NO154054B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HYDROXYPYRIMIDINE DERIVATIVES. - Google Patents

Description

Process for the production of hitherto unknown therapeutically active piperidine derivatives.

The present invention relates to

method for the production of up to now

unknown therapeutically active piperindine derivatives with valuable pharmacological

properties.

It is surprisingly found that

piperidine derivatives of the general formula I,

where R, means a lower alkyl residue,

R2 hydrogen or the methyl residue and

R;l an alkyl radical with a maximum of 4 carbon atoms or together with R, an optionally methyl-substituted trimethylene to hexamethylene radical, R, hydrogen or

the methyl residue and

R5-CO- an alkanoyl residue with in height

5 preferably 2-3 carbon atoms,

and their salts with inorganic and organic acids, possess valuable pharmacological properties, in particular an excellent

analgesic effect with oral and parenteral administration and strong antitussive effect. Unlike other analgesics, they have no parasympatholytic properties, but are rather parasympathomimetic. At the same time, they are relatively non-toxic and are therefore suitable for the relief and elimination of pain of various origins and also for cough irritation.

In the following, test results of the analgesic effect of certain compounds according to the invention in comparison with acetylsalicylic acid are reproduced.

a) Tested compounds.

I 2-(1'-methyl-4'-propionoxy-4'-piperidyl)-cyclohexanone (citrate)

II 1-(1'-methyl-4'-propionoxy-4'-piperidyl)-2-butanone (citrate)

III Acetylsalicylic acid

b) Experiment according to Friebel.

The analgesic effect is determined

according to the method of Gross, whereby the tails of white mice are irritated with the apparatus of Friebel and Reichle (Heiv. Physicol. u. Pharma-kol. Acta 5 C 31 (1947)) by thermal radiation.

The reaction time defined by Gross for the above-mentioned irritation is determined on different groups of 10-20 animals, each weighing 18-25 g, 30 and 15 minutes before the administration of the test substances. All animal groups are then administered a suspension of the test substances with gum arabic in water for an action time of 30, 45 and 60 minutes at doses of 200, resp. 400 mg/kg p. o. During the one side and the average reaction time of the first hour after the administration before the administration of the sample of the test substances is determined every quarter of the substances on the other side, expressed in ter the average reaction time for percentage of the latter ,

each animal group and then determine the differ-

rance between the average re- c) Results.

d) Conclusion.

Those according to the invention that can be produced

compounds according to the present patent document show, as mild analgesics, a great superiority over acetylsalicylic acid.

In connection with the general formula

I and the associated starting substances further mentioned below mean R, e.g. as lower alkyl residues, methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl- or sec. the butyl residue.

R3 is alone, e.g. methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, or tert. the butyl residue.

R., further forms together with R« e.g. a trimethylene, tetramethylene, 1-methyl-tetramethylene, pentamethylene or hexamethylene residue.

The lower alkanoyl residue R--CO- is e.g. the acyl residue of acetic acid, propionic acid, butyric acid, isobutyric acid, valerian acid or isovaleric acid.

To prepare compounds with the general formula I, a hydroxy compound with the general formula II is reacted,

where R 1 , R 2 , R 1 and R 1 have the meanings given above,

with a halide or anhydride of a lower alkanoic acid or with a corresponding ketene.

An excess of the anhydride or halide used is preferably used as the reaction medium; other acylating agents are used in inert organic solvents such as e.g. diethyl ether, tetrahydrofuran or benzene. An acid-binding agent, e.g. a tertiary organic base such as pyridine or triethylamine can be added if desired, but is not necessary for a complete reaction.

Important for the achievement of the turnover according to the invention is punctual compliance with lower reaction temperatures and at a height of approx. 60°, preferably from 0° to room temperature, as the starting material with the general formula II is concerned with tertiary hydroxy compounds which easily react with the acylating agents at higher temperatures during water splitting.

Various methods are available for the production of starting substances with the general formula II, e.g. by reacting a correspondingly substituted piperidone with a ketone, as described in patent no. 111 402.

With inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanedisulfonic acid, |3-hydroxyethanesulfonic acid, acetic acid, propionic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid , phenylacetic acid and mandelic acid form compounds with the general formula I salts, which are partially well water-soluble.

The following examples explain the implementation of the method according to the invention. The temperatures are indicated in degrees Celsius.

Example 1.

17.1 g of 1-(1'-methyl-4'-hydroxy-4'-piperidyl)-2-propanone (produced by reaction of 1-methyl-4-piperidone and acetone in an alkaline environment) is cooled while stirring to 0°, then 10.2 g of acetic anhydride are added, the ice cooling is removed and the mixture is stirred further for 15 minutes. 200 ml of acetone is then added to it under ice-cooling. Without further cooling, 1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-propanone citrate is precipitated by adding a saturated citric acid solution in acetone until an acidic reaction occurs.

filter it off and recrystallize it from acetone-methanol. Melting point 153°.

In an analogous manner using the corresponding 4'-hydroxy compounds, the following is prepared: 1-(r-methyl-4'-acetoxy-4'-piperidyl)-2-butanone, citrate m.p. 139°; 1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-pentanone, citrate m.p. 164°; 1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-hexanone;

1-(1'-methyl-4'-acetoxy-4'-piperidyl)-3-methyl-2-butanone, citrate m.p. 157°; 2-(1'-methyl-4'-acetoxy-4'-piperidyl)-cyclohexanone, citrate m.p. 162—163°; 2-(1'-methyl-4'-acetoxy-4'-piperidyl)-cyclopentanone, citrate m.p. 158°; 2-(1'-methyl-4'-acetoxy-4'-piperidyl)-6-methyl-cyclohexanone; 2-(1'-methyl-4'-acetoxy-4'-piperidyl)-3-pentanone, citrate m.p. 182—184°; 1-(1',3'-dimethyl-4'-acetoxy-4'-piperidyl)-2-propanone, citrate m.p. 127-129°.

Example 2.

If, in the method according to example 1, 13 g of propionic anhydride is used instead of acetic anhydride and the mixture is stirred for 2 hours, 1-(1'-methyl-4'-propionoxy-4'-piperidyl)-2-propanone citrate is obtained

with melting point 129-130°.

In an analogous way, the following is produced:

1 - (1 '-methyl-4'-propionoxy-4'-piperidyl) 2-butanone, citrate m.p. 162°; 1-(r-methyl-4'-propionoxy-4'-piperidyl)-2-pentanone, citrate m.p. 156°; 1-(1'-methyl-4'-propionoxy-4'-piperidyl)-3-methyl-2-butanone, citrate m.p. 146— 148°;

2-(r-methyl-4'-propionoxy-4'-piperidyl)-cyclohexanone, citrate m.p. 150—152°;

2-(1'-methyl-4'-propionoxy-4'-piperidyl) cyclopentanone, citrate m.p. 146°;

2-(r-methyl-4'-propionoxy-4'-piperidyl)-3-pentanone, citrate m.p. 162—163°.

Example 3.

1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-butanone.

2.1 g of acetyl chloride is slowly poured under good cooling into 5 ml of pyridine, the resulting crystalline precipitate is pulverized with a glass rod and added portionwise to 1-(1'-methyl-4'-hydroxy-4'-piperidyl)-2- the butanone, dissolved in 5 ml of pyridine, under cooling. The mixture is then stirred at room temperature for 2 hours (e.g. with a magnetic stirrer), whereby it turns dark and the precipitate disappears. The pyridine is then evaporated in high vacuum on a rotary evaporator at 20°, the residue is added to ice, made alkaline with concentrated caustic soda and extracted with chloroform. The chloroform solution is dried and evaporated. The residue is dissolved in acetone and by adding an acetonic citric acid solution, the citrate is precipitated and filtered off the base. After recrystallization from methanol-acetone, the 1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-butanone citrate melts at 139°, (compare example 1).

Example 4.

3.5 g of 1-(1'-methyl-4'-hydroxy-4'-piperidyl)-2-propanone and 250 ml of p-toluenesulfonic acid are dissolved in 150 ml of chloroform. The ketene prepared freshly from acetone is passed through this solution (apparatus according to Quadbeck, Angew. Chemie 68, 369 (1956)). The further course of the reaction is followed by thin-layer chromatography. After 15-20 minutes, no more starting material can be determined. During the reaction, the solution changes color to yellow and the temperature is kept at 20° by cooling. The solution is dried and concentrated in vacuo. The acidic solution is made alkaline with soda, the precipitated product is extracted 3 times, each time with 100 ml of ether, and dried with anhydrous sodium sulfate and evaporated. The oily 1-(1'-methyl-4'-acetoxy-4'-piperidyl)-2-propanone is transferred to the citrate, m.p. 153°.

Claims (1)

Process for the production of hitherto unknown therapeutically active piperidine derivatives with the general formula I, where R, means a lower alkyl residue, R2 hydrogen or the methyl residue, and R„ an alkyl residue with a height of 4 carbon atoms or together with R„ -an optionally methyl-substituted trimethylene- to hexamethylene residue, R4 hydrogen or the methyl residue, and R5-CO- an alkanoyl residue with a height of 5, preferably 2-3 carbon atoms, and their salts with inorganic and organic acids, characterized in that at no more than 60°C, preferably from 0°C to room temperature, a hydroxy compound with the general formula II is reacted, where R1, R2, R1, and R1 have the meaning given above, with a halide or anhydride of a lower alkanoic acid or with a corresponding ketene, and if desired transfers the obtained compound of the general formula I to a salt with an inorganic or organic acid.