NO135248B - - Google Patents

Description

The present invention relates to an analogue method for the production of new derivatives of α-phenyl-4-piperidine methanols. More specifically, the invention relates to an analogue process for the production of new derivatives of 4-[4-(α-hydroxybenzyl)-piperidino]-4'-fluorobutyrophenones which are neuroleptics useful as sedatives.

The new derivatives of α-phenyl-4-piperidine methanols have the following general formula:

where R is hydrogen, chlorine, bromine or fluorine, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms. trifluoromethyl or phenoxy and may be connected to the phenyl ring in ortho-, meta- or para^tillation, and pharmaceutically acceptable acid addition salts thereof. The preferred compounds according to this invention are those of the above general formula where R is fluorine, chlorine or trifluoromethyl radical substituted in the meta or para position on the phenyl ring. The preferred compounds are represented by the general formula:

where R' is fluorine, chlorine or trifluoromethyl, and the R'^ substituent is connected to the phenyl ring in the meta or para position.

The present invention also includes the preparation of pharmaceutically acceptable acid addition salts of the compound of the above formula, such as salts with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like and with organic carboxylic acids.

Representative compounds produced according to the invention are, for example, 4'-fluoro-4-[4-(p-fluoro-a-hydroxybenzyl)-piperidino]-butyrophenone, 4-[4-(p-chloro-a-hydroxybenzyl)piperidino]-4 '-fluorobutyrophenone, 4'-fluoro-4-[4-(m-trifluoromethyl-α-hydroxybenzyl)piperidino]butyrphenone, 4<1->fluoro-4-[4-(α-hydroxybenzyl)-piperidino]butyrophenone, 4 <1->fluoro-4-[4-(p-methyl-α-hydroxybenzyl)-piperidino]butyrophenone, 4<1->fluoro-4-[4-(p-methoxy-α-hydroxybenzyl)-piperidino]- butyrophenone, 4-[4-(p-tert-butyl-α-hydroxybenzyl)piperidino]-41-fluorobutyrophenone and 4<1->fluoro-4-[4-(p-phenoxy-α-hydroxybenzyl)piperidino]-butyrophenone enon.

The new compounds produced according to the invention are neuroleptic agents which are useful as sedatives for animals in the form of pharmaceutical preparations containing the new compounds suitable for oral or parenteral administration. The pharmaceutical preparations may be available in solid form or as liquids, such as tablets, capsules, solutions, suspensions or emulsions. The amount of it. new compound, in unit doses with a specific amount of pharmaceutically acceptable carrier, can vary within a wide range, e.g. from 0.005 to 10 mg per kg body weight of the animal per dose to provide the desired sedative effect. This is achieved, for example, by consuming 5-25 mg tablets taken 1-4 times a day.

When the compound according to example 1 was administered orally to mice at a dose level of 0.35 mg/kg, the toxic effect of d-amphetamine in the group of mice was inhibited in 50% of the mice when these were tested according to the method described in J. Burn et al., Arch. Int, Pharmacodyn. 113, 290-5 (1958), while

a dose level of 1.2 mg/kg of the known sedative chlorpromazine is required to inhibit the toxic effect of d-amphetamine in 50% of the corresponding group of mice. When the compound according to example

pel 1 was orally administered to mice at a dose level of 1.2 mg/kg, correspondingly pernicious self-taming was inhibited in 50% of the mice when these were tested according to the method described in A, Kandal et al., Fed. Pro. 19 (1 pt. 1) 24 (1960).

The neuroleptic activity of the new compounds is also illustrated by their effectiveness in blocking conditioned avoidance behavior in rats and by inducing catalepsy in mice. Interaction with the forced motor behavior on a rotating rod is demonstrated when the compounds of this invention are administered to mice.

Closely related compounds are known from US patent 3,438,991, for example the compound haloperidol, a known sedative with the following formula:

From French patent document 7.4.31 M is there. for example, the following connection is known:

Comparison data for the above two compounds with the compound prepared according to example 1 in the present reference and with the formula: shows that the compound prepared according to example 1 is superior as a sedative compared to the two reference compounds.

In the above table, the given data in the three tests, i.e. anti-amphetamine, anti-apomorphine and pernicious self-tampering ED^Q doses in milligrams per kg when the compounds are administered orally. Each of these test systems is known to be good indicators of sedative effects and is performed on mice.

The anti-amphetamine test data show that the compound prepared according to Example 1 is approx. 3.6 times more effective as a sedative than compound A.

The pernicious self-tampering data also indicate that the compound prepared according to example 1 is more effective as a sedative than compound A. The test results show that more compound A is needed than the compound prepared according to example 1 to prevent the animals from tampering with themselves. Self-taming is an indication of agitation in the animal, and prevention or reduction in self-taming shows that the compound calms the animal. The compound produced according to example 1 is approx. 24 times more effective than compound A in reducing this agitation-like effect.

The anti-amphetamine data for haloperidol and the compound prepared according to Example 1 are of the same order of magnitude, showing that these are approximately as effective as sedatives. However, the anti-apomorphine data show that the compound prepared according to Example 1 will have less extrapyramidal side effects than haloperidol. It is known that a compound that strongly inhibits apomorphine has a high tendency to induce Parkinson-like side effects or extrapyramidal effects. This appears from Fed. Pro. 3_2, 200 (1973). The given data show that haloperidol is more than 25 times more potent than the compound prepared according to Example 1 in inhibiting apomorphine and thus has a significantly greater propensity to induce the Parkinson-like side effects. Thus, at a dose at which haloperidol will induce a therapeutic sedative effect, i.e. 0.19 mg/kg, a significant probability that the compound will also induce the harmful extrapyramidal side effects. On the other hand, at a dose at which the compound prepared according to Example 1 will produce a therapeutic sedative effect, i.e. 0.35 mg/kg, it is unlikely that any harmful extrapyramidal side effects will be produced, as there is a large margin here, about. 12 times between the •sedative therapeutic dose and the dose necessary to induce the side effect, which dose is 4.6 mg/kg.

The compounds are prepared by reacting optionally substituted α-phenyl-4-piperidine methanols or salts thereof with a slight excess of 4'-fluoro-4-halobutyrophenone in the presence of an excess of an acid acceptor such as e.g. sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate optionally with a small amount of potassium iodide in a suitable solvent. The mixture is reacted over a wide temperature range from 80°C to 180°C, although it is possible to use temperatures above and below this range. Typically, the reaction is carried out over a time period of

from 1 to 3 days, during which any released water can be collected. As examples of suitable solvents for a reaction, toluene, xylene, chlorobenzene, methylisobutyl ketone or lower alcohols such as ethanol, propanol, butanol and the like can be given.

After completion of the reaction, the reaction mixture is filtered, and the product is isolated after removal of the solvent. Alternatively, the filtrate can be treated with mineral or organic acids and diethyl ether, whereby the corresponding salts of the product are obtained. The impure product is filtered off, purified by recrystallization and dried. Suitable solvents for recrystallization are methanol, ethanol, isopropyl alcohol, butanone, acetone, ethyl acetate, diethyl ether and the like.

The usual method for preparing the compounds according to this invention can be illustrated by the following reaction scheme:

where R is as previously indicated and X is a reactive halogen such as bromine, chlorine or iodine. α-Phenyl-β-piperidine methanol derivatives, compound .1, can be prepared by reduction of the corresponding ketone derivatives. This reduction can be carried out by various methods, preferably by catalytic hydrogenation, or metal hydride reduction. Compound 1 can also be prepared by reacting a substituted phenyl Grignard reagent with ^-pyridinecarboxaldehyde or ^-cyanopyridine followed by catalytic reduction of the thus obtained intermediates, the α-phenyl-^-piperidinemethanol derivative can be isolated as the free base or as a salt, e.g. the hydrochloride. Representative substituted α-phenyl-^-piperidine methanol starting materials which find use in the preparation of the compounds according to this invention are listed in Table I.

The substituted phenyl-k-piperidyl ketone intermediates used in the preparation of compound 1 can be prepared by a Friedel-Craft reaction of benzene or a substituted benzene with isonipecotin chloride hydrochloride or N-(trifluoroacetyl)isonipecotin trifluoroacetic anhydride followed by of aqueous potassium carbonate hydrolysis

in the latter case. Reaction of a substituted phenyl Grignard reagent with β-cyanopiperidine, which can be prepared by hydrolysis of N-trifluoroacetyl-β-cyanopiperidine with aqueous potassium carbonate, can also give the ketone intermediates.

h1 -Fluoro-^f-halobutyrophenone, compound 2, is commercially available or can be prepared by reacting w-halobutyryl halide with fluorobenzene in the presence of aluminum chloride. Compound 2 can also be prepared by reacting _p_-fluorophenylmagnesium halide with ω-halobutyronitriles.

The following examples illustrate the invention.

Example 1

h1 - fluoro-*+-["**-( P- fluoro-a- hydroxybenzyl) piperidino]- butyroph enone

To α-(β-fluorophenyl)-β-piperidinemethanol obtained from 26.0 g

(0.11 mol) of the corresponding hydrochloride in 100 ml of toluene was added

added k0 g of potassium carbonate, 23.0 g (0.12 mol) of ^-chloro-V-fluorobutyro-phenone and 0.1 g of potassium iodide. The resulting mixture was stirred on a steam bath for <*>f8 hours and the inorganic residue filtered off and washed with a small amount of butanone. The filtrate was diluted with anhydrous diethyl ether and treated with ethereal hydrogen chloride where

by the hydrochloride of h'-fluoro-1+-[1+-(£-fluoro-α-hydroxybenzyl)piperidino]butyrophenone was obtained. This material was recrystallized from methanol-butanone and then extracted as free base in chloro-

form after treatment with 10$ sodium hydroxide solution. The chloroform extracts were dried over anhydrous magnesium sulfate and concentrated to a residue which was recrystallized from absolute ethyl alcohol to give M-'-fluoro-1+-[1+-(_p_-fluoro-α-hydroxybenzyl)piperidino]butyrophenone, m.p. 1M-8-150°C.

Example 2

By using the method indicated in Example 1, and using suitable substituted α-phenyl-^-piperidinemethanol, the following compounds were prepared:

!+-[ k - (p_-chloro -a -hydr oxybenzyl) p iper idino ] - k1 -fluoro butyroph enone,

sm.p. l<1>+8-l50°C. V-fluoro-^-[W(m-trifluoromethyl-α-hydroxybenzyl)piperidino]-butyrophenone, m.p. 128.5-132.0°C. (mandelic acid salt).

Example

V - fluoro-tf-f1+-(α-hydroxybenzyl)pyr)eridino]butyrophenone

To 75.7 g (0.^ mol) α-phenyl-^-piperidinemethanol in 500 ml toluene was added 88.0 g (0.<*>4f mol) if-chloro-<1>+'-fluorobutyrophenone, 80 .0 g of potassium bicarbonate and 0.1 g of potassium iodide. The reaction mixture was stirred at 100°C for 6 h, filtered and the resulting solution concentrated in vacuo to a solid residue, which was recrystallized from isopropyl alcohol to give the desired product. M.p. 102°C (dec.).

Example 4

By applying the method indicated in Example 3 and using suitable substituted α-phenyl-4-piperidin methanol, the following compounds were prepared: 4'-fluoro-4-[• (p_-methyl-α-hydroxybenzyl) piperidino] butyrof enone, sm.p. 144.5 - 145.5°C 4'-Fluoro-4-[4-(£-methoxy-α-hydroxybenzyl)piperidino]butyrophenone, sm.p. 101 - 102.5 C 4-[4-(£-t-butyl-α-hydroxybenzyl)piperidino]-4<1->fluorobutyrophenone, sm.p. 111 - 112.5°C 4'-fluoro-4-[4-(p-phenoxy-α-hydroxybenzyl)piperidino]-butyrophene, m.p. 195.5 - 196.5°C.

Claims (4)

1. Analpgifi:emgangsmeer"for the preparation of therapeutically active compounds of the general formula: where R is hydrogen, chlorine, fluorine, bromine, alkyl with 1 - h carbon atoms, alkoxy with 1 - h carbon atoms, trifluoromethyl or phenoxy, and pharmaceutically acceptable acid addition salts thereof, characterized in that α-phenyl-*f-piperidinmethanol or a salt thereof of the general formula: is reacted in the presence of an excess of an acid acceptor with an excess of 1+' -fluoro-V-halobutyrophenone of the general formula where R is as previously indicated and X is a reactive halogen. 2. Analogous method according to claim 1 in the preparation of 4<1->fluoro-4-[4-(p-fluoro-a-hydroxybenzyl)piperidino]butyrophenone or a pharmaceutically acceptable acid addition salt thereof, characterized in that a-(p-fluorophenyl) -4-piperidine-methanol or a salt thereof is reacted with 4-chloro-4'-fluorobutyro-phenone. 3. Analogous method according to claim 1 in the preparation of 4'-fluoro-4-[4-(p-chloro-a-hydroxybenzyl)piperidino]butyrophenone or a pharmaceutically acceptable acid addition salt thereof, characterized in that a-(p-chlorophenyl)- 4-piperidine-3-methanol or a salt thereof is reacted with 4-chloro-4'-fluorobutyro-phenone. 4. Analogue method according to claim 1 in the preparation of 4'-fluoro-4-[4-(m-trifluoromethyl-α-hydroxybenzyl)piperidino]-butyrophenone or a pharmaceutically acceptable acid addition salt thereof, characterized in that α-(m-trifluoromethyl-phenyl) )-4-piperidinemethanol or a salt thereof is reacted with 4-chloro-4'-fluorobutyrophenone.