RU1836355C - Method for obtaining substituted imidazole or its nontoxic pharmaceutically acceptable acid-additive salt - Google Patents

Abstract

Usage: as a drug that inhibits aromatase and desmolase. SUMMARY OF THE INVENTION: a product of the general formula H OCHRj-CHRHCH j-CHj-CH-X-Y, YR2 -. "I- &-R; . where Ri, R2, Ri and R2 are H, CH3, C2H5. CsH7, OCHs, N02, Cpz, CHF2, CH2 F, or halogen; R is H or -sn, with & -P1, where Ra is H, CH3 or ... halogen; Ry is H; RS is OH or H, or R and RS together form a bond; x and y, identical or different, are a bond or a straight C-ng-alkyl; Z is 0-2. Reagent 1: 4 (5) -imidazolaldehyde. Reageht 2: Grin RA reagent. Reagent 3: N OH / - (sn-cng sn sig- - hl g R fe Reagent 4: KHSO / i.

Description

The invention relates to a process for the preparation of substituted imidazole derivatives, their non-toxic imidazole, their non-toxic, pharmaceutically acceptable acid addition salts.

The imidazole derivatives of the present invention have the general formula (I):

N

(CHRrCH (V (CH2VCHrCH-XI Y

,"1

I

R

g

in which Ri, R2. Ri and Rz having the same or different meanings are H, CH3. C2H5, C3H, OCH3, N02, CF3, CHF2. CH2F or halogen; R represents H or

-CH;

where RS is H, CH3 or halogen, RH is H and RS is H or OH, or the elements R4 and RS form a common bond, X and Y having the same or different meanings represent a bond, Ci-2 straight chain alkyl, and 2 is an integer from 0 to 2.

00

Cj

about

SA SP SP

with

It has been found that the compounds of the present invention, depending on the substituents Ri, Ra, Ri and Ra1, exhibit, to varying degrees, aromatase and desmolase inhibitory properties. Among them there are aromatase inhibiting compounds which are characterized by a high selective effect on enzymes, which is a valuable quality in the treatment of estrogen-induced diseases such as breast cancer.

An object of the invention is to provide compounds in the range of imidazoles having the above activity.

The goal is achieved in that 4 (5) -imidazolaldehyde (L) is subjected to mutual coupling; reacting with a Grignard (III) reagent to provide a compound of formula (I) in which Re is OH (IV). Grignard reagents are prepared by reacting the corresponding halogenated carbon with magnesium shavings in accordance with a conventional method. Compound (IV) is further dehydrated by heating with KGSSM, which affords compounds of formula (I) in which R4 and RS form a common bond (V).

The unsaturated derivatives are then hydrogenated to form compounds of formula (I) in which R4 and RS are hydrogen.

This invention is illustrated by the following examples.

1 H NMR spectra were determined using a Brucker apparatus WP 80DS (80 MHz). The substance selected for comparison was tetramethylsilane. Mass spectra were determined using a Kratos M 80PF apparatus with an automatic remote control.

Example 1

4- (4,4-diphenylbutyl) -1 H-imidazole.

a) 1-benzyl-5- (1-hydroxy-4,4-diphenylbutyl) -1H-imidazole.

2.0 g of magnesium shavings was coated with 60 ml of dry tetrahydrofuran. To this mixture was then added dropwise a solution of 1-bromo-3,3-dipheoylpropane (22.9 g) in 20 ml of dry tetrahydrofuran at a rate that ensured a uniform reaction. After completion of the addition, the reaction mixture was refluxed for another hour and cooled to room temperature. The reaction mixture was then added dropwise to a solution of 1-benzyl-5-imidazole-carbaldehyde (7.35 g) and 80 ml of tetrahydrofuran at a temperature of 60 ° C. After completion of the addition, the reaction mixture was heated under reflux for 2 hours, cooled and poured into cold water, Tetrahydrofuran was evaporated and concentrated hydrochloric acid was added to the solution. This solution was cooled and the precipitate containing the desired product in the form of a hydrochloride salt was removed by filtration, washed with water and dried. Yield 14.1 g. Melting point 160-168 ° C.

1 H NMR Spectrum (as Hydrochloride, MeOH-cto): 1.50-2.30 (m, 4H), 3.82 (2s, 1H), 4.65 (t, 1H), 5.43 (s, 2H), 7.05-7.50 (m, 16H), 8.62 (d, 1H).

Using a similar method, the following compounds were prepared, 5 which are within the scope of this invention:

1-benzyl-5- 1-hydroxy-4- (2-methylphenyl) -4- pheni. ButylT-1 H-imidazo.

H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.50-2.40 (m, 4H), 0.21 and 2.15 (23, ZN), 4.07 (t, 1H), 4.70 ( m, 1H), 5.49 and 5.46 (2s, 2H), 6.80-7.50 (m, 15H), 8.88 (s, 1H).

1-benzyl-5- 1-hydroxy-4- (3-methylphenyl) -4- phenylbutyl1-1 H-imidazole. 5. H NMR spectrum (as hydrochloride salt, CDCIs): 1.35-2.25 (m, 4H), 2.26. (s, 3H), 3.73 (t. 1H), 4.62 (t, 1H), 5.38 (s, 2H), 6.80-7.40 (t, 15H), 8.51 ( s, 1 H).

1-benzyl-5-1-hydroxy-4- (4-methylphenyl) -4-0 phenyl butyl -1 H-imidazole ,,

H NMR Spectrum (as Hydrochloride, CDCto): 1.40-2.40 (m, 4H). 2.23 and 2.24 (2s, 3H), 3.74 (t, 1H), 4.65 (wide t. 2H), 5.38 (s, 2H), 6.80-7.40 (m, 15H) ), 8.55 (s, 5 Ж).

1-benzyl-5-1-hydroxy-4,4-bis (4-methylphenyl) butyl -1 H-imidazole. The melting point of the hydrochloride salt is 155-158 ° C.

1-benzyl-5- (1-hydroxy-4,5-diphenylpentyl) - 0 1 H-imidazole.

1 H NMR Spectrum (as Acid Sulfate, MeOH-d-i): 1.35-1.90 (m, 4H), 2.82 (broad s, 3H). 4.54 (t, 1H), 5.42 (s, 2H), 6.85-7.50 (m, 16H), 8.80 (s, 1H). 5 1-benzyl-5-1-hydroxy-4- (4-methoxyphenyl) -4-phenyl butyl -1 H-imidazole.

1 H NMR spectrum (as hydrochloride salt, MeOH-di): 1.50-2.30 (m, 4H), 3.70 (s, 3H), 3.79 (t, 1H). 4.69 (t, 1H), 5.46 (s, 0 2H), 6.79 (t, 2H), 7.0-7.55 (s. 13H), 8.85 (d, 1H).

1-benzyl-5-1-hydroxy-4,4-bis (4-methoxyphenyl) butyl -1 H-imidazole.

H NMR spectrum (as base, Me-OH-d4): 1.50-2.20 (m, 4H), 3.66 (t, 1 H), 3.74 (s, 5 6H), 4.50 ( t. 1H), 5.24 (s, 2H), 6.70-7.60 (m. 15H).

1-benzyl-5-4- (2-fluorophenyl) -1-hydroxy-4-phenylbutyl -1 H-imidazole.

The melting point of the hydrochloride salt is 160-1 to 63 ° C.

H NMR spectrum (as hydrochloride salt, CDCb): 1.45-2.45 (m, 4H), 4.17 (t, 1H), 4.67 (t, 1H), 5.43 (s, 2H). 6.80-7.50 (t. 15H); 8.43 (s, 1H).

1-benzyl-5-4- (2-fluorophenyl) -1-hydroxy-4-phenylbutyl -1 H-imidazole. The melting point of the hydrochloride salt is 168-17 ° C.

1 H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.50-2.30 (m, 4H), 3.84 (t, 1H), 4.68 (t. W), 5.49 (s , 2H); 6.80-7.55 (m. 15H) .8.87 (d, G).

1-benzyl-5- (1-hydroxy-5,5-diphenylpentyl) -1 H-imidazole.

H NMR Spectrum (as base, CDCb): 1.2-2.2 (m, 6H), 3.70 (t. 1H). 4.54 (t, 1 N). 5.46 (s, 2H); 6.8-7.3 (t, 16H). 8.58 (s, 1H).

1-benzyl-5- (1-hydroxy-6,6-diphenylhexyl) -1 -1 H-imidazole. The melting point of the hydrochloride salt is 147-149 ° C.

. 1HT NMR spectrum (as hydrochloride salt. MeOH-sM): 1.6-2.2 (m, 8H), 3.85 (t, 1H). 4.60 (t, W); 5.53 (s, 2H). 7.0-7.4 (t, 15H), 7.47 (s, W), 8.90 (s, 1H),

1-benzyl-5-4- (4-ethyl phenyl) -1-hydroxy-4-phenylbutyl-J-imidazole.

1H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.71 (t, 3H), 1.50-2.35 (m, 4H), 2.57 (q, 2H), 3.78 (t, 1 N) 4.68 (t. 1 H), 5.46 (s, 2H), 6.9-7.5 (m, 15H), 8.82 (d, 1 H).

1-benzyl-5-4,4-bis- (4-fluorophenyl) -1-hydroxybutyl} -H-imidazole.

H NMR spectrum (as hydrochloride salt, MeOH-d / i): 1.50-2.00 (m, 4H), 3.86 (t, W). 4.70 (t, W); 5.52 (s, 2H). 6.80-7.50 (m, 14H) .8.89 (d, G) .b) 1-benzyl-5- (4,4-diphenyl-1-butenyl) - 1 H-imidazole.

1-Benzyl-5- (1-hydroxy-4,4-diphenylbutyl) -1H-imidazole hydrochloride (5.0 g) and 30.0 g of anhydrous potassium bisulfate were heated at a temperature of 150 ° C for 4 hours. This mixture was cooled, and 90 ml of ethanol was added dropwise to dissolve the resulting product. This mixture was then filtered, and the filtrate was evaporated to a small volume. Water was added and the mixture was made basic with sodium hydroxide. The resulting product was extracted in methylene chloride, washed with water and evaporated to dryness. The resulting product was then converted to the hydrochloride salt, using dry hydrochloric acid in dry ethyl acetate to achieve this. The yield was 2.9 g. Melting point 204-206 ° C.

Spectrum H (as hydrochloride salt. MeOH-do): 2.88-3.05 (m, 2H). 4.08 {t.

1 H), 5.29 (s, 2H), 6.22-6.32 (m. 2H), 7.00-7.50 (m, 16H), 8.87 (d, W).

Using a similar method, the following compounds were prepared, 5 which are within the scope of this invention:

1-benzyl-5-4,4-bis (3-methylphenyl} -1-butenyl -1 H-imidazole.

The melting point of the hydrochloride salt is 152-156 ° C.

0 1H NMR spectrum (as hydrochloride salt, MeOH-d4): 2.26 (s, 6H), 2.85-3.05 (m, 2H), 3.99 (t, W), 5.27 ( s. 2H), 6.21-6.31 (m, 2H), 76.80-7.50 (m, 14H), 8.86 (d, 1H).

5 1-benzyl-5-4- (3,5-dimethylphenyl) -4- (3-methylphenyl-1-butenyl} -1 H-imidazole.

H NMR spectrum (in the form of a hydrochloride salt, MeOH-d4): 2.22 (s, ЗН), 2.23 (s, ЗН). 2.26 (s, 3H), 2.85-3.05 (m, 2H), 3.94 (t. 0 1 H), 5.26 (s. 2H), 6.20-6.30 (m, 2H) 6.75-7.50 (m, 13H). 8.84 (d. G).

1-benzyl-5-4- (3,5-dimethylphenyl} -4-phenyl-1-butenyl -1 H-imidazole. Melting point 110-112 ° C.

5 1H NMR spectrum (as hydrochloride salt, MeOH-d4): 2.22 (S, 6H), 2.85-3.05 (m.2H), 3.98 (t, W) .5.26 (s, 2H) 7.20-6.30 (m. 2H); 6.75-7.5 (m, 14H); 8.87 (d, G).

1-benzyl-5-4- (2-methylphenyl) -4-phenyl-0 1-butenyl-J-imidazole.

H NMR Spectrum (as Bisulfate, MeOH-d4): 2.19 (s, 3H). 2.80-3.05 {m, 2H); 4.28 (t, 1 H). 5.29 (s, 2H), 6.0-6.60 (m, 2H), 7.0-7.5 (m, 14H), 7.52 (d, 1H), 8.85 (d. W). 51-benzyl-5-4- (3-methylphenyl) -4-phenyl1-butenyl-J-imidazole.

H NMR spectrum (as base, CDCb): 2.27 (s. 3H), 2.75-3.95 (m, 2H), 3.93 (t, W), 4.89 (s. 2H) 5.70-6.10 (m, 2H), 6.80-7.40 0 (m, 16H) ..

1-benzyl-5-4- (4-methylphenyl) -4-phenyl-1-phenyl-1-butenyl -1 H-imidazole.

H NMR Spectrum (as base, CDCb): 2.27 (s, 3P). 2.70-2.95 (m, 2H), 3.93 (t, 5 1 H), 2.89 (s. 2H), 5.60-6.20 (m. 2H), 6.80-7.50 (m; 16H) .

1-benzyl-5-4,4-bis (4-methylphenyl) -1-butenyl-J-imidazole. The melting point of hydrochloride is 128-132 ° C. 01-benzyl-5-4- (4-methoxyphenyl) -4-phenyl-1-butenyl -1 H-imidazole.

H NMR spectrum (as hydrochloride salt, CDCb): 2.70-2.95 (m. 2H), 3.95 (t, 1H), 5.16 (s, 2H), 5.70-6.20 (m, 2H ), 6.70-5.7.40 (m, 15H), 8.99 (s, 1H).

1-benzyl-5- 4,4-bis (4-methoxyphenyl) -1- butenyl -1 H-imidazole. N NMR spectrum (as base. CDCb): 2.60-2.90 (m, 2H), 3.74 (s, 6H), 3.78 (t, W), 4.92 (s, 2H) 5.80-6.00 (m, 2H). 6.65-7.50 (m. 15H).

1-benzyl-5- (4,5-diphenyl-1-pentenyl) - 1 H-imidazole.

1 H NMR spectrum (as base, CDCIs): 2.30-2.55 (m, 2H), 2.88 (m, 3H), 4.93 (s, 2I), 5.5-6.1 (m, 2H), 6.8-7.5 (m, 17H).

1-benzyl-5-4- (2-fluorophenyl) -4-phenyl-1-butenyl 1 H-imidazole.

The melting point of hydrochloride is 195-201 ° C.

1 H NMR spectrum (as base,): 2.75-3.00 (t, 2H), 4.34 (t, 1H), 5.97 (s, 2H), 5.80-6.10 (t , 2H). 6.75-7.50 (t, t6H).

1-benzyl-5- 4- (4-fluorophenyl) -4-phenyl-1-butenyl -1 H-imidazole, H NMR spectrum (as base, CDCb): 2.60-2.95 (m, -2H .), 3.96 (t, 1H), 4.93 (s, 2H), 5.80-6.05 (t, 2H), 6.75-7.50 (t, 16H).

1-benzyl 5- (6,6-diphenyl-1-hexenyl) - 1 H-imidazole. The melting point of the chlorohydrate is 184-186 ° C.

1-benzyl-5-4- (4-ethylphenyl) -4-phenyl-1-butenyl -1 H-imidazole.

Spectrum 1H (as hydrochloride salt, MeOH-d4): 1.17 (t, 3H), 2.56 (q, 2H), 2.93-2.98 (m. 2H). 4.03 (t. 1H), 5.28 (s. 2H). 6.20-6.34 (m, 2H). 7.08-7.41 (m, 14H), 7.52 (d, 1.H), 8.87 (d, 1H).

1-benzyl-5-4,4-bis (4-fluorophenyl) -1-butenyl -1 H-imidazole.

1 H NMR spectrum (as hydrochloride salt, CDCb): 2.78-2.94 (m, 2H), 4.01 (t, 1H), 5.27 (s, 2H), 5.82-6.34 (t, 2H); 6.83-7.40 (t, 14H); 9.21 (d, 1H).

c) 1-benzyl-5- (4,4-diphenylbutyl) -1H-imidazole.

1-Benzyl-5- (4,4-diphenyl-1-butenyl) -1H-imidazole hydrochloride (2.0 g) was dissolved in ethanol and a catalytic amount of Pd / C (10%) was added. The reaction mixture was vigorously stirred at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceased. The mixture was then filtered and the filtrate was evaporated to dryness. The residue, which was the desired product, was purified by flash chromatography, eluting with a mixture of methylene chloride and methanol. The yield was 1.3 g. The melting point of the hydrochloride salt was 200-202 ° C.

H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.30-1.70 (m, 2H), 1.85-2.20 (m, 2H), 2.61 (m, 2H), 3 83 (t, 1H), 5.35 (s, 2H), 7.05-7.50 (m, 16H), 8.89 (s. 1H).

Using a similar method, the following compounds were prepared that are within the scope of this invention:

1-benzyl-5-4- (2-methylphenyl) -4-phenylbutyl -1 H-imidazole. The melting point of hydrochloride is 200-205 ° C.

1H NMR spectrum (as hydrochloride salt, CDCb): 1.30-1.80 (m, 2H), 1.80-2.15 (m, 2H), 2.22 (s, 3H), 2.48 (t . 2H), 4.02 (t, 1 H), 5.31 (s, 2H), 6.96 (s. 1 H), 7.0-7.5 (m, 14H), 9.28 (S, 1H).

1-benzyl-5-4- (3-methylphenyl) -4-phenylbutyl -1 H-imidazole. The melting point of hydrochloride is 148-158 ° C.

H NMR spectrum (as hydrochloride salt, CDCb): 1.30-1.80 (m, 2H), 1.802, 25 (m, 2H), 2.30 (s, 3H), 2.49 (t, 2H) 3.78 (t,

1H), 5.29 (s, 2H), 6.90-7.50 (m, 15H). 9.24 (s.

1H).

1-benzyl-5-4- (4-methylphenyl) -4-phenyl-5 buty H-imidazole. The melting point of hydrochloride is 164-170 ° C.

H NMR spectrum (as hydrochloride, CDCb): 1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.29 (s, 3H), 2.48 (t, 2H), 3.78 (t, 0 1H), 5.31 (s, 2H), 6.80-7.50 (m, 15H), 9.35 (s. 1H).

1-benzyl-5- (4,5-diphenylpentyl) -1H-imidazole. The melting point of hydrochloride is 166-170 ° C.

5 1H NMR Spectrum (as hydrochloride salt, MeOH-d4): 1.15-1.90 (m, 4H),. 2.49 (t.2H), 2.81 (m, 3H) .5.30 (s, 2H), 6.90-7.50 (m, 16H), 8.82 (s, 1H).

1-benzyl-5-4- (4-methoxyphenyl) -4-phe-0 nilbutyl -1 H-imidazole. The melting point of hydrochloride is 180-187 ° C.

1 H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.25-1.70 (m, 2H), 1.85-2.20 (m.2H), 2.62 (t, 2H), 3 74 (s, 3H), 3.78 5 (t, 1H), 5.34 (s, 2H), 6.81 (d. 2H), 7.0-7.5 (m, 13H), 8.84 (d, 1H) )

1-benzyl-5-4- (2-fluorophenyl) -4-phenylbu-H-imidazole. The melting point of hydrochloride is 185-196 ° C.

0 1 H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.65 (t, 2H), 4.18 (t, 1H), 5.37 (s, 2H), 6.80-7.5 (m, 15H), 8.89 (d, 1H).

1-benzyl-5-4- (4-fluorophenyl) -4-phenylbu-5 H-imidazole. The melting point of hydrochloride is 172-174 ° C.

1 H NMR spectrum (in the form of hydrochloride salt, MeonchM): 1.25-1.70 (m, 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3.85 (t , 1H), 5.37 ° (s.2H), 6.80-7.50 (m, 15H), 8.90 (d. IH).

1-benzyl-5- (5.5-diphenylpentyl) -1H-imidazole.

1 H NMR Spectrum (as base, MeOH-d): 1.1-1.6 (m. 4H). 1.8-2.1 (m, 2H), 2.37 5 (t. 2H), 3.72 (t, 1H), 5.11 (s, 2H), 6.67 (s, 1H), 6.9-7.3 (m, 15H); 7.59 (s. 1H).

1-benzyl-5-4- (4-ethylphenyl) -4-phenylbu-H-imidazole.

1 H NMR Spectrum (as Hydrochloride, MeOH-d4): 1.17 (t, 3H). 1.401 .70 (m, 2H), 1.90-2.20 (m, 2H), 2.57 (q, 2H), 3.80 (t, 1H), 5.34 (s, 2H), 7 00-7.50 (m, 15H); 8.87 (d, 1H).

1-benzyl-5- {4,4-bis (4-fluorophenyl) butyl - 1 H-imidazole.

H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.30-1.70 (m. 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3 87 (t, 1H). 5.40 (s, 2H); 6.80-7.50 (m, 14H); 8.92 (d. 1H).

d) 4- (4,4-diphenyl yl butyl) -1 H-imidazole.

1-benzyl-5- (4,4-diphenylbutyl) -1H-imidazole hydrochloride (0.6 g) was hydrogenated in a mixture of 20 ml of 2N. a solution of hydrochloric acid and 10 ml of ethanol at a temperature of 80 ° C and using Pd / C (10%) as a catalyst. After the uptake of hydrogen had ceased, the reaction mixture was cooled, filtered and evaporated to dryness. Water was added and the mixture was made basic with sodium hydroxide. The resulting product was then extracted with methylene chloride, washed with water, dried with sodium sulfate and evaporated to dryness. The residue represented the desired product as a base, which was converted to hydrochloride in ethyl acetate using dry hydrochloric acid. The yield was 0.2 g. Melting point 204-206 ° C.

1H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.40-1.90 (m. 2H), 1.90-2.30 (m, 2H), 2.75 (s, 2H), 3.95 (t , 1H), 7.00-7.40 (m, 11 N), 8.72 (d. 1 N).

Using a similar method, the following compounds were prepared that are within the scope of this invention:

, 4-bis (3-methylphenyl) butyl -1 H-imidazole. The melting point of hydrochloride is 122-129 ° C.

1 H NMR spectrum (as hydrochloride salt, MeOH-do): 1.40-1.90 (m. 2H), 1.90-2.30 (m, 2 N). 2.26 (s, 6H), 2.73 (t, 2H), 3.85 (t, 1H), 6.80-7.25 (m, 9H), 8.73 (d, 1H).

(3,5-dimethylphenyl} -4- (3-methylphenyl) butyl -1 H-imidazole.

The melting point of hydrochloride is 75-82 ° C.

H NMR Spectrum (as hydrochloride salt, MeOH-d / i): 1.40-1.90 (m, 2H),. 1.90-2.30 (m, 2H). 2.22 (s, ZN), 2.23 (s, ZN), 2.27 (S, ZN). 2.74 (t, 2H), 3.81 (t, 1 H), 6.75-7.30 (m, 8H), 8.72 (d, 1H).

4- {4- {3,5-dimethylphenyl) -4 phenylbutyl} - 1 H-imidazole. The melting point of the chlorohydrate is 104-106 ° C.

1 H NMR Spectrum (as hydrochloride salt, MeOH-d4): 1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.23 (s, 6H). 2.74 (t, 2H), 3.85 (t, 1H), 6.84 (m, 3H), 7.22 (m, 6H), 8.72 (d, 1H).

(3,4-dimethylphenyl) -4 phenylbutyl -1 -1 H-imidazole. The melting point of hydrochloride is 118-121 ° C.

(2-methylphenyl) -4-phenylbutyl -1H-imidazole. The melting point of hydrochloride is 151-154.5 ° C.

1 H NMR spectrum (as hydrochloride salt, CDCb): 1.50-2.20 (m, 4H), 2.22 (s, 3H), 2.71 (t, 2H), 4.09 (t, 1H ), 6.81 (s. 1H), 7.0-7.4 (t, 9H). 9.04 (s, 1H).

(3-methylphenyl) -4-phenylbutyl-J-imidazole. The melting point of hydrochloride is 140-153 ° C.

H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.40-1.85 (m, 2H), 1.85-2.25 (m, 2H), 2.27 (s, 3H) , 2.74ft. 2H), 3.90 (t, 1H), 6.80-7.30 (m, UN), 8.69 (d, 1H).

(4-methylphenyl) -4-phenylbutyl-J-imidazole. The melting point of the hydrochloride is 173-177 ° C.

H NMR spectrum (in the form of hydrochloride salt, + 2 drops of MeOH-d4): 1.40-1.80 (m, 2H), 1.80-2.25 (m, 2H), 2.28 (s, 3Н) ), 2.71 (t, 2H). 3.87 (t, 1 H), 6.86 (d, 1 H), 7.09 (s. 4H), 7.21 (m, 5H), 8.71 (d, 1H).

(4-methoxyphenyl) -4-phenylbutyl - 1 H-imidazole. The melting point of the chlorohydrate is 156-159 ° C.

1 H NMR spectrum (as hydrochloride salt): 1.40-1.90 (m, 2H), 1.902, 30 (t, 2H), 2.71 (t, 2H), 3.76 (s, 3H), 3 , 87 (t,

1 H), 6.82 (d. 2H). 6.90 (s, 1H), 7.13 (d, 2H), 7.21

(t, 5H); 8.68 (s, 1H).

4- {4,4-bis (4-methoxyphenyl) boogyl} -1H-imidazole. The melting point of hydrochloride is 138-142 ° C.

1 H NMR Spectrum (as Hydrochloride, CDCIa): 1.40-1.25 (m. 4H). 2.71 (t, 2H), 3.75 (s, 6H), in which case (t, 1 H), 6.78 (d. 4H), 6.83 (s, 1 H), 7.08 (d, 4H); 9.02 (s. W).

4- (4,5-diphenylpentyl) -1 H-imidazole.

H NMR spectrum (as hydrochloride salt. CDCIa): 1.20-1.90 (m, 4H), 2.57 (t, 2H). 2.83 (t, 3H); 6.71 (s, 1 H). 6.80-7.40 (t, UN), 8.84 (s. W).

4- (5.5-diphenylpentyl) -1 H-imidazole.

H NMR spectrum (as hydrochloride salt, MeOH-d4): 1.3-1.5 (m, 2H), 1.5-1.7 (m, 2H), 1.8-2.3 (m, 2H), 2.666 (t, 2H), 3.746 (t, W), 7.06-7.2 (m, 11H), 8.716 (d, 1H). 4- (6,6-diphenylhexyl) -1 H-imidezole; H NMR spectrum (as base, CDCI3): 1.1-1.7 (t. 6H). 1.8-2.2 (t, 2H). 2.530 (t, 2H), 3.847 (t, 1 H), 6.685 (s, 1 H), 7.2 (s, UN), 7.470 (s, 1H), 9.6 (broad s, G).

4- {4,4-bis (4-methylphenyl) butyl -1 H-imidazole. The melting point of hydrochloride is 176-179 ° C.

(4-fluorophenyl) -4-phenylbutyl -1 H-imidazole. The melting point of hydrochloride is 175 182 ° C.

(2-Fluorophenyl) -4-phenyl butyl J-1H-imidazole. The melting point of the hydrochloride is 182-190 ° C.

4- 4- {4-ethylphenyl) -4-phenyl yl butyl -1H-imidazole.

H NMR spectrum (as MeOH-do hydrochloride salt): 1.18 (t, 3H), 1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2, 57 (q, 2H), 2.75 (t, 2HJ, 3.91 (t, 1H), 6.95-7.30 (m, UN), 8.73 (d, 1H),

4-6is (4-fluorophenyl) 6utyl -1 H-imidazole.

1 H NMR spectrum (as hydrochloride salt, MeOH-sM): 1.40-1.85 (m, 2H), 1.90-2.20 (t, 2H), 2.77 (t, 2H), 3.98 (t, 1H ), 6.80-7.40 (t. 9H), 8.72 (d, 1H).

PRI me R 2. (4-fluorophenyl) -4-phenylbutyl} -1 H-imidazole. . 1 A concentrated aqueous solution of ammonium formate (0.98 g, 15.6 mmol) was added dropwise to a boiling mixture of 1-benzyl-5-4- (4-fluorophenyl) -4-phenylbutyl -1 H-imidazole (1 5 g, 3.9 mmol) and 10% Pd / C (0.156 g) in 16 ml of 50% ethanol. This mixture was refluxed for 2 hours, the catalyst was filtered off and the solvent was evaporated. A 2M NaOH solution was added and the resulting product was then extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated to dryness, which afforded the desired product. The yield was 1.02 g. The melting point of the hydrochloride salt (from ethyl acetate) was 175-182 ° C.

H NMR spectrum (as hydrochloride salt. MeOH-d / i): 1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.75 (t. 2H) . 3.96 (t. 1H), 6.85-7.36 (m, UN), 8.74 (d. 1H).

In accordance with the above procedure 1, the following substituted derivative was obtained:

(2-fluorophenyl) -4-phenylbutyl -1H-imidazole. The melting point of the hydrochloride is 182-190 ° C.

H NMR spectrum (as hydrochloride salt, MeOH-d / j): 1.45-1.95 (m, 2H), 1.95-2.30 (m. 2H), 2.77 (t, 2H), 4 29 (t, 1H); 6.85-7.45 (m, UN); 8.74 (d, 1H).

PRI me R 3. 4- (4,4-diphenyl-1-butenyl) - 1 H-imidazole.

a) 4- (1-hydroxy-4,4-diphenylbutyl) -1 H-imidazole ..

A concentrated aqueous solution of ammonium formate (4.0 g) was added dropwise to a boiling mixture of 1-benzyl 5- (1-hydroxy-4,4-diphenylbutyl) -1H-imidazole (4.5 g) and

10% Pd / C (0.5 g) in 50 ml of 50% ethanol. This mixture was heated under reflux for 2 hours. The catalyst was filtered off and the solvent was evaporated.

A 2M NaOH solution was added and the resulting product was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated to dryness, which allowed to obtain the desired product, which was used in the next step b).

b) 4- (4,4-diphenyl-1-butenyl) -1 H-imidazole.

4- (1-hydroxy-4,4-diphenylbutyl) -1 H-imidazole (3.0 g) and 20 g of anhydrous bisulfate

5 potassium was heated at a temperature of 150 ° C for 2 hours. This mixture was cooled and 90 ml of ethanol was added to dissolve the resulting product. The mixture was made basic with sodium hydroxide. Product received

0 was extracted in methylene chloride, washed with water and evaporated to dryness. The desired product was converted to the hydrochloride salt using dry hydrogen chloride in ethyl acetate.

5 Melting point above 240 ° C.

1 H NMR spectrum (in the form of a hydrochloric salt.): 2.904-3.068 (m, 2H), 4.116 (t, 1H), 6.05-6.35 (t, 2H), 6.998 (d, 1H), 7.22-7.25 (t, UN), 8.719 (d. 1H).

0 The compound of the present invention are particularly useful as aromatase inhibitors and therefore have been successfully used in the treatment of estrogen-induced diseases, for example

5 breast cancers.

Estrogens are important steroids in the physiology and normal development of the mammary gland and genitals in women. On the other hand, estrogens stimulate the growth of malignant tumors caused by estrogens, in particular malignant tumors of the breast and uterus, and they can increase the risk of developing a malignant tumor

5 of the mammary gland when administered as pharmaceutical doses over an extended period of time. Excessive production of estradiol can also cause other benign disorders in hormone-dependent organs. The importance of estrogens as stimulators and / or growth regulators of malignant tumors is emphasized by the fact that antiestrogens are central

5 in the treatment of malignant breast tumors having numerous estrogen receptors. The action of antiestrogens is expressed in the binding of estrogen receptors, as a result of which the biological effects of estrogens are inhibited.

Another approach aimed at blocking the action of estrogens is to inhibit the synthesis of estrogens. This has been achieved under clinical conditions using aminoglutethimide inhibiting the synthesis of harmful steroids. The synthesis of estrogens can be blocked by inhibiting the aromatase enzyme, which is a key enzyme in the biochemical synthesis of estrogens. Aromatase inhibition is important because some mammary tumors synthesize estradiol and estrone at this location, as a result of which constant tumor growth is stimulated.

The ability of the compounds of this invention to inhibit the aromatase of an enzyme has been tested under laboratory conditions.

A human aromatase enzyme was used in the study. This enzyme was prepared from human placenta, which has a high content of this enzyme. A microsomal fraction (100,000 x g precipitate) was prepared by centrifugation. The enzyme preparation was used without further purification. Test compounds were added together with 1,2 (3H) -androsten-3.17-dione, whose decay rate was 100,000 decays per minute, and a NADPH generation system. The concentrations of the test compounds were 0.001; 0.01; 0.1 and 1.0 mmol. Incubation was carried out at a temperature of 37 ° C for 40 minutes. Aromatization of 1,2 (H) -androsten-3,17-dione led to the formation of 3H20. The tritium-saturated water and the tritium-saturated substrate were easily separated using an EP-PAK minicolumn, in which the steroid was absorbed and free water was eluted. The radioactivity was counted using a liquid scintillation counter. The degree of aromatase inhibition was determined by comparing 3. H20 radioactivity in samples treated with an inhibitor and in control samples containing no inhibitor. The mean inhibition concentration (1C-50) was calculated as the concentration inhibiting the enzyme activity by 50%. These concentrations are presented in Table 2.

Cholesterol side chain cleavage (C5CC) activity (desmolase) was measured by the method of Pazanen and Pelkonen (Steroids) (43: 517-527, 1984). Incubation was performed in 1.5 ml Eppendorf plastic tubes using an Eppendorf vibrator, centrifuge and thermostat as a single device. In 300 ml incubation volume

a substrate (5 mmol) was prepared according to the method of Hanukoglu and Jeffcoat, to which radioactive ZN-4-cholesterol was then added, the decay rate of which was

100,000 decays per minute, (purity of this compound was checked by thin layer chromatography) in 0.5% Tween 20, 10 mmol MgCte, 5 μmol cyanoketone and 2 mmol NADPH. Control samples contained all of the above substances, but the enzyme preparation was inactivated prior to incubation by adding 900 µl of methanol. As the source of the enzyme, mitochondrial

5 fraction (1 mg protein) from human placenta or adrenal glands of cows. After incubation for 30 minutes at 37 ° C, the reaction was completed by adding 900 µl of methanol; a marker representing 14C-4 pregnenolone was added to each thermostat with a decay rate of 1500 decays per minute, after which the tube was vigorously shaken. After reaching equilibrium for 10 minutes

The 5 methanol-precipitated proteins were separated by centrifugation (8,000 x g for 2 minutes), and the pop-up layer was sucked into a 1 ml plastic syringe and transferred to a pre-balanced (75% methanol) minicoll. This column was washed with one ml of 75% methanol, and then 3 ml of 80% ethanol. An eluate of 80% methanol was placed in a counting tube and 10 ml of scintillation fluid was added. Radioactivity was counted using a two-label program in a liquid scintillation counter (LKB Rack Beta). Typical activity values for human placenta enzyme preparation

0 and the adrenal glands of a cow, respectively, represented 0.5-3 and 50-100 mmol of pregnenolone formed per mg of protein per minute.

Inhibition experiments

5, the resulting substance (in the concentration range from 1 to 100 µmol) was added to the incubation mixture in a volume of 10-20 µl, usually in the form of a solution in methanol or ethanol. The same amount of dissolved

0 substances were added to the control incubation tube. Values of the average concentration of inhibition (concentration causing 50% inhibition) were determined graphically, and the obtained

5 results are presented in table 2.

The antitumor effect was investigated in a living organism with respect to DMBA-induced mammary adenocarcinoma in rats according to the following method. Milk adenocarcinoma

the glands were caused by the administration of DMBA in the walls of rats aged 50 ± 2 days. Treatment with the test compound was started after the appearance of palpable tumors. Tumor size and number of tumors were determined once a week. The size of the tumors in the control group, the treatment in the second group was carried out with a solvent, compared with similar parameters in the test groups. The daily dosage regimen was designed for five weeks, after which the animals were sacrificed. Determined the change in the size of the tumors.

The results were determined as changes in the size of the tumors and were divided into three groups, namely, increasing, stable and decreasing sizes of the tumors. The antitumor activity of 4 - (4,4-d and phenylbutyl} -1 H-imidazole (Compound 9 in Table 2) was tested, the results of which are presented in Table 3.

Acute toxicity, mean lethal dose, was determined using young adult female mice of the MP1 species. The test compounds were administered orally. The mean lethal dose of the test compounds of formula (1) was 350 mg / kg or more.

The daily dose for a patient varies from 20 to 200 mg when administered orally.

This invention is illustrated by the following examples.

H NMR spectra were determined using a Brucker apparatus WP 80DS (80 MHz). The substance selected for comparison was tetramethylsilane. Mass spectra were determined using a Kratos M 80RG apparatus with an automatic remote control.

Shoulder shape

The method of obtaining substituted imidazole formula

N

 jKHR5-CHR4- (CH2) 2-CH2-CH-X- Yv

R1

, "F

kR

,,

where RI, R2, Ri and R2 are the same or different. H, CH3, C2H5, C3H, OCH3, N02, CF3, CHF2, CH2F or halogen;

Ri is hydrogen or. SNU / C & - R

f. Vr q

where Ra is H, CH3 or halogen;

R4-H;

P-S is H or OH, or R4 and RS together form a bond;

X and Y are the same or different, represent a bond or a straight C1-C2-alkyl,

Z 0-2, or a non-toxic pharmaceutically acceptable acid addition salt thereof,

characterized in that 4 (5) -imidazolaldehyde of the formula: M

(SSS;

where R has the indicated meanings,

react with a Grignard reagent of the general formula

sI MgCH2 (CH2) zCH2-CH-X

I y

-rff & 1

where Ri, R2, Ri, R2. X, Y and Z have the indicated meanings to give the compound of general formula

N N

 VCH-CH2- (CH2V-CH-X- NY

fc

g

5

where R, Ri, R2, Ri, Rsi-, X, Y and Z are as defined herein.

5 optionally when R represents a substituted or unsubstituted benzyl group, ..

convert this product using a hydrogen transfer reaction to produce

0 compounds of general formula

N N / e & "

((sn2) 2-sn2-sn x- s #,

1} Mr. YRZ.

5

dehydrate the product when R1 is hydrogen or substituted or unsubstituted benzyl to give a compound of general formula 0N

(i CH 2 —CH 2 CH — X |

N A.

.R,

2

AND

z1 1 R, Ri, R2, Ri, R21, X, Y and Z have the indicated meanings,

optionally hydrogenating the product to give a compound of general formula

sngsn2 (sn gsn7sn-x- L, 7Y

Ri

and optionally, when R represents a substituted or unsubstituted benzyl group, the product is hydrogenated or the product is converted by a hydrogen transfer reaction to give a compound of general formula

0ngsn2 (cng) ghs, Rl

2

N

n

 I y

.

where Ri, R2, Ri. R2, X, Vy2 have the indicated meanings.

10

Tested Compounds

No.

(4- (methylphenyl) -4-phenylbutyl -1H-imidazole 1-benzyl-5- 4- (4-methylphenyl) -4-phenylbutyl} -1H-imidazole 1-benzyl-5-4- (3-methylphenyl) 4 -phenylbutyl} -1H-imidazole (3-methylphenyl) -4-phenylbutyl -1H-imidazole (2-methylphenyl} -4-phenylbutyl -1H-imidazole 1-benzyl-5-4- (2-methylphenyl) -4-phenylbutyl -1H-imidazole 1-benzyl-5- (4,5-diphenylpentyl) -1H-imidazole 4- (4,5-diphenylpentyl) -1H-imidazole 4- (4,4-diphenylbutyl) -1H-imidazole 1-benzyl -5- (4,4, diphenylbutyl) -1H-imidazole (-methoxyphenyl) -4-phenylbutyl -1H-imidazole, 4-bis) 4-methoxyphenyl) butyl -1H-imidazole, 4-bis (3-methylphenyl) butyl -1 H-imidazole 4- {4- (3,5-dimethylphenyl) -4-phenylbutyl -1 H-imidazole (3,4-dimethylphenyl) -4-phenylbutyl -1 H-imidazole (3,5-dimethylphenyl) -4- (3-methylphenyl) butyl -1 H-imidazole.

4- {4,4-bis (4-methylphenyl) butyl -1 H-imidazole 4- {5,5-diphenylpentyl) -1 H-imidazole 4- (6,6-diphenylhexyl) -1 H-imidazole (2- fluorophenyl) -4-phenylbutyl -1 H-imidazole (4-fluorophenyl) -4-phenylbutyl -1 H-imidazole, 4-diphenyl-1-butenyl) -1 H-imidazole, 4-bis (4-fluorophenyl) butyl - 1 H-imidazole, 4-bis (4-nitrophenyl) butyl -1 H-imidazole, 4-bis (4-aminophenyl) butyl -2H-imidazole (4-ethylphenyl) -4-phenylbutyl 1-1 H-imidazole

Table 1

Title

nineteen

Enhancing Aromatase and Dysmolase in the Human Body (CSCC)

under the influence of test compounds. The average inhibition concentration (IC-50) is the concentration that inhibits

50% of the enzyme.

Tabl 3

The number of different types of tumors in the control group and in the group treated with 4- {4,4-diphenylbutyl) -1H-imidazole (which included rats with a breast tumor caused by the introduction

DMBA

1836355

20 table 2