DE1160431B - Process for the preparation of the pharmacologically active ª-phenyl-ª, ª-diallylacetic acid-p-hydroxyanilide - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

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German class: 12 ο-21

C 26411IVb / 12 ο
March 6, 1962
2nd January 1964

The invention relates to the production of α-phenyl-α, α-diallylacetic acid-p-hydroxyanilide the formula

CH ₂ - CH = CH ₂

-CO-NH- / ^

CH ₂ - CH = CH ₂

OH

the one particularly strong pain reliever (analgesic) and has antipyretic (antipyretic) effects.

It is known that p-aminophenol, substituted on the nitrogen by an acetyl group, has an analgesic effect and has antipyretic properties and therefore alone or in admixture with other active ingredients used therapeutically. About the same or even an increased pain reliever and the antipyretic effect of N-acetyl-p-aminophenols substituted in the acetyl group so far nothing has become known.

German Patent 1,064,528 states that the corresponding Phenyläthylacetylp-aminophenol is only choleretic (choleretic).

When Through research the influence of other substituents on the acetyl group at the pharmacological activity has been surprisingly found that the introduction of two allyl groups in addition to the phenyl group in the acetyl one not only the N-acetyl-p-aminophenol, \ o but also other comparable known Compounds opposite causes extraordinarily increased analgesic and antipyretic effects.

The process of the invention for the preparation of the new pharmacologically active α-phenyl-α, α-diallylacetic acid-p-hydroxyanilide (= N-phenyldiallylacetyl - ρ - aminophenol) consists in that one Reacts p-aminophenol in a manner known per se with a-phenyl-a, a-diallylacetyl chloride. The implementation takes place in the presence of an inert, particularly aromatic solvent, such as benzene, and either an excess of p-aminophenol as a hydrogen chloride binding agent or in the presence an organic amine as a hydrogen chloride binding agent with heating to boiling and under reverse.

The examples illustrate the process of the invention.

B e i s ρ i el 1

22 g (V5 mol) of p-aminophenol are in 500 ecm Benzene slurried and after adding 23.5 g method of preparation

the pharmacologically active one

α-Phenyl-α, α-diallylacetic acid-p-hydroxyanilide

Applicant:

Chemical factory Tempelhof Preuss & Temmler, Berlin 42, Oberlandstr. 65

Named as inventor:

Dr.-Ing. Hellmuth Pflugk, Berlin-Wannsee

(Vio Mol) phenyldiallylacetyl chloride with stirring for 3 hours under reflux cooling to boiling heated. The contents of the flask, which are still warm, are shaken out with 400 ecm of warm water in a separating funnel and the aqueous solution is separated from the benzene solution. From the benzene Solution precipitates the N-phenyldiallylacetyl-p-aminophenol which, after recrystallization from benzene, has a melting point of 112 to 113 ° C. The yield is 27 g, that is 88% of theory.

C ₂₀ H ₂ IO ₂ N.
Calculated
found

N 4.56%;
N 4.51%.

Example 2

In a solution of HOG p-aminophenol in 200 cc of pyridine, 237 g Phenyldiallylacetylchlorid are added dropwise with stirring so that the temperature does not exceed 95 ⁰ C by a dropping funnel. After the reaction has ended, the contents of the flask are dissolved in 500 ml of ethyl acetate and the ethyl acetate solution is washed with 750 ml of 20% strength hydrochloric acid. After the ethyl acetate has been distilled off, the residue is dissolved in 2500 ecm hot benzene, the benzene solution is treated with animal charcoal and filtered. After cooling, the N-phenyldiallylacetyl-p-aminophenol precipitates from the benzene solution; M.p. = 112 to 113 ° C. The yield is 273 g, that is 90% of theory.

In the pharmacological test it was found that the N-phenyldiallylacetylp-aminophenol, hereinafter referred to as the new compound, with regard to the antipyretic and analgesic effect, the known, equivalent Compounds, namely the N-acetyl

309 777/401

p-aminophenol, p-acetphenetidine (known under the name "phenacetin"), acetylsalicylic acid and the Dimethylaminophenyldimethylpyrazolon (known under the name "Dimethylaminophenazon") is clearly superior.

In the comparative study, when administered intraperiotoneally to rats, the lethal amount, LD50, was 240 mg per kilogram of animal for dimethylaminophenazone, 1.5 g per kilogram of animal for phenacetin, more than 1 for N-acetyl-p-aminophenol and for the new compound , 5 g per kilogram of animal. After the administration of 50 mg of dimethylaminophenazone per kilogram of animal, a temperature reduction of 2 ° C. is obtained over a period of 1 ^× / ₂ hours. With "Phenacetin" the same effect is achieved with 100 mg per kilogram of animal over a period of 2% hours. 250 mg N-acetyl-p-aminophenol per kilogram of animal work for about 3 hours and lower the temperature by about 2 to 3 ° C.

The new compound brings about a temperature reduction in an amount of 200 mg per kilogram of animal of 3 ° C with a duration of action of 4 hours. As the lethal amount, LD50, for that new compound is higher than 1.5 g per kilogram of animal, the therapeutic range is because of the low Toxicity quite large. The ratio of the lethal amount, LD50, to the amount used therapeutically is about 5: 1 for "dimethylaminophenazone" and about 8: 1 for the new compound. It is to note that the effect against the "dimethylaminophenazon" and also the N-acetylp-aminophenol is stronger and lasts longer.

When increasing the amount of "dimethylaminophenazone" it is noticeable that the animals always get into a state of excitement that is general Cramps can pass. The opposite is the case with the new connection. Even in large quantities outweigh the calming (sedative) effects. They are more pronounced than with acetylsalicylic acid, the "phenacetin" and the N-acetyl-p-aminophenol. A perfect gradation of the effect can not.

The clearest difference emerges when examining the analgesic effect. In the Examination of this effect according to Reinhard and de Beer (see J. H. Burn, Biological Standardization, 2nd edition, 1950, p. 313), based on the electrical stimulation of the tail root of the rat based, there was an increase in the stimulus threshold from 0.25 to 0.5 milliamps (= mA) after 30 minutes and to 0.9 mA after one hour recognizable, the maximum value of 1 mA after a further 90 minutes reached. The stimulation was carried out with single square-wave pulses of 10 milliseconds in duration Frequency of 30 Hertz. Neither acetylsalicylic acid, "phenacetin", "dimethylaminophenazone" or N-acetyl-p-aminophenol showed a similar effect under these conditions. Even after one Administration of 80 mg "Dimethylaminophenazon" per kilogram of animal, administered intraperitoneally, the is one third of the lethal amount, LD50, the stimulus threshold remained below 0.4 mA. at of the new compound, only about an eighth of the lethal amount, LD50, had been used.

The analgesic effect of the new compound was also tested on mice in the hot plate test according to W ο ο 1 fe and McDonald (cf. Journal Pharmacology, Vol. 80, 1944, p. 300). After 100 mg (about one fifteenth of the lethal amount, LD50) of the new compound administered intraperitoneally per kilogram of animal, mice only reacted to the action of heat after twice the time (from 7 to 15 seconds) by licking their paws. The effect only ^{subsided after 3 x} / ₂ hours. In an amount of 50 mg per kilogram of animal, "Dimethylaminophenazon" only increased it from 11 to 13 seconds. So it is less effective as the amount administered was almost a third of the lethal amount, LD50.

Claims (1)

Claim: Process for the preparation of the pharmacologically active a-phenyl-aja-diallylacetic acid p-hydroxyanilide the formula CH ₂ - CH - CH ₂ OH CH ₂ -CH = CH ₂ characterized in that a-phenyl-a.a-diallylacetyl chloride is known per se Way with p-aminophenol in the presence of an inert, particularly aromatic solvent, such as benzene, and either an excess of p-aminophenol as the hydrogen chloride binding agent Medium or in the presence of an organic amine other than the one that binds hydrogen chloride Reacts agent with heating to boiling and under reflux. Considered publications: German Auslegeschrift No. 1064528; B. HcIwig, Modern Medicines, 2nd Edition, 1961, pp. 1 to 56 and 80 to 139.