DE1929330C3 - l-Cinnamyl-4- (di-p-fluorobenzhydryl) piperazine, its therapeutically effective acid addition salts, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

with a compound of the formula

Y - CH, CH = CH- in which Y and Y 'are different ·' '. Id and interchangeable for a halide or the group

HN N -

put, reacted in the presence of a rabbit and optionally therapeutically effective acid addition salts of the products received.

3. Medicaments consisting of a compound according to claim I and the pharmaceutically customary ones Hoof and wear materials.

The invention relates to l-C'innamyl-4- (di-p-fluorobenzhydryl) piperazine, its therapeutically effective acid addition salts and processes for their preparation as well as medicinal products containing them. It was found that this disubstituted pipcrazine

Y - * / -CH - n '

and its therapeutically effective acid addition salts have strong anti-arrhythmic activity to have.

1 -C'innamyl-'Mdi-p-fluorobenzhydryll-piperazine der Formula (I)

N -CH ₁ -CH CH- '

can easily be prepared by condensation of N- (di-p-fluorobenzhydryl-pipinizine of the formula (II) with a cinnamyl halide of the general formula (III). Cinnamylpiperazine of the formula (V) can be prepared. The condensations can be carried out in organic solvents such as aromatic hydrocarbons. /.! <. Benzene, toluene and XvIoI. Lower alkanols or lower alkanones, since one equivalent of the acid (HX) is released during the condensation is, it is expedient, an appropriate amount of a suitable base. z. B. alkali carbonate. trialkylamine or pyridine and use to bind the liberated acid. /. the presence of a catalytic amount of potassium iodide is also useful. the condensations mentioned above may can be illustrated by the following reaction scheme:

and X-CH-CH = CH

(III) KJ

base

and HN N-CH ₁ -CH = CH

(V)

base

(D

Herein X is a halo, preferably a Chlorine atom.

The organic base of the formula (I) can be obtained by reaction with an inorganic acid, e.g. B. Hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid or phosphoric acid, or with one organic acid, e.g. B. acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, Tartaric acid, citric acid, sulfamic acid and ascorbic acid, in the corresponding pharmaceutical harmless acid addition salts are converted. The salts of the formula (I) can in turn can be converted into the corresponding base form by conventional treatment with an alkali compound.

It has been found that the compounds (I) according to of the invention in the form of the base or the salt have valuable pharmacological properties. she are valuable ils remedies against arrhythmias, with cardiac fibrillation in laboratory animals. /. B. anesthetized Dogs, is significantly reduced. Anesthesia is done with morphine sulfate (2.5 mg / kg) s. C, diöarbital sodium (25 mg / kg) and urethane (200 mg / kg) i. v. performed. The dog's chest becomes opened under artificial ventilation, and 1 or 2 drops of a 10% acctylcholine solution is applied to the exposed left atrium, whereupon the atrium is streaked with a blunt chalk. The resulting atrial fibrillation is recorded by a unipolar auricular EKG lead. The atrial fibrillation will at least generated twice during the 30 minute control period. Then the Compound administered intravenously. It has shown. that about 5 mg / kg i.p. v. the connections according to the Invention to restore atrial fibrillation to a normal sinus rhythm.

According to another method, the effectiveness of the pipcrazine according to the invention against arrhythmia can be determined as follows: The test is carried out under neuroleptanalgesia [1 ml of fentanyl (0.4 mg ml) and droperidol (20 mg, ml) per 9.07 kg of body weight] . About 16 hours after ligating the anterior descending branch of the left coronary ureter, dogs show a multifocal ventricular arrhythmia. di <· luifüezeichnel becomes. After a Kontrollperiodc of mj [vrinuten is intravenously administered the compound to be tested. The effective wedge of the piperazines according to the invention against arrhythmia is shown in FIG. 1 is shown graphically as an example. By injecting 2.5 mg / kg, the number of premature beats (Vlurve D) is rapidly reduced and at the same time the number of normal beats is significantly increased (curve £).

The curve is based on the following test connection:

F i;. ·. 1: l-cinnamyl-4- (di-p-fluorobenzhydryl) -piperazu.diliydrochloride (Compound I-c).

This figure shows that the above compound strongly blocks the ventricular arrhythmia. Because in these Parameters marked with letters are defined as follows:

Curve A = number of repetitive pulse-bound pacemakers;

Curve B - total heart rate (beats / minute);

Curve C = blood pressure in mm Hg (arterial pressure recorded by a catheter inserted into the femoral artery), upper curve = systolic pressure, lower curve - diastolic pressure:

Curve D = number of pathological beats / minute;

Curve E = number of normal beats / minute.

The effect against arrhythmia or heart rhythm disturbance observed with the piocrazine according to the invention is an unexpected and exaggerated effect in view of the fact that the corresponding disubstituted piperazines which contain chlorophenyl instead of ν Dn fluorophenyl do not have this effect . This is illustrated by FIG. 2, which shows the influence of the known compound I-cinnamyl -4- (p-chloro- ^ -phenylbenzyl) -piperazine dihydrochloride (described in US Pat Ligation of the anterior descending branch of the dog's left coronary artery was generated, graphically depicting. As the figure shows, 2.5 mg-kg iv of this compound lead to an increase and not to a decrease in the pathological heartbeats (curve D) with a simultaneous negligible increase in the number of normal beats (curve E).

For the manufacture of pharmaceutical preparations containing the i-cinnamyl-4- (di-p-fluorobenzhydryl) -pipcrazine according to the invention of the formula (II or a therapeutically effective acid addition salt thereof Compound as active ingredient, these are intimately mixed with a pharmaceutically acceptable carrier, taking the most varied forms of carriers depending on the form of the preparation that is used for the treatment (oral or parenteral) is desired, can be used. For the production of the preparations Any customary pharmaceutical excipients can be used for oral administration, z. B. water. Glycols. The or alcohols for oral liquid preparations such as suspensions. Flixiere and Solutions or liquid carriers such as starch. Sugar. Kaolin, lubricant. Binders or spreading agents for powder. Capsules and tablets. Because of the l.eichiigkcii del Vci etufiMguiig siciicii ί iUMciicn and capsules represent the most advantageous preparation forms for oral administration, in the case of solid pharmaceuticals Carriers are used. For parenteral injection the wearer ordinarily orders at least in large part sterile water, but can also other ingredients, e.g. B. I. Loan mediator. drawn in will. For example, injection solutions can be used can be prepared in which the carrier consists of a saline solution, a glueosc solution or a mixture consists of saline solution and (ilucose solution. I injectable Suspensions can also be made. In this case, suitable liquid carriers are used or suspending agents are used.

It is particularly advantageous to use the above pharmaceutical preparations in the form of dosage units to facilitate tracking and because of the uniformity of the dosage. The term "dosage unit" used here denotes units that are suitable as unit doses, with each unit being a specific one Amount of the active ingredient calculated in this way. that the desired therapeutic effect is achieved, in Compound with the requisite pharmaceutical carrier. Examples of such dosage units are tablets. Capsules. Pills. Powder packs. Wafers. Teaspoon quantities. Dining spoons and the like, as well as separate multiple cans in these forms. The amount of the active ingredient per unit dosage is about 5 to 500 mg. preferably about 10 to 100 mg. The dose per kg of body weight of the person treated is preferably about 0.5 to 10 mg.

The l-Cmiian ^ 1-4-1 di-p-fluorbcnzhydnll-piperazinc of the formula (I) in the form of the base or of the salt are new compounds. To prove the surprising Technical progress is made in the following comparison tests with the previously known compound l-Cinnamy! -4 - (- »- phenylbenzyl) piperazine dihydrochloride. also known under the name "cinnarizine" and the claimed compound 1-cinnamyl - 4 - (di - ρ - fluorobenzhydryl) - piperazine - hydrochloride. commonly referred to as "flunarizine". Cinnarizine is very similar in its structure to the claimed piperazines and is a remedy the same Direction of action.

In addition to the anti-arrhythmic effect, this compound shows a clear inhibitory effect on vasoconstriction (vascularly different). As a measure of the therapeutic effect, the inhibitory effect of a certain amount of these test compounds on artificially induced vasoconstriction in test animals was taken and / .. B. this effect was investigated in tests on the peripheral vascular system and the coronary system of anesthetized dogs.

These studies were performed on hybrid dogs of both sexes weighing between 7 and 11 kg (average 9 kg). The dogs were initially given 2.5 mg / kg morphine hydrochloride s. c. and one hour later with 0.25 ml kg of an intravenous injection of a mixture 0.4 g urethane. 0.4 g of ethyl urea and 0.1 g of sodium dialkylbarhydrate supplied per ml. The left arm artery and vein and the femoral arteries on either side were cannulated and KKK) units / kg heparin were injected into the arm vein. A tube was inserted into the windpipe introduced. Arterial blood was then drawn from the left femoral artery and with constant

arlerie, for example by means of a Sigma motor pump. The pump will start ties Test adjusted to give a perfusion pressure equal to that of the mean arterial Pressure is. Both the perfusion pressure (measured between the pump and the right hind leg) and the arterial blood pressure (measured on the 1 lal artery) are continuously checked and with a Appropriate device. e.g. with a Watanabe multi-recorder. registered. The heart's activity is also checked during the experiment.

Injections before; single increased doses (0.016. 0.063 ... 16. 63 µg-Bei'Jeh) of I-nor-epinephrine in O.I-m aqueous solutions were injected directly into the perfusion stream at 5-minute intervals and the action curve is registered. After a control period, acidified solutions (pH 3.00) the test compound into the perfusion stream at a constant rate of 0.2 ml min infused using a Braun infusion pump. The dosages used were 0 (solvent, adjusted to pH 3.00). 0.01, 0.0.04, 0.16 and 0.33 mg min the test connection. These dosages correspond to 0.0011. 0.0044. 0.018 and 0.07 mg / kg / min for 9 kg heavy dogs. After a one hour infusion period, another dose of 1-nor-epinephrine was given administered and registered the activity curve. the Change in vasoconstriction induced by 1-nor-epinephrine was used as an index of effect assessed for peripheral resistance in the hind leg.

The investigations carried out in accordance with these experimental arrangements with the piperazines in question showed a clear inhibitory effect on the vasoconstriction caused by I-nor-epinephrine. Flunarizine was found to be 2.6 times more effective than cinnarizine in terms of reduction the peripheral resistance in the vascular system of the hind leg of the test dog.

The systemic arterial blood pressure and the number of heartbeats remained unchanged.

It was also found in rabbit tests that flunarizine has a longer duration of action than Cinnarizine. sh. J. M. ν a η N u e t e n, Europ. J Γ-harmacol .. Vol. 6. pp. 286-293 (1969). After this, the effects of flunarizine and cinnarizine were postulated Administration of vasoconstricting drugs to the isolated cutaneous and saphenic arteries of a test rabbit examined. With flunarizine, the peak action lasted in the resulting time-response curve at dosages from 0.01 to 0.16 mg

7 8

during the entire duration of the experiment (90 min). Linier stirring is heated to reflux. After weighing up the response to C'innari / in a cool the reaction mixture is 8 hours at Dose of 0.01 mg for the central artery already kept after room temperature and then with benzene 30 min and extracted for the saphenous artery after 50 min. The organic layer appears one at a time finish. -. twice with water, twice with a sodium die therapeutic indi / es of llunarizine and hydrocarbonate solution and twice with water C.:.narizin were washed with sea-washed on the basis of experiments. After drying over sodium sulfate schwjinchen determined, the test substances orally, the solution is filtered and the filtrate is evaporated, were administered. The following values were obtained: The oily residue is reduced under reduced pressure medium !: i <> distill !, with di- (4-fluorophenyl) -chloromelhan in front

Boiling point 130-133 C7I, 5mm Hg is obtained. The material not passed over will be added to the above

^f '' ^D '° ^<0 "' by adding separately

(mg kg) fmg kg) ⁵ "I (X) parts, 40 parts or 30 parts more concentrated

ii hydrochloric acid treated, a second fraction of

_,,, . ,,, ... wuwl Di- (4-fluorophynyl) -chloromethane with boiling point

|; ^{lun; irl / ln 0} ^ ⁶ ^ ^{I (KM)} 129 130 C <2 mm Hg is obtained.

ί lllll.lll / lll 2.5 -40 > ΪΟ

Example 2

Summary ■ "H) (X) O hard gelatin capsules, which are used as active ingredients each

25 mg l-C'innamyl ^ -ldi-p-fluorobenzhydryl-piperazine-

llunarizine and Cinnari / .in as a known compound containing dihydrochloride are made up of the following

similar structure and same direction of action components manufactured: have been regarding their therapeutic effects

compared to each other. _> -, active ingredient 250 g

The compounds inhibit and prevent peri-lactose 750 g

phere vasoconstrictions produced in test animals. Strength 250 g

were called. Flunarizine showed a talc of 250 g

Significantly stronger effect than (innarizin and graph- C'alciumstcarat 10 g

p.ie is also characterized by a clearly longer lasting m

Effect. Lin uniform mixture of the active ingredient and the

The values for LD _5n . LD _M) and the therapeutic additives is manufactured and in two-part Harl-

Index show the superior effect of Flunari / .ins gelatin capsules filled. Arrhythmias that occur in dogs

opposite c'innarizine. which weigh about 15 kg, are produced with

In the following example, where the quantities as j-> the capsules satisfactorily suppressed when for

Parts by weight are to be understood, the production will take a few days three times a day

the compound of the invention described. Capsule is administered orally.

Example I Example 4

A mixture of 14.3 parts of di (p-fluorophenyl) - w. . "Chloromethane. 10.1 Share I-C'innamvlpiperazin. uraie suspension 12.7 parts of sodium carbonate and some potassium from the following ingredients 5 l of an iodide crystal in 2 (X) parts of 4-methyl-2-pcnlanon oral suspension are obtained, the 25 mg of 1-cinnamyl is refluxed for 21 hours with stirring. 4- (p-fluoro - «- phenylbenzyl) piperazine dihydrochloride The reaction mixture is cooled and 50 parts of i; as active ingredient per teaspoon (5 ml) contains: water added. The organic layer is separated, dried, filtered and evaporated. The active ingredient 25.0 g

oily residue is anhydrous in 480 parts of sucrose 3 (X) ₁ Og

Dissolved diisopropyl ether. This solution is made with dioctyl sodium sulfosuccinate 0.5 g

Activated charcoal boiled and filtered. To the clear filtrate vi bentonite 22.5 g

is 2-propanol, which was previously mixed with gaseous chloromethylparaben 7.5 g

hydrogen has been saturated, in excess of Propylparaben 1.5 g

ben. The precipitated salt is filtered off and 0.15 g from an anti-foam agent

Recrystallized mixture of 2-propanol and ethanol, propylene glycol 52.Og

wherein 1-cinnamyl-4- (di-p-fluorobenzhydryl) -piper- r. Yellow dye 0.1 g

azine dihydrochloride with a melting point of 251.5 ° C., sodium cyclamate 50.0 g

will hold. Sodium saccharin 5.0 g

The starting compound can be obtained as follows orange flavor 7.5 g

will. Filtered purified water for

A mixture of 138 parts * - (4-fluorophenyl) - «> Replenishment to 5 1

4-fluorobenzyl alcohol and 170 parts more concentrated

Hydrochloric acid is refluxed for 4 hours with stirring. The parabens are dissolved in propylene glycol and added

heated. After cooling to about 70 ° C., one of this solution becomes a solution of sodium cyclamate.

second serving of 100 parts of concentrated hydrochloric acid of sodium saccharin and sucrose in the

added and the mixture for a further 4 hours under b5 half the amount of water. The bentonite is suspended

Stirring heated to reflux. After cooling to about in hot water (about 85 C) and stir for 60 minutes.

70 ⁰ C are another 100 parts of concentrated salt. The bentonite solution is added to the first solution,

acid added, whereupon the mixture again for 6 hours. Dissolve the sulfosuccinate in a little water and

9 10

suspends the active ingredient in the resulting solution. by. One gives <! nii yellow dye that is in a

The antifoam emulsion, which is dissolved with the small amount of water, is added. One gives the

smallest amount of water to the consistency of a lotion flavor zn, fill with water to the volume

has been diluted and mixes well. and stir to a homogeneous mixture. Man

The last-mentioned suspension of the active substance is given pass the mixture through a colloid mill and fill

Substance to the first-mentioned mixture and mixes well in suitable containers.

1 sheet of drawings

Claims (2)

Patent claims:!. l-C'innamyl-4- (di-p-niiorbenzhydryl) -piperazine of the formula F- ^ f / ^ CH - N N - CH, - CH = CH ^ * ^ and its therapeutically effective acid addition salts 2. Process for the preparation of l-cinnamyl-4- (di-p-fluorobenzhydryl) -piperazine and its therapeutic effective acid addition salts according to claim 1, characterized in that one known per se Way a compound of formula CH-Y '