DE1929330A1 - N-cinnamyl-N'-benzhydryl-piperazines and processes for their preparation - Google Patents

Description

PATENT ADVERTISER DR. HANS-GÜNTHER EGGERT, DlBLOMCHEiMIKEE

SKOLN-UNOENTHAL PETER-KINTGEN-STRASSE 2

Cologne, the ..-. Jimi IQf? E _c ; Ax

Janssen Pharn.aceut Lea N..V,, Turahouisebaan Jo, Be erse, Be 1 j . ie iv

M-Ci mta ^ yl-Il '-be-nzhydryl-plporazl ^ e and Verfd.gren for their IIors.tollunA

The invention relates to pharmaceutical preparations, preferably in the form of Dosierun £ units, which a N-arallyl-N'-aralkylpiperazine or a therapeutically effective one Acid addition salt of this compound as an active ingredient contain. These are disubstituted piperazines N-cinnamyl-li'-benzhydrylpiperazines of the formula

: -CH-N ¥ - (

Ar-GH-N Ii-GH ₉ -GH = CH-Ar '(I)

Ar

wherein Ar is a phenyl radical or a fluorophenyl radical, preferably is p-fluorophenyl, but at least one the radicals Ar is a fluorophenyl radical. It has been found that these disubstituted piperazines and their therapeutic effective acid addition salts have a strong effectiveness against arrhythmia.

The disubstituted piperazines of the formula (I) can be by condensation of the corresponding N-benzhydrylpiperazines of formula (II) with a suitable ginnamyl halide of formula (III) easily produce. You can also by condensation of suitable benzhydryl halides Formula (IV) with a suitable N-cinnamylpiperazine der Formula (V) can be prepared. The condensations can

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organic

in suitable / solvents such as aromatic hydrocarbons, e.g. benzene, toluene and xylene, lower. Alkanols and lower alkanones are carried out., Since an equivalent of an acid during the condensation (hX) becomes free, it is advisable to set a corresponding Amount of a suitable base, e.g. 3. Alkali carbonate ,. Irialkylamine or. pyridine, to be used to recover the vacated To bind acid. The presence of a catalytic amount of potassium iodide is also expedient TO called condensations can be illustrated by the following reaction scheme:

Ar-GH-N 3IH and X-CH ₂ -CH = CH-Ar

(II) (III)

base

Ar-CH-X and EIi ΪΓ-CH ^ - CK = GH-Ar Ar

(IV) (V)

Here, Ar has the meaning already mentioned, and X is a halogen atom, preferably a chlorine atom.

The organic bases of the formula (I) can by reaction with a suitable inorganic acid, e.g. hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid, or with a suitable organic acid, e.g. Acetic acid, propionic acid, glycolic acid, Lactic acid, oxalic acid, malonic acid, tartaric acid, Citric acid, sulfamic acid and ascorbic acid, in the corresponding pharmaceutically acceptable acid addition salts are converted. The salts of formula (i) can in turn by usual treatment with a suitable

9 0-9887 / 1779 Rö 0 * 3 ■

no egg. The alkali compound is converted into the corresponding base compound will.

It has been found that the compounds (I) according to the invention in. Fw-Vt-. the base or the salt have valuable pharmacological properties. They are valuable as a means against /.rryt-.nien, as their ability to reduce cardiac fibrillation in experimental animals, e.g. anesthetized dogs, shows. The anesthesia is performed with morphine sulfate (2.5 rag / kg) sc, dibarbital sodium (25 nig kg) and urethane (2oo mg kg) iv. The dog's chest is opened under artificial respiration, and 1 or 2 drops of a 10% acetylcholine solution is applied to the exposed left fore, whereupon the fore-floof with a; with a blunt spatula. The resulting atrial flin-ming is recorded by a single-pole auricular EKG lead. Atrial fibrillation is generated at least twice during the Konti'ollperiode of ^ o minutes. The compound to be tested is then administered intravenously. It has been shown that about 5 ^m g ^ E iv of the compounds according to the invention return the atrial fibrillation to normal sinus rhythm.

Using another method can reduce the effectiveness of the piperazine determined according to the invention against arrhythmia as follows be: The test is carried out under neuroleptanalgesia £ 1 ml of pentanyl (0.4 mg; ml) and droperidol (2o mg / ml) per 9.07 kg of body weight carried out. About 16 hours after the anterior descending branch of the left coronary artery, the dogs show a multifocal ventricular arrhythmia that is recorded. After a coritroll period of 50 minutes

The compound to be tested is administered intravenously to Jo ten. The effectiveness of the piperazines according to the invention against arrhythmia is shown graphically in FIGS. 1 to 4 as an example. By injecting 2.5 mg / kg the number of premature strikes (curve D)

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-A-

rapidly decreases and at the same time the number of -normal Beats clearly increased (curve E).

The curves are based on the following test connections:

Fig. 1: 1- (p-Fluoro-cinnamyl) -4- (p-fluoro-a-phenylbenzyl) -piperazine dihydrochloride (Compound I-a).

Fig. 2: 1-Benzhydryl-4- (p-fluoro cinnarayl) piperazine (compound 1-b).

Fig. 3 s 1-cinnamyl-4- (di-p-fluorobenzhydryl) piperazine dihydrochloride (Compound I-c).

Pig. 4: 1-Cinnamyl_ (p-fluoro-a-phenylbenzyl) piperazine dihydrochloride (Compound I-d).

These figures show that the connections (i) in Base form or salt form the ventricular arrhjTfchtnie strong To block. The invention is not intended to be limited to the test compounds mentioned above, rather, these compounds are only intended to illustrate the valuable properties of the compounds of formula (I), The various parameters identified by letters in these figures are as follows Are defined:

Curve A = / r number crsr repeats ir.ipulse-bound step

doer.

Curve B = ■ total heart rate (beats / minute);

Curve C = blood pressure in mm Hg (arterial pressure, the a catheter inserted into the femoral artery recorded v / ird), upper curve = systolic Pressure, lower curve = diastolic pressure;

Curve D = number of pathological beats / minute; Curve E = number of normal beats / minute.

The 9 0 9 887/17 7 9 _; ;

ORIGINAL

- 19293 "<ü

Effect against arrhythmia is an unexpected and surprising Effect given that the appropriate disubstituted piperazines containing chlorophenyl instead of fluorophenyl do not have this effect exhibit. This is illustrated by Figure 5, which the influence of the known compound 1-cinnamyl-4- (pchlor-a-phenylbenzyl) piperazine dihydrochloride (described in U.S. Patent 2,882,271) to the ventricular Arrhythmia that descends after ligation aes anterior Branch of the dog left coronary artery generated graphically. Like the picture shows 2.5 mg / kg i.v. this connection to an increase and not to a decrease in pathological Heartbeats (curve D) with a simultaneous negligible increase in the number of normal beats (curve E).

To produce the pharmaceutical preparations according to the invention, an N-cinnamyl-Nt-benzhydrylpiperazine is used of the formula (I) or a therapeutically effective acid addition salt of this compound as an active ingredient with a pharmaceutically acceptable carriers intimately mixed, various forms of carrier depending of the form of preparation desired for treatment (oral or parenteral) can be used can. Any customary pharmaceuticals can be used to produce the preparations for oral administration Auxiliary materials are used, e.g. water, glycols, oils, Alcohols and the like for oral liquid preparations such as suspensions, elixirs and solutions or liquid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like for powders, capsules and tablets.

Because of the ease of administration, tablets and capsules represent the most advantageous preparation forms for oral administration in which solid pharmaceutical carriers are used. The carrier usually consists at least in large part by parenteral injection

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■■■ - ■ '- ■' '- ·' * ■ - ■ · ■ ORIGINAL INSPECTED

1 q Ί Q q ί C) - 6 -

from sterile water, but other constituents, such as solubilizers, can also be included. For example injection solutions can be prepared, in which the carrier from a saline solution: ,, a glucose solution or a G-Srr. made of saline and glucose solution consists. Injectable .suspensions can also are manufactured. In these; Case v / earth suitable liquid carriers, suspending agents and the like are used.

in is particularly advantageous, the aforementioned pharmaceutical preparations in the form of dosage units, er. to make the administration easier and because of the ease of use of the dosage. The term "dosage unit ¹¹ ", as used herein, denotes units which are suitable as unit doses, each unit containing a certain amount of the active ingredient, calculated in such a way that the desired therapeutic effect is achieved, in conjunction with the required pharmaceutical carrier. Examples such dosage units are tablets, capsules, pills, powder packs, wafers, teaspoon amounts, tablespoon amounts, etc. and separate multiple doses in these forms. The amount of active ingredient per dosage unit is about 5 to 500 mg, preferably about 10 to 100 mg.

The process according to the invention consists in administering an effective amount of an N-cinnamyl-N'-benzhydrylpiperazine of the formula (I) or a therapeutically active acid addition salt of this compound in intimate mixture with a pharmaceutically acceptable carrier to combat cardiac arrhythmias. The dose per kg of body weight of the person being treated is preferably about 0.5 to 10 mg of the active ingredient which counteracts arrrytmia. The method further comprises the administration of the above-described forms of dosage units for the elimination of arrhythmias.

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1 9 2? ? .? O

The disubstituted piperazines of the formula (I) in the form of Base or the salt are new compounds and as such represent an additional feature of the invention, 3vorzu.Pt are rc-cinnamyl-N'-benzhydrylpiperazines, in two of the three Ar groups in formula (I) are fluorophenyl groups. Ii-cinnamyl-iP-benzhydrylpiperazines are particularly preferred, in which these two fluorophenyl radicals form part of the benzhydryl component, like by the formula

10 Ar ₁ -CH-II N-CH ₂ -CK = C

CH-Ii N-CH ₂ -CK = CH-A Λ

illustrates in which Ar _{1 is} fluorophenyl. The most preferred compound of these is 1-cinnamyl-4- (di-p-fluorobenzhydry1) piperazine.

In the following examples, the Kengen are in parts by weight to be understood unless otherwise stated.

example 1

A mixture of 66.3 parts of p-fluoro-a-phenylbenzyl chloride, 155 parts of piperazine and 800 parts of toluene is first heated for 2 hours with stirring under a reflux condenser with a water separator and then stirred at about 95 ° C. for a further 15 hours. The reaction mixture is ^{cooled to 60 °} C. and washed four times with 150 parts of water each time. The toluene phase is separated off and extracted twice with 15 parts of glacial acetic acid in 100 parts of water. The aqueous extract is made alkaline with ammonium hydroxide and the product is extracted with toluene. The toluene is dried and evaporated. The residue is crystallized from a mixture of ether and petroleum ether, i- (p-fluoro-a-phenylbenzyl) piperazine having a melting point

82 ⁰ C is obtained. .

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SAD ORIGINAL

This example "describes a method of manufacture of compounds of the formula (II) by condensation of a suitable benzhydryl halide with piperazine in the excess,

Example 2

A Geu-ish of 19 parts "! - (p-Fluoro-a-phenylbenzyl) -piperazine, 17 parts of p-fluorocinnamyl chloride, 22.3 parts Sodium carbonate, some potassium iodide crystals in 480 parts of 4-ethyl-2-pentanone v / ird for 14 hours under the Heated reflux condenser with water separator while stirring. The heat mixture is filtered hot and the piltrate evaporated. 1 part of the oily residue solidifies when it is left to stand at room temperature. He will filtered off, stirred in petroleum ether, filtered off again and dried, wherein the free Ease i- (p-fluoro cinnamyl) -4- (p-fluoro-a-phenylbenzyl) piperazine with a melting point of 112-115.4 ° C. "The remaining oily residue is dissolved in 300 parts of acetone. The solution is 2-propanol, which was previously mixed with gaseous hydrogen chloride has been saturated, given in "excess. The precipitated salt is filtered off, washed with acetone, and dried, leaving about 17.5 parts of 1- (p-fluoro-cinnamyl) -4- (p-fluoro-a-phenylbenzyl) piperazine dihydrochloride from melting point 197 »5 ° C can be obtained.

Example 3

50 parts of p-fluoro-a-vinylbenzyl alcohol are dissolved in 160 T _e ilen toluene. This solution is extracted three times with -300 parts of hydrochloric acid. The toluene phase is separated off, dried, filtered and evaporated. The oily residue is distilled, p-fluorocinnamyl chloride with a boiling point of 110 ° C./12 mm Hg being obtained.

This example illustrates a process for the preparation of compounds of formula (III) by treatment a suitable benzyl alcohol with HCl. Referred

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1929 3

is on R.C. Lamb and coworkers, «J.Org.Chem., 3J_, (1966).

Example 4

A mixture of 25.2 parts of 1-benzhydrylpiperazine, 21.5 parts of p-fluorocinnamyl chloride, 42 parts of sodium carbonate and a few potassium iodide crystals in 520 parts of 4-kethyl-2-pentanone is heated for 15 hours under a reflux condenser with a water separator while stirring. The reaction mixture is filtered warm. The filter cake is washed with 4-methyl-2-pentanone and the filtrate is evaporated. The solid residue is recrystallized twice from a mixture of 400 parts of diisopropyl ether and 80 parts of 2-propanol, where (p-fluorcinnamyl) -piperazine is obtained of melting point 139 "C 5 ⁰ 1-benzhydryl-4-.

Example 5

A mixture of 138 parts of a- (4-fluoro-phenyl) -4-fluorobenzyl alcohol and 170 parts of concentrated hydrochloric acid is refluxed for 4 hours with stirring. After cooling to e twa 7O ⁰ C is added a second portion of 100 parts of concentrated hydrochloric acid and the mixture heated for a further 4 hours under stirring. NaOH cooling to about 70 ⁰ C for an additional 100 parts of concentrated hydrochloric acid are added and the mixture again heated for 6 hours under stirring. After cooling, the reaction mixture is kept at room temperature for 8 hours and then extracted with benzene. The organic layer is washed successively twice with water, twice with a sodium hydrogen carbonate solution and twice with water. After drying over sodium sulfate, the solution is filtered and the filtrate is evaporated. The oily residue is distilled under reduced pressure, di- (4-fluoro-phenyl) -chloromethane having a boiling point of 130-133 ° C./1.5 mm Hg. That not over-

90988771779

ORIGtKAL INSPECTED

1 92 π'Γ? Η - ίο -

The material that has gone up is added in the manner described above by adding 100 parts, 40 parts or Treated 30 parts of concentrated hydrochloric acid, with a second fraction of di- (4-fluoro - :, henyl) chloromethane from Boiling point 129-130 ° C / 2 rnr :. hg is obtained,

Example 6

A mixture of 14.3 parts of x) i- (p-iluorphenil) -chloromethane, 10.1 parts of 1-cinnamylpiperazine, 12.7 parts of lithium carbonate and a few potassium iodide crystals in 20% of 4-methylene-2 Pentanone is heated back to 21 times with constant stirring. The reaction mixture is cooled and 50 lines of water are added. The organic layer is separated off, dried, filtered and evaporated. The oily residue is dissolved in 480 parts of anhydrous diisopropyl ether. This solution is boiled with activated charcoal and filtered. 2-Propanol, which has previously been saturated with gaseous hydrogen chloride, is added in excess to the clear filtrate. 4 - - (c [i.-p-fluorbenzhydryl) piperazine dihydrochloride is obtained with a melting point of 251.5 ⁰ C the precipitated salt to give 1-Cinnamyl is abfiitriert AU3 and recrystallized from a mixture of 2-propanol and ethanol.

Example 7

10,000 hard gelatin capsules, each 25 mg 1-cinnamyl-4- (di-p-fluorobenzhydryl) piperazine dihydrochloride are made from the following components:

Active ingredient 250 g

Lactose 750 g

Starch 250 g

Talc 250 g

Calcium te ar at. 10 g

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SAD OfWQlHAt

iq 9 Q --ί ^: f -U--

A simple mixture of the active ingredient and the additives is he'ves ^ ellt and in two-part Hartsel & tinekapdeln filled. Arrhythmias produced in dogs weighing about 15 kg become satisfactory with the capsules suppressed when a capsule is administered orally three times a day for a period of a few days will.

Example 8

5000 tablets containing 10 mg of 1- (p-Pluorcinnamyl.) - 4- (p-fluor-ui-phe nylbenzyl) piper azine dihydro chloride, was made from the following ingredients:

Active ingredient. 50 g

Starch 75 g

Dibasic Calcium Phosphate Hydrate £ 500

Caleium stearate 2.5 g

The finely powdered ingredients are mixed well and granulated with 10 $ fö starch paste. The granulate was dried and pressed into tablets, with citarke as disintegrant and Caleium stearate is used as a lubricant. If dogs in which -arrhythmia have been artificially created If one tablet is orally administered three times a day for a few days, -A-rrhyttaie is effectively suppressed.

Example 9 - Injectable Preparation

The following ingredients become 1 1 of a parentefalen Obtained suspension containing 5 mg of 1-benzhydryl-4- (fluorcinnamyl) piperazine as active ingredient per ml contains: active ingredient 5.0 g

Polysorbate 80 2.0 g

Sodium Chloride 9.0 g:

Sodium carboxymethyl cellulose 10.0 g

Methylρaraben 1.8 g

Propyl paraben '. 0.2 g

9Q9887 / T7-7S.

6AO ORIGINAL

192 °

Water for injection, U ₀ UP to make up to 1 1

Dissolve the parabens, sodium chloride and the carboxymethyl cellulose in the half dor total amount of water by heating AjF 95 ⁰ C to give a clear solution is obtained, han filtered and autoclaved. The polysorbate is dissolved in 1/3 of the total amount of the water. The second solution is filtered and autoclaved. The sterile active ingredient is added to the second solution and the mixture is passed through a sterile colloid mill. The first solution is added to the suspension obtained with uniform stirring. Lan fills up with water and stirs during filling into sterile ampoules.

Example 10 - Oral Suspension

The following ingredients give 5 liters of an oral suspension containing 25 mg of 1-cinnamyl-4- (p-fluoro-aphenylbenzyl) piperazine dihydrochloride as an active ingredient per teaspoon (5 ml) contains:

Active ingredient 25, above

Sucrose 300.0 g

Dioctyl sodium sulfosuccinate 0.5 g

Eentonite 22.5 g

Kethyl paraben 7.5 g

Propyl paraben 1.5 g

Antifoam A.F. Emulsion 0.15 g

Propylene glycol 52, og

FD&C Yellow Hr ₀ 5 0.1 g

Sodium cyclamate 50.0 g

liatric saccharin 5.0 g

Orange flavor 7 »5 g

Filtered purified water to make up to 5 1

The parabens are dissolved in propylene glycol and a solution of sodium cyclamate, sodium aceharine, is added to this solution and the sucrose in half the amount of water, Man

3 · .. 9 H * r / 1 7 7 9

suspends the bentonite in hot water (about 85 C) and stir for 60 minutes. Add the bentonite solution to the first Solution.

I-ian dissolves the sulfosuccinate in a little water and suspends it the active ingredient in the resulting solution. The anti-foam emulsion is added, which has been diluted with the smallest amount of water to the consistency of a lotion, and mixes well.

Wan gives the last-mentioned suspension of the active ingredient to the first mentioned Geraisch and mixes well. One gives the Dye FD? I> C Yellow Ur «5., In a small amount of water is resolved, too. The flavor is added, make up to volume with water and stir to a homogeneous mixture. Pass the mixture through a colloid mill and fill into suitable containers

Example 11

To a warm mixture of 20.2 parts of 1-oinnamylpiperazine, 42 parts of sodium carbonate and a few crystals of potassium iodide in 480 parts of 4-methyl-2-pentanone are given a solution of 26.5 parts dropwise with stirring p-Fluoro-a-phenylbenzyl chloride in 40 parts of 4-methyl-2-pentanone » After the addition has taken place, the mixture becomes water separator with stirring under the reflux condenser for 17 hours heated. The reaction mixture is filtered warm. The filter cake is washed with 4-methyl-2-pentanone and the filtrate evaporated. The oily residue is in 800 parts of diisopropyl ether dissolved, boiled with active charcoal and filtered. 2-Propanol is used for the filtrate has been saturated with gaseous hydrogen chloride, given in excess. An oily salt is precipitated here. The solvent is decanted and the residue from a mixture of 280 parts of acetone and 280 parts 2-Propanol crystallized with cooling. The excellent

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i ^ msmo α * & original inspected

1 9 /

The product is filtered off, washed with 2-propanol and dried, 1-cinnamyl-4- (p-i'luoro-a- ~ phenylbenzyl) piperazine dihydrochloride having a melting point of 208 to 210.6 ⁰ O being obtained.

BATH ORIGINAL

90 9887/1779

Claims (1)

1 q ί η - 15 - P a t e η t a η s ρ r ü c H e 1) Process for the preparation of N-Cinnaniyl-IT'-benzhydrylpiuerazinen the formula Ar-OH-K Ϊ -CH, -OH = OH-Ar in which Ar is a hienyl radical or a fluorophenyl radical, however, at least one of the radicals Ar is a fluorophenyl radical, or the therapeutically active ones acid addition salts of these compounds, characterized in that that one compounds of the formula Ar-CH-Y ¹
Ar with a compound of the formula Y-CH ₂ -CH = CH Ar in which Y and Y ^{1 are} different and interchangeable for a halide or the group HN stand, reacts in the presence of a base and optionally therapeutically effective acid addition saize obtained products. 2) Process for the preparation of 1- (p-fluorocinnamyl) -A- (p-fluoro-a-phenylbenzyl) -piperazine or its thera-. therapeutically active acid addition salts, characterized in that 1- (p-fluoro-cc-phenylbenzyl) piperazine is reacted with p-fluoro cinnamyl chloride in the presence of a base and optionally a therapeutically active acid addition salt of the compound obtained manufactures. . S ü 9 B B 7/1 7 7 9 1929 33 η 3) Process for the preparation of 1-benzhydryl-4- (p-fluoroeinnamyl) piperazine or its therapeutically effective acid addition salts, characterized in that one 1-Benzhydrylpiperazine with p-fluorocinnamyl chloride in Reacts the presence of a base and optionally a therapeutically effective acid addition salt of the reaction product manufactures. . A) Process for the preparation of 1-cinnamyl-4- (di-p-flu.orbenzhydryl) piperazine or its therapeutically active acid addition salts, characterized in that dab one Dirp-fluorophenyl) -chlormethan with 1-cinnamylpiperazine in the presence of a base and, where ^"z 'appropriate, a therapeutically active acid addition salt of the reaction products is prepared. 5) Process for the preparation of 1-cinnamyl-4 ~ (p-fluoro-aphenylt> enzhydryl) ~ piperazine or its therapeutically effective acid addition salts, characterized in that that 1-cinnamylpiperazine with p-fluoro-a-phenylbenzyl chloride reacts in the presence of a base and optionally a therapeutically active acid addition salt of the reaction product. '' 6) ΪΓ-Cinnamyl-N ¹ -benzhydrylpiperazines of the formula Ar-GH- / VcH ₂ -CH = CH-Ar Ar - _.- ■ "■" - wherein Ar is a phenyl radical or a fluorophenyl radical, however, at least one of the radicals Ar. ITluorophenyl radical and their therapeutically effective acid addition salts. 7) N-Oinnamyl-N'-benzhydrylpiperazines of the formula Ar ¹ -CH-N M-GH ₂ -CH = CH- ^ X Ir * 909887 / .1779 OfiißlN rNSPECTEO wherein Ar ^{1 is} a fluorophenyl radical, and their therapeutically effective acid addition salts. 8) 1- (p-Fluoro-cinnamyl) -4- (p-fluoro-a-phenylbenzyl) -piperazine and its therapeutically effective acid addition salts. 9) 1-Benzhydryl-4- (p-fluorocinnamyl) piperazine and its therapeutically effective acid addition salts. 10) 1-ginnamyl-4- (di-p-fluoro "ben2hydryl) piperazine and its therapeutically effective acid addition salts. 11) 1-Cinnamyl-4- (p-fluoro-a-plienylbenzhydryl) -piperazine and its therapeutically effective acid addition salts, 909887/1779 ORtGlNAt tNSf »ECtEO