DE1068720B - Process for the production of locally anesthetically effective anilides - Google Patents

Description

GERMAN

It has been found that anilides of the general formula

At the

wherein R ₁ and R _{2 are} a branched or unbranched alkylene group, Am is a mono- or dialkylated amino group, the pyrrolidino or piperidino radical, R ₃ and R _{4 are} lower alkyl, alkoxy groups or halogen, where the benzene ring Y can also be further substituted have valuable anesthetic properties. They are particularly suitable for surface anesthesia, but can also be used in circuit anesthesia. They are superior to diethylaminoacetic acid 2,6-xylidide in terms of local anesthetic and surface anesthetic effects.

The new compounds can be used in particular in those cases where a faster onset of action, however a very long-lasting effect is also desired (major surgery), can be used in combination with fast, but less long-lasting anesthetics, such as B. Pyrrolidinoacetic acid (2-chloro-6-methylanilide).

The new substances according to the invention can be prepared, for example, by reacting anilines general formula

Method of manufacture
of locally anesthetically effective anilides

Applicant:

CILAG Aktiengesellschaft,
Schaffhausen (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland from June 18, 1954

Dr. Henri Martin, Zurich (Switzerland),
has been named as the inventor

NH ₀

II

or their reactive derivatives with acids of the general formula

HOOC-R ₁ -SR ₂

-At the

III

or their reactive derivatives according to the methods customary for amide formation.

So you can, for example, anilines of the formula II or their salts with acids of the formula III in the presence of dehydrating agents such as phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride. In addition, the isocyanates or carbamic acid halides which can easily be prepared from the anilines, the Phosphazo compounds, the phosphorus or arsenic anilides under appropriate conditions with the React acids of formula III.

Instead of the free acids III, their functional derivatives can also be used to form anilide will. For example, halides, esters, anhydrides, mixed anhydrides can be used.

The method described above can also be modified in such a way that instead of Acids of the formula III acids or their reactive functional derivatives used in place of the basic group Am contain a radical which is easily converted into one of the desired basic groups can be.

Such a radical can for example consist of a halogen atom or a radical reacting analogously, such as z. B. an alkyl or aryl sulfonyloxy radical. These can be converted into an amino or substituted amino group by reaction with ammonia or amines, optionally in the presence of basic condensing agents be transferred.

Such a radical can, for example, also be a carbonyl group, which with the help of ammonia or Amines and reducing agents can be converted into an amino or substituted amino group.

Valuable anilides are obtained by using 2,6-dimethylaniline, 2,4,6-trimethylaniline, 2-chloro-6-methylaniline, 2-bromo-6-methylaniline, 2,6-dichloroaniline, 2,6-dichloro-4-methylaniline, 2,6-dimethoxyaniline with dimethylaminoethylmercapto-acetic acid, dimethylaminoethylmercapto-propionic acid, Dimethylaminoethylmercapto-butyric acid or the corresponding diethylamino, dipropylamino, dibutylamino, pyrrolidino, Piperidino-alkyl mercapto compounds.

Instead of the disubstituted aminoalkyl mercapto acids, monosubstituted aminoalkyl

909 646/401

mercapto acids are used to build, such as. B. Monoäthylaminoäthylmercapto-acetic acid, Monoäthylaminopropylmercapto-acetic acid, Monobutylaminopropyl mercaptoacetic acid.

Anilides, which are also effective, are obtained if, instead of the aminoalkyl mercapto acids, aminoalkylsulfoxy acids or aminoalkylsulfonyl acids are coupled with the aforementioned anilides or their isomers or homologues. λ

The process described above, which consists in the formation of anilide from preformed acid and an anib%, can now also be carried out in stages. ' For example, using the methods described at the outset, anilides of the general formula

N-CO-R ₁ -X '

win and then with compounds of the general formula

X '- R ₂ - Am

continue to implement; here in both formulas R ₁ , R ₂ , R ₃ , R ₄ and Am have the meaning already mentioned, while one of the symbols X 'is a reactive radical, such as. B. halogen, and the other mean the sulfur atom together with a hydrogen atom or another easily split off radical.

According to this process, for example, a haloalkanecarboxylic acid aniiide according to the aforementioned Process and produce this with an unsubstituted or substituted aminoalkanethiol or a Bring the alkali salt of such to reaction. On the other hand, a thiolalkanecarboxylic acid anilide can also be produced and react this with an aminoalkyl halide in the presence of basic condensing agents to get to connections of the same type.

In the anilides of the formula I formed, finally, in the group Am, if this is unsubstituted or only is monosubstituted, one or two substituents by reacting the anilide with alkylating agents to be introduced. Alkylating agents include both reactive esters of alkanols and alkenols and alkynols as well as corresponding aldehydes or ketones and reducing agents.

As mentioned at the outset, the group Am can also be quaternary, in which case the quaternary Desquaternize the ammonium group by heating in the presence or absence of a high-boiling solvent can, as can also, if one or more of the substituents can be split off by hydrogenation (Benzyl groups or substituted benzyl groups) is the quaternary ammonium group by catalytic Can convert hydrogenation into the tertiary or secondary amino group.

The anilides of the formula mentioned at the outset which are formed in this way can advantageously be used in the form of their salts with inorganic compounds or organic acids can be isolated. Inorganic acids that can be used for salt formation are: sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid; as organic acids: Acetic acid, glycolic acid, citric acid, succinic acid, fumaric acid, maleic acid, dioxymaleic acid, methanesulf onic acid, ethanesulfonic acid, hydroxyethanesulfonic acid.

example 1

141.5 g of 2-chloro-6-methylaniline and 92 g of thioglycolic acid are in 600 ecm xylene in a flask with Water separator heated to boiling. After 24 hours, the xylene is distilled off in vacuo and the residue Shaken out several times with 2 η sodium hydroxide solution and ether. The aqueous alkaline solution is made with charcoal treated and filtered. The filtrate is adjusted to pu 1 with concentrated hydrochloric acid, the precipitated one Washed precipitate and recrystallized from ethanol. The thioglycolic acid (2-chloro-6-methylanilide) is in colorless needles melting at 134 ° C. were obtained. the

ίο-, yield is 77 g.

'"53.9 g Thioglykolsäure- ^ -chloro-o-methylanilide) are introduced into 500 cc of ethanol, a solution of 11.5 g of sodium in 500 cc of ethanol is added and then allowed to flow with 36 g Dimethylaminoäthylchlorid hydrochloride in 500 cc of ethanol The reaction mixture is heated to boiling for 6 hours with stirring and, after cooling, the precipitated sodium chloride is filtered off. The filtrate is evaporated in vacuo and the residue is taken up in 2η hydrochloric acid. The acidic solution is extracted twice with ether, then made alkaline and the After drying and distilling off the ether, the residue crystallizes to colorless needles which, after recrystallization from ligroin, melt at 71 to 72 ° C. This gives 56 g of des / I-dimethylaminoethyl mercapto-acetic acid - (2 - chloro-6-methylanilide).

Example 2

20 g of thiolacetic acid (2-chloro-6-methylanilide) are dissolved in 200 ecm of ethanol containing 2 g of sodium, briefly warmed and then evaporated to dryness. 200 ecm of benzene are then added to the residue and added dropwise the resulting slurry 13 g of diethylaminoethyl chloride dissolved in 150 ecm of benzene. It will be during Heated to boiling for 3 hours, then cooled and the diethylaminoethyl thioacetic acid formed (2 - chloro-6-methylanilide) extracted from the benzene with dilute hydrochloric acid. The hydrochloric acid solution is made alkaline, the separating oil is absorbed in ether, the ether is dried and evaporated. The residue results under 0.05 mm at 155 to 158 ° C boiling ^ -Diethylaminoäthyl-thioessigsäure- (2-chloro-6-methylanilide) distilled in a high vacuum. The hydrochloride of the same melts at 65 to 66 ° C.

Example 3

24 g of chloroacetic acid (2,6-dichloroanilide) and 13.3 g of diethylaminoethanthiol are heated to boiling in 80 ecm of chlorobenzene for 20 minutes. During this time the initially clear solution begins to become cloudy and at the end a heavy oil separates. After cooling down 150 ecm of ether are added and the crystal mass, which is extracted from the hydrochloride of diethylaminoethylmercapto-acetic acid (2,6-dichloroanilide) exists, from. This is dissolved in 150 ecm warm isopropanol, mixed with acetone until the onset of turbidity and then set aside for crystallization. 22.7 g of the hydrochloride melting at 67 to 68 ° C. are obtained in this way. The following substances can also be obtained in the same way:

Pyrrolidinoethylmercapto-acetic acid (2,6-dimethylanilide). Bp 0.04 mm: 160 to 161 ° C;
Piperidinoethylmercapto-acetic acid (2,6-dimethylanilide), boiling point 0.06 mm: 165 to 167 ° C;
Di-n-butylaminoethylmercapto-acetic acid (2-chloro-6-methylanilide), melting point of the hydrochloride: 139 ° C;
Diethylaminoethylmercapto-acetic acid (2,4,6-trichloranilide), melting point of the hydrochloride: 68 to 69 ° C.

In the same way can be further produced: Di-n-butylaminoethylmercapto-acetic acid- (2,4,6-trichloranilide), Mp of the hydrochloride: 133 to 135 ° C; Di-n-butylaminoethyl mercapto-acetic acid (2,6-dichloroanilide), Mp. Of the hydrochloride: 146 to 147 ° C.

Claims (3)

Patent claims: 1. Process for the preparation of locally anesthetically effective anilides of the general formula N-CO-R ₁ -SR ₂ -Am wherein R ₁ and R _{2 are} a branched or unbranched alkylene group, Am is a mono- or dialkylated amino group, the pyrrolidino or piperidino radical, R ₃ and R _{4 are} lower alkyl, alkoxy groups or halogen, where the benzene ring Y can also be further substituted , characterized in that one anilines of the general formula -NH, II or salts or reactive derivatives of such anilines with acids of the general formula HOOC-R ₁ -SR ₂ -Am III or their reactive derivatives according to the for Amide formations converts customary methods or anilines of the formula II with acids in place of the basic group Am contain a convertible into the basic group radical, after which one then converts this residue into the basic group in the anilides formed and the formed If desired, anilides are converted into their salts. 2. Embodiment of the method according to claim 1, characterized in that acid anilides are used the general formula N-CO-R ₁ -X ' produces and then with compounds of the general formula X '- R ₉ - Am converts, where in both formulas R ₁ , R ₂ , R ₃ , R ₄ and Am has the meaning already mentioned, while one of the symbols X 'is a reactive, removable radical and the other sulfur together with a hydrogen atom or another easily removable Mean rest. 3. Embodiment of the method according to claim 1 and 2, characterized in that in the anilides formed in Am further alkyl, alkenyl or alkynyl radicals with the aid of introducing such radicals Introducing agents or, if Am is a quaternary amino group, Am by dequaternization and / or hydrogenation converted into a tertiary or secondary amino group. © 909 648/401 11:59