CS203054B2 - Method of preparing imidazolyl compounds - Google Patents

Abstract

A process for the production of compounds having activity as histamine H2-receptor antagonists and having the formula where Y is a lower alkyl group, and pharmaceutically acceptable acid addition salts thereof, in which 4-hydroxy-methyl-5-(2-aminoethyl)thiomethylimidazole is reacted with a dilower alkyl dithioiminocarbonate which is subsequently reacted with an amine of formula YNH2. The salts can be prepared by known methods.

Description

The present invention relates to a process for the preparation of imidazolyl pharmacologically active substances.

The imidazolyl compounds prepared by the process of the invention are antihistamine active substances blocking H2-receptors. These compounds may also be in the form of acid addition salts, but for the sake of simplicity a process for preparing the compounds in free base form is described. H 2 -receptors of histamine are not blocked by 2 - [(2-dimethylaminoethyl) (p-methoxybenzyl) amino] pyridine (mépyramine) and typical antihistamines, but are blocked by N-methyl-N- [4- (4-imidazolyl) butyl] thiourea (burinamide), see Black et al., Nature 236, 385 (197) (2) The antihistamine H2 blocking agents are useful for inhibiting gastric acid secretion, as anti-inflammatory agents and as agents affecting the cardiovascular system.

Accordingly, the present invention relates to a process for the preparation of compounds of formula 1 wherein X is a sulfur atom or an N.CN group, characterized in that an amine of formula 2 is reacted.

BOY. (2) with a molar excess of methyl isothiocyanate or with a molar equivalent amount of dimethyl cyanoimidocarbonate and levers with a molar excess of methylamine in the solvent at room temperature to the reflux temperature of the solvent.

The amines of formula 2 can be prepared according to the general scheme

X ^H OCH _Z CHS ch ₉ cknh-c ^ \ У & 4 2 ч

HN ^ N 3

desulfuration

Raney nickel с, иоос -? - ^Ch : ^30! - · ^ - ^x HN NH

S cyca i

1) hydrolysis

2) ether cleavage

3)

LiAL 1 · 4 or hydrolysis and electrolytic reduction

HOCH ^^., Νη.

2)

The efficacy of the antihistaminic blocking agent of the? -Receptors can be demonstrated by inhibiting histamine-stimulated gastric acid secretion from the perforated stomachs of urethane anesthetized rats at an intravenous dose of active ingredients of 0.5 to 256 micromoles per -1 kg. Pharmaceutical preparations useful as antihistam active agents blocking H 1 -receptors can be prepared by admixing the compound of formula - 1 in the form. bases - or corresponding salts of a pharmaceutically-acceptable acid with a pharmaceutically acceptable. a diluent or carrier.

The invention is further described in the accompanying examples, which are not intended to be limiting in any way.

Example 1

N-methyl-N ⁴ - {2 - [ ^1- (5-hydroxymethyl-4-imidazolyl) methylthio] ethyl] thiurea (i) 24.8 g of α-oxyamido-β-οχο-χ-ethoxybutyric acid ethyl ester 58.5 g of tin (II) chloride dihydrate in 97 ml of concentrated hydrochloric acid are added slowly to a well-stirred and 15 ° C-cooled solution or suspension over 30 minutes, after which 1.2 g of powdered tin is added. After 2 hours, the reaction mixture is diluted with 300 ml of water, cooled to -10 DEG C. and hydrogen sulfide is introduced into the solution; after filtration, the pH of the filtrate is adjusted to about 1.0 by the addition of sodium hydroxide and 10.3 g of ammonium thiocyanate are added along with an additional portion of sodium hydroxide so that the pH remains at about 2.0. The reaction mixture is heated to 95 ° C with stirring for 15 minutes and then cooled to 0 ° C. A sand-colored precipitate is formed on standing, and recrystallized from water to give 11.9 g of 4-ethoxycarbonyl. 162 DEG-163 DEG C. 5-Ethoxymethyl-2-mercaptoimidazole.

(ii) At 40 ° C, 55 g of Raney nickel are added to a stirred solution of 11.9 g of 4-ethoxycarbonyl-5-ethoxymethyl-2-mercaptoimidazole in 700 ml of ethanol, and the reaction mixture is heated to reflux.

After cooling for 2 hours, filtration and evaporation of the filtrate, the residue was recrystallized from water to give 6.1 g of 4-ethoxycarbonyl-5-ethoxymethylimidazole, m.p. 143-144 ° C.

(iii) 6.0 g of 4-ethoxycarbonyl-5-ethoxymethylimidazole are dissolved in 650 ml of a 48o / ₀ hydrobromic acid solution and

the mixture is refluxed for 17 hours after addition of 3.4 g of cysteamine hydrochloride. Concentration of the reaction mixture to dryness and crystallization of the residue from butanol / ether (15:85) gave 4-carboxy-5- [2- (aminoethylthio) methyl] imidazole dihydrobromide in 10.9 g, m.p. 219-220. Deň: 32 ° C.

(iv) A solution of 1.0 g of 4-carboxy-5- [2- (aminoethylthio) methyl] imidazole dihydrobromide in 24 ml of a 10% by volume sulfuric acid solution was electrolyzed for 3 hours at a constant current of 1.0 A and 8 to 10 V in using a rotating mercury cathode and a platinum anode which are separated by a porous plate.

After adjusting the pH to 9-10 by addition of 8.3 g of potassium carbonate and evaporating to dryness, a residue is obtained, which is extracted into hot isopropyl alcohol, and the extract is concentrated to give 0.4 g of 5-hydroxymethyl-4- [2- ( aminoethylthio) methyl] imidazole.

(v) 6 ml of an aqueous-ethanolic solution (1: 5) 0.4 g of 5-hydroxymethyl-4- [2- (aminoethylthio) methyl] -1-midazole is heated to reflux with 0.2 methyl isothiocyanate for 30 minutes at reflux. . After cooling, a solid precipitates and the oil is concentrated by evaporation of the supernatant; crystallization of this portion from acetonitrile further afforded as a white solid 0.1 g of N-methyl-N - (2 - [(5-hydroxymethyl-4-imidazolyl) methylthio] ethylthiourea, m.p.

138.5 - 1319.5 ° C.

Analysis for CaH 2 N 2 OS 2 calculated:

% C, 41.59;% H, 0.37;% N, 21.38; found:

H, 6.19; N, 121.52. Example 2

N-Methyl-N'-cyano-N '- (2 - [ ^: (5-hydroxymethyl-4-imidazolyl) methylthio] ethyl | guanidine

To a solution of 0.4 g of 5-hydroxymethyl-4- (2-aminoethylthiomethylimidazole in 3 ml of ethanol) was added a solution of 0.3 g of dimethyl cyanadithioimide carbonate in ethanol, and the reaction mixture was stirred at 15 ° C for 2 hours. an oily form of S-methyl-N-cyano-N '- (2 - [(5-hydroxymethyl-4-imidazolylmethyl) thio] ethyl} isothiourea to which an excess of 7 g of ethanolic methylamine solution is added. The mixture was stirred for 70 hours and then 0.1 g of N-methyl-N'-cyano-N '- [2 - [(5-hydroxymethyl-4-imidazolyl) methylthio] ethyl] guanidine was obtained as preparative thin layer chromatography. The structure of the product was confirmed by NMR spectra in deuterated water, where the following resonances were detected:

imidazole-244 imidazole-CH 2 -O imidazole-CH 2 -S -CH 21 -N

СНз — NH

S — CH2 — CH2 singlet at δ 8.69 singlet at δ 4.72 singlet at 3 3.93 triplet at δ 3.34 singlet at δ 2.78 triplet at S 2.71 integrated for 0.7 proton calculated 1, 0 proton integration blurred by HDO integrated for 1.9 protons calculated for 2.0 protons integrated for 1.9 protons calculated for 2.0 protons integrated 5.0 protons calculated 5.0 protons

Claims (1)

Process for the preparation of imidazolyl compounds of the general formula 1; CH ^ NU-C ' NHCH ₃ 1) wherein X is a sulfur atom or N.CN, characterized in that the amine of formula 2 is reacted with a molar excess of methyl isothiocyanate or with a molar equivalent amount of dimethyl cyanoimodocarbonate and then with a molar excess of methylamine in the solvent at room temperature to reflux temperature. solvent flow.