DE1021850B - Process for the preparation of new derivatives of benzimidazole - Google Patents

Description

Process for the preparation of new derivatives of benzimidazole It has been found that derivatives of benzimidazole of the following general formula I wherein R, hydrogen, an aliphatic radical with 1 to 5 P_ Ohlenstoffatomen, an optionally substituted araliphatic, heterocyclic or phenyl radical, R2 to R, can be identical or different and are hydrogen or methyl, ethyl, amino, nitro or Oxy groups or stand for halogen atoms and R, hydrogen, an aliphatic radical with 1 to 3 carbon atoms, an optionally substituted phenyl radical or an optionally substituted oxy or carboxylic acid group, R7 is hydrogen or an optionally substituted oxy group and Ra and R9 can be identical or different and for hydrogen or for nitro groups or for optionally substituted amino or oxy groups or for halogen or for aliphatic radicals with 1 to 3 carbon atoms and n stands for the numbers 0 to 2, have valuable therapeutic properties.

In the case of very low toxicity, those to be obtained according to the invention act Strong antihypertensive products. So were z. B. for the compound of the above formula, at R1 = - CH ,; R, to R "Ra, R, = H, R, = OH and n = 0, which is the primary Citrate was administered to animals, the following test results were obtained 1. The DL " is about 1600 mg / kg mouse for the white mouse when administered subcutaneously intravenous application about 115 mg / kg mouse.

2. The smallest dose of the primary citrate of this compound that a decrease of about 25 ° / a in the initial arterial blood pressure in rats and cats causes is between 10 and 15 mg / kg (cats are generally a little more sensitive as, rats). The onset of action begins immediately after intravenous administration and is generally due to a slow decrease in arterial blood pressure marked. The lowering of the blood pressure often lasts for the duration of the whole Attempt (about 4 to 6 hours).

3. If adrenaline triggers an increase in blood pressure, lift if the substance is administered before the adrenaline intake, its effect is completely eliminated or at least considerably attenuates them in smaller doses; when administering the Substance at the peak of an adrenaline spike will drop rapidly below baseline and causes only very slow recovery.

4. The intravenous administration of 1.5 VE of the intestinal toning and ditiresinhibitory fraction of the posterior lobe of the pituitary caused very potent The increase in blood pressure could be completely eliminated in the cat, and even occasionally be reversed.

5. Probably the most impressive result was through the 02 ylangel high pressure to achieve on the cat. The administration of an 02 deficiency gas mixture or a C02 enrichment in the breath becomes the blood pressure reflex described by Heymanns triggered one of the most powerful and impressive emergency functions of the organism. Previously administered the above substance in the form of its primary citrate complete elimination of this reflex.

4- (ß-Amino-y-bromopropyl) -imidazole-dihydrobromide is known from German patent specification 920250. Comparative tests between this substance, which has been closely related to histamine, which has been known for a long time to act on blood pressure, and compounds prepared by the process according to the invention have shown that the new benzimidazole derivatives are superior to the imidazole derivative known from German Patent 920 250 both in terms of the extent of action and in terms of the duration of action are. This finding is particularly surprising since imidazole and benzimidazole derivatives cannot easily be compared with one another with regard to their effectiveness on blood pressure. For example, from the compilation by JB Wright in Chemical Review, 48, p.520 (1951), it is known that 5- (ß-aminoethyl) -benzimidazole (i.e. the benzimidazole analogue of histamine) causes an increase in blood pressure and that the 2- (ß-Aminoethyl) -benzimidazole shows no effect on blood pressure even in high doses.

The new valuable products are produced by a) a benzimidazole derivative of the general formula II in which R1 to R5 have the same meaning as above, with a compound of the general formula III in which R., R, and R9 and n have the same meaning as in formula I and Hal stands for a halogen atom, or with a compound of the general formula IV wherein R6, R $ R, and zt, have the same meaning as in formula I, converts to a compound of formula V. in which R1 to R9 and n have the aforementioned meaning, and these are then converted into a compound of the general formula I (R, = OH) by reduction, preferably by catalytic reduction; or by b) a benzimidazole derivative of the general formula II with a compound of the general formula VI preferably in the presence of a hydrogen halide binding agent; or by c) an o-phenylenediamine of the formula VII wherein R2 to R9 and 7a have the same meaning as in formula I, according to processes known per se with a compound of the formula VIII in which R1 has the same meaning as in formula I and X is hydrogen or an optionally substituted oxy or amino group or a halogen atom; or by d) in an o-nitroaniline derivative of the formula IX wherein R1 to R, and generally have the same meaning as in formula I, converts the nitro group into an amino group and then closes the imidazole ring by heating.

The compounds of general formula I have, if at least one of the radicals R6 and R ,, is different from hydrogen, asymmetric carbon atoms, can therefore optionally in optically active forms, eg. B. by salt formation with optically active acids.

It is expedient to transfer the new compounds for therapeutic purposes in water-soluble salts, e.g. B. in citrates.

Example 1 10 g of 2-methylbenzimidazole ground in 100% of absolute acetone with a solution of 8.5 g of potassium hydroxide in 10 cm 'of water while stirring under reflux heated to boiling. A solution of 20 g of styrene bromohydrin is then added dropwise in 25 cm 'of absolute acetone is added dropwise and heated when the dropwise addition has ended 11 more;:, hours to simmer. Then the acetone is distilled off and the residue Washed out well with water. After recrystallization from about 60o alcohol was 1- (ß-phenyl-ß-oxy-ethyl) -2-methylbenzimidazole with a yield of 12.0 g = 62.8 ° of theory in the form of white crystals with a melting point of 180 to 182-.

Example 2 a) Ground 26.4 g of methylbenzimidazole in 200 cm3 of acetone with a solution of 12 g of potassium hydroxide in 15 cm3 of water is added and the mixture is stirred heated to boiling. To the solution obtained is added dropwise with further Stir a solution of (,) - bromoacetophenone in 100 cm, "acetone" at the boiling point and then cooks for another hour. Then the precipitate is sucked off, washed out with acetone and the acetone is distilled off. The residue is made from propanol or ethyl acetate or rithylene glycol monoethyl ether-water (1: 1) recrystallized.

Mp. 175 to 176. Yield: 36.5 g = 730; o the theory. b) 12.5 g of the 1-phenacyl-2-methylbenzimidazole obtained according to a) are dissolved in 100 cm3 of glacial acetic acid dissolved and after adding 500 g of 511; oiger Pd carbon at 70 to 80 ° without pressure llvdriert. After the uptake of hydrogen has ended, the catalyst is filtered off with suction The filtrate was concentrated in vacuo, the residue was taken up in water, with money treated and made weakly alkaline after filtering again with sodium hydroxide solution, the resulting precipitate is filtered off with suction and recrystallized from 50% alcohol.

Yield 9.5 g = 76% of theory. Mp. 181 to 182 °. Example 3 a) A boiling solution of 19 g benzimidazole, 10 g potassium hydroxide, 10 cm3 water and 200 cm3 of acetone was slowly added dropwise with stirring to a solution of 32 g w-bromoacetophenone in 100 cm3 acetone added. With continued stirring, the reaction mixture was cooked another 2 hours. After filtration, the acetone was distilled off and the residue treated with a little 10 °, oiger nitric acid, whereby it solidified. The solid product was dissolved in boiling, very dilute acetic acid, treated with charcoal, filtered, the product which has crystallized out after cooling is filtered off with suction and dissolved in boiling water and made this solution alkaline. The 1-phenacylbenzimidazole which precipitates out melts at 151 =.

b) 10 g of the 1-phenacyl-benzimidazole obtained according to a) were in 100 cm3 of glacial acetic acid dissolved and with 5% palladium carbon as a catalyst at 70 to 80 'hydrogenated without pressure. After the hydrogenation had ended, the catalyst was filtered off with suction, the filtrate concentrated in vacuo, the residue taken up in water and the resulting Solution made alkaline. The resulting precipitate was a little boiling 5% hydrochloric acid was added and the solution was poured over charcoal. When cooling down the solution crystallizes the hydrochloride of 1- (ß-phenyl-ß-oxyethyl) benzimidazole in the form of white needles with a melting point of 248 to 250 '.

Example 4 a) 6.6 g of 2-methylbenzimidazole were in 75 cm3 absolute Dissolved alcohol and with a solution of 1.2 g of sodium in 25 cm3 of absolute alcohol offset. While stirring, the mixture was heated to boiling on a reflux condenser and then dropwise with a solution of 11.5 g of p-methoxy-co-bromoacetophenone in 50 cm3 of absolute alcohol added. With continued stirring, the reaction mixture was Boiled under reflux for 3 hours. Then the alcohol was distilled off in vacuo and 1- (p-methoxyphenacyl) -2-methylbenzimidazole from 50% alcohol with the addition of carbon recrystallized.

b) 5.6 g of 1- (p-methoxyphenacyl) -2-methylbenzimidazole were analogous for example e, b) catalytically hydrogenated. It became the 1-rß- (p-methoxyphenyl) -ß-oxyethyl] -2-methylbenzimidazole obtain. M.p. 166 '.

Example 5 a) 6.6 g of 2-methylbenzimidazole were mixed with 100 cm3 of acetone and a solution of 2.8 g of potassium hydroxide in 10 cm3 of water with stirring and reflux heated to boiling and slowly with a solution of 10.1 g of p-methylphenacyl bromide offset. After boiling for 3 hours, the acetone was distilled off and the residue recrystallized from 50% alcohol.

Yield 8.8 g = 68% of theory. M.p. 138 '.

b) 5.3 g of the 1- (p-methylphenacyl) -2-methylbenzimidazole obtained according to a) were catalytically hydrogenated according to example e, b) in 75 cm3 of glacial acetic acid. That 1- [ß- (p-methylphenyl) -ß-oxy-ethyl] -2-methy1benzimidazole thus obtained melts at 174 '.

Yield 2.85 g = 53.6 % of theory. Example 6 A solution of 21.4 g of ß-phenyl-ß-methoxy-ethyl bromide in 100 cm 3 of acetone is added dropwise with stirring to a refluxing solution of 13.2 g of 2-methylbenzimidazole, 150 cm 3 of acetone, 5.6 g of potassium hydroxide and 10 cm3 of water. Then it is kept boiling for 3 hours. The residue obtained after the acetone has been distilled off is washed with water and then recrystallized from 50% alcohol with the addition of charcoal. The 1- (ß-phenyl-ß-methoxyethyl) -2-methylbenzimidazole thus obtained melts at 164 to 166 °.

Example 7 A boiling solution of 6.6 g of 2-methylbenzimidazole, 100 cm3 of acetone, 2.8 g of potassium hydroxide and 10 cm3 of water are slowly added while stirring a solution of 13 g of a-bromo-ß-phenyl-ß-methoxypropionic acid, 2.8 g of potassium hydroxide, 10 cm3 of water and 100 cm3 of acetone were added and the mixture was then refluxed for a further 3 hours. The residue remaining after the acetone has been distilled off is made from 30% alcohol recrystallized with the addition of charcoal. That which melts at 173 to 174 'is obtained Potassium salt of ß-phenyl-ß-methoxy-a- (2-methyl-benzimidazolyl-1) -propionic acid in a yield of 10.8 g = 69.5% of theory.

Example 8 a) The procedure is as in Example 4, a), but used 8 g of 2-propylbenzimidazole and 10 g of c) -bromoacetophenone. 1-Phenacyl-2-propylbenzimidazole is obtained in a yield of 7.5 g = 54%. Mp. 155 to 157 '.

b) The 1-phenacyl-2-propylbenzimidazole obtained according to a) is obtained by catalytic reduction into 1- (ß-phenyl-ß-oxyethyl-2-propylbenzimidazole, melting at 132 to 134 ' convicted.

Analogously, 1- (ß-phenyl-ß-oxyethyl) -2-benzylbenzimidazole of melting point 167 to 169 'is obtained from 1-phenacyl-2-benzylbenzimidazole and 1- (ß- Phenyl-ß-oxyäthvl) -2-phenylbenzimidazole.

Example 9 a) A mixture of 6 g of benzimidazole and 11 g of benzalacetophenone is heated and 2 cm3 of absolute pyridine slowly to 105 to 110 ', then holds for half an hour at this temperature and finally heated to 115 to 120 'for a short time. the viscous melt solidifies on cooling. Obtained by recrystallization from ethyl acetate the ß-phenyl-ß- (benzimidazolyl-1) ethyl phenyl ketone melting at 174 to 176 '.

b) 2.4 g of the product obtained according to a) are dissolved in 50 cm3 of n-propanol dissolved and pressureless using Raney nickel as a catalyst at 30 to 40 ' hydrogenated. After the catalyst has been filtered off with suction, the filtrate has been evaporated and the mixture recrystallized of the residue from 50% alcohol is obtained 1,3-diphenyl-1- (benzimidazolyl-1 ') -propanol-3, which melts at 111'.

Example 10 1- (ß-Phenyl-ß-oxy-ethyl) -2-methylbenzimidazole was under Addition of n (-) - tartaric acid dissolved in boiling water. The one that fails when it cools down crystalline precipitate was filtered off with suction and recrystallized twice from water. Then it was dissolved in water and the solution made alkaline with sodium hydroxide solution. The precipitate obtained in this way, which melts between 194 and 195 ', was ili more dilute Dissolved hydrochloric acid and evaporated this solution to dryness: The residue showed in aqueous solution a specific rotation of aD = -23.9 '. the end the corresponding (+) - form was obtained from the first mother liquor.

Example 11 8 g of N- (β-phenylethyl) - o-nitroaiiline were dissolved in glacial acetic acid dissolved and catalytically hydrogenated after the addition of 500 mg of 5 °, oiger palladium carbon. After the catalyst had been filtered off with suction, the filtrate was refluxed for 5 hours and then the glacial acetic acid is distilled off in vacuo. The residue was diluted in Acetic acid dissolved, the solution heated to boiling and poured over charcoal. The filtrate was made alkaline, the 1- (f-phenylethyl) -2-methylbenzimidazole initially precipitates in oily form, but crystallizes after washing with water and rubbing.

Mp. 66 to 68 ' . Yield 6.6 g = 67.7 of theory.

Claims (2)

PATENT CLAIMS 1. Process for the preparation of new derivatives of benzimidazole of the general formula where R, hydrogen, an aliphatic radical with 1 to 5 carbon atoms, an optionally substituted araliphatic, heterocyclic or plienyl radical, R. to R, can be identical or different and represent hydrogen or methyl, ethyl, amino, nitro or Oxy groups or halogen atoms and R6 are hydrogen, an aliphatic radical having 1 to 3 carbon atoms, an optionally substituted phenyl radical or an optionally substituted oxy or carboxylic acid group, R, hydrogen or an optionally substituted oxy group and R $ and R3 can be identical or different and stand for hydrogen or for nitro groups or for optionally substituted amino or oxy groups or for halogen or for aliphatic radicals with 1 to 3 carbon atoms and n stands for the numbers 0 to 2, characterized in that a) a benzimidazole derivative of the general formula wherein R1 to RS have the same meaning as above, with a compound of the general formula wherein R6, R $ and R9 and n have the same meaning as in formula I and Hal stands for a halogen atom, or with a compound of the general formula in which R6, Re, R9 and n have the same meaning as in formula I, to form a compound of formula V. in which R1 to R9 and it have the aforementioned meaning, and these are then converted into a compound of the general formula I (R7 = O H) by reduction, preferably by catalytic reduction; or that b) a benzimidazole derivative of the general formula II with a compound of the general formula VI preferably in the presence of a hydrogen halide binding agent; or that c) an o-phenylenediamine of the formula wherein R .. to R ,, and n have the same meaning as in formula I, according to processes known per se with a compound of the formula in which R1 has the same meaning as in formula I and: i represents hydrogen or an optionally substituted oxy or amino group or a halogen atom; or that d) in an o-nitroaniline derivative of the formula wherein R1 to R9 and it have the same meaning as in formula I, converts the nitro group into an amino group and then closes the imidazole ring by heating. 2. The method according to claim 1, characterized in that the compounds of the general formula I, in which at least one of the radicals R6 and R4 is hydrogen is different, by salt formation with optically active acids in the optically active Separates forms. Publications considered: German Patent No. 920 250.