7,60 (4H, m, Ph); 5.94 (2H, s, _CH2); 2.37 (3H, s, CH ₃ ).

¹⁹ F NMR? [Ppm] -35.60.

¹³ C NMR? [Ppm]: 190.73 (d, ⁴ JC-f = 2 Hz C = O); 162.17 (d, ¹ JC-f = 246 Hz, C3-Ph); 146.49 (C2-imi); 143.27 (C4-imi); 135.78 (d, ³ JC-F = 7 Hz, C1-Ph); 131.31 (d, ³ JC-F = 8Hz, C5-Ph); 124.64 (d, ⁴ JC-F = 3Hz C6-Ph); 121.54 (d, ² JC-F = 21 Hz, C4-Ph); 115.14 (d, ² JC-F = 23Hz, C2-Ph); 107.68 (C5-imi), 53.62 (CH2); 13.46 (CH3-imi).

as well as 4-bromo-1- (3-fluorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 3%, t.t = 128-130 ° C;

¹ H NMR 5 [ppm]: 8,00-7,62 (4H, m, Ph); 6.03 (2H, s, _CH2); 2.49 (3H, s, CH3).

¹⁹ F NMR 5 [ppm] -35.63 5 ¹³ C NMR? [Ppm]: 191.12 (d, ⁴ JC-F = 3 Hz, C = O); 162.18 (d, ¹ JC-f = 246 Hz, C3-Ph); 150.69 (C2-imi); 135.98 (d, ³ JC-F = 7Hz, C1-Ph); 134.98 (C5-imi); 131.32 (d, ³ JC-F = 9 Hz, C5-Ph); 124.52 (d, ⁴ JC-F = 3 Hz, C6-Ph); 121.33 (d, ² JC-F = 22 Hz, C4-Ph); 119.77 (C4-imi); 114.88 (d, ² JC-F = 23 Hz, C2-Ph); 53.72 (CH2);

13.48 (CH3-imi).

P r z k ł a d 10

Under the conditions of example 2, a reaction between 1.81 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 2.00 g of α-bromo-2,4-dimethylacetophenone in the presence of 0.74 g of NaHCO ₃ . The reaction product was isolated by crystallization

There was obtained 5-bromo-2-methyl-1- (2,4-dimethylphenacyl) -4-nitroimidazole in an efficiency of 25%, t.t = 167-170 ° C;

¹ H NMR 5 [ppm]: 8.06 (1H, d, J = 8Hz, 6-Ph); 7.28 (1H, d, J = 8 Hz, 5-Ph); 7.23 (1H, s, 3-Ph); 5.85 (2H, s, CH2) 2.43 (3H, s, CH3C2-Ph); 2.37 (6H, s, CH 3 C4-Ph, CH 3 -imi).

¹³ C NMR? [Ppm] 193.15 (C = O); 146.46 (C2-imi); 143.17 (C4-imi), 143.60 (Ph); 139.13 (Ph); 132.86 (Ph); 130.74 (Ph); 130.10 (Ph); 126.68 (Ph); 107.71 (C5-imi); 53.68 (CH2); 21.19 (CH3C2-Ph); 21.00 (CH3C4-Ph); 13.48 (CH3-imi).

P r x l a d 11

Under the conditions of example 2, a reaction between 1.81 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 2.00 g of α-bromo-3,4-dimethylacetophenone was carried out in the presence of 0.74 g of NaHCO ₃ . The reaction product was isolated by crystallization.

There was obtained 5-bromo-2-methyl-1- (3,4-dimethylphenacyl) -4-nitroimidazole in a 47% yield, t.t = 170-172 ° C;

¹ H NMR 5 [ppm]: 7.19 (1H, s, 2-Ph); 7.86 (1H, d, J = 8 Hz, 6-Ph); 7.40 (1H, d, J = 8 Hz 5-Ph); 5.85 (2H, s, CH2), 2.37 (6H, s, CH3-3-Ph, CH3-4-Ph), 2.35 (3H, s, CH3imi).

¹³ C NMR? [Ppm]: 191.00 (C = O); 146.49 (C2-imi); 143.20 (C4-imi); 144.20 (Ph); 137.22 (Ph); 131.58 (Ph); 130.00 (Ph); 129.25 (Ph); 126.08 (Ph); 107.76 (C5-imi); 52.36 (CH2); 19.72 (CH3-4-Ph); 19.26 (CH3-3-Ph); 13.46 (CH3-imi).

PL 213 730 B1

P r z k ł a d 12

Under the conditions of example 2, a reaction between 1.81 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 2.00 g of α-bromo-2,5-dimethylacetophenone in the presence of 0.74 g of NaHCO ₃ . The reaction product was isolated by crystallization.

There was obtained 5-bromo-2-methyl-1- (2,5-dimethylphenacyl) -4-nitroimidazole in 50% yield, t.t = 146-148 ° C;

¹ H NMR 5 [ppm]: 7.98 (1H, s, 6-Ph); 7.40 (1H, d, J = 8 Hz, 3-Ph), 7.29 (1H, d, J = 9 Hz, 4-Ph); 5.78 (2H, s, CH2); 2.40 (6H, s, CH3-C2-Ph, CH3-4-Ph), 2.38 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 194.05 (C = O); 146.48 (C2-imi); 143.20 (C4-imi); 135.65 (Ph); 135.47 (Ph); 133.61 (Ph); 133.41 (Ph); 132.05 (Ph); 130.10 (Ph); 107.77 (C5-imi); 53.91 (CH2); 20.63 (CH3-5-Ph); 20.40 (CH3-2-Ph); 13.51 (CH3-imi).

P r x l a d 13

Under the conditions of example 2, a reaction between 1.84 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 2.40 g of α-bromo-2,4-dichloroacetophenone in the presence of 0.75 g of NaHCO ₃ .

There was obtained 5-bromo-1- (2,4-dichlorophenacyl) -2-methyl-4-nitroimidazole in an efficiency of 17%, t.t = 187-188 ° C;

¹ H NMR 5 [ppm]: 8,12-7,72 (3H, m, Ph), 5.80 (2H, s, _CH2); 2.40 (3H, s, CH3).

¹³ C NMR? [Ppm]: 192.06 (C = O); 146.45 (C2-imi); 143.30 (C4-imi); 138.04 (Ph); 132.77 (Ph); 132.39 (Ph); 131.90 (Ph); 130.76 (Ph); 127.79 (Ph); 107.63 (C5-imi); 54.39 (CH2); 13.52 (CH3-imi).

as well as 4-bromo-1- (2,4-dichlorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 10%, t.t = 154-156 ° C;

¹ H NMR 5 [ppm]: 8,05-7,57 (3H, m, Ph), 5.90 (2H, s, _CH2), 2.46 (3H, s, CH3).

¹³ C NMR? [Ppm]: 192.01 (C = O); 150.71 (C2-imi); 137.98 (C4-imi); 137.15 (Ph); 132.73 (Ph); 131.92 (Ph); 131.06 (Ph); 130.06 (Ph); 127.84 (Ph); 119.82 (C5-imi); 55.40 (CH2); 13.51 (CH3-imi).

P r z k ł a d 14

Under the conditions of example 2, a reaction between 153 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 2.00 g of a-bromo-3,4-dichloroacetophenone in the presence of 0 , 62 g of NaHCO ₃ .

There was obtained 5-bromo-1- (3,4-dichlorophenacyl) -2-methyl-4-nitroimidazole in a 27% yield, t.t = 199-200 ° C;

¹ H NMR 5 [ppm]: 8.41 (1H, s, Ph); 8.05 (1H, d, J = 9 Hz, Ph) 7.93 (1H, d, J = 8 Hz, Ph); 5.69 (2H, s, CH2); 2.36 (3H, s, CH3).

¹³ C NMR? [Ppm]: 190.12 (C = O); 146.49 (C2-imi); 143.30 (C4-imi); 137.47 (Ph); 133.78 (Ph); 132.09 (Ph); 131.37 (Ph); 130.61 (Ph); 128.31 (Ph); 107.70 (C5-imi); 52.59 (CH2); 13.50 (CH3-imi).

as well as 4-bromo-1- (3,4-dichlorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 18%, t.t = 143-145 ° C;

¹ H NMR 5 [ppm]: 8.32 (1H, s, Ph); 8.01 (1H, d, J = 10Hz, Ph); 7.94 (1H, d, J = 8 Hz, Ph), 6.04 (2H, s, CH2); 2.43 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 190.51 (C = O); 150.72 (C2-imi); 137.24 (Ph); 134.96 (Ph); 134.04 (Ph); 132.10 (Ph); 130.28 (Ph); 128.21 (Ph): 119.84 (C5-imi); 55.08 (CH2); 13.51 (CH3-imi).

P r z k ł a d 15

In the same conditions as in example 2, a reaction between 115 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 1.50 g of α-bromo-2,5-dichloroacetophenone in the presence of 0.10 g. 47 g NaHCO ₃ .

There was obtained 5-bromo-1- (2,5-dichlorophenacyl) -2-methyl-4-nitroimidazole in a yield of 16%, t.t = 185-186 ° C;

¹ H NMR 5 [ppm]: 8.20 (1H, s, Ph); 7.78-7.68 (2H, m, Ph); 5.83 (2H, s, _CH2); 2.40 (3H, s, CH3).

¹³ C NMR? [Ppm]: 192.09 (C = O); 146.39 (C2-imi); 143.33 (C4-imi); 135.33 (Ph); 133.51 (Ph); 132.91 (Ph); 132.26 (Ph); 129.93 (Ph); 129.60 (Ph); 107.66 (C5-imi); 54.42 (CH2); 13.52 (CH3-imi.) And 4-bromo-1- (2,5-dichlorophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 7.7%, mp = 119-122 ° C;

¹ H NMR 5 [ppm]: 8.13 (1H, s, Ph); 7.78-7.68 (2H, m, Ph); 5.93 (2H, s, _CH2); 2.40 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 191.88 (C = O); 150.63 (C2-imi); 135.49 (C4-imi); 135.33 (Ph); 133.51 (Ph); 132.75 (Ph); 132.21 (Ph); 129.93 (Ph); 129.60 (Ph); 119.82 (C5-imi); 55.36 (CH2); 13.52 (CH3).

P r z k ł a d 16

Under the conditions of example 2, 1.04 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was reacted with 1.80 g of a-bromo-2,4-dibromoacetophenone in the presence of 0.42 g of NaHCO ₃ .

5-bromo-1- (2,4-dibromophenacyl) -2-methyl-4-nitroimidazole was obtained with a yield of 19%,

mp = 201 ° C;

¹ H NMR 5 [ppm]: 8.16 (1H, s, Ph); 8.02 (1H, d, J = 8 Hz, Ph); 7.92 (1H, d, J = 8 Hz, Ph); 5.81 (2Hs CH2); 2.42 (3H, s, CH3-imi).

GB 213 730 B1 5 ¹³ C NMR? [Ppm] 193.17 (C = O); 146.39 (C2-imi); 143.29 (C4-imi); 136.38 (Ph); 135.02 (Ph); 131.66 (Ph); 131.17 (Ph); 126.58 (Ph); 120.37 (Ph); 107.62 (C5-imi); 54.11 (CH2); 13.53 (CH3-imi).

as well as 4-bromo-1- (2,4-dibromophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 11%, t.t = 177-178 ° C;

¹ H NMR 5 [ppm]: 8.15 (1H, s, Ph); 7.98-7.90 (2H, m, Ph); 5.91 (2H, s, CH-); 2.48 (3H, s, CH _3- th).

¹³ C NMR δ [ρριη]: 193.03 (C = O); 150.63 (C2-imi); 136.49 (C4-imi); 136.49 (Ph); 134.86 (Ph);

131.65 (Ph); 131.08 (Ph); 126.52 (Ph); 120.61 (Ph); 119.78 (C5-imi); 55.08 (CH2) 13.50 (CH3-imi).

P r z k ł a d 17

Under the conditions of example 2, 0.92 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.60 g of a-bromo-3,4-dibromoacetophenone were carried out in the presence of 0.38 g of NaHCO ₃ .

There was obtained 5-bromo-1- (3,4-dibromophenacyl) -2-methyl-4-nitroimidazole with a yield of 28%), mp = 164-166 ° C;

¹ H NMR δ [ppm]; 8.49 (1H, s, Ph); 8.14-7.87 (2H, m, Ph); 5.79 (2H, s, CHi: 2.41 (3H, s, CH-imi).

¹³ C NMR δ [ppm]: 193.17 (C = O); 146.49 (C2-imi); 143.29 (C4-imi); 136.38 (Ph); 135.04 (Ph); 133.50 (Ph); 131.65 (Ph); 128.06 (Ph); 126.58 (Ph); 107.71 (C5-imi); 54.12 (CH2); 13.54 (CH3imi).

as well as 4-bromo-1- (3,4-dibromophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 17%, t.t = 150-153 ° C;

¹ H NMR δ [ppm]; 8.41 (1H, s, Ph); 8.13-7.88 (2H, m, Ph); 5.89 (2H, s, CH-); 2.43 (3H, s, CH _3- th).

¹³ C NMR δ [ppm]: 193.04 (C = O); 150.72 (C2-imi); 136, 51 (C4-imi); 134.88 (Ph); 131.66 (Ph); 131.09 (Ph); 128.53 (Ph); 126.53 (Ph); 120.62 (Ph); 119.79 (C5-imi); 55.08 (CH2); 13.51 (CH3-imi).

P r x l a d 18

Under the conditions of example 2, 0.81 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out with 1.40 g of a-bromo-2,5-dibromoacetophenone in the presence of 0.33 g of NaHCO ₃ .

There was obtained 5-bromo-1- (2,5-dibromophenacyl) -2-methyl-4-nitroimidazole in 47% yield, t.t = 192-195 ° C;

¹ H NMR δ [ppm]: 8.16 (1H, s, Ph); 8.02 (1H, d, J = 8 Hz, Ph); 7.92 (1H, d, J = 8 Hz, Ph); 5.81 (2H, s, CH2); 2.42 (3H, s, CH3-imi).

¹³ C NMR δ [ppm]: 193.17 (C = O), 146.39 (C2-imi); 143.29 (C4-imi); 136.38 (Ph); 135.02 (Ph);

131.66 (Ph); 131.17 (Ph); 126.58 (Ph); 120.37 (Ph); 107.62 (C5-imi); 54.11 (CH2); 13.53 (CH3-imi). as well as 4-bromo-1- (2,5-dibromophenacyl) -2-methyl-5-nitroimidazole at an efficiency of 27%, mp = 168-172 ° C; ¹ H NMR δ ^ η]: 8.15 (1H, s, Ph); 7.98-7.90 (2H, m, Ph); 5.91 (2H, s, CH-); 2.48 (3H, s, CH _3- th). ¹³ C NMR δ [ppm] 193.03 (C = O); 150.63 (C2-imi); 136.49 (C4-imi); 136.49 (Ph); 134.86 (Ph);

131.65 (Ph); 131.08 (Ph); 126.52 (Ph); 120.61 (Ph); 119.78 (C5-imi); 55.08 (CH2); 13.50 (CH3-imi).

P r z k ł a d 19

1.10 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole were reacted under the conditions of example 2 and 1.40 g of a-bromo-4-fluoro-3-nitroacetophenone. in the presence of 0.45 g of NaHCO ₃ .

There was obtained 5-bromo-2-methyl-1- (4-fluoro-3-nitrophenacyl) -4-nitroimidazole in a yield of 64%, t.t = 163-167 ° C;

¹ H NMR δ [ppm]: 8.77 (1H, d, J = 7 Hz, Ph); 8.55-8.50 (1H, m, Ph); 7.92-7.86 (1H, m, Ph); 6.03 (2H, s, CH2); 2.37 (3H, s, CH3-imi).

¹⁹ F NMR δ [ppm] -33.88.

¹³ C NMR δ [ppm]: 189.41 (C = O); 157.83 (d, ¹ J _C- f = 270 Hz, C4-Ph); 146.51 (C2-imi); 143.32 (C4imi); 130.48 (d ⁴ JC-F = 4Hz, C1-Ph); 119.50 (d ² JC-F = 22Hz, C5-Ph) 137.22 (d, ² JC-F = 9Hz, C3-Ph) 136.20 (d, ³ JC-F = 11 HZ, C2-Ph ); 126.80 (C6-Ph), 107.66 (C5-imi); 52.63 (CH2); 13.48 (CH3-imi).

as well as 4-bromo-2-methyl-1- (4-fluoro-3-nitrophenacyl) -5-nitroimidazole at an efficiency of 8%, t.t = 138-140 ° C;

¹ H NMR δ [ppm]: 9.00 (1H, dd, ³ J = 9 Hz, ⁴ J = 3 Hz Ph); 7.87 (1H, d J = 11 Hz, Ph), 8.50-8.45 (1H, m, Ph); 6.10 (2H, s, CH2); 2.45 (3H, s, CH3-imi).

¹⁹ F NMR δ [ppm]: -34.12.

¹³ C NMR δ4]: 189.85 (C = O); 157.74 (d, ¹ Jcf = 269Hz, C4-Ph); 150.75 (C2-imi); 134.98 (C5-imi), 119.86 (C4-imi) 130.73 (d, ⁴ JC-F = 4Hz, C1-Ph); 119.58 (d, ² JC-F = 22 Hz, C5-Ph); 137.27 (d, ² JC-F = 8 Hz, C3-Ph); 136.01 (d, ³ JC-F = 11 Hz, C2-Ph); 126.48 (C6-Ph); 53.68 (CH2); 13.50 (CH3-imi).

P r z k ł a d 20

Under the conditions of example 2, a reaction between 1.03 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was carried out and 1.20 g of α-bromo-4-acetylacetophenone in the presence of 0 , 42 g of NaHCO ₃ .

There was obtained 5-bromo-1- (4-acetylphenacyl) -2-methyl-4-nitroimidazole in an efficiency of 40%, t.t = 194-195 ° C;

¹ H NMR δ [ppm]: 8.26 (2H, d, J = 9Hz, Ph); 8.16 (2H, d, J = 9 Hz, Ph); 5.97 (2H, s, CH 3): 2.68 (3H, s, CO-CH 3); 2.38 (3H, s, CH3-imi).

GB 213 730 B1 5 ¹³ C NMR? [Ppm]: 197.77 (C = O-CH3); 191.46 (C = O-CH2); 146.52 (C2-imi); 143.29 (C4-imi); 140.87 (Ph); 136.70 (Ph); 128.77 (Ph); 128.56 (Ph); 107.66 (C5-imi); 52.57 (CH2); 27.13 (CO-CH3); 13.53 (CH3-imi).

as well as 4-bromo-1- (4-acetylphenacyl) -2-methyl-5-nitroimidazole at an efficiency of 6%, t.t = 168-170 ° C;

¹ H NMR 5 [ppm] 8.26 (4H, d, J = 9 Hz, Ph); 6.06 (2H, s, CHi: 2.67 (3H, s, CO-CH3): 2.45 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 197.75 (C = O-CH3); 191.87 (C = O-CH2); 150.72 (C2-imi); 134.97 (C4-imi); 140.70 (Ph); 136.97 (Ph); 128.58 (Ph): 119.77 (C5-imi); 53.81 (CH2); 27.10 (CO-CH3); 13.49 (CH3-imi).

P r z k ł a d 21

10 ml of DMF was dispensed into a 50 ml round bottom flask equipped with an anhydrous calcium chloride tube and 0.70 g of Na2SO4 was added as a water binding agent. Then 0.64 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 0.32 g of NaHCO3 were added.

The reaction mixture was stirred at room temperature for 15 minutes until the evolution of carbon dioxide ceased. Then 1.00 g of α-bromo-2-iodoacetophenone was added. The mixture was stirred at 75 ° C for 2 h. Then the contents of the flask were poured into 150 ml of distilled water and left at 5 ° C for 3 h. The precipitate was filtered off and dried. A mixture of 4-bromo-2-methyl-1- (2-iodoophenacyl) -5-nitroimidazole and 5-bromo-2-methyl-1- (2-iodo-fenacyl) -4-nitroimidazole was obtained. The isomer mixture was separated on a silicon gel column chromatography using EtOAC as the mobile phase. There was obtained 5-bromo-2-methyl-1- (2-iodophenacyl) -4-nitroimidazole in an efficiency of 28%, t.t = 150-152 ° C;

¹ H NMR 5 [ppm] 8.10 (1H, d, J = 1.6 Hz, 3-Ph); 8.03 (1H, d, J = 7.6 Hz, 6-Ph); 7.65 (1H, t, J = 8.0 Hz, 5-Ph); 7.38 (1H, t, J = 7.6 Hz, 4-Ph) 5.78 (2H, s, CH2); 2.42 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 194.58 (C = O); 146.48 (C2-imi); 143.31 (C4-imi); 141.36 (C1-Ph); 138.52 (C3-Ph); 133.84 (C6-Ph); 129.83 (C4-Ph); 128.44 (C5-Ph); 107.63 (C5-imi); 93.09 (C2-Ph); (CH2) 53.75, 13.63 (CH3-imi).

as well as 4-bromo-2-methyl-1- (2-iodoophenacyl) -5-nitroimidazole at an efficiency of 13%, t.t = 167-168 ° C.

¹ H NMR 5 [ppm] 8.10 (1H, d, J = 7.6 Hz, 3-Ph); 7.96 (1H, d, J = 8.0 Hz, 6-Ph); 7.65 (1H, t, J = 7.2 Hz, 5-Ph); 7.37 (1H, t, J = 7.6 Hz, 4-Ph); 5.89 (2H, s, CH2); 2.49 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 194.59 (C = O); 150.62 (C2-imi); 141.42 (C1-Ph); 138.40 (C3-Ph); 134.97 (C5imi); 133.72 (C6-Ph); 129.72 (C4-Ph); 128.46 (C5-Ph); 119.77 (C4-imi); 93.27 (C2-Ph); (CH2) 54.79, 13.61 (CH3-imi).

P r z k ł a d 22

50 ml of anhydrous ethanol 0.19 g of NaOH were measured into a 100 ml round bottom flask equipped with an anhydrous calcium chloride tube and 0.70 g of anhydrous Na2SO4 was added as a water binding agent. Then 0.95 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole was added.

The resulting suspension was stirred with a magnetic stirrer at room temperature for 10 minutes. Then 1.50 g of α-bromo-2-iodoacetophenone was added. The mixture was stirred for 5 h at reflux. Stirring was continued for another 48 h at room temperature. The contents of the flask were then poured into 250 g of ice and left for 12 hours. The resulting precipitate was filtered off and dried. The precipitate was a mixture of 4-bromo-2-methyl-1- (2-iodophenacyl) -5-nitroimidazole and 5-bromo-2-methyl-1- (2-iodophenacyl) -4-nitroimidazole.

The isomer mixture was separated on a silicon gel column chromatography using EtOAC as the mobile phase. There was obtained 5-bromo-2-methyl-1- (2-iodophenacyl) -4-nitroimidazole in 48% yield, t.t = 150-152 ° C;

as well as 4-bromo-2-methyl-1- (2-iodophenacyl) -5-nitroimidazole at an efficiency of 15%, t.t = 167-168 ° C. The spectroscopic characteristics of both compounds are given in Example 21.

P r z k ł a d 23

30 ml of DMF was dispensed into a 50 ml round bottom flask equipped with a tube with anhydrous calcium chloride. Then 1.95 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.31 g of potassium carbonate were added.

The reaction mixture was stirred at room temperature for 15 minutes until the evolution of carbon dioxide ceased. Then 1.60 g of e-chloro-1-phenyl propanone was added.

The mixture was transferred to a water bath at 50 ° C with a 150 W ultrasonic generator at 21.5 kHz and sonicated for 2 h. The mixture was then transferred to a magnetic stirrer and stirred at room temperature for 48 hours. After the completion of the reaction, the contents of the flask were poured into 150 ml of distilled water and left at 5 ° C

For 3 h. The precipitate was filtered off, dried and recrystallized from ethyl acetate. 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1-phenylpropanone was obtained in 32% yield, mp = 134-135 ° C; Compound Spectroscopic Characterization ¹ H NMR? [ppm]: 7.98 (2H, d, J = 7.1 Hz, 2.6-Ph), 7.78-7.53 (3H, m, Ph); 4.40 (2H, t, CH2-N, J = 8Hz); 3.58 (2H, t, J = 8 Hz, CO-CH2) 2.50 (3H, s, CH3-imi).

¹³ C NMR? [Ppm] 197.00 (C = O), 145.80 (C2-imi); 143.18 (C4-imi); 135.88 (Ph); 133.62 (Ph); 128.73 (Ph); 128.04 (Ph); 106.74 (C5-imi); 41.49 (CH2-N); 37.27 (CO-CH2); 13.66 (CH3-imi).

The thin-layer chromatography method revealed the presence of the 3- (4-bromo-2-methyl-5-nitro-1H-imidazol-1-yl) -1-phenylpropanone isomer in amounts that prevented its preparative isolation.

P r z k ł a d 24

The reaction was carried out under the same conditions as in Example 23 between 1.69 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.50 g of 3-chloro-1- (4-methylphenyl) -propanone in the presence of 1.14 g K2CO3.

3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-methylphenyl) propan-1-one was obtained in 42% yield, t.t = 121-125 ° C;

¹ H NMR 5 [ppm] 7.90 (2H, d, J = 8 Hz, 2.6-Ph); 7.35 (2H, d, J = 8 Hz, 3.5-Ph); 4.41 (2H, t, J = 8 Hz, CH2-N); 3.56 (2H, t, J = 8 Hz, CO-CH2); 2.52 (3Hs CH3Ph); 2.39 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 196.51 (C = O); 145.78 (C2-imi); 144.08 (Ph); 143.17 (C4-imi); 133.46 (Ph); 129.27 (Ph); 128.15 (Ph); 106.70 (C5-imi); 41.54 (CH2-N); 37.12 (CO-CH2); 21.14 (PhCH3); 13.66 (CH3-imi).

P r z k ł a d 25

The reaction was carried out as in Example 23 between 1.77 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.18 g of 3-chloro-1- (4-fluorophenyl) propanone in the presence of 1.60 g K2CO3. 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-fluorophenyl) propan-1-one was obtained in a yield of 45%. mp = 183-184 ° C;

¹ H NMR? [Ppm] 8.09 (2H, m, 2.6-Ph) 7.38 (2H, m, 3.5-Ph); 4.41 (2H, t. J = 7 Hz, CH2-N); 3.58 (2H, t, J = 7 Hz, CO-CH2); 2.50 (3H, s, CH3-imi).

¹⁹ F NMR? [Ppm] -29.40.

¹³ C NMR? [Ppm]: 195.60 (C = O); 165.23 (d, ¹ Jcf = 252Hz, C4-Ph); 145.79 (C2-imi); 143.17 (C4-imi); 132.68 (d, ⁴ JC-FHz Cl-Ph); 128.73 (d ³ JC-F = 10 Hz, C-2.6-Ph); 115.74 (d, ² JC-F = 22 Hz, C-3.5-Ph); 106.72 (C5-imi); 41.42 (CH2-N); 37.25 (CO-CH2), 13.65 (CH3-imi).

P r z k ł a d 26

A reaction between 2.03 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 2.00 g of 3-chloro-1- (4-chlorophenyl) was carried out under the conditions of Example 23. -propanone in the presence of 1.36 g K2CO3. There was obtained 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-chlorophenyl) propan-1-one in a yield of 37%, t.t = 170-172 ° C;

¹ H NMR? [Ppm]: 8.01 (2H, d, J = 9 Hz 2.6-Ph), 7.62 (2H, d, J = 9 Hz, 3.5-Ph); 4.41 (2H, t, J = 8 Hz, CH2-N); 3.59 (2H, t, J = 8 Hz, CO-CH2) 2.52 (3H, s, CH3-imi).

¹³ C NMR? [Ppm]: 196.21 (C = O); 145.97 (C2-imi); 143.27 (C4-imi); 138.65 (C4-Ph); 134.68 (C1-Ph); 130.08 (C2.6-Ph); 128.96 (C3.5-Ph); 106.85 (C5-imi); 41.46 (CH2-N); 37.40 (CO-CH2); 13.76 (CH3-imi).

P r x l a d 27

A reaction between 1.49 g of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole and 1.60 g of 3-chloro-1- (4-bromophenyl) was carried out under the same conditions as in Example 23. -propanone in the presence of 1.00 g K2CO3. 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-bromophenyl) propanone was obtained in a 40% yield, t.t = 177-179 ° C;

¹ H NMR? [Ppm]: 7.93 (2Η, d, J = 9 Hz 2.6-Ph); 7.77 (2H, d, J = 9 Hz 3.5-Ph); 4.41 (2H, t, J = 7 Hz, CH2-N); 3.59 (2H, t, J = 7 Hz, CO-CH2); 2.52 (3H, s, CH3-imi).

¹³ C NMR δ [ρριη]: 196.78 (C = O); 146.31 (C2-imi); 143.68 (C4-imi); 135.42 (Ph); 132.29 (Ph); 130.56 (Ph), 128.23 (Ph), 107.26 (C5-imi); 41.84 (CH2-N), 37.82 (CO-CH2); 14.17 (CH3-imi).

P r z l a d 28

In order to evaluate the cytostatic / antitumor activity of 4-bromo-2-methyl-1- (2-methylphenacyl) -5-nitroimidazole, an MTT test was performed on HeLa tumor cells. The observation of the viability and proliferation of the studied neoplastic cells consisted in a colorimetric study of the transformation process of the yellow bromide (4,5-dimethylthiazo-2-yl) -2,5-diphenyltetrazole (MTT) into the purple product of metabolism, i.e. 2 - {(E) - [(E) -phenyl (phenylhydrazono) methyl] -diazenyl} -1,3-thiazole (formazan).

PL 213 730 B1

This transformation takes place only in the mitochondria of living cells under the influence of reductases. The amount of formazan formed is a measure of the viability and number of viable cells in the cultured colony.

Cells were grown in bottles that allowed free gas exchange, but protected against contamination with microorganisms from the external environment. The incubation medium was Dulbecco's Modified Eagle's Medium (DMEM) containing 10% bovine serum and 1% penicillin and streptomycin. Incubation was carried out for 72 hours under the following conditions: humidity 95%, CO2 concentration 5%, temperature 37 ° C.

A solution of the test compound at a concentration of 1 mg / ml was prepared ex tempore by dissolving 1 mg in 100 µl of DMSO + 900 µl of culture medium. The solvent for further dilutions was the culture medium.

Cytotoxicity studies were performed in sterile 96-well plates, into which the previously cultured cells were transferred at 5,000 cells per 100 μl of medium into each well. Incubation lasted 72 hours, then the medium was changed to medium containing only 2.5% of bovine serum and then a solution of 4-bromo-2-methyl-1- (2-inethylphenacyl) -5-nitroimidazole in DMSO was applied in amounts of 50; 25; 10; 5; 2.5; 1.0; 0.1 mm. The incubation was continued under the same conditions for 72 h. The same medium and MTT were then added to each well to give a final MTT concentration of 0.5 mg / ml. A 4 hour incubation was performed. 100 μl of 10% sodium dodecyl sulfate solution was added to dissolve the resulting formazan and incubation was continued for 24 h. After the formazan was completely dissolved, the absorbance was read at λ = 570 nm. Table 1 shows the IC50 parameter (concentration inhibiting the growth of 50% of the colony cells).

T a b e l a 1

Relationship IC50 [pg / ml] IC50 [μΜ] 4-bromo-2-methyl-1- (2-methylphenacyl) -5-nitroimidazole 9.72 28.77 4-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-5-nitroimidazole 27.44 70.20 5-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-4-nitroimidazole 31.50 85.13

P r z k ł a d 29

The MTT test with 4-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-5-nitroimidazole was performed analogously to Example 28. Table 1 shows the IC50 parameter.

P r z k ł a d 30

The MTT test with 5-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-4-nitroimidazole was performed analogously to Example 28. Table 1 shows the IC50 parameter.

Examples 31-54

The compounds listed in Table 2 were tested with the MTT assay measuring the inhibition of proliferation of promyelocytic leukemia cells.

Human promyelocytic leukemia HL-60 cells were used in the research. HL-60 cells were grown in RPMI 1640 + GlutaMax medium supplemented with 10%> FCS. The medium contained glutamine (2 mM), glucose 4.5 g / L, 1 mM pyruvate, and 100 µg / ml streptomycin and 100 U / ml penicillin. Cells were cultured in a humidified atmosphere of 5% CO2 at 37 ° C. The studies were performed using the MTT test in a 96-hour in vitro culture.

In each experiment, samples containing specific concentrations of the preparation were applied in triplicate. The experiments were repeated at least three times.

5-bromo-1- (4-chlorophenacyl) -2-methyl-4-nitroimidazole was used as a reference known substance.

Table 2 shows the cytotoxic activity of test compounds against HL-60 human promyelocytic leukemia cells

T a b e l a 2

Example Relationship IC ₅₀ test compounds Mean [pg / ml] Mean [μΜ] 1 2 3 4 31 5-bromo-1- (4-chlorophenacyl) -2-methyl-4-nitroimidazole 17.07 47.60 32 4-bromo-2-methyl-1- (2-methylphenacyl) -5-nitroimidazole 16.63 49.18

PL 213 730 B1 cont. table 2

1 2 3 4 33 5-bromo-2-methyl-1- (2-methylphenacyl) -4-nitroimidazole 2.55 7.54 34 4-bromo-1- (2-chlorophenacyl) -2-methyl-5-nitroimidazole 3.04 8.48 35 5-bromo-1- (2-bromophenacyl) -2-methyl-4-nitroimidazole 3.08 7.64 36 5-bromo-1- (2-fluorophenacyl) -2-methyl-4-nitroimidazole 16.69 48.78 37 5-bromo-1- (3-chlorophenacyl) -2-methyl-4-nitroimidazole 2.85 7.95 38 4-bromo-1- (3-bromophenacyl) -2-methyl-5-nitroimidazole 2.86 7.10 39 5-bromo-1- (3-bromophenacyl) -2-methyl-4-nitroimidazole 2.48 6.15 40 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole 2.65 7.75 41 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole 2.57 7.51 42 5-bromo-2-methyl-1- (2,4-dimethylphenacyl) -4-nitroimidazole 3.2 9.09 43 5-bromo-2-methyl-1- (3,4-dimethylphenacyl) -4-nitroimidazole 2.2 6.25 44 5-bromo-2-methyl-1- (2,5-dimethylphenacyl) -4-nitroimidazole 1.89 5.37 45 5-bromo-1- (3,4-dichlorophenacyl) -2-methyl-4-nitroimidazole 1.58 4.02 46 4-bromo-1- (3,4-dichlorophenacyl) -2-methyl-5-nitroimidazole 2.45 6.23 47 4-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-5- nitroimidazole 0.37 0.96 48 5-bromo-1- (4-fluoro-3-nitrophenacyl) -2-methyl-4- nitroimidazole 0.86 2.22 49 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-methylphenyl) propan-1-one 2.29 6.50 50 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- (4-fluorophenyl) propan-1-one 2.9 8.14 51 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- - (4-chlorophenyl) propan-1-one 4.47 12.01 52 3- (5-bromo-2-methyl-4-nitro-1H-imidazol-1-yl) -1- - (4-bromophenyl) propan-1-one 4.91 11.77 53 1- (4-acetylphenacyl) -5-bromo-2-methyl-4-nitroimidazole 5.43 14.83 54 1- (4-acetylphenacyl) -4-bromo-2-methyl-5-nitroimidazole 2.82 7.70

Examples 55-61

The tested strains of Staphylococcus aureus Enterococcus faecalis and pathogenic fungi of the species Candida Albicans in the number of 1 colony forming unit (cfu-colony forming unit) were applied to the solid agar medium of the Muller-Hinton type prepared in accordance with the microbiological testing procedures. Then, crystals of the test substances were placed on the prepared substrate. After 48 hours of incubation at 37 ° C and 24 hours of incubation at room temperature, zones of growth inhibition of the test strains were determined using a triple plus scale. Table 3 shows the results of the test, in which individual determinations correspond to:

• "0" corresponds to the growth inhibition zone below 1 mm, • "+" corresponds to the growth inhibition zone from 1 to 2 mm, • "++" corresponds to the growth inhibition zone from 2 to 3 mm, • "+++" corresponds to the growth inhibition from 3 to 4 mm, • "++++" correspond to the growth inhibition zone above 4mm.

PL 213 730 B1

T a b e l a 3

Results of microbiological tests of selected compounds.

Example Relationship Antimicrobial activity on a triple scale Staphylococcus aureus Enterococcus faecalis Candida albicans 55 4-bromo-1- (3-bromophenacyl) -2-methyl-5-nitroimidazole +++ + +++ 56 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole + ++ 0 57 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole + ++ 0 58 5-bromo-2-methyl-1- (2,4-dimethylphenacyl) -4- -nitroimdazole + + 0 59 5-bromo-1- (3,4-dichlorophenacyl) -2-methyl-4- -nitroimdazole + + ++ 60 4-bromo-1- (3,4-dichlorophenacyl) -2-methyl-5- -nitroimdazole ++ ++ ++ 61 1- (4-acetylphenacyl) -4-bromo-2-methyl-5- -nitroimidazole + ++ 0

4-bromo-1- (3-bromophenacyl) -2-methyl-5-nitroimidazole has a particularly strong antibiotic effect against both Staphylococcus aureus bacteria and Candida albicans fungi.

5-bromo-1- (3,4-dichlorophenacyl) -2-methyl-4-nitroimdazole and 4-bromo-1- (3,4-dichlorophenacyl) -2-methyl-5-nitroimdazole show positive activity against Enterococcus faecalis bacteria as well as Candida albicans fungi.

5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole, 5-bromo-1- (3-fluorophenacyl) -2-methyl-4-nitroimidazole and 1- (4-acetylphenacyl) -4- bromo-2-methyl-5-nitroimidazole show positive activity against Enterococcus faecalis.

Claims (18)

1.Imidazole derivatives of the general formula I, in which: 1 2 1 - R ¹ is Br when R ² is nitro; or R ¹ is nitro when ₂ R ² is Br; ₃ - when n is from 1 to 4 then R ³ is 2-halogenophenyl, 3-halophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethyl phenyl _3, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,3-dimethylphenyl; or R ³ is 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl in which both halo substituents are equal; or R ³ is 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4-acetophenyl - when n takes a value from 2 to 4 then R ³ is phenyl, 4-halogenophenyl or 4-methylphenyl. 2. The method of obtaining imidazole derivatives of general formula 1 PL 213 730 B1 in which: - R ¹ is Br when R ² is nitro; or R ¹ is nitro when R ² is Br; - n takes a value from 1 to 4; - R ³ is phenyl, 2-halogenophenyl, 3-halogenophenyl, 4-halogenophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2,4 -dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,3-dimethylphenyl; or R ³ is 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl in which both halo substituents are equal; or R ³ is 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4-acetophenyl, characterized by the reaction between a suitable ω-haloacyl benzene derivative of general formula 2, O in which X is halogen and R ^{3 and} n are as defined above and 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole in organic solvents, optionally in the presence of alkalizing and / or dehydrating compounds, and optionally the reaction is activated by sonication. 3. The method according to p. The process of claim 2, characterized in that the reaction is carried out in solvents selected from the group: polychlorinated hydrocarbons containing more than 1 chlorine atom, aliphatic mono and polyhydroxy alcohols containing C1-C20 alkyl, aromatic mono and polyhydroxy alcohols containing from 6 to 20 carbon atoms, aromatic hydrocarbons mono- and polycyclic and their homologues containing from 6 to 20 carbon atoms; cyclic and acyclic aliphatic ketones, aromatic and aromatic-aliphatic ketones containing from 3 to 50 carbon atoms; cyclic and acyclic aliphatic ethers, aromatic and aromatic-aliphatic ethers containing from 2 to 50; esters of aliphatic and aromatic carboxylic acids and aliphatic and aromatic alcohols containing from 2 to 50 carbon atoms; 1st, 2nd and 3rd order amides containing from 1 to 20 carbon atoms, aliphatic and aromatic nitriles containing from 2 to 20 carbon atoms. 4. The method according to p. 3. A process as claimed in claim 3, characterized in that the reaction is carried out with solvents selected from the group: chloroform, dichloromethane, aliphatic alcohols containing -C1-C5 alkyl, benzene, toluene, o-xylene, m-xylene, p-xylene, acyclic aromatic ketones containing from 3 to 6 carbon atoms, tertiary amides containing from 3 to 7 carbon atoms, Ν, Ν-dimethylformamide, nitriles containing from 2 to 7 carbon atoms. 5. The method according to p. The process of claim 4, wherein the reaction is carried out in N, N-dimethylformamide. 6. The method according to p. 2-5, characterized in that the reaction is carried out in the presence of an alkalizing agent selected from the group: inorganic salts, hydrogen salts and hydroxysols, metal hydroxides, ammonia and its aqueous solutions; Tertiary amines, aromatic and non-aromatic heterocyclic bases having in their structure a tertiary nitrogen atom in sp2 or sp3 configuration, preferably imidazole, pyridine. 7. The method according to p. The process according to claim 6, characterized in that the alkalizing agent is a compound selected from the group: hydroxides, carbonates or bicarbonates of metals from groups I and II, aliphatic tertiary amines, imidazole, pyridine. 8. The method according to p. 7. The process as claimed in claim 7, characterized in that the alkalizing agent is a compound selected from the group: K2CO3, Cs2CO3, KOH, NaOH, triethylamine. PL 213 730 B1 9. The method according to p. 6-8, characterized in that the alkalizing agent is added prior to introducing the benzene derivative into the ω-haloacyl reaction mixture. 10. The method according to p. 2-5, characterized in that the reaction is carried out in the presence of an excess of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole. 11. The method according to p. A process as claimed in claim 10, characterized in that an excess of 5 (4) -bromo-2-methyl-4 (5) -nitro-1H-imidazole is used. 12. The method according to p. 2-11, characterized in that the reaction is carried out in the presence of a dehydrating agent selected from the group of CaCl2, CaSO4, CuSO4, MgSO4, Na2SO4, K2SO4, K2CO3, silica gel from 6-16 Mesh and molecular sieves 3 A, 4 A and 5 A . 13. The method according to p. 2-12, characterized in that the reaction mixture is sonicated. 14. The method according to p. The process of claim 13, wherein in the initial phase of the reaction, the reaction mixture is sonicated for 0.25 to 10 hours. 15. The method according to p. 14. The method of claim 14, wherein the sonication is carried out for 2-4 hours. 16. The use of imidazole derivatives of general formula I in which: - R ¹ is Br when R ² is nitro; or R ¹ is nitro when R ² is Br; - when n takes a value from 1 to 4, then R ³ is 2-halogenophenyl, 3-halogenophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2,4 -dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,3-dimethylphenyl; or R ³ is 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl in which both halo substituents are equal; or R ³ is 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4-acetophenyl, - when n takes a value from 2 to 4, then or R ³ is phenyl, 4-halogenophenyl or 4-methylphenyl, and physiologically acceptable salts of these derivatives for the production of drugs for the treatment or support treatment of neoplastic diseases and / or bacterial, protozoal and fungal infections in people or animals. 17. The use according to claim 1 16 for the manufacture of a medicament for the treatment of leukemia, colorectal cancer, myeloma, estrogen-dependent and estrogen-dependent breast cancer. 18. The use of imidazole derivatives of the general formula I includes Br; PL 213 730 B1 ₃ - when n takes a value from 1 to 4 then R ³ is 2-halogenophenyl, 3-halogenophenyl, 2-methylphenyl, 3-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 2,4-dimethylphenyl, ₃ 2,6-dimethylphenyl, 3,5-dimethylphenyl or 2,3-dimethylphenyl; or R ³ is 2,4-dihalophenyl, 3,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,5-dihalophenyl, 2,3-dihalophenyl ₃ in which both halo substituents are equal; or R ³ is 4-halo-3-nitrophenyl, 3-halo-4-nitrophenyl or 4-acetophenyl ₃ when n takes a value from 2 to 4 then or R ³ is phenyl, 4-halogenophenyl or 4-methylphenyl, and the physiologically acceptable salts of these derivatives for the production of a radiosensitizing agent in radiotherapy.