DE1770273A1 - New basic ketones - Google Patents

Description

New basic ketones The invention relates to new basic ketones of the general formula where R is an n- or iso-alkoxy group of chain length C3-Cb, R1 is a dibutylamine, piperidine, pyrrolidine, 4-ethylpiperidine, morpholine or hexamethyleneimine radical.

The compounds according to the invention are distinguished by a strong anesthetic effect the end.

There are already highly effective anesthetics in the form of 4-alkoxy-ß-piperidinopropiophenones known (GDR patent specification No. 268).

Substances of this series, starting with the 4-propoxy compound, have a very strong anesthetic effect both on the surface and on the surface in local anesthetic terms. The propoxy compound was under the name Propoxypiperoc ainumhydrochloricum included in the DAB 7 and has been on the market since 1952.

However, the substances in the marked series are relatively toxic, which, however, is not very disadvantageous in their application, since the strong one anesthetic effectiveness of Propoxypiperocainum hydrochloricums, the # 10-12fold is as large as that of cocaine or 4-aminobenzoic acid diethylaminoethyl ester, only very low percentage solutions are necessary.

It has been found that by introducing an ethyl group into the ring system in the 3-position to the keto group a very substantial reduction in toxicity is achieved.

Table 1: Toxicity of ß-R1-3-ethyl-4-alkoxypropiophenone hydrochlorides Base content R1 alkoxy group R toxicity (mg / kg mouse) Piperidino n-Propoxy 460 + 25 po, 520 ~ 45 sc, 44.5, + 2.0 iv, Piperidino n-Butoxy 440 ~ 25 po,> 2000 sc., 48 + 1.2 iv., Piperidino n-amyloxy 530 + 21 po, 1250 + 100 sc. 44 + 3.5 iv. Piperidino iso-amyloxy 600 ~ 27 po,> 2000 sc., 54 + 2.5 iv. Piperidino n-Hexyloxy 620 ~ 52 po, # 3000 sc. 53 ~ 4.1 iv. 4-thylpiperflino n-propoxy 270 + 5 po,> 2000 sc., Hexamethyleneimino n-propoxy 450 + 10 po, 780 + 70 sc. Comparative substance PropoxypiperocainumbZldrochlorScum It was also found that substances with an ethyl group in the 3-position to the keto group not only have an extremely reduced toxicity compared to the ethyl-free compounds, but that they also exceed the comparative substance in terms of duration of action, so that they are used as long-term anesthetics can.

The anesthetic strengths given in the tables below were after Profft (E. Profft, opening and lecture conference Chem. Ges. DDR, Leipzig, Conference reports 1954, Dtsch. Verlag der Wissenschaften Berlin, p. 134) with help of the tongue test determined as follows: 0.5 ml of the one percent aqueous solution the compound in question was left to act on the tongue for 45 seconds. After immediately rinsing the mouth three times, the sensation of anesthesia became in Determined as a function of time. Anesthesia strength 1 = weak, 2 = medium, 3 = strong, 4 = very strong.

Table 2: Anesthesia of ß-piperidino-3-ethyl-4-alkoxypropiophenone hydrochlorides Alkoxy group R anesthetic anesthetic strength duration (min.) n-propoxy 3 53 iso-propoxy 2 34 n-butoxy 3 115 iso-3utoxy 2.5 69 n-Amyloxy 3 116 iso-amyloxy 225> 104 n-hexyloxy 3> 180 n-heptyloxy 2.5> 330 n-Octyloxy 2 270 Table 3t anesthesia of β-R1-3-ethyl-4-alkoxypropiophenone hydrochlorides Base content R1 alkoxy group R anesthetic anesthetic strength duration (min.) Dibutylamino n-propoxy 3 90 4-ethylpiperidino n-propoxy 4110 Pyrrolidino n-hexyloxy 2.5 165 Hexamethyleneimino iso-amyloxy 3 108 Morpholino iso-amyloxy 3 64 Comparative substance Propoxypiperocainum hydrochloricum: Anesthetic strength: 3.5 Anesthetic duration: 40 minutes.

The new compounds of the general formula (I) according to the invention are obtained in the following way: 2-Ethylpilenol, obtained from the waste product the chloramphenicol synthesis, the o-nitroethylbenzene, is in the form of the acetate subjected to the Friesian shift, the hydroxy group etherified and the 4-alkoxy-3-äthylacetophenone converted into the corresponding keto bases according to Mannich.

A major advantage in obtaining the active ingredients is that that in the Friesian shift no isomer is produced, but exclusively the connection with the keto group in the 1-position is obtained.

The individual process stages can be carried out in very good yields.

But you can also use 2-ethyl-phenylaIkyläther according to Friede 1-Crafts Subject to condensation with ß-Chlorpropionylchlorid and the substituted ß-Chlorpropiophenone Implement with the appropriate basic compounds, which is even easier designed.

As basic components can be used to achieve the intended Effect both aliphatic and heterocyclic secondary amines are used, e.g. n-dibutylaniline, piperidine, 4-ethylpiperidine, hexamethyleneimine, morpholine, Pyrrolidine et al.

The compounds of the general formula (I) according to the invention represent white, crystalline, odorless compounds that are readily soluble in water and alcohol and can be used in many ways as anesthetics.

They can e.g. in the form of injection solutions, ointments, powders, tablets, Suppositories and sprays can be used. In these preparations they are used for Local, mucous membrane and conduction anesthesia suitable.

For example, 0.25 - Q.5% solutions can be obtained with a low addition of arterenol or adrenaline, as injection solutions in stomatology, 0.02 - 0.2% solutions as infiltration anesthetics, 0.5 - 2% solutions in the epidural anesthesia and 0.1-0.5% solutions for the circuit anesthesia for Use.

Solutions of the substances according to the invention are also used in ophthalmology, so for superficial anesthesia of the cornea, for strabismus operations and the various Interventions on the conjunctiva are suitable.

They are used for bronchoscopy, bronchography, esophagoscopy, Gastroscopy, cystoscopy, endobronchial and endoesophageal interventions, foreign body removal erungen, etc., The epidural anesthesia has a special application in the Gynecology.

In combination with e.g. Bismutum subgallicum and Oleum pedum tauri suppositories are obtained that treat hemorrhoids, anal fissures, anal fissures i.a. are effective.

The substances according to the invention are in the form of sprays for preparation suitable for interventions, especially in otology, rhinology and stomatology.

The following examples are intended to illustrate the preparation of the new compounds of the general formula I explain and characterize their properties, the In no way limit the invention.

Example 1: 2-Xthylphenol (1 mole) is obtained by heating for half an hour converted into the acetate with 1.1 mol of acetic anhydride and a drop of sulfuric acid.

1 mole of 2-ethylphenyl acetate in 300 g of nitrobenzene or o-nitroethylbenzene 170 g of anhydrous aluminum chloride are added. After 3 hours Reaction at 500 C is poured into ice / hydrochloric acid and nitrobenzene or o-nitroethylbenzene with Water vapor driven off. From the residue is 3-ethyl-4-hydroxy-acetophenone, the Remains as an oil in a mixture with water and soon solidifies, won. 1 mole of this is with 1.1 mol of alkyl bromide by 5 hrs. Heating in the presence of 1.1 moles of anhydrous Potassium carbonate and 150-200 ml of acetone etherified, whereupon 1 mol of the ether with 0.95 Moles of piperidine hydrochloride and 2.5 moles of paraformaldehyde in 140 ml of alcohol for 5 hours will. The keto base hydrochloride is obtained by treating the reaction mixture separated with ether and purified by reprecipitation.

Example 2s 1 mol of ethylphenol is mixed with 1.1 mol of n-hexyl bromide as in Example 1 etherified.

1 mol of ß-chloropropionyl chloride, 1 mol of 2-Äthylphenyi-nhexyläther and 500 ml of carbon disulfide are mixed with 148 g of aluminum chloride while stirring. After the reaction has subsided, the mixture is heated to boiling for a further 60 minutes.

The reaction mixture is poured onto ice / hydrochloric acid, the organic Phase separated, dried with calcium chloride and the solvent fails.

It is then dissolved in 500 ml of methanol and mixed with 120 g of anhydrous potassium acetate heated to boiling. After cooling, 3 moles of piperidine in 500 ml of alcohol are added. After the reaction has ended, water is added, the mixture is acidified and ether is added extracted. The keto base separates out with caustic soda, which is converted into the hydrochloride is convicted.

Example 3: ß-Piperidino-3-ethyl-4-alkoxypropiophenone hydrochloride: Al @ oxy group Yield Solubility Properties mp (° C) R% in water u. Ethanol n-Propoxy 55 very good white crystals 142 ° iso-propoxy 65 very good "" 1390 n-butoxy 72 very good "" 143 ° iso-butoxy 68 very good "" 1470 n-amyloxy 62 good "" 139 ° iso-amyloxy 65 good "" 135 ° n-Hexyloxy 77 good """154 ° n-Heptyloxy 47 in water: "" 161 ° moderate - in Alcohol: good n-octyloxy 30 in water; "" 164 ° moderate - in Alcohol: good Example 4: β-R1-3-ethyl-4-alkoxypropiophenone hydrochloride Base content Alkoxy group From solubility. Own melting point (° C) beu- i. Water sciences R1 te% and ethanol Dibutyl-n-propoxy 63 very good white 67 amino crystals 4-Ethylpin-n-Propoxy 62 "" white 170 peridino crystals Pyrroline-hexyloxy 32 good white 127 d no crystals Hexameiso-amyloxy 37 "white thylenimino crystals Morpholino iso-amyloxy 52 'white 150 Crystals

Claims (1)

Claims: 1. New basic ketones of the general formula where R is an n- or iso-alkoxy group of chain length C3-C8, R1 is a dibutylamine, piperidine, pyrrolidine, 4-ethylpiperidine, morpholine or hexamethyleneimine radical 2. ß-piperidino-3-ethyl-4- hexyloxypropiophenone 3. Procedure for the preparation of new basic ketones of the general formula where R and R1 have the above meaning, characterized in that 2-ethylphenol is converted in a known manner into 3-ethyl-4-hydroxy-acetophenone, this is etherified with alkyl halides, preferably with propyl bromide, amyl bromide or hexyl bromide, and then subjected to a Mannich condensation . 4. Process for the preparation of new basic ketones of the general formula wherein R and R1 have the above meaning, characterized in that 2-ethyl-phenylalkylethers are condensed according to Friedel-Crafts with ß-chloropropionyl chloride and the substituted ß-chloropropionyl chloride obtained are reacted with amines.