SE431455B - SET TO MAKE AMINOIMIDAZOISOKINOLIN DERIVATIVES - Google Patents

Description

10 15 20 25 30 35 40 aooozsz-8 2 in which A and D have the meanings given above, are heated in a solvent or in a melt at a temperature above 10000, whereupon the obtained compound with formula II is optionally converted to an acid addition salt thereof or the base with the general formula I is optionally liberated from a salt thereof.

The solvent used is xylene or 1,2,3,4-tetrahydronaphthalene.

The reaction takes place at a temperature above 10000. I VêttGH1ÖSHlH9 HV fl lk fl llm9tö11 ~ hydroxide, the reaction is effected by boiling. The associations with the general Formula II can be prepared by the Bischler-Napieralsky reaction by cyclize the corresponding N- (2-phenylethyl) -1,2,4-oxadiazolone-5,3yl acetamide vaten.

In comparative experiments, in which the compound of the invention HE-36: 3-Ben- zylamino-5,6-dihydro-8,9-dimethoxy-imidazo [5,1-a] isoquinoline hydrochloride (compare Example 4c), is compared in particular with respect to antiarrhythmic action on the heart with the compound well known for this purpose for its good effect, Chinidine, was obtained following results: LD5Ui.v. in rats Antiarrhythmic effect Atrium Chamber relatively therapeutic relatively therapeutic activity index activity index HE-36 17 mg / kg 8.66 90.00 '2.80 32.9 Quinidine 46 mg / kg 1.00 17.7 1.00 20.0 Antiarrhythmic activity was determined on the basis of the effect exerted on the the electrical-fibrillar threshold of the maxillary and ventricular muscle. The surveys are were found in cats with a body weight of 2.2 - 3.5 kg and which were anesthetized with chloralose urethane at a dose of 50/300 mg / kg i.v. The electrically fibrillar threshold (the lowest current intensity required for atrial and ventricular fibrillation flutter) was performed according to the methods described in the literature: Szekeres, Mëhes and Papp: Brit. J. Pharmacol. 17. 167, 1961: and Szekeres and Papp: Experimental car- diac arrhythmias and antiarrhythmic drugs. Akadëmiai Kiadö, Budapest, 1971.

The chest was opened on the experimental animals and applied during the examinations continuous artificial respiration. They through the small opening made in the pericardium performed stimulating electrodes are attached to the right atrium at the auricular residual respectively was attached to the anterior surface of the ventricle. Right-angled stroke by electric current with a duration of 1 msec and with a frequency of 20 Hz for a period of 4 sec. The intensity of the impulses increased until fibrillo flutter appeared and this was determined by ECG partly after the sudden the drop in blood pressure and by immediate observation of the heart.

Under such conditions, the assumption of the electro-fibrillar threshold shows C71 10 20 25 30 35 40 8000253-8 3 the antifibrillary activity and the antiarrhythmic activity.

The compounds I and salts thereof can be used in pharmacy in the form of preparations rat containing the active constituent in admixture with non-toxic, inert. pharmaceutically usable organic or inorganic carriers. The preparations are prepared in solid form (e.g. tablets, fibrous tablets, dragéer, enterosoivent- dragëer, piiier, kapsiar) e11er in liquid form, for example in the form of suspensions, solutions e11er emuitions. As a carrier, you can use, for example, taik. starch, geiatin, water, poiyaikyiengiykoi etc. The preparations may iikaiedes contain other auxiliaries, such as wetting agents, emuctors, dispersants, such as buffers. substances that alter the osmotic pressure and facilitate the uptake of the preparation solution and / or other pharmaceutically active substances.

Bâfl fl ßllf 0.5 g of 3- [6,7-dimethoxy-3,4-dihydro-1-isoquinyl] -methyl-4-ethyl-α diazoion-5-one is forged on an oil bath at a temperature of 15,000 and the melt is healed then for another 5 minutes at said temperature. Then the reaction mixture The kaiinate was added 20 ml of water. There was thus obtained 0.45 g of 3-ethylamino-5,6- dihydro-8,9-dimethoxy-imidazo [§, 1 ~ §7isoquinoline monohydrate with a melting point of 128-130 ° C (after recrystallization from 50 3 g of ethanol).

Anaiysz C15H19N302.H20 theoretically found 61.83% 62.11% 7.26 2 7.23% 14.39 2 14.56% * íï.> i <fl Pf fl_ š = 2 g of 3- [6,7-dimethoxy-3,4-dihydro-1-isoquinyl] -methyl-4-benzyl- [2,2-1,2,4-oxa- diazoiin-5-one is forged on a metai bath. After cooling, the product was recrystallized. 1,2 g of 3-benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo. [,, 11§7-isoquinoline with a melting point of 135 ° C.

Analysis: C 21 H 21 N 3 O 2 theoretically found 71.62% 71.52% 6.31% 5.98% 12.53 to 12.42% In the NMR spectrum of the product, the proton appeared in the position 1 - 6.85 ppm.

Example 3: _ 10 ml of Xylene were added to 1.5 g of 3- [6,7-dimethoxy-3,4-dihydro-1-isoquinyl] -methyl- 4-Benzyl-ZX 2-1,2,4-oxadiazolin-5-one and the mixture were boiled under reflux in two hours. On cooling, 1.1 g of 3-benzylamino-5,6-dihydr-8,9-dimethoxy-imi- dazo [§Å11§] -isokinoiin in crystallized form. The product turned out to be identical with the only example 2.

Claims (2)

10 15 20 8030253-8 'i A process for the preparation of novel aminoimidazoisoquinoline derivatives of the general formula i -v / wíï, 'LA / k D represents a 1-4 carbon atoms containing alkyl group or one in the alkyl moiety 1-4 carbon atoms containing phenyl-alkyl group, characterized in that compounds of the general formula k // ï / 1 11 'l' n M fl vsfr fl: Fb _ c _ 1: - I) i. J, l '. \ o, .b §_O where A and D have the meanings given above, heated at a temperature above 100 ° C in a solvent or in a melt, whereupon the so obtained compound I is optionally converted to acid addition salts or the bases of general formula I are liberated from their salts. IN 2. A method according to claim 1, characterized in that the agent uses xylene or 1,2,3,4-tetrahydronaphthalene. BACKGROUND OF THE INVENTION This invention relates to a process for the preparation of novel aminoimidazoisoquinoin derivatives having the same form of fc. N and acid addition sites thereof, in which form A represents a 1-4 carbon atoms containing alkoxy group and D represents a 1-4 carbon atoms containing alkyl group or a 1-4 carbon atoms containing phenylalkyl group. In this process, a compound of the general form A \\ .// \ /, \\ 1 1 II AIX: v l / ÄJH HC _ c _ 1: ~ I »f; (in which A and D have the meanings given above, at a temperature above 100 ° C in a solvent medium or in a melt, then the compound thus obtained of the above-defined formula I may be converted to an acid addition salt or a base of the general form I is liberated from any of its sites.