NO142911B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYL PIPERAZINE DERIVATIVES - Google Patents

Description

This invention relates to the preparation of new racemic or optically active 1-phenyl-propyl (2)-piperazines with the general formula

and the acid addition salt thereof, where R. means chlorine and means chlorine, or means methyl and R- means methoxy. From German official publication 16 70 144 it is known that compounds with the general formula

where Ar means an aromatic residue with two linked rings, of which the ring that is not bound to the residue molecule, -can be an iso- or heterocyclic, saturated or an aromatic ring, and R^ and R£ mean hydrogen, halogen, the group CF ^or an alkyl or alkoxy group with 1-4 C atoms, and acid addition salts thereof, exhibit valuable central depressant properties.

It has now been found that the compounds with the above formula I and the acid addition salts thereof, which are not described in German official publication 16 70 144, in addition to the central depressant effect also have an excellent blood lipid level and cholesterol-lowering effect and can therefore be used in preparations which should serve to lower the blood fat level. For this purpose, they are better than the compounds known from German official documents 16 70 144 and 21 36 929 as well as British patent 1,176,672. An amount of 25-75, preferably 40-60 mg can be used as a daily dose. 5-75 mg can be used as a single dose for administration 1-5 times a day.

The toxicity of the active compounds of the general formula I is very low, so that they have a particularly favorable therapeutic index.

For preventive treatment of coronary thrombosis, the active substances of formula I can also be combined with coronary dilators, e.g. dipyridamole (= 2,6-bis-(diethanolamino)-4,8-dipiperidino-pyrimido-[5,4-d]-pyrimidine), and a daily dose of 50-15o mg can then be used (single dose 10-150 mg) of the coronary dilators.

The new compounds can be introduced into pharmaceutical preparations in a manner known per se. They can be prepared in the usual galenic application forms such as tablets, dragées, emulsions, powders, capsules or depot forms, and for the preparation of the preparations one can use usual pharmaceutical excipients and usual preparation methods.

The new compounds are prepared according to the invention by introducing a 1-(3,4-methylenedioxyphenyl)propyl(2)-residue into a piperazine compound with the general formula

where and R ? has the above meaning. The introduction takes place by reaction of a compound of the general formula III with an electrophilic 1-(3,4-methylenedioxyphenyl)propyl-(2)-derivative such as a 1-(3,4-methylenedioxyphenyl)-propyl-(2)- chloride, bromide,

-mesylate or -tosylate in the presence of an acid-binding agent or by reacting a compound of the general formula III with

1-(3,4-methylenedioxyphenyl)-propanone-(2) in the presence of reducing agents such as catalytically generated hydrogen or metal hydrides (eg lithium aluminum hydride or sodium borohydride).

The output connections for the method are partial

knew. The previously unknown compounds can easily be

is set by methods that are described in common chemical handbooks, e.g. by suitable methods from Houben-Weyl 1st and 2nd edition.

The compounds with the general formula III can e.g. are produced by those in J. Am. Chem. Soc. 76/s. 1853 (1954) and J. with. Chem. 8/S. 332 (1965) described methods. The electrophilic 1-(3,4-methylenedioxyphenyl)propyl-(2)-derivatives such as 1-(3,4-methylenedioxyphenyl)propyl-(2)-chloride, -bromide, -tosylate or -mesylate can e.g. e.g. is produced by esterification of l-(3,4-methylenedioxyphenyl)-propane-(2) (see example 1), while l-(3,4-methylenedioxyphenyl)-propanone-(2) e.g. can be produced by the method according to Org. Synth. Coll. Vol. IV/p. 573.

The compounds of the general formula I have an asymmetric C atom in the -CHCCH^) grouping and therefore occur in the form of racemates and in the form of optically active antipodes. The optically active compounds can be obtained by the method either starting from an optically active starting material which already contains the grouping - CE (CR^)-, or by the racemates obtained by the method being transferred to the diastereomeric salts by means of optical active auxiliary acids, e.g. dibenzoyl-D-tartaric acid or bromocamphorsulfonic acid, and these salts are separated by fractional precipitation or fractional crystallization.

The new connections can in the usual way, e.g. by reaction with suitable acids, are transferred to the physiologically

similar acid addition salts. Suitable acids for this purpose are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, succinic acid and tartaric acid.

The following examples shall serve to further illustrate the invention.

Example 1

N-[ 1-( 3, 4- methylenedioxyphenyl) propyl-( 2)]- N'-( 2- methyl- 4- methoxy-phenyl) piperazine

29.0 g (0.14 mol) (2-methyl-4-methoxy)phenylpiperazine

together with 41.5 g (0.16 mol) of 1-(3,4-methylenedioxyphenyl)-propanol-(2)-methanesulfonate (prepared by esterification of the propanol with mesyl-

chloride) and 44 g of anhydrous pot ash in 250 ml of xylene are boiled for 7 hours under reflux, and the solvent is distilled off in a vacuum. The residue is recrystallized from aqueous methanolic hydrochloric acid. The hydrochloride of the title compound melts at 256-259°C.

Example 2

N-[ 1-( 3, 4- methylenedioxyphenyl)- propyl( 2)]- N'-( 2, 4- dichlorophenyl)-piperazine

32.5 g (0.14 mol) of 2,4-dichlorophenylpiperazine together with 41.5 g (0.16 mol) of 1-(3,4-methylenedioxyphenyl)-propanol-(2)-methanesulfonic acid ester and 44 g of anhydrous pot ash in 250 ml of xylene is boiled for 7 hours under reflux cooling. The preparation is carried out as in example 1. Melting point for the hydrochloride of the title compound: 259-263°C.

Example 3

N- [ 1-( 3, 4- methylenedioxyphenyl)- propyl( 2)]- N'-( 2- methyl- 4- methoxy)-phenylpiperazine

1.78 g of 1-(3,4-methylenedioxyphenyl)-propanone-(2) and 1.76 g of N-(2-methyl-4-methoxy)phenylpiperazine are hydrogenated in 20 ml of methanol

in the presence of 0.2 g platinum oxide at 60°C. After absorption of the theoretical amount of hydrogen, the title compound formed is isolated. Melting point for the monohydrochloride is 256-259°C.

In the same way, one can prepare N-[1-(3,4-methylenedioxyphenyl)-propyl-(2)]-N'-(2,4-dichloro)-phenylpiperazine hydrochloride with m.p. 261-263°C.

Pharmacological trial data for the central nervous system effect.

The experiments were carried out on mice of the strain NMRI. In the sliding test, the mice were placed on an inclined glass plate, and they were observed to find which dose caused them to start sliding downwards, i.e. they lost the holding reflex. With the ataxia test, the dose at which ataxia appears (uncoordinated walking) is found. The compound was administered in suspension orally by throat tube. The calculation took place according to the so-called "probit" method. The results show that the new compounds (compared to the known substances) are almost not centrally active, which is desirable for cholesterol-lowering agents. The good cholesterol-lowering effect is evident from the following.

In the present experiment, a comparative investigation was carried out of the substances Me 317, Me 318, Me 358, Ren 88 and Ren 89 (meanings: see above) with regard to cholesterol-lowering properties. The commonly used lipid-lowering drug clofibrate was used as a positive control.

During the experimental period of 3 weeks, the serum level of cholesterol was measured in a total of 85 male rats at 1-week intervals.

Material and methodology

Experimental animals: 85 male rats of the strain Chbb:Thorn (SPF) with a body weight of approx. 2 50 g. The animals were kept individually in macrolon cages under SPF conditions. Except for the day before blood sampling, the animals were given as much food and water as they wanted.

Administration: Administration was carried out daily p.o. by

with the help of a gastric tube.

Dosage and

Trial duration: 3 weeks

Analysis method: Total cholesterol in serum mg/100 ml with Auto-Analyzer according to Liebermann-Burchard,

Lit.: J. Levine et al. Technicon Symposium, 1967, vo1. 1, p. 25.

research

time: The total cholesterol content was determined in all the animals before the beginning of the experiment (day 0) as well as on experimental days 8, 14 and 21. The blood sample was taken

in the retrotubular venous plexus. Before determining the serum cholesterol, the animals were kept fasting for approx. 16 hours.

Results

The results from the serum cholesterol tests are summarized in the following table. The group mean values and standard deviations at the individual survey times are indicated there. In the figure, the mean values for the individual substance groups are shown graphically as curves over the course of the experiment.

As can be seen from the table, all the substances examined in this experiment cause a significant reduction of the total cholesterol content in the serum, based on the group of control animals that were included at each time of examination and that only received a 0.9% sodium bicarbonate solution. Admittedly, there are very significant differences with regard to the potency of the individual substances. While Me 317 at a dosage of 50 mg/kg is clearly weaker than 300 mg/kg clofibrate, the lowering of the cholesterol level in the animals treated with 50 mg/kg Me 318 was approximately as high as with the comparison substance. Clearly more active were the substances Me 358, Ren 88 and Ren 89. Although given only at a dose of 25 mg/kg, the cholesterol-lowering effect was better than that obtained with 300 mg/kg clofibrate.

From the figure, it appears that with all substances one already got after approx. 14 days a maximum effect. The changes in the last week of the experiment were only insignificant.

If one considers the percentage reduction of the serum level of the total cholesterol content at the end of the experiment,

in relation to the current starting values (day 0) for the treated group, the following order of the effectiveness can be established: Me 317 -» 27%; Me 318 41%; clofibrate ->45%; Me 357 -> 70%;

■Pure 89 -* 78%; Pure 88 87%.

Summary and assessment

As a summary, it can be said that in the present experiment on male rats, all the investigated substances led to a reduction of the overall cholesterol content in serum. Me 317

(50 mg/kg) was weaker and Me 318 (50 mg/kg) was approximately as potent as the comparison compound clofibrate (300 mg/kg). A clearly stronger cholesterol reduction than clofibrate was achieved with the substances Me 358, Ren 88 and Ren 89, although they were only given at a dose of 25 mg/kg.

With regard to the strength of action, the following order can be drawn up for the dosages used:

Me 317 < Me 318 < Clofibrate < Me 358 < Pure 89 < Pure 88

Claims (1)

Analogy method for the preparation of therapeutic active phenylpiperazine derivatives of the general formula where R means chlorine and R2 chlorine, or means methyl and R,, methoxy, and physiologically compatible acid addition salts thereof, characterized in that a compound of the general formula where R^ and R^ have the meanings given above, reacted with an electrophilic 1-(3,4-methylenedioxyphenyl)propyl-(2) derivative such as a 1-(3,4-methylenedioxyphenyl)propyl-(2)-chloride, -bromide, -mesylate or -tosylate in the presence of an acid-binding agent, or with 1-(3,4-methylenedioxyphenyl)-propanone-(2) in the presence of reducing agents such as catalytically activated hydrogen or metal hydrides.