DE1284427B - Process for the preparation of the N-dimethylaminoaethanol salt of 3- (ª ‡ -acetonylbenzyl) -4-oxycoumarin - Google Patents

Claims (1)

1 2 The invention relates to a method of production. Furthermore, the cumulative effect occurs only at the end of the N-dimethylaminoethanol salt of 3- (a-acetonyl- the treatment on, and the prothrombin level benzyl) -4-oxycoumarin. then stabilizes, and when the treatment It is known that various coumarin derivatives do not experience an abrupt increase in prothrombin, for example the SjS'-methyl-bis- ^ hydroxy-dicuma- 5 reflects on dangerous values ("rebound" phenomenon) rin, 3-ethylbenzyl-4-hydroxycoumarin and that instead, as is the case with other anticoagulants. S-a-Acetonylbenzyl- ^ hydroxycoumarin a hypokoa- The N-dimethylaminoethanol salt of 3 - («- Aceto- have a regulating effect. One of the anticoagu- nylbenzyl) -4-oxycoumarins is because of its pharmaceutical lating derivatives of coumarin, the most frequently used for the treatment of interesting codynamic activity is is the sodium salt of 3-a-Acetonyl- io lung and used to prevent thromboembolic benzyl-4-oxycoumarins. This connection has affections, especially in the therapy of myocardial excellent anticoagulant properties, it is infarcts and phlebetic and cerebral embolisms. but also desirable in human therapy. The N-dimethylaminoethanol salt of 3 - («- aceto- pie via a hypocoagulating agent of faster nylbenzyl) -4-oxycoumarin is made by that and have a more stable effect. 15 one 3- (a-acetonylbenzyl) -4-oxycoumarin in itself Furthermore, salts of dicumarol with amines are known in the presence of a polar solution Alkanolamine bases known. by means of reacting with dimethylaminoethanol. It has now been found that the N-dimethylamino is expediently used for the preparation as Ethanol salt of 3- (a-acetonylbenzyl) -4-oxycoumarins starting material a pure 3- (a-acetonylbenzyl) -bei low toxicity a fast and stable ao 4-oxycoumarin used in a known manner Has an effect as a hypocoagulant and compared to the commercially available corresponding sodium salt is superior to known coumarin compounds. Animal or commercially available acid by cleaning Experiments in vivo have shown that, for example, it can hold. Guinea pigs the absolutely lethal dose (DL ₁₀₀ ) _. . , 677 mg / kg and the lethal half dose (DL ₈₀ ) 3.5 mg / kg a ₅ example while the absolutely lethal dose of sodium is 30.8 g of pure 3- (a-acetonylbenzyl) -4-oxycoumarin, salt of S-ix-acetonylbenzyM-oxycoumarins 543mg / kg which have been obtained by 33 g is (method K η äff ell-Lent s). Therefore, the commercially available sodium salt of 3 - («- Acetonylben- the new compound has a significantly lower absolute cyl) -4-oxycoumarin in 330 ecm of distilled water Toxicity than the corresponding sodium salt. 30 dissolves the solution after adding 15 g of activated charcoal In comparative experiments, the anticoagulant was filtered off if the filtrate obtained is not colorless, The effect of the N-dimethylaminoethanol salt of the treatment with activated charcoal is repeated for as long as 3- (a-Acetonylbenzyl) -4-oxycoumarin (example) against until a completely colorless solution is obtained, over known substances, namely these then with three times the volume of distilled (1) the dimethylaminoethanol salt of 3,3'-Ws-Me- ^{3 system} water dilutes the colorless solution then mixed with ethylene-4-hydroxycoumarins (F. - 135 to 136 ⁰ C) ^a ™ excess of _i hydrochloric acid shakes the _u j precipitate formed is filtered off and this so long . " _X ,, -.....,. ,. _., t ι ,., -, / 1_- », washes with distilled water until the wash water (2) the diethylaminoethanol salt of 3 3 -bis-Me- _{emm pH} . _{Has reached a value of 6 and is free of} chlorine ethylene-4-hydroxycumanns (F. = 175 C), _{40 Ιοηβη} ^ ^ d _{then the} resulting precipitate checked. 105 ⁰ C dries to constant weight, are in Each test series was dissolved with five rats by 2OO ecm of methanol, then 8.9 g of pure N-di- guided. Here, the substances to be tested methylaminoethanol were added, and then it is gastric route to the animals in a dose of the mixture in the water bath until complete 100 y / kg administered and the following values that _{heated the 45} solution. Then the solution is cooled, The mean value of the coagulation times found is then filtered and in vacuo at a temperature of 20 set, found: ^{concentrated up to 40 0} C to constant weight. as The middle residue is obtained from the N-dimethylaminoethanol , "". Coagulation _{of the} ^ ₃ _ _(a _ y _{lbeMyl acetone)} 4_ _{oxycumarins m form} Nonmle rats 12 minutes _emer ^ ^ _{086n liquidj the very} ^ _in ? Ä ^{g (Beis} Pif?! ^ ^{Nu en} Wasse? And in methyl and ethyl alcohol, but not 1 ™ ^y ϊ ^{ε VOn} S \ l iii ^{nu en} is soluble in ether and gasoline. The salt possesses im 100y / kgvon (2) 12Minuten uy, spotting _t rum a minimum at 258 to 260μ and It was thus shown that the known clubs have a maximum at 308 μ. Eio / _O === 357 (at 308 μ in binds not the slightest anticoagulant We- 55 0,0 In-NaOH). The yield is about 20% kung, while the N-dimethylaminoethanol theory,
salt of 3 - («- Acetonylbenzyl) -4-oxycoumarin at a Dose of 2.5 y / kg an increase in the coagulation time from 12 to 22 minutes. Process for the preparation of the N-dimethyl In addition, clinical trials have shown that 60 aminoethanol salts of 3 - (<x-AcetonylbenDzyl) - that the N-dimethylaminoethanol salt of 3- (a-aceto-4-oxycoumarin, characterized nylbenzyl) -4-oxycoumarin a faster and more intensive that you can use 3- (a-acetonylbenzyl) -4-oxycoumarin in sivere hypocoagulant effect with equivalent known manner in the presence of a polar one Can has known hypocoagulants, e.g. the solvent with dimethylaminoethanol Sodium salt of S-α-acetonylbenzyl - ^ - oxycoumarins. 6g sets.