GB2054371A - Long-acting parenteral compositions of haloperidol and bromperidol derivatives - Google Patents

Abstract

Long-acting neuraleptic compositions for parenteral, in particular intramuscular or subcutaneous, administration, comprise a decanoate ester of haloperidol or bromperidol in sesame oil as a solvent. The esters may be prepared by known methods.

Description

SPECIFICATION Long-acting parenteral compositions of haloperidol and bromperidol derivatives Haloperidol, being chemically designated as 4 -L4 (4 - chlorophenyl) -4 - hydroxy - 1 - piperidinylj - 1 - (4 -fluorophenyl) - 1 - butanone, and bromperidol, being chemically designated as 4 -[4 - (4 bromophenyl) -4 - hydroxy - 1 - piperidinylj - 1 - (4 - fluorophenyl) - 1 - butanone, are both well-known psychotropic agents belonging to the class of4 piperidinols which are described in Japanese Pat.

No.300,049.

Structurally, haloperidol and bromperidol are represented by the formula

wherein X is respectively chloro (haloperidol) or bromo (bromperidol).

The compounds are powerful psychotropic drugs which can be used in psychotropic therapy permitting the return to normal pursuits of patients who otherwise might require prolonged or repeated hospitalization.

After initial recovery or discharge of the patients it is advisable and mostly indispensable to continue the therapy with a maintenance dose to prevent the frequent relapses which are recorded at varying lengths of time after the suspension of treatment.

Although parenteral administration is replaced by oral administration, as soon as possible, many times it is not practicable and then the frequency of injection gets burdensome. This frequency of injection, which is oftentimes accompanied by tissue irritation, makes it desirable to find a composition for intramuscular administration which preserves the psychotropic properties of haloperidol or bromperidol while the frequency of administration can be reduced.

In U.S. Pat. No. 3,408,356 there are described a series of longchain esters of piperidinols and in particular, long-chain esters of 1 - (4 - fluorophenyl) - 4 {4 -[ - 3 - (trifluoromiethyl) phenyl )J -4 - hydroxy - 1 - piperidinyl} - 1 - butanone, which is generally known as trifluperidol ortriperidol. Also disclosed are pharmaceutical compositions comprising said long-chain esters in suitable vehicles. According to U.S. Pat. No. 3,408,356 the concerned compounds exhibit prolonged tranquilizing activity, particularly in the treatment of mental disorders.

The present invention is specifically concerned with pharmaceutical compositions comprising a decanoic acid ester of haloperidol or bromperidol in sesame oil as a solvent.

The decanoic acid esters, which are used as active ingredients in the compositions according to the present invention, may be represented by the formula

wherein X is chloro or bromo.

The subject compositions of the present invention are highly efficaceous and at the same time remarkably safe and almost completely free of any undesired side-effects. More especially, when administered to warm-blooded animals, the said compositions provoke a long-lasting and nevertheless uniform psychotropic effect, which can be varied in duration to up to several weeks depending upon the concentration and the amount of decanoic acid ester which is present in the composition.

The compositions of the present invention have been found remarkably free of excitatory and extrapyramidal side-effects which are rather frequently encountered during trifluperidol therapy. It is evident that a reduction or even complete absence of such side-effects are a prerequisite to a therapy with long-acting psychotropic agents since such effects, if existing, will continue during a long period of time, even after interruption of the treatment. The reduction of these side-effects or even the complete disappearance thereof renders the compositions of the present invention particularly attractive for longterm parenteral therapy. In this respect the subject compositions show a marked superiority over any long-acting psychotropic compositions presently in use.

It has been found that the intramuscular or subcutaneous administration of piperidinols such as haloperidol and bromperidol is often associated with tissue irritation. Quite unexpectedly, the compositions of the present invention are found to be sub stantial ly free of any tissue irritation.

The compounds of formula (II) may easily be prepared by acylating haloperidol (I-a) or bromperidol (I-b)with decanoyl chloride (III).

(I-a) X = Cl (I-b) X Said acylating reaction is preferably carried out following art-known acylating procedures, such as by stirring the reactants together, if desired, in the presence of a suitable solvent, e.g., N,N -dimethyl- formamide, N,N dimethylacetamide, acetonitrile, 2 - propanone, and the like. Somewhat elevated temp eratures are appropriate to enhance the rate of the reaction. Most preferably the reaction is carried out in the presence of an appropriate base, e.g., sodium carbonate, pyridine and the like, to captivate the hydrochloric acid which is liberated during the course of the reaction.

The preparations of the piperidinols of formula (I) are generally known. They may be prepared following one of the procedures described in the literature, e.g., following one of the procedures described in Japanese Pat. No. 300,049.

The effectiveness and the extended duration of action ofthe compositions comprising a decanoate ester of haloperidol or bromperidol can be demonstrated by apomorphine emesis studies. Apomorphine hydrochloride is a central emetic which induces vomiting within a few minutes after subcutaneous injection, except when the test-animals are pretreated with effective neuroleptics. The duration of effectiveness may be determined by chronic induction of apomorphine emesis.

Appropriately selected dogs are injected intramuscularly in the biceps femoris with a test dose. Four hours after dosing and 90 minutes following feeding, apomorphine hydrochloride (0.31 mg/kg) is injected subcutaneously. The animals are observed during 30 minutes following the injection.

Thereafter, the apomorphine hydrochloride is administered daily, 90 minutes following feeding, and observations of the response made during 30 minutes. The duration of action is the period between the first absence of emetic response and the first of three consecutive positive emetic responses.

Table I illustratesthe median duration of action, the test being carried out on 5 dogs.

Table I

Compound Dose Median duration of mg/kg action (days) haloperidol 2.5 5 haloperidol decanoate 2.5 21 bromperidol 1.5 4 bromperidol decanoate 1.5 19 The compositions according to the present invention may contain a suitable antimicrobial preservative but other additives normally are not necessary.

An example of such a preservative is benzyl alcohol.

The compositions may be prepared in a conventional manner, e.g., by admixing the ester with the preservative, if present, and then with the sesame oil. The concentration of the decanoic acid ester may be from about 30 to about 150 mg per milliliter.

By the present invention there is also provided a method of effecting psychotropic therapy which comprises administering to a subject needing such therapy, a psychotropically effective amount of a compound of formula (II) in a composition according to the invention. Psychotropic therapy may generally be effected by administering such compositions in an amount sufficient to supplyfrom 0.4 to 20 mg of active ingredient per kg of body weight.

The preferred route of administration is intramuscular although subcutaneous administration may also be employed.

The following examples are intended to illustrate and not to limit the scope of the present invention.

Example I To a warmed suspension of 37.6 parts of 4 -[4 - (4 chlorophenyl) -4 - hydroxy -1 - piperidinylj - 1 - (4 - fluorophenyl) - 1 - butanone in 320 parts of prop anone are added successively 15.3 parts of N,N diethylethanamine and 28.9 parts of decanoyl chloride. The resulting mixture is heated and refluxed for 18 hours. After cooling the mixture is filtered and the filtrate is evaporated under reduced pressure, yielding a residue which is triturated with 1,1' -oxybisethaneto separate the triethylamine hydrochloride by-product.The filtrate is concentrated and purified by column-chromatography using 1,1' - oxybisethane as eluent, yielding 33 parts (66.3%) of 4 - (4 - chlorophenyl ) -1 - L4 - (4 - fluorophenyl) - 4 - oxobutylj - 4- piperidinyl decano- ate, as a viscous oil.

Example II To a stirred and warm (60"C) solution of 10 parts of 4 (4 - (4!- bromophenyl) -4 - hydroxy -1 piperidinylt - t - (4 - fluorophenyl ) - 1 - butanone in 90 parts of N,N - dimethylformamide are added dropwise 5.76 parts decanoyl chloride. Upon completion, stirring at 600C is continued overnight. The reaction mixture is cooled and poured onto water. The mix ture is alkalized with a sodium hydroxide solution 2N. The aqueous phase is decanted and the sticky oil is dissolved in 1,1' - oxybisethane at room tempera- ture whereupon the unreacted starting material is filtered off. The 1,1' oxybisethane -phase is washed twice with water, dried, filtered and evaporated. The oily residue is purified by columnchromatography over silica gel using 1,1' oxybisethane as eluent, yielding 8.4 parts of4 - (4 - bromophenyl) - 1 -[4 - (4 fluorophenyl) - 4 - oxobutylj - 4- piperidinyl decanoate as an oii.

Example III Injectable compositions are prepared by intermixing the components: composition A: Haloperidol decanoate 70.5 grams Benzyl alcohol 12 grams Sesame oil, q.s. ad 1 liter composition B: Haloperidol decanoate 141 grams Benzyl alcohol 12 grams Sesame oil, q.s. ad 1 liter composition C: Bromoperidol decanoate 34 grams Benzyl alcohol 12 gram Sesame oil, q.s. ad 1 liter composition D: Bromperidol decanoate 136 grams Benzyl alcohol 12 grams Sesame oil, q.s. ad 1 liter.

Claims (8)

1. A psychotropic composition, suitable for parenteral administration, comprising sesame oil as a solvent and as an active ingredient an effective psychotropic amount of a decanoic acid ester having the formula:

wherein X is a chlorine or bromine atom.

2. A composition as claimed in claim 1 comprising from 30 mg to 150 mg of 4 - (4 - chlorophenyl) -1 -[4-(4-fluorophenyl )-4-oxo-butylJ -4 piperidinyl decanoate per ml.

3. A composition as claimed in claim 1 comprising from 30 mg to 150 mg of 4 - (4 - bromophenyl) - 1 -[4-(4-fluorophenyl)-4-oxo-butylj - 4 - piperidinyl decanoate per ml.

4. A composition as claimed in claim 2 which is suitable for intramuscular and subcutaneous administration.

5. A composition as claimed in claim 3 which is suitable for intramuscual and subcutaneous administration.

6. Acomposition as claimed in any one ofthe preceding claims which contains an antimicrobial preservative.

7. A composition as claimed in claim 6 wherein the preservative in benzyl alcohol.

8. A composition as claimed in claim 1 substantially as hereinbefore described.