FI59407B - FRUIT PROCESSING OF NEUROLEPTIC 1- / N- (P-FLUORBENZOYLPROPYL) -4-PIPERIDYL / -IMIDAZOLIDINONE (2) -DERIVATIVES FOR DERAS SYRAADDITIONSSALTER - Google Patents

Description

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, Federal Republic of Germany-Förbundsrepubliken lyskland (EE) P 2U23896.8 (71) C.H. Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (72) Adolf Langbein, Ingelheim / Rhein, Gerhard Walther, Bingen / Rhein,

Peter Danneberg, Ockenheim, Franz Josef Kuhn, Bingen / Rhein, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (7U) Leitzinger Oy (5U) Method for neuroleptic 1- (N- (p-fluorobenzoylpropyl) -U-piperidyl / imidazolidinone (2 for the preparation of derivatives and their acid addition salts - For the preparation of derivatives of neuroleptic 1- (N- (p-fluorobenzoylpropyl) -U-piperidyl] imidazolidinone (2) derivatives and derivatives

The invention relates to a process for the preparation of neuroleptic 1- [N- (p-fluorobenzoylpropyl) -4-piperidyl] imidazolidinone (2) derivatives of formula I

0

II

R1 C

Y T-O - CH2 - CU2 - CH2 - CO-^-^ -F (I) CH2 - CH2 having a hydrogen atom or an acetyl group, and for the preparation of their physiologically harmless acid addition salts.

The invention is characterized by the method alternatives a) and b) described below.

a) Correspondingly substituted 1- (piperidyl) -4- (4)) - imidazolidinone of general formula II (2) 2 59407

O

R1 \ N- ('NH (II) ch2-: ακ2 in which is as defined above can be alkylated with p-fluorobutyrophenone of formula III

F —— co “CH2” CH2 “CH2“ Y (HD

wherein Y is a group which is cleavable under the reaction conditions, in particular a residue of a strong inorganic or organic acid such as hydrohalic acid, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or an organic sulphonic acid, for example benzene or toluenesulphonic acid or alkyl sulphonyl sulphonic acid.

The alkylation takes place in the usual manner, preferably in the presence of an acid scavenger, in which case a calculated amount or excess of the compound of formula III is used. Acid binding agents which may be mentioned are, in particular, triethylamine, dicyclohexylethylamine, sodium carbonate, potassium carbonate, calcium oxide or, preferably, sodium hydrogen carbonate.

Although a solvent is not absolutely necessary, it has proved expedient to add an inert solvent, such as a lower alcohol, chloroform, toluene, nitromethane, tetrahydrofuran or, preferably, dimethylformamide, or also a mixture of two or more of said solvents.

The reaction temperature depends essentially on the starting materials used in each case; it can vary within wide limits, is generally between 50 and 150 ° C; best performed at the reflux temperature of the reaction solution. In many cases, it has proved advantageous to add a catalytic - equal molar amount of potassium iodide or sodium iodide to the course of the reaction.

3 59407 b) Compounds of formula I in which R 1 is an acetyl group are obtained by acetylation with acetyl chloride or acetic anhydride of compounds of formula I having a hydrogen atom.

The final products of general formula I thus obtained can be converted into their acid addition salts in the customary manner. Suitable acids for this reaction are those which give physiologically acceptable salts, for example hydrohalic acid, nitric acid, sulfuric acid, o-phosphoric acid, oxalic acid, citric acid, tartaric acid, fumaric acid, maleic acid, propionic acid, acetic acid, butyric acid, butyric acid, acetic acid, , marine resin, etc.

The starting compounds used in process a) are known or can be obtained by known methods. The compounds of the formula II can be prepared according to German Offenlegungsschrift No. 2,341,229.

For example, the following end products can be prepared by the above methods, optionally as their acid addition salts: 1- [N- (3- {p-fluorobenzoyl} propyl) -4-piperidyl] imidazolidinone- (2).

The novel compounds of the general formula I have a typical neuroleptic activity profile and can therefore be used as central nervous system depressants, sedatives and sedatives.

In contrast to known neuroleptics, which can show a strong antagonistic effect against adrenaline, amphetamine and apomorphine in animal experiments, the compounds according to the invention have a strong anti-adrenaline effect but not an anti-amphetamine and apomorphine effect. The potent anti-apomorphine activity of the known neuroleptics is the reason for the more or less obvious extrapyramidal side effects, especially when the medicine lasts for a long time and the dose is 59,407 high. From the fact that the compounds according to the invention do not have an anti-apomorphine and amphetamine effect, it can be concluded that said adverse side effects on the dopaminergic extrapyramidal system are at least greatly reduced, although they cannot be completely attenuated.

In addition, the new compounds have substantially lower toxicity; when the LD50 of haloperidol is about 170 mg / kg p.o., the compounds of the invention generally have this value between 1000 and 2000 mg / kg p.o. and in many cases even substantially higher.

Pharmacological comparative tests

The pharmacological properties of the compounds prepared according to the invention and the structurally similar compounds according to the prior art have been compared on the basis of the experiments described below. As the prior art, the Finnish publication 5617KIV compound) and U.S. Patent 3,161,637 (compound i-m) are used.

1. The adrenaline antagonistic effect was examined by the method described by P.A.J. Janssen et al., Arzneimittelforschung (Drug Research) 13, 203 (1963). The ED_n value refers to a dose that protects 50% of the experimental animals against a lethal dose of adrenaline.

2. The explosion-suppressing effect was studied by J.R. By the method developed by Borssin et al., Therapie 19, 571 (1964). The ED 50 value refers to the dose that provides 50% exploration attenuation in the Planche-d-Trous situation.

3. Exercise damping was determined by the method developed by P.A.J. Janssen et al., Psychopharmacologia 1, 389 (1960). The ED, -g value refers to the dose that provides 50% attenuation in motility in the Open-Field test.

4. The toxicity of the compounds was determined by a 24-hour monitoring experiment. The LD 2 value was calculated by J.T. Litchfield and F. Wilcoxon, J. Pharm. Exp. Ther. 9J5, 99 (1949).

Mice were used as experimental animals.

59407

The experiments gave the results shown in the following table, which show that the compound according to the invention is considerably more effective but at the same time more non-toxic than the compounds according to the prior art.

R-CO-N- ^ ^ N-CH2-CH2-CH2-CO-1 ·

Background Art Invention; r, = C6H5 R '= CgH5 R' ^ CgHg R '= H R + R' = j

Test R = CH3 R * C2H5 R = i-C3H7 R ^ NHCgHg NH- (CH2) 2 ~

Adrenaline antagonism 47> 90> 90 3.3 0.33 (ED50, mg / kg)

Explosion attenuation> 90> 140> 140 45 3.8 (ED5q, mkg / kg):

Exercise damping 125> 140> 140 135 2.1 (ED50, mg / kg

Toxicity 350 500 780 300 840 (LD50, mg / kg)

Example 1 1- [N- (3- {p-Fluorobenzoyl} propyl) -4-piperidyl] imidazolidinonione- (2) 1.69 g (10 mmol) of N- (4-piperidyl) imidazolidinone- ( 2), 2.2 g (11 mmol) of p-fluoro-β-chlorobutyrophenone, 1.26 g (15 mmol) of sodium hydrogen carbonate and 1.66 g (10 mmol) of potassium iodide are stirred in 25 ml of dimethylformamide for 2 hours at 100 ° C. The suspension is largely evaporated on a rotary evaporator at 70 ° C. The residue is partitioned between methylene chloride (250 ml) and water (100 ml). The organic phase is then shaken vigorously five times with 125 ml of water. After separation of the organic phase, it is dried over sodium sulfate, filtered and evaporated. The residual oil is dissolved in 10 ml of ethanol and 2 ml of 5N ethanolic hydrochloric acid are added. Careful addition of 60 ml of ether causes the hydrochloride of the above compound to crystallize. 1.9 g or 51.5% of theory are obtained, melting point 250-252 ° C.

Example 2 1-Acetyl-3- [1- (3-p-fluorobenzoylpropyl) -4-piperidyl] imidazolidinone-2-hydrochloride 3.3 g (10 mmol) of 1- [N-3- {p-fluorobenzoyl} - propyl) -4-piperidyl-imidazolidinone (2) is dissolved in 25 ml of benzene, 4.71 ml = 5.1 g (50 mmol) of acetic anhydride are added and the mixture is refluxed for 5 hours. It is then evaporated on a rotary evaporator, the residue is made alkaline with ammonia and extracted three times with 50 ml of methylene chloride. The organic phase is separated, dried and evaporated. The residue is dissolved in ethanol, converted into the hydrochloride using a calculated amount of ethanolic hydrochloric acid and crystallized by adding ether. 3 g or 73% of theory of the hydrochloride with a melting point of 257-258 ° C are obtained.

Claims (1)

A process for the preparation of neuroleptic 1- [N- (p-fluorobenzoylpropyl) -4-piperidyl] imidazolidinone (2) derivatives of the formula I q NN - ^ \ - CH2 - CH2 - CH2 - CO - F (I) ch2-ch2 in which R1 is a hydrogen atom or an acetyl group, and for the preparation of their physiologically innocuous acid addition salts, characterized in that a) a compound of the general formula II R o Χ \ η (f \ C \ / \ / \ NN - ( NH (II) II ch.9 - »CH2 in which R1 is as defined above is alkylated with a p-fluorobutyrophenone of the formula III F -co-CH2-CH2-ch2-Y (III) in which Y is a strong inorganic or organic acid group, such as hydrohalic acid, for example hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an organic sulphonic acid, for example benzene or toluenesulphonic acid or alkylsulphonic acid, or that b) a compound of formula I in which R 1 is an acetyl group, in which R 1 is a hydrogen atom, is reacted with an acetylating agent such as acetyl halide or acetic anhydride, and that, if desired, the final product of the formula I thus obtained is converted into a physiologically harmless acid addition salt in a manner known per se. 8 59407 For the preparation of neuroleptic 1- (N- (p-fluorobenzoyl-propyl) -4-piperidyl-imidazolidine (2) -derivatives and the addition of hydrogen compounds to the compounds of formula I 9 ^ "" O 'CH2 "CH2' ™ 2 '00 “V / F m CH2 - CH2 is a hydrogen atom or an acyl group and a physiologically acceptable compound, which is present at the time, a) in the case of a compound of formula II 0 R1 c X / \ / —VNN - (NH (II) I 1 CH2 - CH2 from the group R ^ har ovan angivna betydelser, alkyleras med p-fluorbutyropenone enligt formuleln III f —CO - ch2 - ch2 - ch2 - Y (III) där Y är en Stark oorganisk eller organisk syragrupp, säsom halogenväte-syra, t.ex.chlorotesyrara, bromoätesyra or iododätesyra, svavel-syra eller en organic sulfonyl, t.ex. benzene- or toluenesulfonyl-syra eller en alkylsulfonsyra, eller b) for framställ I, color R ^ är en acetylgrupp, en föreningen enligt formuleln I, color R ^ är en väteatom, omsättes med ett acety leningsmedel, säsom acetylhalogenid eller acetanhydride, och att om sk savskas, den erhällna slutprodukten enligt formuleln I överföres pä känt sätt account sitt physiologiskt godtagbara syraadditionssalt.