DE1118204B - Process for the preparation of basic theophyllinyl acetic acid esters - Google Patents

Description

Process for the preparation of basic theophylline acetic acid esters In the German patent 862 301 are esters of theophyllinyl- (8) -acetic acid with basic alcohols of the type des, B-dimethylaminoethanol. It was found that basic esters of oc - phenyl - N - theophyllinyl - (7) - acetic acid or their salts or quaternary ammonium compounds excellent pharmacological Properties which the first-mentioned basic esters of theophyllinyl- (8) -acetic acid have not or only to a small extent.

The preparation of the new compounds of general formula II is carried out according to methods known per se by converting oc-phenyl-o; -theophyllinyl- (7) -acetic acid or one of its derivatives, modified in the carboxyl group and capable of ester formation with the reactant, into the reaction suitable combinations with a compound of the general formula: Here R1 and R2, which can be identical or different from one another, denote hydrogen atoms or low molecular weight alkyl groups, Am denotes the radical of a secondary aliphatic or cyclic amine and X denotes a hydroxyl group or a halogen atom.

The most common method is the reaction of a salt of oc-phenyl-oc-theophyllinyl- (7) -acetic acid with a p-aminoethyl halide of the above general formula I according to the following general scheme, where R1, R2 and Am have the meaning given above and Hal a halogen atom is: Compared to the known compounds, the compounds prepared according to the method are distinguished by an increased effect on the coronary flow.

So has z. B. «-Phenyl-x-theophyllinyl- (7) -acetic acid- (ß'-dimethylamino) ethyl ester bitartrate on the Langendorff heart an ED50 value of 0.05 mg, while the toxicity determination this compound has a DL50 value of 850 mg per kilogram of mouse when administered subcutaneously results. In contrast, shows the example in German patent specification 862 301 1, theophyllinyl (8) acetic acid (P-dimethylamino-ethyl ester) described on the Langendorff heart in the same experimental setup up to a dosage of 2 mg no coronary dilatation whatsoever Effect. On the contrary, it became one even at doses of 0.1 mg and up slight, but clearly recognizable, coronary vessel constriction noted.

Example 1 33.6 g of the sodium salt of α-phenyl-Lx-theophyllinyl (7) -acetic acid were heated to 150 "C (oil bath) in 75 ml of dimethylformamide, for this purpose a solution of 10.8 g of ß-dimethylaminoethyl chloride in 50 ml of anhydrous benzene and 20 minutes refluxed. After the reaction mixture had cooled, the precipitated product was sucked off Saline off, removed the solvents in vacuo on the steam bath and took the Residue with 35 ml of boiling ethyl acetate.

It was filtered quickly and 100 ml of petroleum ether were gradually added when it was warm (high boiling) to. When cooling and rubbing on the glass wall, the ' x-Phenyl - theophyllinyl (7) acetic acid (fl'-dimethylamino) ethyl ester from. He melted blurred at 80 to 90 "C. The acidic salt of D-tartaric acid melted at 151 to 153" C. Yield: 75 to 80% of theory.

Example 2 According to Example 1, 13.6 g of β-diethylaminoethyl chloride were obtained instead of the corresponding dimethyl derivative a - phenyl - x - theophyllinyl - (7) - ethyl acetate (ß'-dimethylamino). Recrystallized from ethyl acetate petroleum ether, melted the compound at 101-102so. Yield 70 to 75% of theory.

Example 3 According to Example 1, 15.0 g of β-morpholinoethyl chloride were obtained instead of ß-dimethylaminoethyl chloride x - phenyl - a - theophyllinyl - (7) - acetic acid - (ß'-morpholino) -ethyl ester, which, from ethyl acetate-petroleum ether, recrystallizes, melted at 98 to 101 "C.

The hydrochloride could be recrystallized from isopropanol and melted at 132 to 135 "C. Yield: about 70% of theory.

Example 4 According to Example 1, 15.1 g of fl-piperidinoethyl chloride were obtained as a basic component oc-phenylx-theophyllinyl- (7) -acetic acid - (ß '- piperidino) - ethyl ester, which, recrystallized from ethyl acetate-petroleum ether, at 110 to 113 "C. melted. Yield: about 75% of theory.

Example 5 According to Example 1, 13.4 g of β-pyrrolidinoethyl chloride were obtained as a basic component z-phenylo [theophyllinyl- (7) -acetic acid- (ß'-pyrrolidino) ethyl ester, which was recrystallized from ethyl acetate and melted at 102 to 104 "C. Yield: about 60 per cent of theory.

Claims (3)

PATENT CLAIMS: 1. A process for the preparation of basic theophyllinyl-acetic acid esters, characterized in that o; -phenyl-o; -theophyllinyl- (7) -acetic acid or one of its derivatives modified in the carboxyl group and capable of ester formation with the reactant with a compound the general formula: in combinations suitable for the reaction in a known manner, where R, and R2 can be the same or different and hydrogen atoms or low molecular weight alkyl groups, Am is the radical of a secondary aliphatic or cyclic amine and X is a hydroxyl group or a halogen atom and the resulting basic ester of the general formula in which R 1, R 2 and Am have the above meanings, optionally converted into their salts or quaternary ammonium compounds. 2. The method according to claim 1, characterized in that X is the general Formula I denotes a halogen atom and that the reactant is a salt of a-Phenyl-a-theophyllinyl- (7) -acetic acid is used. 3. The method according to claim 2, characterized in that the reaction is carried out in dimethylformamide. Publications considered: German Patent No. 862 301; "Chemical abstracts", Vol. 47 (1953), Col. 5360f.