DE1225658B - Process for the preparation of coumarin derivatives - Google Patents

Description

Process for the production of coumarin derivatives The invention relates to a process for the production of coumarin derivatives of the general formula in which R1 is an alkyl, phenyl or phenylalkyl radical.

R2 and Ro are hydrogen or halogen and R4 is lower Mean dialkylaminoalkylene group having 2 to 4 carbon atoms in the alkylene group.

It has been found that these compounds are analgesic, anti-inflammatory and have antipyretic activity. They are suitable e.g. B. for pain relief and for the treatment of rheumatic patients, either per os or parenterally can be administered.

In comparative experiments, the analgesic effectiveness of the invention produced 3-phenyl -4- (p-dimethylamino-ethylamino) -coumarins (compound I) compared to the known 1-phenyl-2,3-dimethyl-4-dimethylamino-5-pyrazolone (compound II) according to the method of G r o s s (Helvetica Physiologica Acta, 5. C 31 [1947]) certainly.

Here, the tails of white mice were irritated by thermal radiation using the Friebel and Reichle apparatus (Archive for Experimental Pathology and Pharmacology, 229, p. 400 [1956]). and the reaction time defined according to G ross for this irritation was determined in different groups of ten to twenty mice (body weight 18 to 25 g) 30 and 15 minutes before the administration of the substances to be tested. An aqueous solution of the hydrochloride of one of these substances was then administered intraperitoneally in various individual doses to all animal groups. 30, 45, 60, 90 and 120 minutes after the administration of the substances in question, the mean reaction time of each group of animals was determined and then the difference between the mean reaction time after 30, 45 and 60 minutes and the mean reaction time before the administration of the compounds to be tested determined and given as a percentage of the mean response time. The following results were obtained: Compound Dose mg / kg Olo Response Time- Mouse ip extension 25 42 1 50 86 75 toxic 100 29 II 150 79 200 35 The values found were evaluated in such a way that the doses with the same effect were determined by linear interpolation on the basis of the results with 25 and 50 mg / kg of compound I and with 100 and 150 mg / kg of compound II. where the effect level is 600/0 of the reaction time; extension. as the mean of the results taken into account. The interpolated doses for 60 ovo extension of the reaction time are then 35 mg / kg for compound I and 131 mg / kg for compound II. The acute toxicity in the iv mouse is 51 mg / kg for compound 1 and 205 mg / kg for compound II; the DL50 ratio of I to II is thus 1: 4.0.

The results obtained show that the 3-phenyl-4- (B-dimethylamino- äthylamino) - coumarin compared to the 1-phenyl-2, 3-dimethyl-4-dimethylamino-5-pyrazolone in animal experiments the same analgesic effects were already three to four times lower Has dosage. This finding is in spite of the higher toxicity of the Process product approximately the same therapeutic index for the two substances, especially for parenteral application, to be assessed as progress. There, moreover the products of the process are stronger bases than l-phenyl-2,3-dimethyl-4-dimethylamino-5-azolone therefore neutral to weakly acidic salt solutions can be produced without further ado, as they are most suitable for intravenous injection.

The coumarin derivatives of the general formula given above are prepared according to the invention by a) compounds of the general formula being prepared in a manner known per se with an amine of the general formula R4-NH2 in which Hal represents a chlorine or bromine atom and R1, R2, R3 and R4 have the meaning given above, in the presence of an acid-binding agent, or b) compounds of the general formula with reactive esters of compounds of the formula R4-OH in which R1, R2, R3 and Rq have the meaning given above, and the bases obtained according to a) or b) are converted into their salts, if appropriate with inorganic or organic acids.

In method a) temperatures of 10 to 250 "C are used, and it can, in the presence or absence of organic solvents or diluents as well as catalysts such as copper powder, sodium or potassium iodide, worked will. To bind the released hydrogen halide, it is expedient an excess of the amine to be reacted is used.

Suitable acids for salt formation are, for. B.

Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, Athandisulfonic acid, acetic acid, lactic acid, succinic acid, maleic acid, fumaric acid, Malic acid, tartaric acid, citric acid, benzoic acid, phthalic acid, and salicylic acid Mandelic acid.

The following examples illustrate the processes according to the invention. Parts mean weight parts, these relate to parts by volume like grams to cubic centimeters. The temperatures are given in degrees Celsius.

Example 1 10 parts of 3-phenyl-4-chloro-coumarin are used together with 15 parts of dimethylaminoethylamine and 300 parts of anhydrous ethanol in the autoclave Heated to 1200 for 15 hours. The reaction mixture is then cooled, in vacuo freed from the solvent, the residue with 200 parts of a chloroform-ether mixture (1: 3) extracted and the extract filtered. The filtrate is washed with water and then extracted with 50 parts of dilute hydrochloric acid. The hydrochloric acid extract is now made alkaline in the cold with dilute sodium hydroxide solution. That which is separated out in the process Dl is dissolved in 100 parts of chloroform, the chloroform solution with sodium sulfate dried and evaporated, the 3 - phenyl - 4- [fl - dimethylamino - äthylamino] coumarin when Dl stays behind. The compound crystallizes from methanol-ether (1: 1) as colorless Crystals from F. 131 ". The yield is 630/0 of theory.

To produce the hydrochloride, 3-phenyl -4- [ß-dimethylamino - äthylamino) - coumarin dissolved in anhydrous benzene and put into the solution with cooling introduced dry hydrogen chloride.

The precipitated hydrochloride is made from methanol-ether (1: 1) crystallized, the hydrochloride being in the form of yellowish crystals with a melting point of 201 ° which are easily soluble in water.

Following the method described above, make the following compounds obtained: 3-phenyl-4- [γ-dimethylamino-propylamino] -coumarin, F. 138 ", yield: 72 per cent of theory; 3-phenyl-4- [ß-dimethylamino-ethylamino] -6-chloro-coumarin, F. 193 °, yield: 700 / o of theory; 3-Benzyl-4- [iß-dimethylamino-ethylamino] -7-chloro-coumarin, M.p. 109 °, yield: 510/0 of theory 3-butyl-4- [ß-dimethylamino-ethylamino] -coumarin Bp 163 °, yield: 770/0 of theory; 3-butyl-4- [γ-dimethylamino-propylamino] -coumarin, Kp.o, ol 167 °, yield: 800/0 of theory.

Example 2 To a suspension of 7 parts of 3-phenyl-4-amino-coumarin in 300 parts of dimethylformamide are added with thorough stirring at room temperature 1.5 parts of a sodium hydride mineral oil suspension (1: 1). The mixture is heated 4 hours to 80 °, this then cools to room temperature and sets 3.2 parts freshly distilled dimethylaminoethyl chloride released from the hydrochloride was added. Then the reaction mixture is 1 hour at room temperature and 2 Stirred for hours at 80 ", then cooled and then poured onto ice. The precipitated crystalline product is filtered off and on neutral aluminum oxide by means of a Chloroform-ether mixture (1: 2) chromatographed. The eluted fractions 1 and 2 are evaporated and extracted with dilute hydrochloric acid.

Then the acidic solution is mixed with dilute sodium hydroxide solution alkaline placed, the precipitated oil dissolved in chloroform, the chloroform solution dried with sodium sulfate and evaporated to dryness. The residue obtained is recrystallized from methanol-ether (1: 2), the 3-phenyl-4- [ß-dimethylamino-ethylamino] -coumarin from F. 130 to 131e is obtained. The yield is 28% of theory.

Claims (1)

Claim: Process for the preparation of coumarin derivatives of the general formula in which R1 denotes an alkyl, phenyl or phenylalkyl radical, R2 and R3 denotes a hydrogen or halogen atom and R4 denotes a lower dialkylaminoalkylene group having 2 to 4 carbon atoms in the alkylene group, and salts thereof, characterized in that a ) Compounds of the general formula with an amine of the general formula R4-NH2 in which Hal denotes a chlorine or bromine atom and R1, R2, R3 and R4 have the meaning given above, in the presence of an acid-binding agent, or b) compounds of the general formula with reactive esters of compounds of the general formula R4-OH in which R1, R2, R3 and R4 have the meaning given above, and the 3ases obtained according to a) or b) are converted into their salts, if appropriate with inorganic or organic acids. ~~~~~~~ Publications taken into consideration: German Patent No. 936 571; H ó uben - W ey 1, Methods of Organic Chemistry, IV. Edition (1957) Vol. XI / 1, pp. 24 to 33, pp. 63 to 73, pp. 108 to 110 and 160; W agner - Zook, Synthetic Organic Chemistry, 1953, p. 666, item 436, to p. 668.