DE2109524A1 - 2,3-dihydr-dioxo-imidazo (1,2-a) imidazoles or pyrimidines - with hypotensive and neuroleptic activity - Google Patents

Abstract

Cpds. of formula (I): (where A is -CO(CH2)n- or -(CH2)n-CO-; R1 is phenyl or benzyl, opt. mono-, di- or tri-substd. by Me, Et, F, Cl, Br, CF3 or MeO; n is 0 or 1) and their acid addn. salts are hypotensives and neuroleptics. Cpds. (I) may be prepd. by reacting X-CO-A-Y (where X and Y are OR, SR or NRR1; R and R1 are H, 1-3C alkyl or halogen, pref. Cl) with a 2-R1NH-2-imidazoline, pref. in a solvent at 40-170 degrees C and opt. in the presence of a basic condensing agent.

Description

2, 3-iihydro-dioxo-imidazoFl, 2-a] -imidazoles or pyrimidines, their acid addition salts and processes for their preparation The invention relates to new heterocyclic compounds of the general formula in the A one or Group and R1 denotes a phenyl or benzyl radical which is unsubstituted or substituted by methyl or ethyl groups, fluorine, chlorine or bromine atoms, trifluoromethyl or methoxy radicals, where n = 0 or 1, and acid addition salts thereof.

The compounds according to the invention are available as 2,3-dihydro-5'6-dioxo-iniidazo [1,2-a] imidazoles or 2,3-dihydro-5,6- or 5,7-dioxo-imidazo [1,2-a] pyrimidines.

The compounds of the formula I are prepared by reacting a substituted amino-1,3-diazacycldpentene of the formula wherein R1 is defined as given above, with a bifunctional compound of the general formula in which A has the abovementioned meaning and X and Y, which can be identical or different, OR, SR or NRR 'groups, where R and R' denote hydrogen atoms or alkyl groups with 1-3 carbon atoms, or halogen atoms, preferably Mean chlorine.

The condensations are usually protonic or polar aprotic solvents at elevated temperature, preferably 40 - 1700C carried out. In the condensation of imidazolines of the formula II in which R1 is a phenyl radical means, higher temperatures are normally required than with the usual ones Solvents are obtained so that in these cases it is most expedient to be solvent-free work is carried out at temperatures of 155-190 ° C. When implementing with connections of formula III, in which X and Y denote a halogen atom, is expedient in the presence of a basic condensing agent such as sodium carbonate or triethylamine, condensed.

The intermediate stages that occur in the condensation can normally be do not isolate. They cyclize to the compounds even at room temperature of formula I.

The compounds of the formula I according to the invention can be based on customary Way are converted into their physiologically acceptable acid addition salts. Acids suitable for salt formation are, for example, mineral acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, Phosphoric acid, nitric acid or organic acids such as acetic acid, propionic acid, Butyric acid, caproic acid, capric acid, valeric acid, oxalic acid, malonic acid, succinic acid, Maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, Ascorbic acid, methanesulfonic acid, 8-chlorotheophylline and the like.

The compounds of the general formula I according to the invention and their acid addition salts are characterized by valuable therapeutic properties the end. In particular, they have an antihypertensive and neuroleptic effect with low toxicity.

The compounds of general formula I and their acid addition salts can be used orally, enterally or parenterally. The dosage for that oral use is 0.5 to 50 mg. The compounds of the formula I or their Acid addition salts can also be used with other types of active ingredients. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, Suppositories, solutions, emulsions, or powders; this can lead to their production the commonly used pharmaceutical auxiliaries, carriers, disintegrants or lubricants or substances are used to achieve a depot effect. The production Such galenic dosage forms are carried out in the usual way according to the known ones Manufacturing methods.

The following examples illustrate the invention without restricting it.

Example 1 7- (2,6-dichlorophenyl) -2,9-dih! Dro-, 6-dioxo-imidazo-rl, 2-al imidazole 10 g (0.043 mol) 2- (2,6-dichlorophenylamino) -2-imidazoline are in 50 ml Diethyl oxalate heated at 170 ° C. for 3 hours.

After adding activated charcoal, the reaction mixture is filtered hot and leave the filtrate in the refrigerator overnight.

The precipitated white crystalline substance is filtered off with suction, with a little Oxalsdurediethylester and absolute ether and washed in a vacuum drying cabinet dried at 50 ° C. Together with the mother liquor, which has been concentrated by half obtained substance, the yield is 3.9 g, corresponding to 31.5% of theory. Bp 210-21 100.

The substance is pure according to thin-layer chromatography.

Example 2 7- (2,6-Dichlorobenzy1) - ?, 3-dShydro-5 6-dioxo-imidazorl.2-a imidazole 4.9 g (0.02 mol) of 2- (2,6-dichlorobenzylamino) -2-imidazoline are combined heated with 30 ml of oxalic acid diethyl ester in a boiling water bath for 1/2 hour. The clear solution is then cooled and the precipitated crystalline precipitate sucked off. After washing with absolute ether and drying in a vacuum drying cabinet the yield is 4.0 g, corresponding to 67.2% of theory.

Mp 166-168 ° C.

Example 3 7- (2-Chlorobenzyl) -2.3-dShydro-5§6-dthydro-imidazo r 1.2-a imidazol 5 g (0.024 mol) 2- (2-chlorobenzylamino) -2-imidazoline are used together with 10 ml of diethyl oxalate in 20 ml of hexamethylphosphoric triamide for 4 hours heated at 12500. After cooling, the reaction mixture is about 20 times Volumetric amount of absolute ether is added and the precipitate that separates out is sucked off. After washing with absolute ether and drying in a vacuum drying cabinet a yield of 4.8 g of imidazorl, 2-agimidazole is obtained, corresponding to 76.2 Theory.

Mp 169-171 ° C.

Example 4 8- (2,6-Dichlorotenzyl) -2,3-dihydro-5,7-dioxo-imidazo r 1.2-a pyrimidine hydrochloride 7.3 g (0.03 mol) 2- (2,6-dichlorobenzylamino) -2-imidazoline are heated to 160 ° C for 4 hours in 40 ml of diethyl malonate. After this Cooling in the refrigerator, the precipitated crystals are sucked off and with little washed ice-cold methanol. The base is dissolved to produce the hydrochloride using an equivalent narrow ethereal hydrochloric acid in absolute methanol, cleans on activated charcoal and crystallizes the imidazo [1,2-ajpyrimidine hydrochloride by means of absolute ether. After recrystallization from a mixture absolute Methanol / absolute ether gives 5.8 g of pure hydrochloride corresponding to one Yield of 55.7% of theory.

Mp 199-201 ° C.

Example 5 8- (2,6-Dichlorophenyl) -2§3-dShydro-5,6-dioxoimidazo r 1,2-a pyrimidine To a mixture of 6.9 g (0.03 mol) 2- (2,6-dichlorophenylamino) -2-imidazoline and 6.35 g of anhydrous sodium carbonate in 50 ml of absolute chloroform are added dropwise within a short time a solution of 6.25 g (105%) ethyl bromobenzyruvate in 25 ml of absolute chloroform with stirring and gentle cooling. Afterward the reaction mixture is refluxed for 2-3 hours. After narrowing the dark brown, solid residue is dissolved in 1N hydrochloric acid in vacuo, the hydrochloric acid Solution extracted several times with ether (ether extracts are discarded) and over activated charcoal cleaned. Then will the imidazo [1,2-a] pyrimidine base from hydrochloric acid Solution precipitated with 5N sodium hydroxide solution at pH 5-6, filtered off with suction and washed. After this Drying in a vacuum drying cabinet at 50 ° C. gives 3.6 g of the new compound corresponding to a yield of 40.2% of theory. The melting point is 279 - 281 ° C. The substance is uniform according to thin-layer chromatography.

The examples listed in the tables can be analogous to the examples mentioned Manufacture substances.

Table 1 2,3-Dihydro-5,6-dioxo-imidazo [1,2-a] imidazoles of the formula I example no. R1 n Yield mp, 0 6 2-CH3-C6H4-CH2- o 55.7% 137 - 139 7 4-CH3O-C6H4-CH2- o 25.3 ffi 135 - 136 8 2-C1-6-CH3-C6H- o 23.5% 188 - 190 9 2,6- (C2H5) 2C6H3-o 33.7 % 152-153 10 2,4,6-Br3C6H2- o 40.2% 277-279 11 2,6-Br2C6H3- o 52.0% 209-210 12 2-F-C6H4-CH2- o 26.9% 111 - 112 13 C6H5-CH2- o 25.4% 139 - 140 Table 2 2,3-Dihydro-5,7-dioxo-imidazo [1,2- a] pyrimidines of formula I example no. R1n yield mp, ° C 14 2-CH3O-C6H4-CH2-1 33.1% 225-227 15 2,4-CL2C6H3-CH2- 1 44.9% 212 - 214 16 C6H5-CH2- 1 38.4% 235 - 239 17 4-CH3O-C6H4-CH2- 1 51.1% 223-226 Example No. R1 n yield mp, ° C 18 2-Cl-C6H4-CH2- 1 25.5% 231 - 232 19 3-CH3-C6H4-CH2- 1 24.8 ffi 246 - 248 20 2,4,6- (CH3) 3C6H2-CH2- to C6H3-CH2- 1 54.4% 191 - 192 21 2-CH3-C6H4-CH2- 1 63.6 ffi 199 - 200 22 4-CH3-C6H4-CH2- 1 81.6% 218-219 23 2,6-C12-C6H3 1 19.3% 280-281 Example 24 7- (3-Trifluoromethylbenzvl ) -2 3-dihvdro-5'6-dioxo-imidazo F 1, 2-a 1 imidazole 7.3 g (0.03 mol) 2- (3-trifluoromethylbenzyl) -2-imidazoline are heated together with 30 ml of oxalic acid diethyl ester at 90 ° C. for 1 hour. After this time, the implementation is almost complete. The excess is drawn in a vacuum Oxalic acid diethyl ester from, and receives as a residue a mixture of substances which contains in the main the desired imidazo [1,2-a] imidazole, which as in the previous examples described is worked up.

Formulation Examples Example A: Tablets 7- (2,6-dichlorophenyl) -2,3-dihydro-5,6-dioxo- 10 mg imidazo [l, 2-a] imidazole lactose 35 mg corn starch 30 mg colloidal silica 1 mg magnesium stearate 1 mg total 75 mg Production: The active ingredient is mixed with some of the auxiliary materials, kneaded with starch paste and granulated in the usual way with the help of a sievex The granulate is mixed with the rest the excipients are mixed and compressed into tablets weighing -75 mg each.

Example B: Dragees 7- (2,6-dichlorophenyl) -2,3-dihydro-5,6-dioxo-15 mg imidazorl, 2-a) imidazole lactose 35 mg corn starch 30 mg colloidal silica 1 mg magnesium stearate 1 mg total 75 mg Manufacture: From lactose, corn starch and colloidal silica, granules are made with starch paste that Active ingredient and magnesium stearate mixed in and the mixture compressed into tablets, which are then coated in the usual way with talc and gum arabic.

- patent claims -

Claims (7)

P atent to 5 proven compounds of the general formula in the A one or Group and R1 denotes a phenyl or benzyl radical which is unsubstituted or substituted by methyl or ethyl groups, fluorine, chlorine or bromine atoms, trifluoromethyl or methoxy radicals, one to three times, where n = 0 or 1, and acid addition salts thereof. 2. Process for the preparation of compounds of the general formula I and their acid addition salts, characterized in that a substituted 2-amino-1,3-diazacyclopentene of the formula wherein R1 is defined as given above, with a bifunctional compound of the general formula in which A has the abovementioned meaning and X and Y, which can be identical or different, denote an OR, SR or M 'group, where R and R' are hydrogen atoms or alkyl groups having 1-3 carbon atoms, or halogen atoms, preferably Denote chlorine, converts; and optionally converting the compounds obtained into their acid addition salts. 3. The method according to claim 2, characterized in that the Implementation in a protonic or aprotic solvent. 4. The method according to claim 2 and / or 3, characterized in that the reaction is carried out in the presence of a basic condensing agent. 5. The method according to claim 2 to 4, characterized in that one the reaction is carried out at a temperature of 40 to 1700C. 6. Pharmaceutical preparations, characterized in that they as active ingredient one or more compounds of the general formula I or their Contain acid addition salts. 7. A method for the production of medicaments according to claim 6, characterized characterized in that one or more compounds the general Formula I or their acid addition salts with customary galenic auxiliaries, carriers, Disintegrants or lubricants or substances compounded to achieve a depot effect.