DE1618877A1 - Novel 3,4,5-trimethoxyphenoxyacetic acid amides and process for making the same - Google Patents

Description

Patent attorney

Dipl. Phys. Df.Waiiher Duruus September 23, 196g

Hanover, Abbestr. 20 -iw τ / ττ

Dr * u / na

File number: P 16 18 877.5
Applicant: Spofa ...
My reference: 1284

Heue 3,4 »5-imethoxyphenoxyessig8äureamide and method to manufacture the same

The present invention relates to new 3 »4,5- £ rimethoxy · phenoxyacetic acid amides of the general formula I

OH ₃ O
OH ₃ O
OH ₃ O- -

wherein R is a hydrogen atom or an alkyl radical with

2 ^: 1-4 carbon atoms, R a hydrogen atom, an amino group, an alkyl radical with 1-4 carbon atoms, an aminoalkyl, a diaminoalkyl or an aralkyl radical, or in which the entire KR H grouping is the radical of a secondary, saturated, heterocyclic Forms amine with 2-5 carbon atoms, as well as a process for the preparation thereof.

- 2 - ■ 109820/2143 Copy

BATH ORIGINAL

Documents (Art. 7 SI Aba. 2 No.! Sentence 3 of the amendments. Of 4 September 1966

- 2 - ■. ■ ■ '

The compounds of general formula I are distinguished by pharmacodynamic activity. Some of them possess a moderate antihypertensive and diuretic effectiveness, others a pronounced antiarrhythmic and vasodilatory effect the coronary vessels. A typical inventive Compound is the 3 »4-» 5-! Crimethoxyphenoxyacetic acid e-2-diethylaminoäthylamid, which in the form of the hydrochloride when testing on guinea pig heart an approximately twice stronger coronary vasodilator Has effectiveness as an aminophylline. Furthermore, when tested on isolated rats, it shows excellent results antiarrhythmic (antifibrillatory) activity, about the same level as procainamide. Xm Compared with this known preparation, the advantage of the new substance lies in that already mentioned coronary vasodilator activity. The substance is only slightly toxic (the acute intravenous toxicity Mice LD 50 is 175 mg / kg), so he thanks to his favorable therapeutic index suitable for healing purposes is. It can, for example, be used in gardiology in the treatment of the ventricular t achy car die, the ventricular extrasystole and atrial arrhythmia. He can also become proficient in anesthesiology used by arrhythmias during anesthesia will.

According to the invention, see the compounds of the general Prepare formula I so that you get a 3,4,5- -! Erimethoxyphenoxyesslgsäureester the general Formula II

10882072143

ΊΒΤ8Β77

II

wherein E is an alkyl radical having 1-4 carbon atoms means with compounds of the general iOrmel III

B ¹ R ² HB; III

where R ¹ and R ^{2 are the} same as in Pörmel I, whereupon the products obtained are neutralized in the case of their basic character with physiologically acceptable acids. ν

The reaction can be carried out either in a suitable organic solvent, for example an alkanol with 1-4 carbon atoms, at normal temperature or at the boiling point of the reaction mixture or in the presence of an excess of the compound of the general formula III, at temperatures from 100 ° to 20 ° ⁰ carry out.

The through neutralization of basic compounds of the general formula I obtained with the above acids Salts are suitable for the production of medicinal preparations. '^

Example 1 e

1. To a solution of 2.5 g of 5 »4 * 5-Trimethoxyphenpxy-

109820721 -

IbI8877

methyl acetate in 20 ml of ethanol is added to 100 ml of a saturated ethanolic ammonia solution, the reaction mixture is left to stand for 2 hours at room temperature, ethanol is evaporated and the residue is recrystallized from ethanol. In a yield of 94 $ is obtained 3,4, 5-> Trimethoxyphenoxyacetamid with F. 124-125 ⁰ C.

The methyl ester used as the starting material is obtained from 3,4,5-trimethoxyphenoxyacetic acid as follows: 13 g of dimethyl sulfate, 30 ml of water and 14 g of anhydrous, finely ground potassium carbonate are added to a solution of 24 g of the acid mentioned in 250 ml of acetone and the mixture is boiled the reaction mixture under reflux with stirring for 4 hours. Acetone is then distilled off and the residue is partitioned by shaking between chloroform and 200 ml of a 5% sodium carbonate solution. The chloroform extract is dried with sodium sulfate and evaporated. The residue crystallizes on standing; it can also be purified by vacuum distillation. This gives 21.0 g of pure Methylesters with Kp _c 168 ⁰ C and I. 79-81 ⁰ C (methanol).

2. A mixture of 5.0 g of methyl 3,4,5-trimethoxyphenoxyacetate and 30 ml of morpholine are heated to boiling under reflux for two hours. The volatile components is evaporated under reduced pressure and, the The residue is partitioned by shaking between chloroform and a 5 # strength sodium carbonate solution. The chloroform solution it is washed with 3NHCl, water, saturated NaCl solution, dry them with potassium carbonate and evaporate them.

1 09820/2 1 A3

By crystallizing the residue from a benzene-ether mixture we get 3.0 g ^, ^

acetic acid morpholide with a melting point of 108-109 ° 0.

3. A mixture of 1.0 g of 3,4,5-Trimethoxyphenoxyessigsäuremethylester and 0.4 g of benzylamine heated "to just below reflux for up to 190 ⁰ C. Kach cooling crystallized to the resulting crude product from aqueous ethanol to. In a yield of 1.2 g are obtained 3,4,5-iurimethoxyphenoxyessigsäurebenzylamid with F. 98 99 ⁰ O (aqueous methanol).

4. To a solution of 1.5 g of 80% hydrazine hydrate in 5 ml of ethanol is added a solution of 4.2 g of methyl 3,4,5-! Erimethoxyphenoxyessigsäuremethylester in 12 ml of ethanol. The reaction mixture is refluxed for 2 hours and then cooled, and 3,4f5-2irimethoxyphenoxyacetic acid hydrazide crystallizes out. F. 142 ⁰ C (ethanol)

5. 82 g of 3,4,5-Srimethoxyphenoxyessigsäuremethyleter are added to a solution of 38 g of 2-diethylaminoethylamine in 200 al of ethanol and the reaction mixture is refluxed for 2 hours. After standing over half at room temperature, the volatile components are evaporated in vacuo, the residue is dissolved in a little ethanol and the 3,4,5-2! Rimethoxyphenoxye88igeäur2-diethylaminoethylamide is precipitated by adding the necessary amount of an ethereal anhydrous oil solution -Hydrofluoride off. A yield of 75 g is obtained as a crystalline product with a melting point of 157-158 ⁰ O (ethanol).

- 6 -109820 / 21 43

BAD ORIGINAL

Claims (1)

Claims t 1. New 3,4,5-afcimethoxyphenoxyessigsäureamide der general formula I. 0 (/ \ s OCH ₀ COMR ¹ E ' ^X 2 \ /
CH ₃ O wherein R is a hydrogen atom or an alkyl radical ο
with 1-4 carbon atoms, R a lass he substance atom, an amino group, an alkyl radical with I-4 carbon atoms, an aminoalkyl, a dialkylaminoalkyl or an aralkyl radical, or in which the whole WrR group is the radical of a secondary, saturated, forms heterocyclic amines with 2-5 carbon atoms. 2. Process for the preparation of new 3 _i 4,5-! EE'imethoxyphenoxyessigsäureamiden of the general formula I, characterized in that that one has a 3 »4} 5-trimethoxyphenoxyacetic acid ester of the general formula II OCH ₂ COOR II wherein R is an alkyl radical having 1-4 carbon atoms, with compounds of the general formula III 109820/2143 New documents (Art. 7 _S 1 Ahn. 2 _N - l So * · »■ <1- Amendment nqegee. V. 9.1967V. 4 Ϊ & Τ8877 - R ¹ R ² UH; IiI; wherein R ¹ and R ² mean the same as in Ibrmel Ϊ, whereupon the products obtained are neutralized with physiologically acceptable acids in the case of their basic character. ; 5. The method according to claim 2 _r
characterized, that the reaction in alkanols with 1-4 carbons * substance atoms, "at ordinary temperature or at the boiling point of the reaction mixture. 4 «method according to claim 2, characterized by ^ - That you can do the implementation in the presence of excess the compound of the general formula 11 »at temperatures from 100 ° to 200 °. - 5. 3,4,5-trimethoxyphenoxyacetamide. 6. 3> 4,5-TrimethoxyphenQxyessigsäuremorpholide » 7. 5 »4> 5-trimethoxyphenoxyacetic acid benzylamide · 8 · 3,4, S-trimethoxyphenpxyacetic acid-a-diethy.laminoethylamide-Hy drochloride ■ · ... 109 8 20/2143