FI81093C - NYA SOM MELLANPRODUKTER ANVAENDBARA 4 (5) - (2,3-DIHYDRO-1-OXI-1H-INDEN-2-YL) -IMIDAZOLE DERIVATIVES. - Google Patents

Description

81093

New 4 (5) - (2,3-dihydro-1-oxy-1H-inden-2-yl) -imidazole derivatives useful as intermediates - Nya som raellanprodukter användbara 4 (5) - (2,3-dihydro-1-oxy- H-inden-2-yl) -imidazolderivat

This invention relates to novel intermediates in the preparation of therapeutically valuable 4 (5) -substituted imidazole derivatives and their non-toxic salts.

The imidazole derivatives according to the basic application FI 854335 are new potent and selective α2-receptor antagonists of the general formula r.3? 2 R1 r4 ά wherein X is -CH2-, -CH2CH2- or -O-, is H or contains 1-4 carbon atoms. lower alkyl, R 2 is H, CH 3, CH 2 CH 3, OCH 3 or OH, R 3 is H, CH 3, CH 2 CH 3, OCH 3 or Hal, R 4 is H, CH 3, CH 2 CH 3, OCH 3 or Hal and Hal is halogen.

Compounds of formula (I) wherein R 2 is H or OH and X is

is -CH2-, can be prepared, for example, by the following method: 2 81093 <* 3 j? »1« 3 R1 0 'V-v. // halogenation S ^ 'y \ / H-C-NH2 R4 0 R4 0 R3 0 RX R3 OH R10 0 ./ \ / NaBH4 X. —V // "<lT> ./ ^ -x I!

H A

γβ H2, Pd / C H2 Pd / C,} β '/

R3 M X

.//r>κ IL /

A

Intermediates of formula R3 0 Ri ϊι> ^ τ> R4 '' ^ -n

B

wherein R 1, R 3 and R 4 are as defined above are new.

In the examples showing 1 H-NMR spectrometric shifts, the NMR spectra were taken on a Bruker WB 80 I) S instrument using an internal tetramethylsilane standard from which

II

The chemical shifts (6, ppm) shown in 3,81093 are tabulated. The letters s, d, t and m indicate whether it is a singlet, a doublet, a triplet or a multiplet. The number of hydrogen atoms is also indicated in the same context.

Example 1 4 (5) - (2,3-Dihydro-2-ethyl-1-hydroxy-1H-inden-2-yl) imidazole a) 4 (5) - (2,3-Dihydro-2-ethyl -1-Oxo-1H-inden-2-yl) imidazole 2-Acetyl-1-indanone (Liebigs Ann. Chem. 347 (1906) 112) is alkylated with ethyl bromide in acetone in the presence of sodium carbonate to give 2-acetyl-2-ethyl -L-inda-fluoroacetophenone. 2.2 g of 2-acetyl-2-ethyl-1-indanone are dissolved in 10 ml of methanol. Bromine (1.60 g) dissolved in methanol (2 ml) is rapidly added at 40-50 ° C. The reaction is monitored by gas chromatography. After the reaction, water is added. The product is extracted into toluene and the toluene solution is washed with 10% Na2CO3 solution and finally with water. The toluene solution is dried and evaporated. A mixture of 2-bromo-1- (2-ethyl-2,3-dihydro-1-oxo-1H-inden-2-yl) ethanone (2.2 g) and formamide (20 ml) is heated at 130-140 ° C for one day.

The mixture is cooled, poured into water and acidified with hydrochloric acid. The acidic solution is washed with toluene. The aqueous solution is then basified and the product is extracted into methylene chloride. The methylene chloride solution is washed with water, dried and evaporated to dryness. The product is crystallized as a base from ethyl acetate, m.p. 126-7 ° C.

b) 4- (S) - (2,3-Dihydro-2-ethyl-1-hydroxy-1H-inden-2-yl) -imidazole

The carbonyl group of the oxoindene imidazole (step a) is reduced with NaBH 4 in ethanol to the alcohol group. The product is a mixture of 4,81093 cis-transstereoisomers and is purified by liquid chromatography.

cis-isomer as hydrochloride (mp 184-185 ° C): 1 H NMR (80 MHz, MeOH-d 4): δ 0.73 (3H t), 1.86 (2H, m), 3.36 (2H, m), 3.61 (3H, s), 5.15 (1H, s), 7.06 (1H, d), 7.2-7.4 (4H, m), 8.69 (1H, d) trans-isomer in hydrochloride 1 H NMR (80 MHz, MeOH-d 4): δ 0.80 (3H, t), 1.84 (2H, m), 3.15 (2H, m), 3.24 (3H, s), 5.15 (1H, s), 6.87 (1H, d), 7.2-7.4 (4H, m), 8.54 (1 H, d)

Example 2 4 (S) - (2,3-Dihydro-2-ethyl-1H-inden-2-yl) -imidazole

The oxo derivative prepared according to step a) of Example 1 or the hydroxy derivative prepared according to step b) is hydrogenated in 2N HCl at 70 ° C using 10% Pd / C as a catalyst. When the consumption of hydrogen ceases, the reaction mixture is filtered and made alkaline. The product is extracted with methylene chloride, which is washed with water, dried and evaporated. The final product, which is the base form of the product, is converted to the hydrochloride in ethyl acetate with dry HCl. Mp 2LL-215 ° C.

il

Claims (1)

5,81093 Claim 4 (5) - (2,3-dihydro-1-oxy-1H-inden-2-yl) imidazole derivative of the formula Ro O R 1 H wherein R 1 is H or lower alkyl having 1 to 4 carbon atoms the group and R 3 and R 4, which may be the same or different, are H, -CH 3, -CH 2 CH 3, -OCH 3 or halogen. 6,81093 to 4 (S) - (2,3-dihydro-1-oxy-1H-inden-2-yl) imidazole derivatives, especially formula H is R 1 or H or an alkyl group containing 1-4 cholaters and R 3 and R 4, which may be sickly or ol, H, -CH 3, -CH 2 CH 3, -OCH 3 or halogen. II