IE43339B1 - Pharmaceutical compositions - Google Patents

Description

The present invention relates to pharmaceutical compositions comprising N- Q-(31, 41-methylenedi oxphenyl)-prop-2-yl] -N1-(2-chlorophenyl)-pi perazi ne and acid addition salts thereof.

It is known from Irish Patent Specification No. 31348 that compounds of general formula (wherein Ar represents a fused bicyclic aromatic group in which the ring remote from the remainder of the molecule may, if desired, be a carbo- or heterocyclically saturated or aromatic ring; and R-j and R2, which may be the same or different, each represents a hydrogen or halogen atom or trifluoromethyl group or an alkyl or alkoxy with 1 to 4 carbon atoms) and acid addition salts thereof, possess a depressant activity on the central nervous system and, therefor, appear to be suitable for use as sedatives, neuroleptics or major tranquilizers.

The present invention is based upon the discovery that a compound, i.e. N-jj-(3', 4'-methylenedioxyphenyl)-prop-2-yl] -N‘-(2-chlorophenyl)-piperazine and the physiologically compatible acid addition salts thereof, possess the property 3f decreasing the level of lipids and the cholesterol level in the blood.

In particular tests which have been conducted show that PJ-Q-(3',4'nethylenedioxyphenyl)-prop-2-j3 -N'-(2-chlorophenyl)-piperazine and its physioljgically compatible acid addition salts are even superior to the compounds disposed in Irish Patent Specification No. 36586. Furthermore, the toxicity - 2 4 3 3 3 9 of the compounds of the present inyention is low, so that these compounds are suitable for therapeutic use.

Thus according to one feature of the present invention there are provided pharmaceutical compositions in the form of dosage units comprising as active i ngredient N- [l·· (3',41-methylenedi oxyphenyl)-prop-2-yT] -N ’ -(2-chlorophenyl)piperazine or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient, each dosage unit containing greater than 40 mg, but no greater than 60 mg of active ingredient.

The compositions advantageously also contain a coronary dilator.

The coronary dilator to be employed in the pharmaceutical compositions of the present invention may, for example, include any of the following: 3-(B-di ethyl ami noethyl)-4-methyl-7-carbethoxymethoxy-2-oxo-?#-chromen; 3,3'-(N,N'-dimethylethylenediamino)-bis-(propyl) 3,4,5-trimethoxybenzoate; N-31-phenyl propyl -(2')-1,1-di phenyl-(3)-ami ne; α-isopropyl-a-[N-(methyl-Nhomoveratryl)-Y-aminopropyj] -3,4-dimethoxyphenyl-acetonitrile and L-w-(B-hydroxya-methyl-phenylethylamino)-3-methoxy-propiophenone, but is preferably dipyri damoT. Thus, for example, for the prophylactic treatment of coronary thrombosis, compositions according to the invention contain N-[?-(3,4-methy1enedioxyphenyl )-prop-2-yl] -Ν' -(2-chlorophenyl)-pi perazine or a physiologically compatible acid addition salt thereof and a coronary dilator such as 'dipyridamol' (i.e. 2,6-bis-(diethanolamino)-4,8-dipiperidinopyrimido (5,4]-pyrimidine].

Pharmaceutical compositions comprising as active ingredient N-[l-(3,,4'methylenedioxyphenyl)-prop-2-y|]-Nl-(2-chlorophenyl)-piperzine or a physiologically compatible acid addition thereof and a coronary dilator together with a pharmaceutical carrier or excipient are described and claimed in our copending British Patent Application No. 36147/75 (Serial No. 1521051) although no claim is made therein to pharmaceutical compositions in dosage unit form, wherein each dosage unit contains a coronary dilator, a pharmaceutical carrier or excipient and greater than 40 mg but no greater than 60 mg of N- 1-(31,4'-methylenedioxyphenyl )-prop-2-yTj -N'-(2-chlorophenyl)-piperazine or a physiologically compatible acid addition salt thereof.

N-[l-(31,4'-methylenedi oxyphenyl)-prop-2yl] -N1 -(2-chlorophenyl)-piperazi ne or a physiologically compatible acid addition salt thereof is preferably administered in a daily dosage of from 40 to 60 mg.

Where the compositions according to the invention are in the form of dosage units containing a coronary dilator each dosage unit preferably contains from 10 to 150 mg of the coronary dilator. The daily dose of coronary dilator is advantageously from 50 to 150 mg. Ν- [ϊ- (31,41-methylenedi oxyphenyl)-prop-2y]| -N1-(2-chlorophenyl)-pi perazine contains an asymmetric carbon atom and thus exists not only in racemic form but - 3 43339 also in the form of optically active isomers. It will be appreciated that pharmaceutical compositons containing any or all such forms of this compound (and physiologically compatible acid addition salts therof) are within the scope of the present invention.

N- [l_- (31 -4 '-methyl enedi oxyphenyl) - pro p-2 -yTJ -N' - (2-chl orophenyl) -pi peraxine, in either racemic or optically active form, and its physiologically compatible acid addition salts thereof may, for example, be prepared as described in Irish Patent Specification No. 31348.

The compositions may be presented in a package in association with instructions for the use thereof. Such directions may be written or printed and may, for example, be physically attached to a container for the composition or the package may comprise a container for the compositions and separate instructions. Pharmaceutical products are conventionally marketed in, for example, a bottle (e.g. containing tablets or capsules), ampoules or vials, the container bearing itself printed or written instructions for the intended use of the product and/or being accompanied by separate printed or written instructions for such use. Pharmaceutical products are thus commonly marketed together vith a leaflet, offen called a package insert which describes the intended nedical use of the product concerned and may, for example, reconmend daily doses, jossible side effects (if any) and provide other useful medical information to :he medical practitioner.

The pharmaceutical compositions may be presented, for example, in a form iuitable for oral, parenteral or rectal administration. Thus the compositions lay, for example, be presented in the conventional pharmacological forms of dministration such as, for example, tablets, coated tablets, emulsions, powders, apsules or in a form suitable for obtaining sustained release. These compositons ay, for example, be produced by the use of conventional pharmaceutical excipients mploying the conventional methods of preparation.

Tablets may be produced, for example, by mixing the active ingredients with nown excipients, such as inert diluents e.g. calcium carbonate, calcium phosphate r lactose, disintegrants such as corn starch or alginic acid, binders such as tarch or gelatin, lubricants such as magnesium stearate or talcum and/or agents )r obtaining a sustained release such as carboxypolymethylene, carboxymethylsllulose, cellulose acetatephthalate or polyvinyl acetate. The tablets may, r desired, also consist of several layers.

Coated tablets e.g. sugar-coated tablets may be produced in a similar inner by coating cores, produced in a similar manner to the tablets, with lents generally used for tablet coatings, such as polyvinylpyrrolidone, shellac, m arabic, talcum, titanium dioxide or sugar. In order to obtain sustained lease effects or in order to avoid incompatibilities, the core may consist of veral layers. The tablet coat may also consist of several layers in order - 4 43339 to obtain a sustained release, in which case the excipients mentioned aboye for tablets may be used.

Syrups of the active ingredient or active ingredient combinations according to the invention may, if desired, additionally contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, and/or a taste improving agent such as flabourings, e.g. vanillin or orange extract.

They may also contain suspension agents or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxy-benzoates.

Capsules containing an active ingredient or active ingredient combinations may, for example, be produced by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling the mixture into gelatine capsules.

Suitable suppositories may be produced, for example, by mixing the active ingredient or active ingredient combinations with the conventional carriers envisaged for this purpose such as neutral fats or polyethylene glycol or derivatives thereof.

For parenteral administration, the carrier may be a sterile, parenteraily compatible liquid such as sterile water, or a parenteraily compatible oil e.g. arachis oil, in the form of injection solutions contained in ampoules.

The cholesterol decreasing action of N-[l-(3',4'-methylenedioxyphenyl)prop-2ylj Ν'-(2-chlorophenyl)-piperazine and the physiologically compatible acid addition salts thereof was examined in a trial lasting 18 days and involving rats of the FW49 strain. The compound was administered perorally, once daily by stomach-probe, in emulsion form together with the solubilizer Tween 80 (the word 'Tween' is a registered Trade Mark). The controls received physiological, common salt soluti on together with 'Tween' 80.

The serum-cholesterol was determined according to the methods of Levine, and J. and 8. Zak in Clin. Chem. Acta'zfo, pages 381-384 (1964). The doses of Clofibrate, a preparation at present on the market, were 6 times higher than doses of'other substances. The results are presented in the following table: Compound Day 0 Day 4 Day 8 Day 18 A. Comparison Compounds Clofibrate 93.3 72.8 65.6 78.1 N-[T-(3' ,4'-Methylenes. dioxyphenyl)-prop-2-yl] Ν'-phenylpiperazine, HCl (-22%) (-30%) (-16%) 89.9 70.8 55.7 51.3 (-21%) (-38%) (-43%) B. Compound employed in the compositions of the present invention N-jj- (3 ’, 4' -Methyl ened i oxyphenyl )-prop-2-yl| -Ν'-(2- chlorophenyl) piperazine. HCl 75.0 33.7 (-55%) 20.3 (-73%) 5.9 (-92%) The total cholesterol content (average over 10 animals) in mg per 100 ml serum and the percentage decrease over the course of the examination is stated in each case together with the final value for each group (Day 0 = 100$).

The following non-limiting Examples serve to illustrate the invention.

In each case the compositions were packaged together with printed directions for the use of the compositions in reducing the blood lipid level and the blood cholesterol level.

EazrapZe I (Tablets) N-{T-(3',4’-methylenedioxyphenyl)prop-2-yl] -N-(2-chlorophenyl)piperazine. HCl lactose corn starch sec. calcium phosphate water soluble starch magnesium stearate colloidal silicic acid mg 50 mg 93 mg 47 mg 3 mg mg mg 250 mg Produotion: The active ingredient is mixed with part of the excipients, thoroughly kneaded with an aqueous solution of the starch and granulated with the aid of a screen in the conventional way. The granulate is mixed with the remaining excipients and pressed into tablets each weighing 250 mg.

Example 2 (Tablets) li- ¢-(31,4'-methylenedioxyphenyl)prop-2-yl] -N‘-(2-chlorophenyl)piperazine. HCl 3,31-(Ν,N1-di methy1 ethylenedi ami no)bis-(propyl -3,4,5-trintethoxy benzoate) lactose corn starch sec. calcium phosphate water soluble starch magnesium stearate colloidal silicic acid mg mg 50 mg 93 mg 47 mg 3 mg mg mg 295 mg •Oduation: As described in Example 1.

Claims (7)

1. Pharmaceutical compositions in the form of dosage units comprising as active piperazine or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient, each dosage unit con5 taining greater than 40 mg, but no greater than 60 mg of active ingredient. Compositions as claimed in claim 1 which further contain a coronary dilator.

2. 3. Compositions as claimed in claim 2 wherein the coronary dilator comprises 2,6-bis-(diethanolamino)-

3. 4,8-dipiperidino-pyrimido |δ,4-^ pyrimidine. 10 4. Compositions as claimed in claim 2 where the coronary dilator comprises 3-(e-diethyl ami noethyl)-4-methyl-7-carbethoxymethoxy-2-oxo-2tf-chromen; 3,3'(N,N'-dimethylethylene-diamino)-bis-(propyl 3,4,5-trimethoxybenzoate); N-3‘phenyl-propyl-(2 1 )-1,1-diphenyl-(3)-amine; a-isopropyl-a- ^-(methyl-N-homoveratryl)-Y-aminopropy| -3,4-dimethoxyphenylacetonitrile or L-u-(e-hydroxy-

4. 5. Compositions as claimed in any one of claims 2 to 4 wherein each dosage unit contains from 10 to 150 mg of a coronary dilator.

5. 6. Compositions as claimed in any one of the preceding claims in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, 20 suspensions, powders, drops, suppositories or injection solutions.

6.

7. Compositions as claimed in claim 1 substantially as herein described in either Example 1 or Example 2,