DD295631A5 - NEW 1H-PYRAZOLE-1-ACETAMIDES AND METHOD OF PREPARING THEM - Google Patents

Abstract

The invention relates to novel 1H-pyrazole-1-acetamides and to processes for their preparation. They are defined by the formula I in which R 1 is hydrogen or lower alkyl, R 2 is hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylamino, lower alkylamido, lower alkylsulfonamido, nitro, amino, cyano or halogen, R4 and R3 independently of one another are hydrogen, lower alkyl or hydroxy, lower alkyl or R4 and R3 together form a straight or branched alkylene chain of four to six carbon atoms and n is an integer from two to eight. The process for preparing a compound of formula I comprises the reaction of a pyrazole-1-acetate or a -1-acetic acid with an amine. The compounds of the invention are suitable for the treatment of cardiac arrhythmias in mammals. Formula I {1H-pyrazole-1-acetamide; Method; manufacture; Pyrazole-1-acetate; Pyrazole-1-acetic acid; amine; cardiac arrhythmia; Mammal}

Description

and the reaction of the compound last obtained with a compound of formula VII

R ⁴

to obtain the corresponding compound of formula I in which A is (CH ₂ J _n and X is a nucleophilically displaceable group,

and, when R ^{5 is} hydrogen, activating the free acid of formula II before reacting with a compound of formula III or IV, · ;

and, if desired, converting a resulting 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 5 in an amount effective to treat cardiac arrhythmias together with one or more pharmaceutically acceptable carriers or diluents.

The invention relates to novel 1 H-pyrazole-1-acetamides, which are suitable for the treatment of cardiac arrhythmias in mammals, and their preparation.

Heinemann et al. in US-PS 4,695,566 1 H-pyrazol-3-yl (and 1 H-pyrazol-5-yl) oxyacetamide of the general formula

O-C-CO-N-Z-N

R ⁶ R ⁷

R ⁸ R ⁹

described as antiarrhythmic drugs.

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

U.S. Patent 4,182,895 by Bailey is used as an intermediate in the synthesis of 1-amino-lower-alkyl-3,4-diphenyl-1H-pyrazoles "β- [1- (3,4-diphenyl-1H) pyrazolyl)] - N, N-dimethylpropionamide "in column 8, lines 63 to 64.

Bondavelli et al. (Farmaco, Ed. 43, 2725-743 [1988]) describes N-alkyl carbamates of 1- (2-hydroxyethyl) -3,5-diphenyl-1H-pyrazole as antihypertensive, antiarrhythmic, analgesic, anti-inflammatory and hypoglycemic agents. Specifically described are ethyl, isopropyl, phenyl and 1-naphthyl carbamates.

German Published Application No. 3620825 (Chemical Abstracts 108: 112467 [1987]) appears to describe 3-phenyl-1H-pyrazole-1-acetamide as an intermediate in the synthesis of optical brightening agents.

U.S. Patent No. 4,072,498 to Moon and Kornis discloses a series of α-methyl-3-phenyl and 5-phenyl-1H-pyrazole-1-acetamides and a 3-phenyl-1H-pyrazole-1-propanamide as herbicides. Specifically described are the o-chloro, m-chloro and m-nitroso and the unsubstituted 3- and 5-phenyl-N, N, α-trimethyl-1H-pyrazole-1-acetamides (Examples 15, 21, 16, 25 or 2). Example 124 describes N, N-dimethyl-S-phenylpyrazole-i-propionamide. Example 142 describes N, N, α-trimethyl-3- (of-fluorophenyl) pyrazole-1-acetamide and the corresponding o-bromo and o-ethyl analogues.

Ezrin et al. (FASEB Journal 2, A1557 [1988]) describes the antiarrhythmic activity 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-pyrazole-1-alkanamides as antiarrhythmic agents.

This invention relates to compounds of the formula I.

CH ₂ -CN- (CH ₂ ) _n N

or acid addition salts thereof, wherein R ^{1 is} hydrogen or lower alkyl, R ^{2 is} hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylamino, lower alkylamido, lower alkylsulfonamido, nitro, amino, cyano or halogen , R ⁴ and R ³ are independently hydrogen, lower alkyl or hydroxy-niedererAlkylrest or R ⁴ and R ³ together form a straight or branched alkylene chain of four to six carbons, and η is an integer of two to eight is. Lower alkyl as used herein means linear or branched hydrocarbon chains of four or fewer carbon atoms; lower alkoxy as used herein denotes linear or branched alkoxy substituents having four or fewer carbon atoms; Halogens are bromine, chlorine or fluorine. Compositions for the treatment of cardiac arrhythmias include compounds of formula I together with pharmaceutically acceptable fillers or diluents as needed. The treatment of cardiac arrhythmias in a nipple may be accomplished by administering an antiarrhythmic effective amount of a compound of Formula I. A process for the preparation of a compound of formula I comprises the reaction of a pyrazole-1-acetate or-i-acetic acid with an amine.

Other methods for preparing a compound of formula I include reacting a 4 or 5-disubstituted pyrazole-1-acetate or -1-acetic acid with a ω-aminolinearalkanol, converting the resulting alcohol to a group which is a good substrate for the nucleophilic substitution, and the substitution of this group with an amine. The synthesis of compounds of the invention can be outlined as illustrated in Scheme A, wherein R ^{s is} hydrogen or lower alkyl.

Scheme A

CH ₂ -C-OR ⁵

(ID

R ¹

I HN- (CH ₂ ) _n N

R ³ R ⁴

(III)

CH ₂ -CN- (CH ₂ ) _n N

(I)

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

However, the compounds of the invention can also be synthesized according to Scheme B when A is (CH ₂ J _n .

Scheme B

(II)

CH ₂ C-OOR

R ¹ I HN (CH ₂ ) _n OH

(IV)

R ¹

I is CH ₂ CN (CH ₂ ) _n OH

(V)

(Vl)

CH ₂ CN (CH ₂ ) _n X

HN

R ⁵

(VII)

CH ₂ CN (CH ₂ ) _n N

I

R ⁴

(I)

A lower alkyl ester, preferably a methyl or ethyl ester, of an appropriately substituted 3-, 4- or 5-phenyl-1H-pyrazole-1-alkanoic acid (II) is reacted with an excess of a primary or secondary aminoalkanol (IV), optionally in the presence an external base at 20 to 150 ° C, preferably at 90 to 100 ⁰ C, reacted to produce an N - [- hydroxyalkyl] pyrazole-1-alkanamide of the formula V. The hydroxyalkylalkanamide (V) is preferably activated by sulfonylation, preferably with methanesulfonyl chloride, in the presence of a base / solvent such as pyridine at -20 to 20 ^° C., preferably at 0 ^° C., to produce an alkylalkanamide of the formula VI wherein X is is a group which undergoes nucleophilic substitution, e.g. For example, methanesulfonate.

Alternatively, the hydroxyalkylalkanamide (V) is converted to the corresponding halide (VI, X = Cl, Br or I) by phosphorus trihalide, phosphorus pentahalide, thionyl halide or tetrahalomethane with trialkylphosphine. The group X is then replaced by reaction with a corresponding primary or secondary amine (VII) in the presence or absence of a solvent at 20 to 100 ^° C.

The ester II may be selected from the appropriately substituted pyrazole by alkylation of the sodium salt with a a-haloacetate or ß-Halogenpropanoat, preferably ethyl bromoacetate or ethyl 3-bromopropionate in an inert solvent, preferably DMF, are synthesized from 20 to 100 ⁰ C.

The appropriately substituted 3-phenyl-1H-pyrazoles are well known in the literature. 4-phenyl-1H-pyrazoles can be prepared by condensation of hydrazine hydrate in an inert solvent, preferably ethanol, at 0 to 100 ⁰ C, preferably at ca.

25 ⁰ C, are prepared with the corresponding substituted 2-aryl-3- (dimethylamino) acrolein. The acroleins are from the method of Coppola et al. (J. Het. Chem. 11, 51-56 [1974]).

The 3- or 5-aryl isomers of ester II can also be prepared from the appropriately substituted .beta.-keto enol ether

Il (R ₂ -C ₆ H ₄ -C-CH = CH-O-Alk) and a Hydrazinesigsäureester be synthesized.

Alternatively, the compounds of 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 5-phenyl-1H-pyrazol-1 -acetic acid (II, wherein R ⁵ is hydrogen) is activated by techniques well known in the art, for example 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 ⁰ C to 75 ° C with a stoichiometric amount or a slight excess of a primary or secondary amine of formula III.

The compounds of formula I 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, such 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 desirable to form the hydrochlorides of 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 as well as solvates, e.g. Hydrates, 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 as an intermediate only, 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 degrees Celsius and uncorrected. The abbreviation THF stands for tetrahydrofuran, DMF stands for Ν, Ν-dimethylformamide, and Ac stands for acetyl rest, CH ₃ CO.

Example 1 4-phenyl-1H-pyrazole

Vilsmeier's reagent was prepared by adding 84 ml (0.9 mol) of phosphorus oxychloride to 81 g (1.1 moles) of DMF with cooling. The reagent was stirred for 5 minutes and 40.8 g (0.3 mol) of phenylacetic acid in 150 mL of DMF was added dropwise. The mixture was heated at 70 ° C for 18 hours, poured onto ice, basified with 35% aqueous NaOH, filtered free from a solid by-product and extracted into methylene chloride. The methylene chloride solution was dried over magnesium sulfate and drained. The residue of 2-phenyl-3- (dimethylamino) acrolein was dissolved in about 350 ml of ethanol and to it was added 0.75 mol of hydrazine hydrate. The mixture was stirred at room temperature for 18 hours and the solid product was filtered off. It was recrystallized from ethanol to give 35 g of 4-phenyl-1H-pyrazole.

Following a substantially similar procedure, 4- (4-chlorophenyl) -1H-pyrazole, 4- (4-methoxyphenyl) -1H-pyrazole, 4- (3-methylphenyl) -1H-pyrazole, and 4- (2N-methylphenyl) -1H-pyrazole; Nitrophenyl) -1H-pyrazole can be prepared from the corresponding acroleins and hydrazine.

Example 2 Ethyl 3-phenyl-1H-pyrazole-1-acetate and ethyl 5-phenyl-1H-pyrazole acetate

A. To a slurry of 8 g (0.2 mol) of sodium hydride in 100 ml of DMF was added at room temperature 23 g (0.16 mol) of 3-phenylpyrazole. The mixture was stirred for 1 hour and 17.8 ml (0.16 mol) ethyl bromoacetate added. The reaction mixture was heated at about 100 ° C for 2 hours, poured into water, extracted into methylene chloride, dried over magnesium sulfate and drained. The resulting oil was chromatographed on silica gel using 25% ethyl acetate in hexane. The 3-isomer is the first and most important component that has been eluted. It was recrystallized from ether-hexane to give 6.0 g of ethyl 3-phenyl-1H-pyrazole-1-acetate having an R _f of 0.66 on silica gel in 1: 1 ethyl acetate-hexane. The third component to be eluted from the HPLC separation was a smaller fraction containing the 5-isomer. Upon stripping of the solvent, 1.0 g of ethyl 5-phenyl-1H-pyrazole-1-acetate was obtained as an oil with an Rf of 0.51 on silica gel in 1: 1 ethyl acetate: hexane.

B. Alternatively, 1.18 g (0.01 mol) of ethylhydrazine acetaldehyde chloride and 1.76 g (0.01 mol) of 3-ethoxy-1-phenyl-2-propen-1-one were combined with an excess of triethylamine; the reaction was heated at 100 ° C for 20 minutes. The reaction mixture was cooled, poured into water and extracted into ether. Thin-layer chromatography of the ether solution on silica gel with 1: 1 ethyl acetate-hexane showed a similar distribution of ethyl 3-phenyl-1H-pyrazole-1-acetate and ethyl 5-phenyl-1H-pyrazole-1-acetate such as which was found in Example 2 A.

Example 3 Ethyl 4-phenyl-1H-pyrazole-1-acetate

To a slurry of 3.0 g (0.075 mol) of sodium hydride in 30 mL of DMF was added 10 g (0.069 mol) of 4-phenyl-1H-pyrazole of Example 1 at room temperature. The mixture was stirred for 1 hour, and with cooling, 7.8 ml (0.07 mol) of ethyl bromoacetate was added. The reaction mixture was stirred for 3 hours at room temperature, briefly at 100 ⁰ C and poured into ice. The product was filtered off, rinsed with water, dried and washed with hexane to give 14.0 g of ethyl 4-phenyl-1H-pyrazole-1-acetate.

Example 4 N- [3- (diethylamino) propyl] -4-phenyl-1H-pyrazole-1-acetamide

A solution of 13.5 g (0.059 mol) of ethyl 4-phenyl-1H-pyrazole-1-acetamide from Example 3 and 12.6 ml (0.08 mol) of 3- (diethylamino) propanamine in 130 ml of DMF was at 100 ⁰ C stirred for 4 hours. The reaction mixture was poured into water, extracted into methylene chloride and drained. The residue was triturated in ether and the resulting solid was recrystallized from ether-hexane to give 3,70g product created with a melting point of 55-57 ⁰ C.

Example 5 N-p-Idiethylaminolpropyl J-S-phenyMH-pyrazole M-acetamide hydrochloride

Following a procedure analogous to that of Example 4 but omitting the DMF solvent, the free base of N- [3- (diethylamino) propyl] -5-phenyl-1H-pyrazole-1-acetamide hydrochloride of 1 , 0g (4.3mmol) of ethyl 5-phenyl-1H-pyrazole-1-acetate and 3- (diethylamino) propanamine. The hydrochloride salt was prepared by dissolving the free base (an oil) in ethanol, adding a solution of hydrogen chloride in anhydrous ether, and recrystallizing the resulting solid from ethanol ether. On drying, the white, crystalline product disintegrated to a brownish, amorphous solid.

Example 6 3- (3-Chlorophenyl) -N- [6- (dimethylamino) hexyl] -1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 4, 3- (3-chlorophenyl) -N- [6- (dimethylamino) hexyl] -1H-pyrazole-1-acetamide can be prepared from ethyl 3- (3-chlorophenyl ) -1H-pyrazole-1-acetate and 6- (dimethylamino) hexanamine.

Example 7 4- (4-Methoxyphenyl) -N- [2- (piperidinyl) ethyl] -1H-pyrazole-1-acetamide

By a procedure substantially similar to that of Example 4, 4- (4-methoxyphenyl) -N- [2- (1-piperidinyl) ethyl] -1H-pyrazole-1-acetamide can be prepared from ethyl 4- ( 4-methoxyphenyl) -1H-pyrazole-1-acetate and 1- (2-aminoethyl) piperidine.

Examples

1-J- [3- (Diethylamino) propyl] -5- (3-nitrophenyl) -1H-pyrazole-1-acetamide

Following a procedure substantially similar to that of Example 4, N- [3- (diethylamino) propyl] -5- (3-nitrophenyl) -1H-pyrazole-1-acetamide can be prepared from ethyl 5- (3 nitrophenyl) -1H-pyrazole-1-acetate and 3- (diethylamino) -N-methylpropanamine (N, N-diethyl-N'-methylpropylenediamine).

Other embodiments of the invention may be synthesized from the corresponding phenylpyrazoles by additional methods described in U.S. Patent No. 7398C to Denis M. Bailey, incorporated herein by reference. The antiarrhythmic activity of compounds of the invention was demonstrated by the following procedure.

Duncan-Hartley guinea pigs (600-900 g) of both sexes were anesthetized with urethane (1.4 g / 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 was placed 1 cm ³ of physiological saline as an intravenous bolus 10 minutes front Aconitinreizung.

The compounds to be tested were given intravenously 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 cm 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 contractions (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 no.

PVC

Minutes to VTACH

VFIB

control

1.8-1.9

8.0

6.0

2.4-2.5 13.4 8.3 »

4.2-7.0 43.2 14.8

* not statistically significant

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 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 (6)

claims: 1. Compound of the formula CH ₂ -CN- {CH ₂ ) _n N (I) or an acid addition salt thereof, wherein R ^{1 is} hydrogen or lower alkyl; R ^{2 is} hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkylamido, lower alkylamido, lower alkylsulfonamido, nitro, amino, cyano or halogen; R ³ and R ⁴ independently of one another are hydrogen, lower alkyl or hydroxy-lower alkyl or R ³ and R ⁴ together are a straight-chain or branched alkylene chain having 4 to 6 C atoms and
η is an integer from 2 to 8. 2. A compound according to claim 1, wherein R ^{1 is} hydrogen. 3. A compound according to claim 2, wherein η is 2 or 3. A compound according to claim 3, wherein R ³ and R ^{4 are} ethyl. 5. N- [3- (diethylamino) propyl] -4-phenyl-1H-pyrazole-1-acetamide according to claim 4. 6. A process for the preparation of a compound according to claim 1, which comprises the reaction of a compound of formula II (II) CH ₂ C-O-O-FT in which R ^{5 is} lower alkyl or hydrogen, a) a compound of formula III R ¹ HN- (CH ₂ ) _n N , R ³ (IN THE) for the preparation of a corresponding compound of formula I or
b) a compound of the formula IV f ¹ HN (CH ₂ ) _n OH (IV) for the preparation of a corresponding compound of the formula V R ¹ (V) CH ₂ CN (CH ₂ ) _n OH and reacting the compound last obtained with a substance capable of converting the alcoholic function into a nucleophilic attack-appropriate group to form a corresponding compound of formula VI R ¹ CH ₂ CN (CH ₂ ) _n X