DD295374A5 - NEW N - [(ALKYLAMINO) ALKYL] -4, -5-DIARYL-1H-PYRAZOLE-1-ACETAMIDE AND METHOD OF PREPARING THEREOF - Google Patents

Abstract

The invention relates to novel * and methods for preparing these compounds. The compounds and their acid addition salts have the general formula wherein R 1 is hydrogen or lower alkyl; R 2 and R 3 independently of one another are hydrogen, lower alkyl or hydroxy-lower alkyl or R 2 and R 3 together form a non-branched or branched alkylene chain having 4 to 6 C atoms and A is CH 2 CH (OH) CH 2 or (CH 2) n, where n is an integer from 2 to 8; Ar1 and Ar2 independently of one another are pyridinyl, phenyl or phenyl substituted by methoxy, hydroxy or halogen and at least one radical of Ar1 and Ar2 is pyridinyl. The compounds of the invention are suitable for the treatment of cardiac arrhythmias in mammals. Formula {* Procedure; manufacture; cardiac arrhythmia; Treatment; Mammal}

Description

V f

CH-CN (CH ₀₎ OH 2 || 2 η

and reacting the compound last obtained with a substance capable of converting the alcoholic function into a nucleophilic attack-appropriate group to form a compound of formula VIII

Ar '

X ₁₁ ^ R ¹ (VIII)

ι ι

CH-C-N (CH-) X 2 Ii 2 η

Ar *

0 and the last obtained compound with a compound of formula IX

to produce the corresponding compound of formula I in which A is (CH ₂ I _n and X is a nucleophilic-to-replace group,

and when R ^{4 is} hydrogen, the free acid is activated prior to reaction with a compound of formula V or VI

and, if desired, converting a obtained free base into an acid addition salt thereof.

A composition for the treatment of cardiac arrhythmias comprising a compound according to any one of claims 1 to 7 in an amount effective to treat cardiac arrhythmias together with one or more pharmaceutically acceptable carriers or diluents.

The invention relates to novel N - [(alkylamino) alkyl) -4,5-diaryl-i-H-pyrazole-1-acetamides and to processes for preparing these compounds which are suitable for the treatment of cardiac arrhythmias in mammals. US Pat. No. 4,695,566, issued to Heinemann et al., Describes as anti-arrhythmic agents 1H-pyrazol-3-yl (and 1H-pyrazol-5-ylloxyacetamide of the general formula

More specifically, (1) N- [2- (diethylamino) ethyl] -2- | (5-phenyl-1H-pyrazol-3-yl) oxy] acetamide, Embodiment 5, and (2) N- [3- (3) Diethylamino) propyl] -2 - ((5-phenyl-1H-pyrazol-3-yl) oxy) acetamide, Example 24.

U.S. Patent 4,182,895 to Baily, discloses as an intermediate in the synthesis of 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles a "β- (-1- (3,4-diphenyl-1H-pyrazolyl) ] -N, N-dimethylpropionamide "in column 8, line 63 to 64.

U.S. Patent 4,074,498 to Moon and Kornis discloses N, N, a, α-tetramethyl-3,4-diphenylpyrazole-1-acetamide (Example 160), N, N, α-trimethyl-5- (2-thienyl) pyrazole 1-acetamide (Example 29) as herbicide.

Ezrin et al. (FASEB Journal 2, A1557 [1988J] describes the antiarrhythmic activity of N- [3- (diethylamino) propyl] 4,5-diphenyl-1H-pyrazole-1-acetamide fumarate.

European Patent Application 299407, published January 18, 1989, describes a series of 4,5-diaryl-1H-pyrazole-1 alkanamides as antiarrhythmic agents.

The present invention relates to compounds of the formula I.

Ar ¹

(I)

or acid addition salts thereof in which R 'is hydrogen or a lower alkyl, R ² and R ^{3 are} independently hydrogen, hydroxy, lower alkyl groups or R ² and R ³ together form a non-branched or branched alkylene chain having 4 to 6C atoms, A = CH ₂ CH (OH) CH ₂ or (CH ₂ I _n / wherein η is an integer from 2 to 8. Ar ¹ and Ar ² are independently pyridinyl, phenyl or phenyl substituted with methoxy, hydroxy or halogen groups and at least one Radical of Ar 'and Ar ² is pyridinyl.

The lower alkyl as used herein means linear or branched hydrocarbon chains having 4 or less carbon atoms; Lower alkoxy groups represent linear or branched alkyloxy substituents containing 4 or fewer carbon atoms; Halogen is bromine, chlorine or fluorine.

Compositions for the treatment of cardiac arrhythmias include compounds of formula I when necessary together with pharmaceutically acceptable carriers or diluents. One may treat cardiac arrhythmias in a nipple by administering an antiarrhythmic effective amount of a compound of formula I.

Processes for the preparation of a compound of formula I include the reaction of a pyrazole-1-acetate or of pyrazole-1-acetic acid with an amine.

The synthesis of the compounds according to the invention is illustrated by the scheme A, in which R ^{4 is} a lower alkyl or hydrogen.

SCHEMA A

O is Ar ^ -C-CH ₂ -Ar ¹

(Π)

(CH ₃ ) ₂ NCH (OCH ₃ ) 2

(M)

NH ₂ NHCH ₂ COOR *. HCI

CH (OH ⁴ ) ₃

O Il

Ar ^ -C-CH-Ar! CH (0fi ^J ) ₂

NH ₂ NH ₂

XCH ₂ COOR ^

CH ₂ CNAN

R ³

An appropriately substituted diarylethanone (II) is reacted with an excess, preferably 10% excess, of dimethylformamide dimethylacetal in an inert solvent, preferably methyl t-butyl ether at 2O ⁰ C and 10O ⁰ C, preferably 53 to 56 ⁰ C. , The diarylethanone can be synthesized by the method of Nahm and Weinreb (Tet. Lett. 1981, 3815-3818) from the appropriate acid and the appropriate hetaryllithium or hetarylmethyllithium via the N-methoxy-N-methylamide of said acid.

The ß-Ketoenamin (III), which results from the reaction of diarylethanone and DMF acetal is reacted with dom salt of a Niederalkylhydrazinacetats, preferably Ethylhydrazinacetathydrochlorid in a suitable solvent, preferably ethanol, at 20 ° Π to 10O ⁰ C, preferably 4O ⁰ C to 5O ⁰ C, reacted so that virtually pure 4,5-diaryl-1 H-pyrazole-1 acetate of the forms! IV arises.

Alternatively, in cases where the diarylethanone appears mainly as its enolate, the diarylethanone is reacted with an orthoformate ester and a Lewis acid, preferably ethyl orthoformate and boron trifluoride etherate, in an inert solvent, preferably methylene chloride, at -78 ° C to 0 ° C ⁰ C reacted so that a 3,3-dialkoxy-1-propanone is formed. The propanone is reacted with hydrazine at 0 ⁰ C to 100 ° C, preferably at about 78 ⁰ C, in a suitable solvent, preferably ethanol to the reaction, so that a 3,4- (4,5-) diaryl-1 H-pyrazole is formed. The pyrazole is prepared by alkylation with an a-haloacetate ester (X = Cl or Br), preferably ethyl chloroacetate, using a base, preferably sodium hydride, in an inert solvent, preferably DMF at ⁰ C to 100 ⁰ C, preferably at room temperature in pyrazole- Converted to 1-acetate.

The lower alkyl, preferably a methyl or ethyl ester, an appropriately substituted 4,5-diarylpyrazole-1 alkanoic acid (V) is reacted with an excess of a primary or secondary amine of formula V at 2O ⁰ C and 15O ⁰ C, preferably at 9O ⁰ C up to 100 ° C. When the amine is valuable, the ester IV is preferably reacted with about one equivalent of the amine V in the presence of a tertiary amine, preferably diisopropyl hypochloramine, optionally in an inert solvent.

However, the compounds according to the invention can also be synthesized according to another possibility, as shown in Scheme B, where A = (CH ₂ I _n .

CH ₂ C-CO ?. ⁴

O)

(VI)

CH ₀ CN (CH ₁ ) X 2 Ii 2 η

(VIII)

IX

CH ₁ CN (CH.) N 2 μ 2 η

A lower alkyl ester, preferably a methyl or ethyl ester of a correspondingly substituted 4,5-diaryl-1H-pyrazole-1-alkanoic acid (IV) is reacted with an excess of a primary or secondary co-aminoalkanol (VI), optionally in the presence of an external Base at 20 ⁰ C to 15O ⁰ C, preferably reacted at tO ° C to 100 ⁰ C, so that an N [-ü) -hydroxyalkyl] pyrazole-1-alkanamide of the formula VII is formed. The Hydroxyalkylalkanamid (VII) is preferably activated by sulfonylation, preferably with methanesulfonyl chloride, in the presence of a ßase / a solvent such as pyridine at -20 ° C to 20 ⁰ C, preferably at ^{0 0} C, so that an alkylalkanamide of the formula VIII in which X is a group such as toluenesulfonate or methanesulfonate, ie OSO ₂ R ₈ , wherein R _{8 is} alkyl or aryl, ζ. Toluyl or methyl, which is subjected to nucleophilic substitution. Alternatively, the hydroxyalkylalkanamide (VII) is converted to the corresponding halide (VIII, X = Cl, Broder J) by phosphorous trihalide, phosphorus pentahalide, thionyl halide or tetrahalomethane with trialkylphosphine. The X-Gru | : Is substituted in the presence Oüer in the absence of a solvent, then by reaction with a corresponding primary or secondary amine (IX) at 20 ° C to 100 ^c C. Alternatively, the compounds of the present invention can be synthesized from free acids which can be obtained by hydrolysis of the corresponding esters.

Thus, an appropriately substituted 1,5-diphenylm H -pyrazole-1-acetic acid (IV in which R ^{4 is} hydrogen) is activated by the methods known in the art, for example by reaction with an acid chloride to form an anhydride mixture, by reaction with a Carbodiimide to form an O-acylisourea or by reaction with carbodiimidazole to form imidazolide. The activated acid in an inert solvent is then combined at -2O ⁰ C to 75 ⁰ C with a stoichiometric amount or a slight excess of a primary or secondary amine of formula V or omega-aminoalkanol of formula VI.

The compounds of the formula I are useful both in the form of the free base form and in the form of the acid addition salts, both forms being within the scope of the present invention. The acid addition salts are easier to handle in some cases and, in practice, the use of the silicone mold is more or less due to the use of the basic form. The acids that can be used to recover the acid addition salts preferably include those acids which produce medically acceptable salts in conjunction with the free base, i. H. Salts whose anions in medical doses are relatively harmless to the animal organism so that the beneficial properties contained in the free base are not offset by the side effects attributed to the anions. In the practice of the present invention, the preparation of the hydrochloride, fumarate, toluenesulfonate, methanesulfonate or mint salts is convenient. Other medically acceptable salts in the context of the present invention are those derived from other mineral acids or organic acids. The acid addition salts of the basic compounds are prepared by dissolving the free base in an aqueous alcohol solution containing the appropriate acid and isolating the salt by evaporating the solution or by reacting the free base and an acid in an organic solvent, in which case the Salt deposited directly, precipitated with a second organic solvent or can be obtained by thickening the solution. Although the medically acceptable salts of the basic compounds are preferred, all acid addition salts, as well as solvates, e.g. As hydrates, the compounds formed in the context of the present invention. All acid addition salts are suitable sources of free base form, even if the salt in question is only an intermediate, for example if the salt in question is needed only for cleaning or detection purposes or if it is used as an intermediate in the manufacture of a medically acceptable salt by ion exchange techniques , The structures of the compounds according to the invention were determined by synthesis, by elemental analysis and by infrared, ultraviolet and NMR spectroscopy. The course of the reactions and the identity and homogeneity of the products were assessed by thin layer chromatography (TLC) or gas liquid chromatography (GLC). The starting materials are either commercial substances or those which can be prepared by the known relevant processes.

In the following embodiments, the melting points are given in ⁰ C and not corrected. The abbreviation THF stands for tetrahydrofuran, DMF - for Ν, Ν-dimethylformamide and Ac - for acetyl residue CH ₃ CO.

General Procedure 1 N-methoxy-N-methylamide

To the solution of one equivalent of the appropriate acid chloride in methylene chloride was added 1.2 equivalents of solid methoxymethylamine hydrochloride. 2.5 equivalents of triethylamine were added at ca. ⁰ ° C. and the reaction was stirred at room temperature for 48 hours. The triethylamine hydrochloride was filtered off, the methylene chloride solution rinsed with water, dried and stripped to give the amine as an oil.

According to this process, (1) N-methoxy-N-methyl-S-pyridinecarboxamide, (2) N-methoxy-N-methylbenzeneacetamide, (3) N-methoxy-N-methylbenzamide and (4) N-methoxy-N- methyl-2-pyridinecarboxamide.

General procedure 2 Desoxybenzolnanaloge

A solution of 1.2 equivalents of the appropriate picoline or bromopyridine in ether was treated at -78 "C in the presence of nitrogen with 1 equivalent of n-butyllithium in hexane and then stirred for 1 hour without cooling to produce the anion was again cooled to -78 ° C and added dropwise to an ether solution containing 1 equivalent of the appropriate N-methoxy-N-methylamide from Method 1. After the addition was completed, the reaction product was allowed to stand until it reached room temperature and Excess butyllithium was quenched with isopropyl alcohol, water was added at room temperature and the ether was driven off, the product was treated with excess 0.25M NaOH, leached in methylene chloride and stripped.

According to this process, (1) 1,2-bis (2-pyridinyl) ethanone, (2) 1- (3-pyridinyl) -2- (2-pyridinyl) ethanone, (3) 2-phenyl-1- (3 -pyridinyl-ethanone, (4) 1-phenyl-2- (2-pyridinyl) ethanone.

example 1 Ethyl 5-phonyl-4- (2-pyridinyl) -1H-pyrazole-1-acetate

A solution of 26 g (0.132 mol) of 1-phonon-2- (2-pyridinyl) ethanone and 19.3 ml (0.145 mol) of dimethylformamide dimethyl acetal in 10 mM of methyl t-butyl ether was refluxed for 4 hours. Since the CC on silica gel with 10% isopropylamine in ethyl acetate showed a low success of the reaction, an additional 20 ml of HMF-dimethylacetal were added and the solution was refluxed for a further 6 h. The solvent was removed by evaporation and the resulting oily crude β-ketoenamine wu.de in 400ml ethanol aufrjelöst. The ethanol solution was heated to 40 ° C with 22 g (0.143 mol) of ethylhydrazine acetaldehyde chloride ca.

Heated for 1.5 hours. The solvent was removed and the impure product was dissolved in a small amount of methylene dichloride and placed in a column of 850 g of silica gel. The column was rinsed with 2: 1 hexane to ethyl acetate to give 25 g of a yellow solid, mp 98 ⁰ C to 100 ⁰ C after evaporation of the solvent.

Example 2 Ethyl-4-phenyl-5- (3-pyrldinyl) -1H-pyrazole-1-acetate

By a method practically similar to that of Example 1, 23 g of ethyl 4-phenyl-5- (3-pyridinyl) -1H-pyrazole-1-acetate. Melting point 9O ⁰ C to 91 ⁰ C from cyclohexane, from 29g (0.147 mol) of 2-phenyl-1- (3-pyridinyl) ethanone, 21.5M (0.162 mol) of DMF-dimethylacetal and 20.6 g (0.133 mol) of ethyl hydrazine acetate hydrochoride recovered.

Example 3 Ethyl 4- (2-pyridinyl) -5- (3-pyridinyl) -1H-pyrazolo! -1-acetate

Following a procedure that is similar practically to that of Example 1, 9 g of ethyl 4- (2-pyridinyl) -5- (3-pyridinyl) -1 H-pyrazol-1 acetate, melting point 43 to 46 ⁰ C. , from 11, Og (0.055 mol) of 1- (3-pyridinyl) -2- (2-pyridinyl) ethanone, 8.1 ml (0.061 mol) of DMF-dimethylacetal and 9.8 g (0.064 mol) of Ethylhydrazinacetathydrochlorid won. Chromatographic purification was carried out using hexane-acetone in the ratio 3: 1 instead of hexane-ethyl acetate in the ratio 2: 1 of Example 1.

Example 4 Ethyl 4,5-bis (2-pyridinyl) -1H-pyrazole-1-acetate

A solution of 15 ml (0.089 mol) Triethylorthoformatin 100 ml of methylene chloride was stirred in the presence of nitrogen at -78 ⁰ C and 13,2ml (0.108 mole) of boron trifluoride etherate was added. The solution was warmed to 0 ⁰ C, cooled again to -78 ⁰ C and added a solution of 8.0 g (0.04 mol) of 1,2-bis (2-pyridinyl) ethanone in 75 mL of methylene chloride, after 30 minutes, Added 22 ml (0.132 mol) of diisopropylethylamine in 30 ml of methylene chloride. The reaction mixture was stirred at -78 ⁰ C m'j minutes, poured into 400ml of water containing 10 g NaHCO3, and stirred for 20 minutes. The phases were separated and stripped of the methylene chloride layer over MgSO ₄ and stripped to give about 17 g of crude 3,3-diethoxy-1,2-bis (2-pyridinyl) -1-propanone.

The Propani. Was dissolved in 11 ethanol, added 5.8 ml (0.12 mol) of hydrazine hydrate and the mixture heated at reflux for 1 h lanu. The ethanol was driven off under reduced pressure and the residue was passed through 600 g of silica gel and spooled with 1: 1 hexane: acetone to give approx. 4 g of 4,5-bis (2-pyridinyl) -1H-pyrazole as an easy tanning substance incurred the removal of the solvent.

The 4 g pyrazole was added to a suspension of 0.52 g (21.6 mmol) sodium hydride (0.86 g of a 60% dispersion in oil) in 50 mL DMF. The mixture was stirred for 15 minutes and 2.3 ml (21.6 mmol) of ethyl chloroacetate added. After 30 minutes, water was added cautiously to remove excess sodium hydride. The solvent was removed in vacuo, the residue partitioned between ethyl acetate and water, and the organic layer dried and stripped. It

left a yellow oil. The oil was dissolved in acetone-hexane in a 1: 1 ratio and filtered through silica gel to give 4 g of ethyl 4,5-bis (2-pyridinyl) -1H-pyrazole-1-acetate as an oil, which was ca. Contained 5% of an admixture.

Example 5 N [3- (diethylamino) propyl] -5-phenyl-4- (2-pyridinyl) -1H-pyrazol-1-ocetamid

A solution of 10g (0.032 mole) of ethyl-5-phenyl-4- (2-pyridinyl) pyrazole-1-acetatvon Example 1 in 15 ml (0.095 mole) of 3- (diethylamino) propanamine was heated at 100 ⁰ C for three h , The excess amine was stripped off under vacuum and the residue partitioned between water and ether. The ether solution was dried over magnesium sulfate, stripped and passed through 350g of silica gel in a small amount of methylene chloride. The column was washed with 20: 1 acetone-purged triethylamine, and it is obtained a light yellow oil which crystallized after trituration with cyclohexane to 5.4 g, melting point of 82 ⁰ C to 83 ⁰ C.

Examples N-tf-IDiethylaminoJpropyn ^ phenyl-S - ^ - pyridinyll-IH-pyrazol-i acetumidhemlhydrat

By a method practically similar to that of Example 5, 6.7 g of N- [3- (diethylamino) propyl] -4-phenyl-5- (3-pyridinyl) -1H-pyrazole-1-acetamide hemihydrate mp 61 ⁰ C to 62 ⁰ C, of 10 g (0.032 mole) of ethyl-4-phenyl-5- (3-pyridinyl) -1 H-pyrazole-1-acetate of example 2 and 15ml (0.096 moles) of 3- ( Diethylamino) propanamine won.

Example 7 N- [3- (Diethylamlno) propyl] -4- (2-pyridinyl) -5- (3-pyridinyl) -1H-pyrazole-1-acetamide dihydrochloride

Following a procedure that is similar practically to that of Example 5, [3- (diethylamino) ^pr opyl] -4- (2-pyridinyl) -5- (3-pyridinyl) were 2.9 g of N- -1 H- pyrazom-acetamide dihydrochloride from 2 g (6.5 mmol) of ethyl 4- (2-pyridinyl) -5- (3-pyridinyl) -1H-pyrazole-1-acetate from Example 3 and 3.1 ml (19.5 mmol) 3 - (Diethylamino) -propanamine won. The free base was converted to the dihydrochloride by dissolution in ethanol, addition of the excess HCl in ether, and recrystallization of the resulting solid from ethanol-ether to give 2.6 g of the product, mp 149-150 ° C.

Examples N- [3- (Diethylamino) propyl] -4,5-bis (2-pyridinyl) -1H-pyrazole-1-acetamide

By a method practically similar to Example 5, N- [3- (diethylamino) propyl) -4,5-bis (2-pyridinyl) -1H-pyrazole-1-acetamide can be prepared from ethyl bis ( 2-pyridinyl) -1H-pyrazole-1-acetate of Example 4 and 3- (diethylamino) propanamine.

Example 9

N- [3- (Diethylamino) propyl] -5- (3-methoxyphenyl) -N-methyl- ('1- (4-pyridinyl) -1-acetamide Following a procedure practically similar to that of Example 5, For example, N- [3- (diethylamino) propyl] -5- (3-methoxyphenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazole-acetamide can be prepared from ethyl 5- (3-methoxyphenyl) -4 - (4-pyridinyl) -1H-pyrazole-1-acetate and N-methyl-N ', N'-diethyl-1,3-propanediamine are synthesized It is believed that the desired ester of 4-picoline and m-Anisoyl chloride can be synthesized according to general methods 1 and 2, followed by a method comparable to that of example 1.

Example 10 N- [3- (Diethylamino) -2-hydroxypropyl] -4- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole-1-acetamide

Following a procedure similar to that of Example 5, N- [3- (diethylamino) -2-hydroxypropyl] -4- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole can be prepared. 1-acetamide can be synthesized from ethyl 4- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole-1-acetate and 1-amino-3- (diethylamino) -2-propanol. It is believed that the desired ester of 1- {4-pyridinyl) -2- (4-fluorophenyl) ethanone (Lantos 11 al., J. Org., Ex., 53, 4223-4227, 1988]) is synthesized by a process can be comparable to that of Example 1 or Example 4.

Other embodiments of the invention can be synthesized from the appropriate 4,5-diaryl-1H-pyrazole-1-acetates. The starting materials for the compounds of the invention having varying R ¹ , R ² and R ³ are described in co-pending United States application DN 7398C to Denis Bailey, incorporated herein by reference.

The antiarrhythmic activity of the compounds of the present invention was demonstrated by the following procedure.

Duncan Hartley guinea pigs (600-900g) of either sex were anesthetized with urethane (1.4g / kg, ip) and supplemented as needed. A venous catheter for the administration of the drug! was prepared by inserting micro-tubes into the jugular vein. The induction of arrythmia by Accnitin hydrochloride (34g / kg) was evaluated in guinea pigs injected intravenously 10 minutes before Aconitingabo Ί cm ³ physiological saline.

The compounds to be tested were administered intravenously 10 minutes prior to the addition of Aconite at a starting dose of 30 mg / kg. This dose was reduced in the following experimental animals when severe cardiac arrhythmias lasted more than 2 minutes after injection in the first test animal. All antiurrhythmics were tested at the maximum permissible dose (which was determined by the absence of arrhythmias in the ECG before Aconiting administration). The compounds were administered in physiological saline as 1 cm ³ bolus injections (n = 5 to 9). The time intervals between the aconitine injection and the occurrence of the arrhythmias were determined. Specifically, the time to onset of (i) the first premature ventricular contraction (PVC); (ii) the first sustained series of ventricular tachycardias consisting of 10 or more ventricular beats (VTACH); and (iii) determines the time to onset of ventricular fibrillation (VFIB) for more than 15 seconds. The mean time and standard error from the mean to the onset of these arrhythmias were determined for each experimental group and compared to the parallel consumptions using irreversible precancer analysis. Efficacy was calculated as a statistically significant delay in the onset of the PVC, VTACH and VFIB timings and compared to the control trial values.

The following table summarizes the results obtained from the testing of the representative compounds of the invention.

Example minutes until insertion d.

No PVC VTACH VFIB

Experiment 1.0-1.2 1.0-2.0 4.0-6.0

5 18.9 23.2 44.9

6 7,6 16,2 19,9

7 10.2 60.0 60.0

The compounds of the invention may be prepared by conventional pharmaceutical methods for dib use: d. H. dissolving or suspending these compounds or their pharmaceutically acceptable salts in a pharmaceutically acceptable carrier, e.g. Water, aqueous alcohol, glycol, oil solution or oil-water emulsion for parenteral or oral administration; or by their processing in a basic dosage form as capsules or tablets for orak ι administration either alone odor in conjunction with herförnmlichen adjuvants or binders, eg. As calcium carbonate, starch, lactose, talc, magnesium stearate, gum arabic, etc.

The percentage of active ingredient in the composition and the methods for treating or preventing the arrhythmias can be varied to achieve a favorable dosage. The dose to be administered to a particular patient may be varied depending on the judgment of the clinician based on the following criteria: route of administration, duration of treatment, size and condition of the patient, the strength of the drug, and the patient's response thereto.

An effective dose of the active ingredient can thus be determined by the clinician, taking into account all the criteria of the best professional competence in the interest of the patient.

Claims (8)

or their acid addition salt, wherein R ^{1 is} hydrogen or lower alkyl; R ² and R ^{3 are} independently hydrogen, lower alkyl or Hydroxyniederalky! or R ² and R ³ together represent a straight or branched alkylene chain having 4 to 6 carbon atoms are; A is CH ₂ CH (OH) CH ₂ or (CH ₂ ) n, wherein η is an integer from 2 to 8; Ar ¹ and Ar ^{2 are} independently pyridinyl, phenyl or phenyl substituted by methoxy, hydroxy or halogen and at least one of Ar ¹ and Ar ^{2 is} pyridinyl. 2. A compound according to claim 1, wherein Ar ¹ and Ar ^{2 are} independently pyridinyl or phenyl. 3. A compound according to claim 2, wherein R ^{1 is} hydrogen. A compound according to claim 3, wherein A is (CH ₂ ) ₃ . 5. N, N- (3- (diethylamino) propyl] -5-phenyl-4- (2-pyridinyl) -1H-pyrazole-1-acetamide or its acid addition salt according to claim 4. 6. N, N- (3- (diethylamino) propyl] -4-phenyl-5- (3-pyridinyl) -1H-pyrazole-1-acetamide or its acid addition salt according to claim 4. 7. N- [3- (diethylamino) propyl] -4- (2-pyridinyl) -5- (3-pyridinyl) -1H-pyrazole-1-acetamide according to claim 8. A process for the preparation of a compound according to claim 1, which comprises the reaction of a compound of formula IV Ar ¹ CH ₂ COOR ^ wherein R ^{4 is} a lower alkyl or hydrogen, with a) a compound of formula V R "R ² (V) H-N-A-N ^ to produce a corresponding compound of formula I or b) a compound of formula VI
R ¹ I (Vi) HN (CH ₀ ) OH
2 η to a corresponding compound of formula VII
Ar '