CH615178A5 - Process for the preparation of novel substituted N-[1-(3,4-methylenedioxyphenyl)-propyl-(2)]-N'-phenylpiperazines - Google Patents

Abstract

Novel substituted N-[1-(3,4-methylenedioxyphenyl)-propyl-(2)]-N'-phenylpiperazines of the formula I shown, wherein either R1 and R2 denote chlorine or R1 denotes methyl and R2 denotes methoxy, are prepared by reacting N-[1-(3,4-dihydroxyphenyl)-propyl-(2)]-N'-(2,4-dichlorophenyl)-piperaz ine or N-[1-(3,4-dihydroxyphenyl)-propyl-(2)]-N'-(2-methyl-4-methoxyphenyl)-p iperazine with a compound of the formula X-CH2-X, wherein X denotes a radical which can easily be cleaved anionically, preferably chlorine or bromine. The reaction is advantageously carried out with addition of an acid-binding agent and with heating. The compounds of the formula I may be obtained in the form of the racemates or of the optically active antipodes. The products of the process show a good central-depressant action as well as an excellent blood lipid level-lowering and cholesterol-lowering action. <IMAGE>

Description

The invention relates to a method according to the preamble of patent claim 1.

From DE-OS 1 670 144 it is already known that compounds of the formula II

(II),

wherein

Ar is an aromatic radical with two rings fused together, of which the ring not bound to the residual molecule can be an iso- or heterocyclic, saturated or aromatic ring; and

Ri and R2 are hydrogen, halogen, trifluoromethyl or an alkyl or alkoxy group with 1 to 4 carbon atoms, and their acid addition salts have valuable central depressive properties.

It has now been found that the compounds of the formula I, which are not described in DE-OS 1 670 144 themselves, and their physiologically tolerated acid addition salts, in addition to the central depressive action, also have an excellent blood lipid and cholesterol-lowering action and accordingly in preparations for lowering blood lipid levels can be used. They are still superior to the compounds known from DE-OS 2 136 929.

The compounds of formula I are prepared using the method defined in the characterizing part of patent claim 1.

The reaction is expediently carried out with the addition of an acid-binding agent and in the heat. Of the compounds of formula IV, those in which X is chlorine or bromine are preferred.

Some of the starting compounds are known and can be prepared by processes known from the literature.

The starting compounds of formula III can advantageously be prepared by combining 3,4-dihydroxyphenyl (2) chloride or bromide with a compound of formula V.

6s implemented.

The following acids are suitable, for example, for converting the process products into their physiologically tolerable acid addition salts: hydrochloric acid, hydrobromic acid,

3rd

615178

Sulfuric acid, methanesulfonic acid, succinic acid and tartaric acid.

The compounds of the formula I have an asymmetric carbon atom on the —CH (CH3) grouping and accordingly occur in the form of racemates, as well as optically active antipodes. The optically active compounds can be obtained either by starting from the optically active starting material which already contains the -CH (CH3) grouping or by adding the racemates to the diastereo using optically active auxiliary acids, for example dibenzoyl-D-tartaric acids or bromocamper sulfonic acid - transferred older salts and separated them by fractional precipitation or fractional crystallization.

As already mentioned, the compounds of the formula I obtainable according to the invention have, in addition to a good central depressive action, an excellent blood fat level and cholesterol lowering action and can therefore be used in preparations for lowering the blood fat level.

The toxicity of the compounds of the formula I is very low, so that there is an extraordinarily favorable therapeutic index.

An amount of 25 to 75, preferably 40 to 60 mg is suitable as a daily dose. Accordingly, an amount of 5 to 75 mg can be considered as a single dose to be administered 1 to 5 times a day.

For the prophylactic treatment of coronary thrombosis, the compounds of formula I can also with coronary dilators, for. B. Dipyridamole (= 2,6-bis- (diethanolamino) -4,8-dipiperidino- [5,4-d] pyrimidine), can be combined, with a daily dose of 50 to 150 mg (single dose 10 to 150 mg) for the coronary dilators.

The compounds of the formula I can be processed with the aid of customary packaging methods to give medicaments of the corresponding indication. They can be brought into the usual galenical forms of use, such as tablets, dragées, emulsions, powders, capsules or depot forms, it being possible to use the customary pharmaceutical auxiliaries and the customary production methods for their preparation.

In addition to the auxiliaries and carriers customary in galenics, the tablets can also be added to achieve a depot effect. The tablets can also consist of several layers. Correspondingly, dragées can be produced by coating cores produced analogously to the tablets with agents which are usually used in dragée coatings. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, whereby the galenical auxiliaries usual for tablets can be used.

Juices produced using compounds of the formula I can additionally contain sweeteners or taste-improving agents. They can also contain suspending aids or thickeners, wetting agents or protective substances, such as p-hydroxybenzoates.

Capsules suitable for oral administration can be prepared, for example, by mixing the compounds of the formula I, if appropriate together with other active ingredients, with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing the compounds of the formula I, optionally together with other active ingredients, with customary carriers, such as neutral fats or polyethylene glycol or its derivatives.

The following example illustrates the invention without restricting it.

example

N- [l- (3,4-methylenedioxyphenyl) propyl- (2)] - N '- (2,4-dichlorophenyl) piperazine • HCl

7.6 g (0.02 mol) of N- [l- (3,4-dihydroxyphenyl) propyl- (2)] - N '- (2,4-dichlorophenyl) piperazine together with 4.1 g of methylene bromide heated in the presence of 5.3 g of potassium carbonate and a spatula tip of copper powder in 50 ml of dimethylformamide under reflux. After working up the title compound with a yield of 52% of theory. Th. Received. Mp of the monohydrochloride: 259 ° C.

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Claims (3)

615178 PATENT CLAIMS 1. Process for making new, racemic or CK ch2-ch-n optically active, substituted N- [l- (3,4-methylenedioxyphenyl) propyl- (2)] - N'-phenylpiperazines of the formula I. -f! K-M M— ('x w (I), where either Ri and R2 are chlorine or Ri is methyl and R2 is methoxy, and their physiologically tolerable ck. ch2-ch-i> acid addition salts, characterized in that a compound of the formula III HD with a compound of formula IV X-CH2-X (IV), net that a racemate of the formula I obtained is separated into its optically active antipodes by means of optically active auxiliary acids. in which X denotes a residue which can be split off easily by an anion, and the process products are then optionally converted into their physiologically tolerable acid addition salts. 2. The method according to claim 1, characterized in that one uses a compound of formula IV, wherein X is chlorine or bromine. 3. The method according to claim 1, characterized in CII 3rd Ar - CH2 - CH