DE1179556B - PROCESS FOR THE PREPARATION OF FREE OR ACYLATED N- (4-DIETYLAMINOBUTYL) -SALICYCLIC ACID - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German KL: 12 q-1/01

Number 1 179 556

File number: S 83 125 IV b / 12 q

Filing date: December 31, 1962

Opening day: October 15, 1964

The invention relates to a method for the production of free or acylated N- (4-Diäthylaminobutyl) -salicylsäureamid which is characterized Dekennzeichnet that Salicylsäurechlorid Salicylsäurechlorid or acylated with 4-Diäthylaminobutylamin in an anhydrous solvent with stirring at 0 to 5 ⁰ C in about equimolar amounts is implemented.

The analgesic effect of N- (diethylaminoethyl) salicylic acid amide and N- (diethylaminopropyl) salicylic acid amide is known.

Now the compounds of this series and those whose phenol group is acylated became systematic after it has been possible to investigate also higher members of this series, i. H. with increasing number of methylene groups and their acyl derivatives, as already indicated. This investigation was based on the therapeutic index and toxicity of the compounds studied. The therapeutic one Index expresses the relationship between the lethal dose and the effective dose and is therefore, the higher it is, the cheaper it is. The toxicity was determined by the method of Miller and Tainter determined on homogeneous groups of mice.

The systematic investigation has led to a double surprising finding: The two the aforementioned compounds are homologous derivatives that have one more methylene group in their side chain, have a much better therapeutic index, while the compounds with even more Methylene groups show a decreasing index. N- (4-diethylaminobutyl) salicylic acid amide therefore possesses maximum therapeutic effectiveness.

The second surprising finding is that the acylation of the phenol group is in the o-position to the side chain leads to an increase in the therapeutic index and a decrease in toxicity, these phenomena were very pronounced in the acetylated derivative. The therapeutic effectiveness des N- (4-diethylaminobutyl) acetylsalicylic acid amide is three to four times larger, with its toxicity is more than twice less than that of the known compounds mentioned.

Finally, it has been found that for practical reasons it is advantageous to use the new basic compounds to be administered as citrate. These salts are white and crystalline, therefore easier to isolate, to clean and handle.

The table below shows the values for the therapeutic index and the lethal dose for the various connections listed.

Process for the preparation of free or acylated N- (4-diethylaminobutyl) salicylic acid amide

Applicant:

S. A. Laboratoires Biosedra, Malakoff, Seine (France)

Representative:

Dr. W. Beil, A. Hoeppner and Dr. H. J. Wolff, lawyers,

Frankfurt / M.-Höchst, Antoniterstr.

Named as inventor: 'France) - 2 link Thera
more peutic DL ₆₀ Kurt Binovic, Boulogne, Seine index (mg / kg) Claimed priority: France October 2, 1962 N- (ct) -Diethylaminoethyl) - (7532 Bas-Rhin) salicylic acid amide 15th 748 N- (co-diethylamonipropyl) - salicylic acid amide 16 487 N - ((w-diethylaminobutyl) - salicylic acid amide 18th 609 N- (cü-diethylaminopentyl) - salicylic acid amide 4th 289 N- (a) -Diethylaminoethyl) - acetylsalicylic acid amide 9 590 N- (co-diethylaminopropyl) - acetylsalicylic acid amide 11 726 N- (a) -Diethylaminobutyl) - acetylsalicylic acid amide 48 1464 N- (co-diethylaminopentyl) - acetylsalicylic acid amide 15th 976 409 707/340

From this table it is clear that the butyl derivatives, regardless of whether the phenol group is acylated or not, and more clearly in the case where the phenol group acetylated have maximum therapeutic efficacy and minimal toxicity. This latter finding is all the more surprising since the acetylation of the phenol group in the ethyl and propyl derivatives have the opposite effect, d. H. a decrease in effectiveness and an increase corresponds to the toxicity compared to the corresponding non-acetylated compound.

The drop in effectiveness from the butyl derivatives to the pentyl derivatives is also surprising, if you consider that the favorable increase in these properties regularly from a homolole to the next in the same row until the butyl derivative increases.

It is therefore a special one of the series of compounds, some of which have already been established Compound has been found whose properties and those of its acyl derivatives are clearly positive from differ from those of the other members of this series.

In practice, the compounds of the invention can be used as analgesics in human therapy in doses of the order of 0.25 g (calculated as citrates) as tablets, suppositories or injectables Administer solutions.

The invention is illustrated in more detail by the following examples.

30 Example 1

Manufacture of the citrate of
N- (4-Diethylaminobutyl) salicylic acid amide

^{144 g (1 mol) of 4-diethylaminobutylamine dissolved in 200 cm 3 of} anhydrous benzene are slowly added to a solution of 172.1 g (1.1 mol) of salicylic acid chloride dissolved in 1 liter of anhydrous benzene, the mixture being stirred and maintains the temperature at 0 to 5 ° C. When the addition is complete, stirring is continued for 1 hour at the same temperature and then for 1 hour at the boiling point of benzene. The solvent is then decanted from the viscous reaction product and washed twice with 250 cm ^{3 of} anhydrous benzene, which is decanted each time. The remaining product is treated with 1.5 l of a 20% strength sodium carbonate solution and stirred until the product becomes oily (about 2 hours). It is then extracted three times with 500 cm ^{3 of} ether. The combined ether extracts are dried over sodium sulfate. It is then filtered, the sodium sulfate is washed with 350 cm ^{3 of} ether and the ether is distilled off. The last traces of ether are removed under vacuum.

The residue is weighed and the necessary amount of citric acid C ₆ H ₈ O ₇ · H ₂ O is calculated. For 264 g (1 mol) of the residue consisting of the N- (4-diethylaminobutyl) salicylic acid amide, 220 g (1, 05MoI) citric acid with 1 mol of crystal water required. The residue is dissolved in about 700 cm ^{3 of} absolute alcohol. The citric acid is dissolved in about 600 cm ^{3 of} absolute alcohol. The two solutions are mixed and then all alcohol is removed under reduced pressure. The residue is then recrystallized with 1.21 isopropyl alcohol. The crystallization is allowed to proceed at 0 to 5 ° C. within 72 hours. It is then filtered rapidly through a Buchner funnel and a white, pasty product is obtained which is more or less crystallized and which is dried at about 35 ° C. under reduced pressure. The yield is 60 to 70 ° / _0th

Analysis: C ₁₅ H ₂₄ N ₂ O ₂ -C ₆ H ₈ O ₇

Calculated ... C 55.04, H 7.02, N 6.14, O 31.58 ° /); Found ... C 55.12, H 7.09, N 6.16, O 31.70 ° / ₀ .

Example 2

Preparation of the citrate of N- (4-diethylaminobutyl) acetylsalicylic acid amide

^{144 g (1 mol) of 4-diethylaminobutylamine, which are dissolved in 150 cm 3 of} anhydrous ether, are slowly added to a solution of 218.4 g (1.1 MoJ) of acetylsalicylic acid chloride in about 1 1 of anhydrous ether, the mixture being stirred and keeps the temperature between 0 and 5 ° C. After the addition is complete, stirring is continued for 1 hour at the same temperature and for 1 hour at the boiling point of the ether. The ether is then decanted and the remaining viscous reaction product is ^{washed twice with 250 cm 3 of} anhydrous ether, which is decanted off each time. The product obtained is washed with a mixture of 1.41 of a 20% strength sodium carbonate solution and 55 cm ^{3 of} a 10% strength sodium hydroxide solution. Stirring is continued until the product becomes oily (about 2 hours). Then it is extracted three times with 500 cm ^{3 of} ether. The ether extracts are combined and dried over sodium sulfate. It is then filtered, the sodium sulfate is washed with 350 cm 'of anhydrous ether and the ether is distilled. The last traces of ether are distilled off under reduced pressure. The residue is weighed and the necessary amount of citric acid C ₆ H ₈ O _{7 .H 2} O is calculated. For 306 g (1 mol) of the residue consisting of N- (4-diethylaminobutyl) acetylsalicylic acid amide, 220 g (1.05 Mole) citric acid with 1 mole water of crystallization required. The residue is dissolved in about 750 cm ^{3 of} absolute alcohol. The citric acid is dissolved in about 600 cm ^{3 of} absolute alcohol. The two solutions are mixed and distilled under reduced pressure until the alcohol is completely removed. The residue is then recrystallized with 1.21 isopropyl alcohol. The crystallization is allowed to proceed ^{at 0 to 5 ° C. for about 72 hours.} It is then quickly filtered through a Buchner funnel, and receives a white, paste-like, more or less crystallized product, which is dried under reduced pressure at about 35 ⁰ C. The yield is 60 to 70 ° / _0th

Analysis: C ₁₇ H ₂₆ N ₂ O ₃ • C ₆ H ₈ O ₇
Calculated ... C 55.42, H 6.82, N 5.62, O 32.13%; Found ... C 55.35, H 6.85, N 5.58, O 32.02%.

Claims (3)

Patent claims: 1. Process for the preparation of free and acylated N- (4-diethylaminobutyl) salicylic acid amide, characterized in that approximately equimolar amounts of salicylic acid chloride or acylated salicylic acid chloride and 4-diethylaminobutylamine in an anhydrous Solvent with stirring at a temperature 5 6 between 0 and 5 ⁰ C and the reaction is characterized by the fact that the reaction product product isolated by methods known per se. isolated in the form of citrate. 2. The method according to claim 1, characterized shows that the starting compound is acety- Considered publications: lated salicylic acid chloride is used. 5 German Auslegeschrift No. 1 098 001; 3. The method of claim 1 or 2 characterized in U.S. Patent No. 2,810,718. 409 707/340 10.64 ® Bundesdruckerei Berlin