DE1053515B - Process for the production of locally anesthetically effective anilides - Google Patents

Description

It has been found that anilides of the general formula

CO-R ₁ -NR ₂ -Am

wherein R ₁ and R _{2 are} a branched or unbranched alkylene group, R _{3 is} hydrogen, alkyl or aralkyl, Am is a mono- or dialkylated amino group, the pyrrolidine or piperidine radical and R ₄ and R _{5 are} lower alkyl, alkoxy groups or halogen, where the Benzene nucleus Y can also be further substituted and 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 quick onset of action, but also a very long-lasting effect is desired (major surgery), combined 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

NH ₉

or their reactive derivatives with acids of the general formula

HOOC-R ₁ -NR ₂ -Am

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. The isocyanates or carbamic acid halides, which can be easily prepared from the anilines, can also be used. the phosphazo compounds, the phosphorus or arsenic anilides under appropriate conditions with the React acids of formula III.

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

Instead of the free acids III, their

Used for anilide we re ZJ functional derivatives. 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 base Group Am contain a radical which can easily be converted into one of the desired basic groups can.

Such a radical can for example consist of a halogen atom or a radical reacting analogously, such as

z. B. an alkyl or arylsulfonyloxy radical. These can, if appropriate, by reacting with ammonia or amines in the presence of basic condensing agents, into an amino or substituted amino group 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-dichloro-4-methylaniline, 2,6-dimethoxyaniline with dimethylaminoethylaminoacetic acid, Dimethylaminoethylaminopropionic acid, N - dimethylaminoethyl - N - methylaminoacetic

809 787/545

acidic, N - dimethylaminoethyl-N-ethylammoacetic acid, or the corresponding diethylammo, dipropylammo, Dibutylammo, pyrrolidino, piperidino compounds implements

<\ n Instead of the disubstituted Ammoalkylammosauren monosubstituted Ammoalkylammoalkan carboxylic acids can be used for the structure, such as ζ Β Monoathylammoath} 1 ammoessigsaure, N-Mono ^ hyl ammo athjJ-N methylammoessigsaure, N-Mono- y -N-butylammoessigsaure 1

The method described above involves the formation of an amlid from preformed acid and an amine exists, can now also be carried out in stages. For example, following the steps described above Methods anilides of the general formula

Y> - N - CO - R ₁ H

X '

win and then my formula with compounds

X '- R ₂ - Am

further implement, here m both formulas R ₁ , R ₂ , R ₄ , R ₅ and Am have the meaning already mentioned, while one of the symbols X 'is a reactive radical such as ζ B halogen and the other the hetero group

together with a hydrogen atom or something else means easily split off residue

According to this process, for example, em haloalkanecarboxylic acid can be added according to the aforementioned Manufacture process and this with an unsubstituted th or substituted aminoalkylamine to react. On the other hand, an Ammoalkancarbonsaureamhd and make this with an aminoalkyl halide in the presence of basic condensing agents move to get to connections of the same type

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

_{Furthermore, if R 3} is hydrogen, it can be replaced in the amlides formed by alkyl, alkenyl or aralkyl radicals by reacting the anilides with hydrogen halide esters or sulfuric acid esters on alkanols, alkenols or aralkanols

The group Am can, moreover, as mentioned at the beginning, also be quaternary, whereby one then the quaternare Desquatermize 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), the quaternary Ammonium group converted into the tertiary or secondary amino group by catalytic hydrogenation can

The anilides of those mentioned at the beginning formed in this way Formula can be beneficial in the form of their salts with inorganic or organic acids can be isolated. Inorganic acids can lead to salt formation become 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, methane sulfonic acid Athanesulfonsauie, Hydroxyathansulfonsaure

example 1

109 g of chlorine essigsaure- (2-chloro-6-methylanihd) are heated with 165 g Diathylaminoathylamin m 150 cc of absolute ethanol for 4 hours at 60 ⁰ C. Then the reaction mixture is treated with water vapor and the aqueous solution then with sodium chloride saturated and extracted with ether The ethereal solution is evaporated after drying and the residue is distilled in vacuo. 140 g of the diethylammoethylammoessigsaure - (2 - chloro-6-methylanihdes) boiling below 0.11 mm at 177 ° C. are obtained. The hydrochloride of the new compound melts at 202 to 203 ° C

Example 2

58 g of chloroacetic acid (2 chloro 6 methyl anilide) are in 300 ecm of dioxane with 38 g of 2-diethylammoethyl methyl amine and 35 g of sodium carbonate are heated to boiling for 6 hours. The sodium chloride formed is then added filtered off and the filtrate evaporated in vacuo. The residue is a light yellow oil. This is in diluted hydrochloric acid and the acidic solution with Acetone is added after standing in the cold for a while the N- / 3-diethylaminodth dihydrochloride formed> 1 N methylamine) acetic acid (2-chloro-6-meth \ lamlids) suctioned and washed with acetone. 70 g of des are obtained Dihydrochlorides, which melts at 206 to 208 ° C

Example 3

From 35 g of chloroacetic acid (2 chloro-6-methylanilide) and 25 g of 2 diethylaminoethylethylamine are obtained through Hourly heating in 250 ecm ethanol in the presence of 25 g of dry sodium carbonate 5IgN / S-Diethylammoathyl N athylammoessigsaure- (2-chloro 6 methylanilide), which boils below 0.15 mm at 165.5 to 167 ° C Dihydrochlond of the base shows in 2% aqueous solution a pn value \ on 6.5

Example 4

1 mol of chloroacetic acid (2 chloro 6 methylanilide) is heated to boiling for 6 hours with 1.2 mol of N- / S-ammopropyl pyrrolidine in absolute ethanol with the addition of 0.5 mol of calcined potassium carbonate. Then the reaction mass is evaporated to dryness, the residue with triturated 2 η sodium hydroxide solution and extracted with ether several times the ethereal solution is erdampft after drying over potassium carbonate \ and the residue under high vacuum distilled are obtained, so that less than 0.05 mm at from 159 to 161 ° C boiling N β pyrrolidino propylammo-tssigsaure- ( 2-chloro 6-methylamlide) in a yield of 65% of theory

Example 5

27.5 g of chloroacetic acid (2-chloro-6 methylanilide) become with 28 g of diethylammoethylbenzylamine in 200 ecm Propyl alcohol in the presence of 19 g of anhydrous sodium carbonate for 6 hours with stirring on the The water bath is then heated distilled off, the residue dissolved in dilute hydrochloric acid, the solution filtered and made alkaline that formed Amlid exudes as oil this one becomes in

Ether absorbed, the ethereal solution dried over potassium carbonate and evaporated. The residue obtained is distilled under high vacuum, 44 g (or 76 ° / ₀ of theory) of N-ß-diethylaminoethyl-N-benzylaminoessigsäure- (2-chloro-6-methylanilide). The anilide obtained in this way forms a colorless, acid-soluble oil which ^{boils below 0.06 mm at 213 °} C. and solidifies to coarse crystals after some time. The dihydrochloride of anilide shows a ρπ value of 6.6 in 2% aqueous solution.

- ~ Example 6

27 g of N - β - diethylaminoethyl - N - methylamino - acetic acid chloride dihydrochloride are stirred with 13 g of 2-chloro- 6-methyl aniline in 100 ecm of absolute benzene at 20 ° C. for 4 to 5 hours. The mixture is then heated on the water bath until the evolution of hydrogen chloride has subsided, then 500 ecm of water are added and the layers are separated. The aqueous layer is made alkaline, leached with ether and, after drying, the ether is evaporated. The residue is distilled in vacuo, the N - ^ - diethylaminoethyl-N-methylamino-acetic acid (2-chloro-6-methylanilide) passing over below 0.15 mm at 161 to 163 ° C. The yield is 21 g. The basic anilide obtained in this way can be converted into the dihydrochloride which melts at 206 to 208 ° C with the help of ethereal hydrochloric acid.

The following anilides can be prepared in the same way as described in the examples:

/ Y V-NH-CO-R ₁ -NR ₂ -Am

R ₃

Y R, Ra -CH ₃ y -CH ₂ - R, At the - N QH ₅ Sdp.
(Mp. Dihydrochloride) QH ₅ QH ₅
/ 2,6-dimethyl -CH ₂ - -CH ₂ - ^ -CH ₂ - CH ₂ - - N
\
QH ₅ - N
QH ₅ (193 to 196 ° C
Decomposition) - CH ₂ - / -CH ₂ - QH ₅ QH ₅ 2,6-dimethyl -CH ₂ - CH ₂ - - N
QH ₅ - N
\
QH ₅ M.p. base
71 to 72 ° C -CH ₂ - / ■
\ CH ₂ - -N ^ ~ H QH ₅ (187 to 189 ⁰ C
Decomposition) 2,6-dimethyl -CH ₂ - -CH ₂ - / -CH ₂ - QH ₅ QH ₅ (186 to 187.5 ° C
Decomposition) O JTL 2 \ / ~ " ^C1 -CH ₂ - - N
QH ₅ 2,6-dimethyl -CH ₂ - CH ₂ - C ₂ H ₅ (100 ⁰ C
blurred) -CH ₂ - -CH ₃ \ - Cl -CH ₂ - CH ₂ - - N
QH ₅ (188.5 to 190 ° C
Decomposition) - N H 2,6-dimethyl -CH ₂ - CH ₂ (220 to 222 ° C) - C ₃ H ₇ n -CH ₂ - QH ₅ 2,6-dimethyl -CH ₂ - - C ₃ H ₇ iso ■ v> -H. ο CH ₂ - (123.5 to 126 ° C
Decomposition) 2,6 dichloro -CH ₂ - - C ₄ H ₉ iso -CH ₂ - CH ₂ (200 to 203 ° C
Decomposition) -CH ₂ - CH ₂ - 0.05 mm: 169 ^° C 2-chloro-6-methyl 2-chloro-6-methyl 2-chloro-6-methyl

Y R ₁ R ₃ -CH ₁ R ₂ At the - Ν C ₂ H ₅ Sdp.
(Mp dihydrochloride) -CH ₂ - - C ₂ H ₅ -CH ₂ - CH ₂ - —Ν Η 2-chloro-6-methyl -CH ₂ - -CH ₂ -CH = CH ₂ C TT C TT
^ XX 2 ^ XX 2 - N H - Ν Η
\
\ (217 to 22O ⁰ C
Decomposition) 2-chloro-6-methyl -CH ₂ - CH ₃ ρ tj f tj
v ^ XX ₂ "^^ 2 - N H C ₂ H ₅
—N '
\ (207 to 209 ° C
Decomposition) 2-chloro-6-methyl -CH ₂ -CH -N H \
C ₂ H ₅ (132.5 to 135 ° C
Decomposition) -CH ₂ - CH ₃ -CH ₂ -CH ₂ - - N H 2-chloro-6-methyl - N H C ₂ H ₅
- N (177 to 180 ⁰ C) - CH ₂ - ^^ V \ C ₂ H ₅ -CH ₂ - - C H2 - C Xi ₂ - C H2 - CnHc
Δ Ο C ₂ H ₅
- N 2-chloro-6-methyl- -CH ₂ - / * V C ₂ H ₅ 0.06 mm: 222 ^° C -CH ₂ - CH ₃
—N ' 2-chloro-6-methyl -CH ₂ - - ^CH > - <Z> C TT Γ * TT C * TT CH ₃ (190 to 192 ⁰ C
Decomposition) -CH ₂ - -CH ₂ - / V- Cl -CH ₂ -CH ₂ - - N H (205 to 207 ° C
Decomposition) 2-chloro-6-methyl - NH
\ _ (~ 100 ° C
Decomposition) 2-chloro-6-methyl -CH ₂ - -CH ₂ - / S-Cl -CH ₂ -CH ₂ - -CH ₂ - - C ₂ H ₅ -CH ₂ - CH ₂ - (194 to 195 ° C
Decomposition) 2-chloro-6-methyl 0.03 mm: 167 ^° C 2,4,6-trichloro -CH ₂ - - C Xx ₂ - CH ₂ - y ν
² Y / 0.02 mm: 180 ^° C -CH ₂ - - CH ₂ - CH2 - 2,4,6-trichloro - C ₂ H ₅ 0.05 mm
140 to 142 ° C -CH ₂ - C TT C TT
Vv XX2 \ s ± Ln 2,4,6-trimethyl -CH ₂ - -CH ₂ - </ V - CH ₂ ~ - CH ₂ - 0.06 mm:
218 to 220 ⁰ C 0.05 mm:
225 to 227 ° C 2,4,6-trimethyl -CH ₂ - ^ V-Cl 2,4,6-trimethyl

Claims (3)

Patent claims: 1. Process for the preparation of locally anesthetically effective anilides of the general formula R, N-CO-R ₁ -NR ₂ -Am R, 10 wherein R ₁ and R _{2 are} a branched or unbranched alkylene group, R _{3 is} hydrogen, alkyl or aralkyl, Am is a mono- or dialkylated amino group, the pyrrolidine or piperidine radical, R ₄ and R _{5 are} lower alkyl, alkoxy groups or halogen, where the Benzene nucleus Y can also be further substituted, as well as salts of such anilides, characterized in that anilines of the general formula -NH, or salts or reactive ones
Anilines with acids of the formula II Derivatives of such HOOC-R ₁ -NR ₂ -Am
R ₉ III 30th or their reactive derivatives according to the methods customary for amide formations or Anilines of the formula II with acids which, instead of the basic group, Am one in the basic group contain convertible radical, after which this radical is then converted into the anilides formed 35 10 converted into the basic group and the anilides formed, if desired, converted into their salts. 2. embodiment of the method according to claim 1, characterized in that acid anilides of the general formula CO-R ₁ -X ' with compounds of the general formula X '- R, At the reacted, where in both formulas R ₁ , R ₂ , R ₄ , R ₅ and Am has the meaning already mentioned, while one of the symbols X 'is a reactive, cleavable radical and the other is the hetero group together with a hydrogen atom or another easily split off radical means. 3. Embodiment of the method according to claim 1 and 2, characterized in that one is formed in the Anilides in Am and / or in - N - R ₃ if R ₃ = H, further alkyl, alkenyl, alkynyl or aralkyl radicals are introduced with the aid of means introducing such radicals or, if Am is a quaternary amino group, Am is converted into a tertiary or secondary amino group by dequaternization and / or hydrogenation convicted. When the application was announced, a comparison experiment was laid out. © 809 787/545 3.