DD295633A5 - NEW N - [(HETEROCYCLIC) ALKYL] -3,4 (OR 4,5) -DIARYL-1H-PYRAZOLE-1-ACETAMIDES OR PROPIONAMIDES AND METHOD OF PREPARING THEM - Google Patents

Abstract

The invention relates to N- & * * or -propanamide and process for their preparation. They are compounds of the formula Ia or Ib or acid addition salts thereof, in which R1 is hydrogen or lower alkyl, R2 and R3 independently of one another are hydrogen, hydroxyl, lower alkyl, lower alkoxy, lower alkylamino, lower alkylamido, R4 is hydrogen or hydroxy, m is one or two, p is one, two or three, and A is a five- or six-membered heterocyclic compound selected from the group consisting of carbon and .alpha Nitrogen is bonded to a carbon at (CH 2) p and optionally substituted with a lower alkyl group. Methods are described for the preparation of a compound of formula I in which a pyrazole-1-acetate or -propanoate ester or a pyrazole-1-acetic acid or -propanoic acid is reacted with an amine. The compounds of the invention are suitable for the treatment of cardiac arrhythmias in mammals. Formulas 1 a u. 1 b {N- & * * N- & * * method; manufacture; Pyrazole-1-acetate; Pyrazol-1-propanoatester; Pyrazole-1-acetic acid; Pyrazol-1-propansaeure; amine; cardiac arrhythmia; Mammal}

Description

wherein R ^{5 is} lower alkyl or hydrogen, with a corresponding compound of formula III

R ¹ HN- (CH ₂ ) pA III

wherein R ^{5 is} lower alkyl or hydrogen, and in the latter case, the free acid of formula Ha or Hb is activated prior to reaction with the compound of formula III and, if desired, a recovered free base is converted to an acid addition salt thereof. A composition for the treatment of cardiac arrhythmias comprising a compound according to any one of claims 1 to 8 in an amount effective to treat cardiac arrhythmias together with one or more pharmaceutically acceptable excipients or diluents.

Novel N-H-heterocyclic-alkyl-S ^ (or 4,5) -diaryl-1H-pyrazole-1-acetamides or -propanamides and methods of preparation

The invention relates to novel N - [(heterocyclic) alkyl] -3,4 (or 4,5) -diaryl-1H-pyrazole-1-acetamides or -propanamides which are suitable for the treatment of cardiac arrhythmias in mammals, and to the production thereof ,

U.S. Patent 4,695,566 to Heinemann et al. describes as antiarrhythmic agents 1 H-pyrazol-3-yl (and 1 H-pyrazol-5-yOoxyacetamide the general formula

O-C-CO-N-Z-N

R ⁶ R ⁷

Specifically described are (1) N- [2- (diethylamino) ethyl] -2 - [(5-phenyl-1H-pyrazol-3-yl) oxy] acetamide, Example 5, and (2) N- [3- (Diethylamino) propyl] -2 - [(5-phenyl-1H-pyrazol-3-yl) oxy] acetamide, Example 24.

U.S. Patent No. 4,182,895 to Bailey describes as an intermediate in the synthesis of 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazole "β- [1- (3,4-diphenyl-1H) pyrazolyl)] - N, N-dimethylpropionamide "in column 8, lines 63 to 64.

European Patent Applications 248594, 293220 and 293221 of Ortho Pharmaceutical Corporation describe the synthesis of 1,5-diphenyl-1H-pyrazole-3-alkanoic acids and the use of these acids and their esters as cyclooxygenase and lipoxygenase inhibitors.

Bondavalli et al. [Farmaco, Ed. Be. 43, 725-743 (1988)] describes N-alkylcarbamates of 1- (2-hydroxyethyl) -3,5-diphenyl-1H-pyrazole as antihypertensive, antiarrhythmic, analgesic, antiinflammatory and hypoglycemic agents. Specifically described are ethyl, isopropyl, phenyl and 1-naphthyl carbamates.

U.S. Patent 4,072,498 to Moon and Kornis discloses N, N, a, α-tetramethyl-3,4-diphenyl-1H-pyrazole-1-acetamide as a herbicide (Example 160).

Ezrin et al. [FASEB Journal 2, A1557 (1988)], a publication from our own laboratory, describes the antiarrhythmic * '

Effectiveness of N- [3- (diethylamino) propyl] -4,5-diphenyl-1H-pyrazole-1-acetamide fumarate.

European Patent Application No. 299,407, published Jan. 18, 1989, describes an extensive series of ™ 4,5-diaryl-1H-pyrazol-1-alkanamides as antiarrhythmic agents.

This invention relates to compounds of the formula Ia or Ib

(La)

(CH ₂ ) mC-N- (CH ₂ ) _p -A

(Ib)

(CH ₂ ) _m CN- (CH ₂ ) p -A '

Il

or acid addition salts thereof, wherein R ^{1 is} hydrogen or lower alkyl, R ² and R ^{3 are} independently hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylamino, lower alkylamido, lower alkylsulfonamido, nitro, amino, , Cyano or halogen, R ^{4 is} hydrogen or hydroxy, m is one or two, ρ is one, two or three and A is a five or six membered heterocyclic compound consisting of carbon and nitrogen, attached to a carbon - (CH _{2 is} Ip- bonded and optionally substituted with a lower alkyl group.

Lower alkyl as used herein means linear or branched hydrocarbon chains of four or fewer carbon atoms; lower alkoxyl, as used herein, refers to linear or branched alkoxy substituents having four or fewer carbon atoms; Halogen describes bromine, chlorine or fluorine.

Examples of heterocyclic compounds in the context of the invention are pyrrolidine, piperidine, piperazine, imidazole, pyrrole, pyridine, pyrimidine, pyrazine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N-methylpiperazine and N-ethylpiperazine.

Compositions for the treatment of cardiac arrhythmias include compounds of formula I together with pharmaceutically acceptable fillers or diluents as needed. Treatment of cardiac arrhythmias in a mammal can be accomplished by administering an antiarrhythmic effective amount of a compound of Formula I.

Methods are described for the preparation of a compound of formula I in which a pyrazole-1-acetate or -propanoate ester or a pyrazole-1-acetic or propanoic acid is reacted with an amine.

The synthesis of the compounds of this invention can be outlined as shown in Scheme A, wherein R ^{5 is} hydrogen or lower alkyl.

Scheme A

(CH ₂ ) _m C-OR ⁵

(CH ₂ ) _m C-OR ⁵

(Ha)

R ¹

HN- {CH ₂ ) _p -A

(Πι;

(CH ₂ ) _m CN- (CH ₂ ) pA

When R ^{s is} lower alkyl, the lower alkyl ester, preferably a methyl or ethyl ester, of an appropriately substituted 3,4- or 4,5-diphenylpyrazole-1-alkanoic acid (II) is reacted with an excess of a primary or secondary amine of formula III at 20 to 150 ⁰ C, preferably at 90 to 150 ° C, reacted. When the amine is valuable, the ester II is preferably reacted with about one equivalent of the amine III in the presence of a tertiary amine, preferably diisopropylethylamine, in an inert solvent.

However, the compounds according to the invention can also be synthesized from the free acids, which can be obtained by hydrolysis of the corresponding esters. Thus, an appropriately substituted 3,4- or 4,5-diphenyl-1 H-pyrazol-1 acetic acid or propanoic acid (IIa or II b, wherein R ⁶ is hydrogen) is activated by techniques well known in the art, eg. By reaction with an acid chloride to form a mixed anhydride, by reaction with a carbodiimide to form an O-acylisourea, or by reaction with carbonyldiimidazole to form an imidazolide. The activated acid in an inert solvent is then combined at -20 to 75 ° C with a stoichiometric amount or a slight excess of a primary or secondary amine of formula III.

The ester Il a, in which R ^{4 is} hydrogen and m is 1, or II b, in which m is 1, can be prepared from the correspondingly substituted deoxybenzoin by formylation according to known methods [Rüssel et al. J. Am. Chem. Soc. 76.5714 (1954)] are synthesized followed by condensation with a Hydrazinessigsäureester in a suitable solvent, preferably in ethanol, at 20 to 100 ⁰ C, preferably at 25 ° C. The hydrazine acetate is preferably used in the form of a mineral acid salt from which the free hydrazine may be released in situ by the addition of about one equivalent of a base, preferably pyridine.

The ester Ha in which R ^{4 is} hydrogen and m is 2 or Hb in which m is 2 can be synthesized from the correspondingly substituted diarylpyrazole by a two-step process resulting from the reaction with acrylonitrile in the presence of a base in an inert Solvent at 0 to 50 ⁰ C, preferably at about 20 ⁰ C, followed by hydrolysis of the nitrile using methanol and hydrogen chloride in an inert solvent at 0 to 30 ⁰ C and then water at 0 to 30 ⁰ C.

When only the 4,5-Diphenylisomer of the products of formula Ia where m is 1 and R ⁴ is hydrogen, is desired, the 4,5-diphenyl Ha where R ⁴ is hydrogen may be synthesized from the appropriately substituted desoxybenzoin , Namely, according to a two-stage process consisting of the reaction with Ν, Ν-dimethylformamide dimethyl acetal in an inert solvent, preferably methyl tert-butyl ether, at 20 to 100 ⁰ C, preferably at about 55 ° C, followed by cyclization with a lower Alkyl ester of hydrazine acetic acid as described above.

Other methods for preparing the ester Ha, where R ^{4 is} hydrogen and m 2, or the ester Il b, where m is 2, and a detailed description of the determination of the identity of specific isomers, are disclosed in US Pat. 895. The ester Il a, where R * is hydroxy, can be prepared from the corresponding 3,4-diphenyl-5-pyrazolone by alkylation with an ω-haloalkanoate in the presence of about one equivalent of a base, preferably potassium carbonate, in an inert solvent at 20-10O ° C, preferably at about 55 ° C, are synthesized.

The compounds of formulas Ia and Ib are useful in both the free base form and in the form of acid addition salts, both of which are within the scope of the invention. The acid addition salts are in some cases a more suitable form for practical use and, in practice, the use of the salt form inherently results in the use of the base form. The acids which can be used to prepare the acid addition salts preferably include those which, when combined with the free base, produce medically acceptable salts, i. H. Salts whose anions are relatively harmless to the animal organism in medicinal doses of the salt so that the beneficial properties inherent in the free base are not offset by side effects attributable to the anions. In the practice of the invention it is convenient to form the hydrochloride, fumarate, toluenesulfonate, methanesulfonate or maleate salts. Other suitable medically acceptable salts in the invention are those derived from other mineral acids and organic acids. The acid addition salts of the basic compounds are prepared either by dissolving the free base in aqueous alcoholic solution containing the corresponding acid and isolating the salt by evaporation of the solution or by reacting the free base and an acid in an organic solvent. wherein the salt precipitates directly, is precipitated with a second organic solvent or can be recovered by thickening the solution. Although medically acceptable salts of the basic compounds are preferred, all acid addition salts and solvates, e.g. Hydrates, of the compounds formed within the scope of the invention. All acid addition salts are suitable sources of the free base form, even if the particular salt is desired to be only an intermediate, e.g. when the salt is formed for the sole purpose of purification or identification, or when 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, elemental analysis and by infrared, ultraviolet, nuclear magnetic resonance and mass spectroscopy. The course of the reactions and the identity and homogeneity of the products were assessed by thin-layer chromatography or gas-liquid chromatography. The starting materials are either commercially available or can be prepared by methods known in the art.

In the following methods, the melting point is given in each case in ⁰ C and uncorrected. The abbreviation THF stands for tetrahydrofuran, DMF stands for Ν, Ν-dimethyrformamide, and Ac stands for acetyl residue, CH ₃ CO.

Example 1A

Ethyl 4,5-diphenylm H-pyrazole-1-acetate

A slurry of 200 g (0.89 mol) of formyldeoxybenzoin and 138 g (0.89 mol) of ethylhydrazine acetaldehyde chloride in 21% ethanol was stirred at room temperature and treated dropwise with 72 mL (0.89 mol) of pyridine. The reaction was stirred at room temperature and the progress of the reaction was evaluated by periodic thin-layer chromatography using 3% acetic acid, 25% acetone and 72% toluene on silica gel. When, after addition of another 3 ml of pyridine over 18 hours, the reaction was judged complete by TLC, the solvent was removed in vacuo and the residue was slurried in ethyl acetate. The ethyl acetate solution was filtered free of solid impurities, washed with water, then washed with saturated sodium chloride solution and dried over magnesium sulfate. The ethyl acetate was stripped to a reddish oil which was triturated in pentane to give 156 g of solid. The product was carefully recrystallized from ether-pentane to give 44.6 g of ethyl 4,5-diphenyl-1 H-pyrazole-1-acetate having a melting point of 79-81 ⁰ C emerged. By repeated careful crystallization from ether-pentane, an additional 99.6 g of the 4,5-diphenyl isomer can be obtained with an overall yield of 144.2 g (53% yield).

Example 1B

Ethyl 4,5-diphenyl-1H-pyrazole-1-acetate

If only the 4,5-diphenyl isomer is desired, the following procedure is preferred. A mixture of 778 g (3.96 moles) of deoxybenzoin, 580 mL (4.38 moles) of Ν, Ν-dimethylformamide dimethyl acetal and 775 mL of methyl tert-butyl ether was refluxed for 3 hours. The reaction mixture was cooled to 0-5 ⁰ C on ice. The precipitated solid was collected by filtration, the filter cake was washed twice with 250 ml of cold methyl tert-butyl ether and dried in the vacuum chamber at 65 ° C., so that 913 g (92%) of 3- (dimethylamino) -1,2-diphenyl- 2-propen-1-one with a melting point of 128-133 ° C emerged. A slurry of 913 g (3.64 mol) of 3- (dimethylamino) -1,2-diphenyl-2-propen-1-one in 3.41 absolute ethanol was treated with 618 g (4 mol) of ethyl hydrazine acetal hydrochloride in an amount. The mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate was treated with 71% (50%) aqueous ethanol with stirring. By cooling the resulting solution to 0-5 ⁰ C was a white solid, which was collected by filtration, washed with 250 ml cold 50% ethanol twice and dried under vacuum at 40 ⁰ C so that 970g (87%) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate having a melting point of 76-80 ⁰ C were formed, wherein none of the detectable by gas-liquid chromatography 3,4-diphenyl isomers was included.

Example 2

Ethyl 3,4-diphenyl-1H-pyrazole-1-acetate

Chromatography of the mother liquors of Example 1A on silica gel using 1: 1 chloroform-hexane gave up to 20% of the 3,4-diphenyl isomer. The 3,4-diphenyl isomer (Example 2) can be distinguished from the 4,5-diphenyl isomer (Example 1) by its higher Rf value in thin layer chromatography. An analytical sample can be recovered by distillation at 0.2mm, boiling range 186-189 ° C.

Example 3 '

Ethyl 4,5-bis (4-fluorophenyl) -1H-pyrazole-1-acetal and ethyl 3,4-bis (4-fluorophenyl) -1H-pyrazole-1-acetate Following the procedure of Example 1 were added 19.7 g (0.076 mol) of 1,2-bis (4-fluorophenyl) -3-hydroxy-2-propen-1-one, 11.8 g (0.076 mol) of ethylhydrazine acetaldehyde chloride and 6.3 ml (0.078 mol) of pyridine Room temperature to form 19.9 g of the mixed 4,5- and 3,4-diphenyl isomers reacted. The isomers were separated by high pressure liquid chromatography on silica gel eluting with 97% toluene, 3% ethyl acetate. The peak with k '= 2.0 gave 1.8 g of the 3,4-diphenyl isomer having a melting point of 98-99 ° C, and the peak with k' = 4.0 gave 11.16 g of the 4,5-diphenyl isomer a melting point of 83-84 ° C.

Example 4

Methyl 3,4-diphenyl-1H-pyrazole-1-propanoate and methyl 4,5-diphenyl-1H-pyrazole-1-propanoate 30g (0.136mol) 3,4 (4,5) diphenylpyrazole and 11, 2 ml (0.166 mol) of acrylonitrile were combined in 450 ml of methylene dichloride and 0.56 g (0.01 mol) of sodium methoxide was added. The mixture was stirred with stirring under nitrogen for 4 hours and allowed to stand under nitrogen for 18 hours. The reaction mixture was filtered and evaporated under vacuum below 30 ° C. The residue was taken up in hot absolute alcohol and cooled. The first product of 22.7 g wet solid contained 30% 3,4-isomer and 70% 4,5-isomer, as shown by NMR. It was recrystallized a second time from about 350 ml of ethanol, so that 11g of pure 4,5-diphenyl with a melting point of 123-124 ⁰ C emerged. A second product of 9 g of wet solid from the first crystallization was essentially pure 3,4-diphenyl isomer with a melting point of 82-85 ° C, which was shown by NMR.

In an ice bath under nitrogen, hydrogen chloride gas was passed through a suspension of 100 mg (0.4 mol) of 4,5-diphenylpyrazole-1-propionitrile and 2 ml of dry methanol for 5 to 10 minutes. Since the starting nitrile was not in solution, 2 ml of THF and 2 ml of methanol were added. The mixture was treated again with hydrogen chloride gas. The temperature shot above 20 ° C and the hydrogen chloride gas was turned off. The reaction was stirred for 48 hours at room temperature and 70 mg of crystalline imino ether hydrochloride was filtered off (melting point 90-91 ⁰ C). The imino ether hydrochloride was dissolved in 5 ml of methylene chloride, cooled to 0 ⁰ C, and 10 drops of water were added. The reaction was a few minutes at 0 ⁰ C and then stirred for a few minutes at room temperature. The methylene chloride layer was separated and dried over magnesium sulfate, filtered and evaporated to give 30mg of methyl 4,5-diphenyl-1H-pyrazole-1-propanoate of melting point 72-74 ° C.

Example 5

Ethyl 4- (4-methoxyphenyl) -5-phenyl-1H-pyrazole-1-acetate

According to the procedure of Example 1B, 11 g (0.39 mol) of 3- (dimethylamino) -2- (4-methoxyphenyl) -1-phenyl-2-propen-1-one and 6.6 g (0.43 mol) of ethylhydrazine acetoacetate hydrochloride in 55 ml of absolute methanol under nitrogen for reaction. After 1.5 hours, 11.2 g of solid product (melting point 81-84 ⁰ C) were filtered off.

Example 6

Ethyl 5- (4-hydroxyphenyl) -4-phenyl-1H-pyrazole-1-acetate

Following the procedure of Example 1B, 15 g (0.05 mol) of 3- (dimethylamino) -1- (4-hydroxyphenyl) -2-phenyl-2-propene-1-one and 9 g (0.058 mol) of ethylhydrazine acetaldehyde chloride in 75 mL of absolute ethanol reacted. After 1.5 hours, 14.38 g of solid product (melting point 130-135 ° C) were filtered off.

Example 7

Ethyl 4- (4-fluorophenyl) -5-phenyl-1H-pyrazole-1-acetate

By the procedure of Example 1B, 13.8 g (0.0645 mol) of 2- (4-fluorophenyl) -1-phenylethanone were reacted with 20 ml of dimethylformamide dimethyl acetal to give 13.6 g of 3- (dimethylamino) -2- (4-fluorophenyl) - 1-phenyl-2-propen-1-one (melting point of 115-116 ° C from isopropyl acetate) reacted. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazine acetal hydrochloride to give 12.1 g of product having a melting point of methyl acetobutyl ether of 86-87 ° C.

Examples

Ethyl 4- (4-nitrophenyl) -5-phenyl-1H-pyrazole-1-acetate

By a procedure analogous to that of Example 7, 11.9 g of ethyl 4- (4-nitrophenyl) -5-phenyl-1H-pyrazole-1-acetate having a melting point of 78-79 ° C from methyl t-butyl ether from 17 , 6g (0.073mol) of 2- (4-nitrophenyl) -1-phenylethanone, 35ml of dimethylformamide dimethyl acetal and 7.04g (0.0456mol) of ethylhydrazine acetaldehyde hydrochloride.

Example 9

Ethyl 4- (4-chlorophenyl) -5-phenyl-1H-pyrazole-1-acetate

ⁿ According to a procedure analogous to that of Example 7 were 8.5 g of ethyl 4- (4-chlorophenyl) -5-phenyl-1 H-pyrazole-1-acetate with

h a melting point of 75-76 ° C from triethylamine from 11.48 g (0.049 mol) of 2- (4-chlorophenyl) -1-phenyl-ethanone, 12 ml

', Dimethylformamide dimethyl acetal and 4.95 g (0.032 mol)

Ethylhydrazinacetathydrochlorid synthesized.

Example 10

Ethyl 4- (4-cyanophenyl) -5-phenyl-1H-pyrazole-1-acetate

By a procedure analogous to that of Example 7, 6.7 g of ethyl 4- (4-cyanophenyl) -5-phenyl-1H-pyrazole-1-acetate having a melting point of 124-125 ° C from methyl t-butyl ether 7 from , 72 g (0.035 mol) of 2- (4-cyanophenyl) -1-phenyl-ethanone, 10 ml of dimethylformamide dimethyl acetal and 3.7 g (0.024 mol) of ethylhydrazine acetaldehyde hydrochloride.

The 2- (4-cyanophenyl) -1-phenylethanone was synthesized from 4-cyanobenzyl bromide and cyano-N, N-diethylbenzenemethanamine. 3.95 g (0.16 mol) of sodium hydride were suspended in 80 ml of DMF under nitrogen, and 29.9 g (0.16 mol) of methanamine in 20 ml of DMF were added dropwise. After hydrogen evolution ceased, 31.2 g (0.16 mol) of benzylbromidine in 30 ml of toluene were added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was stripped, 300 ml of 6N HCl was added, and the suspension was stirred for 4 hours, allowed to stand for 18 hours, and extracted with chloroform. The chloroform extract was stripped, dissolved in ethyl acetate and filtered through silica gel to remove a purple color contaminant. The ethyl acetate solution was stripped, the residue was triturated in ether and recrystallized from methanol to give 7.72 g of 2- (4-cyanophenyl) -1-phenylethanone having a melting point of 113-114 ° C.

Example 11 Ethyl 5- [4- (dimethylamino) phenyl] -4-phenyl-1H-pyrazole-1-acetate Following a procedure analogous to that of Example 7, 13.7 g of ethyl 5- [4- (dimethylamino) phenyl] 4-phenyl-1H-pyrazole-1-acetate (mp 99-101 ° C from ether) from 13.0 g (0.054 mol) of 1- [4- (dimethylamino) phenyl] -2-phenylethanone, 27.6 ml (0.196 mol) of dimethylformamide dimethyl acetal and 7.9 g (0.05 mol) of ethylhydrazine acetal hydrochloride were synthesized.

Example 12

4,5-Diphenylm H-pyrazole-1-acetic acid 12g (0.04 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate from Example 1 was dissolved in 40 ml of water, 40 ml of ethanol and 5 ml of 35% aqueous sodium hydroxide for 1.5 hours under reflux. The ethanol was expelled, water was added and the slurry was acidified with an excess of 6N HCl. The resulting precipitate was filtered off and rinsed with water to give 10.4 g of free acid having a melting point of 169-170 ⁰ C emerged.

Example 13 4,5-Diphenyl-N- [2- (1-piperidinyl) ethyl] -1H-pyrazole-1-acetamide A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1 acetate of Example 1 and 10.2 ml (0.072 mol) of N- (2-aminoethyl) piperidine in 62 ml of diisopropylethylamine was stirred at 100 ° C for 18 hours. Upon cooling and standing, a solid precipitate formed, which was filtered off and recrystallized very slowly from 250 ml of 1: 3 THF ether to give 10.6 g of 4,5-diphenyl-N- [2- (1-piperidinyl) ethyl ] -1 H-pyrazole-1-acetamide having a melting point of 95-97 ° C emerged.

Example 14

4,5-Diphenyl-N- [3- (1-pyrrolidinyl) propyl] -1H-pyrazole-1-acetamide A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1 acetate and 60ml N- (3-aminopropyl) pyrrolidine was stirred at 100 ° C for 48 hours. The Aminopropylpyrrolidinüberschuß was stripped under vacuum and the residue was triturated in ether to give 5.5 g of product with a melting point of 75-79 ⁰ C.

Example 15 4,5-Diphenyl-N- [2- (1-pyrrolidinyl) ethyl] -1H-pyrazole-1-acetamide Following a procedure substantially similar to that of Example 13, 6.67 g of 4.5 diphenyl-N- [2- (1-pyrrolidinyl) ethyl] -1 H-pyrazole-1-acetamide having a melting point of 80-84 ⁰ C from 15g (0.049 mol) of ethyl 4,5-diphenyl-1 H -pyrazole-1-acetate of Example 1.9 ml (0.072 mol) of N- (2-aminoethyl) pyrrolidine and 62 ml (0.36 mol) of diisopropylethylamine.

Example 16

4,5-diphenyl-N- [3- (1-piperidinyl) propyl] -1H-pyrazole-1-acetamide hemihydrate A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1 acetate of Example 1.10.2 g (0.02 mol) of 3-aminopropylpiperidine and 62 ml of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The excess amine was driven off under vacuum. The residue was taken up in about 300 ml of ether and washed twice with water.

The product was extracted into 150 ml of cold water with 18 ml of 10% hydrochloric acid. The water layer was washed twice with ether, treated with decolorizing carbon, filtered, cooled and basified with solid sodium carbonate. The product was extracted into methylene dichloride, dried over sodium sulfate, filtered and stripped to a solid residue of 14.7g. The residue was triturated in water, filtered, yielding 12.36 g of 4,5-diphenyl-N- [3- (1-piperidinyl) propyl] -1H-pyrazole-1-acetamide hemihydrate, m.p. 81-85 ° C dried.

Example 17 3,4-Diphenyl-N- [2- (1-piperidinyl) ethyl] -1H-pyrazole-1-acetamide Following a procedure substantially similar to that of Example 13, 14.0 g of 3,4 -Diphenyl-N- [2- (1-piperidinyl) ethyl] -1H-pyrazole-1-acetamide from 16.4 g (0.054 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 10 g ( 0.07 mol) of 2-aminoethylpiperidine and 65 ml (0.37 mol) of diisopropylethylamine. The product was not recrystallized, but pulverized in ether (mp 120-124 ⁰ C). By recrystallization from ethyl acetate, a second polymorphic product melting at 142-144 ° C can be recovered.

Example 18

S ^ -Diphenyl-N-tS-1-piperidinylpropyl-IH-pyrazole-i-acetamide (E) -2-butenedioate (1: 1) A mixture of 20 g (0.065 mol) of ethyl-3,4-diphenyl-1H pyrazole-1-acetate from Example 2.13,7g (0.096 mol) of N- (3-aminopropyl piperidine and 78 ml of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours.

The reaction mixture was stripped to dryness, the residue was dissolved in dichloromethane, washed twice with water and washed once with saturated sodium chloride solution. The product was dissolved in approx. 100 ml of cold water with approx.

Extracted 12 ml of 10% HCl. The water layer was basified with solid sodium carbonate and the product was extracted into methylene dichloride, dried over sodium sulfate and stripped. The product was purified by chromatography on silica gel eluting with 5% triethylamine in chloroform. The purified product was crystallized from acetone as the fumarate salt and recrystallized from ethanol to give 8.56 g of product having a melting point of 179-180 ° C.

Example 19 IM-fZ-d-Methyl-a-pyrrolidine-DethyUAS-diphenyl-IH-pyrazole-i-acetamidiEja-butenedioatile: A solution of 10 g (0.033 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1 acetate of example 1 in 9,6ml (0,066mol) 2- (2-aminoethyl) -1-methylpyrrolidine was stirred at 100 ⁰ C for 18 hours. The reaction mixture was dissolved in methylene chloride, washed several times with water, dried over magnesium sulfate and stripped to a brownish yellow oil. The oil was dissolved in ethanol, 1 equivalent of fumaric acid added, and the solution stripped under vacuum. The resulting foam was crystallized from acetonitrile-ether to give 10.6 g of product with a melting point of 109-110 ⁰ C emerged.

Example 20

N- [2- (1H -imidazol-4-yl) ethyl] -4,5-diphenyl-1H-pyrazole-1-acetamide (4: 1) hydrate A solution of 5.5 g (0.02 mol) 4 , 5-diphenyl-1 H-pyrazol-1 -acetic acid of example 12 and 3.6g (0,022mol) of carbonyldiimidazole in 150 ml of dioxane was heated for 2 hours under reflux and cooled to about 10 ⁰ C. 3.7 g (0 , 02 mol) of histamine dihydrochloride and 5.7 ml (0.04 mol) of triethylamine were added and the suspension stirred for 18 hours at room temperature The suspension was cooled, filtered, the filtrate was stripped to approximately 95 ml and cooled, the resulting needles were filtered off and rinsed with a very small amount of water that 3.8 g of product with a melting point of 198-199.5 ° C emerged.

Example 21 N-Methyl-N- [2- (1-piperidinyl) ethyl] 4,5-diphenyl-1H-pyrazole-1-propanamide

Following a procedure substantially similar to that of Example 19, N-methyl-N- [2- (1-piperidinyl) ethyl] -4,5-diphenyl-1H-pyrazole-1-propanamide can be prepared from methyl-4 , 5-diphenyl-1H-pyrazole-1-propanoate of Example 4 and 1- [2- (methylamino) -ethyl] piperidine.

Example 22 4- (4-Chlorophenyl) -N - [(1-methyl-3-piperidinyl) methyl] -5-phenyl-1H-pyrazole-1-acetamide Following a procedure substantially similar to that of Example 19, For example, 4- (4-chlorophenyl) -N - [(1-methyl-3-piperidinyl) methyl] -5-phenyl-1H-pyrazole-1-acetamide can be prepared from ethyl 4- (4-chlorophenyl) -5-phenyl 1-H-pyrazole-1-acetate of Example 9 and i-methyl-3-piperidinemethanamine.

Example 23 5- [4- (Dimethylamino) phenyl] -4-phenyl-N - [(3-pyridinyl) methyl] -1H-pyrazole-1-acetamide. By a procedure substantially similar to that of Example 19, 5- [4- (Dimethylamino) phenyl] -4-phenyl-N - [(3-pyridinyl) methyl] -1H-pyrazole-1-acetamide from ethyl 5- [4- (dimethylamino) phenyl] -4- phenyl-1H-pyrazole-1-acetamide of Example 11 and 3- (aminomethyl) pyridine.

Example 24 Ethyl 3-hydroxy-4,5-diphenyl-1H-pyrazole-1-acetate or ethyl-1,2-dihydro-3-oxo-4,5-diphenyl-3H-pyrazole-1-acetate

A suspension of 3.3 ml (0.03 mol) ethyl bromoacetate, 3.9 g (0.028 mol) anhydrous ground potassium carbonate and 6.7 g (0.028 mol) 1,2-dihydro-4,5-diphenyl-2H-pyrazole-3 on, obtained according to the method of Gruenanger and Finzi [Chemical Abstracts 58: 516f (1963)] in 67 ml of acetone was stirred under reflux for 24 hours. The solvent was removed in vacuo and the residue was chromatographed on a 45 x 300 mm silica gel column eluting with a gradient of up to 10% ethyl acetate in hexane with 75 ml fractions each. Fractions 50-65 contained the O-alkylated product; Fractions 75-79 gave 1.1 g of the desired N-alkylated product with a melting point of 181-183 ° C.

Example 25 N- (1-ethyl-4-piperidinyl) -3-hydroxy-4,5-diphenyl-1H-pyrazole-1-acetamide

Following a procedure substantially similar to that of Example 19, N- (1-ethyl-4-piperidinyl) -3-hydroxy-4,5-diphenyl-1H-pyrazole-1-acetamide can be prepared from ethyl-3-ene hydroxy-4,5-diphenyl-1H-pyrazole-1-acetate of Example 25 and 1-ethyl-4-piperidinamine.

Other examples of the (heterocyclic) alkyl-substituted pyrazole-1-alkanamides can be synthesized using procedures analogous to those above. Many compounds that could be used as starting materials are described in co-pending U.S. application D.N. 7398C to Denis M. Bailey, which is incorporated herein by reference.

The antiarrhythmic activity of compounds of the invention was demonstrated by the following procedure. Duncan Hartley guinea pigs (600-90g) of both sexes were anesthetized with urethane (1.4g / kg, ip) and supplemented as needed. An intravenous route for administration of the drug was made using micro-tubes inserted into the jugular vein. The induction of arrhythmias by Aconitinhydrochlorid (34g / kg) was evaluated in control guinea pigs, which 1 cm ³ of physiological saline as • t. I was given an intravenous bolus 10 minutes before aconitine challenge.

The compounds to be tested were intravenously administered intravenously 10 minutes prior to aconitine challenge at a starting dose of 30 mg / kg. This dose was reduced in subsequent animals when severe cardiac arrhythmias lasted for more than two minutes after injection on the first guinea pig examined. All medications were tested at the maximum permissible dose (as evidenced by the absence of cardiac arrhythmias on the ECG prior to aconitine challenge). The compounds were administered in saline as 1 m ³ bolus injections (n = 5-9).

The time span between the administration of aconitine and the occurrence of cardiac arrhythmias was determined. Particular attention was paid to the time to onset of 1st premature ventricular contraction (PVC), 2. the first sustained episode of ventricular tachycardia consisting of 10 or more ventricular beats (VTACH), and 3. the time to onset of ventricular fibrillation over more than 15 seconds (VFIB). The mean time and standard error from the mean to the onset of these cardiac arrhythmias were calculated for each treatment group and compared to concurrent control tests using a single variance analysis. Efficacy was defined as a statistically significant delay in the onset of PVC, VTACH and VFIB versus the control values. The table below summarizes the results obtained from testing the representative compounds of the invention.

example PVC Minutes until VFIB No. 1.0-1.9 VTACH 3.1 to 4.3 control 7.9 1.4-2.5 35.4 13 5.1 10.7 25.7 14 2.9 6.3 15.5 15 5.2 3.0 27.6 16 3.6 15.4 30.0 17 3.6 9.6 29.0 18 16.8 8.0 34.4 19 6.3 20.9 29.0 20 9.3

The compounds of the present invention may be prepared for use by conventional pharmaceutical methods: for parenteral or oral administration by dissolving or flooding the compounds or their pharmaceutically acceptable salts in a pharmaceutically acceptable carrier, e.g. Water, aqueous alcohol, glycol, oil solution or oil-water emulsion; or by incorporating the compounds in a base dosage form as capsules or tablets for oral administration, either alone or in combination with conventional adjuvants or fillers, e.g. Calcium carbonate, starch, lactose, talc, magnesium stearate, acacia gum and the like.

The percentage of active ingredient in the composition and the method of treating or preventing cardiac arrhythmias may be varied to achieve a suitable dosage. The dosage prescribed to a particular patient may be varied depending on the judgment of the clinician, which takes as criteria the route of administration, the duration of treatment, the size and condition of the patient, the strength of the drug and the response of the patient to it. In this way, an effective dosage amount of the active agent can be determined by the clinician, who takes into account all criteria and acts to the best of the knowledge in the interest of the patient.

Claims (9)

-1- 295 claims: 1. Compound of the formula m \ la (CH ₂ ) _m CN- (CH ₂ ) pA ib I i (CH ₂ ) mC-N- (CH ₂ ) pA or an acid addition salt thereof, wherein R ^{1 is} hydrogen or lower alkyl; R ² and R ^{3 are} independently hydrogen, hydroxy, lower alkyl, lower alkoxy, lower Al kylamino-, lower Al kylamido-, lower Al kylsulfonamido-. Nitro, amino, Cyano or halogen radical; R ^{4 is} hydrogen or hydroxy; m is 1 or 2; ρ is 1,2 or 3; and A is a five- or six-membered heterocyclic radical which is carbon, hydrogen and nitrogen and is bonded to a carbon atom on (CH ₂ ) _P or A is a five- or six-membered heterocyclic radical containing a lower one Substituted alkyl group containing carbon, hydrogen and nitrogen and is bonded to a carbon atom of (CH ₂ ) _p . 2. A compound according to claim 1, wherein m is 1. 3. A compound according to claim 2, wherein in formula Ib R ^{4 is} hydrogen and m is 1. 4. A compound according to claim 3, wherein ρ is 2. 5. A compound according to claim 4, in which A is imidazole. 6. N- [2- (1H-imidazol-4-yl) ethyl] -4,5-diphenyl-1H-pyrazole-1-acetamide according to claim 5. A compound according to claim 4 wherein A is a lower alkyl substituted pyrrolidine. 8. N- [2- (1-Methyl-2-pyrrolidinyl) ethyl] -4,5-diphenyl-1H-pyrazole-1-acetamide according to claim 7. 9. A process for the preparation of a compound according to claim 1, characterized by the reaction of a corresponding compound of the formula IIa or IIb R ³ ^ _x. / R ² R ⁴ (CH ₂ ) _m C-OR ⁵ hb