N-[(alkylamino)alkyl]-4,5-diaryl-1H-imidazole-1-acetamides useful for treating cardiac arrhythmias in mammals, are prepared by reacting a lower-alkyl ester of a diaryl imidazole-1-acetic acid with an appropriate diamine.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to novel 
N-[(alkylamino)alkyl]-4,5-diaryl-1H-imidazole-1-acetamides, processes for 
the synthesis of said imidazole-1-acetamides, and methods for treating 
cardiac arrhythmia in mammals utilizing said imidazole-1-acetamides. 
2. Information Disclosure Statement 
Iradyan et al. [Chemical Abstracts 88: 152498y (1978)] disclose ethyl 
4-(substituted-phenyl)-1H-imidazole-1-acetates wherein the substituted 
phenyl is 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 
4-nitrophenyl, 4-ethoxyphenyl, or 4-propoxyphenyl. 
Iradyan et al. [CA 83: 79153x (1975)] disclose the reaction of a potassium 
salt of a 4-arylimidazole with .alpha.-chloroacetamide to produce 
4-phenyl-and 4-(substituted-phenyl)-1H-imidazole-1-acetamides wherein the 
substituted phenyl is 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, or 
4-butoxyphenyl. No utility is disclosed in the abstract. 
Ezrin et al. [FASEB Journal 2, A1557 (1988)] disclose 
N-[(diethylamino)propyl]-4,5-diphenyl-1H-pyrazole-1-acetamide fumarate as 
an antiarrhythmic agent. 
European patent application No. 299407, published Jan. 18, 1989, discloses 
a series of 4,5-diaryl-1H-pyrazole-1-alkanamides as antiarrhythmic agents. 
SUMMARY OF THE INVENTION 
In a product aspect the invention relates to compounds of the formula I 
##STR1## 
or acid-addition salt or solvate thereof wherein R.sup.1 and R.sup.2 are 
independently hydrogen, hydroxy, lower-alkyl, lower-alkoxy, nitro, or 
halo; R.sup.3 and R.sup.4 are independently hydrogen, lower-alkyl, or 
hydroxy lower-alkyl, or R.sup.3 and R.sup.4 together form a straight or 
branched alkylene chain of four to six carbons; and A is CH.sub.2 
CH(OH)CH.sub.2 or (CH.sub.2).sub.n where n is an integer from two to 
eight. 
Lower-alkyl as used herein describes linear or branched hydrocarbon chains 
of four or fewer carbon atoms; lower-alkoxy as used herein describes 
linear or branched alkyloxy substituents containing four or fewer carbon 
atoms; halogen describes bromine, chlorine or fluorine. 
In a further product aspect, the invention relates to compositions for 
treating cardiac arrhythmia which comprise compounds of the formula I 
together with pharmaceutically acceptable excipients or diluents as 
required. 
In a process aspect, the invention relates to a method for treating cardiac 
arrhthmia in a mammal which comprises administering to said mammal an 
antiarrhythmically effective amount of a compound of formula I. 
Processes for preparing a compound of formula I comprise reacting an 
imidazole-1-acetate with an amine.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
The synthesis of compounds of the invention may be outlined as shown in 
scheme A wherein R.sup.5 is lower-alkyl. 
##STR2## 
The lower-alkyl ester, preferably a methyl or ethyl ester, of the suitably 
substituted 4,5-diphenylimidazole-1-alkanoic acid (II) is reacted with an 
excess of a primary or secondary amine of formula III at 20.degree. to 
150.degree. C., preferably at 90.degree. to 150.degree. C. 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, optionally in an inert solvent. 
The ester II may be synthesized from the appropriate 4,5-diarylimidazole by 
alkylation of an alkaline metal salt of the imidazole, preferably the 
sodium salt, with an .alpha.-haloacetic ester, preferably ethyl 
bromoacetate, in an inert solvent, preferably DMF, at 0.degree. to 
100.degree. C. In the case where R.sup.1 does not equal R.sup.2, two 
isomers will be obtained which may be readily separated by crystallization 
or chromatography, or the mixture of isomers may be carried through the 
next step and separated as the amides. The diaryl imidazoles are 
commercially available, known in the art, or may be synthesized by methods 
well-known in the art. 
The compounds of formula I are useful both in the free base form and the 
form of acid-addition salts, and both forms are within the purview of the 
invention. The acid-addition salts are in some cases a more convenient 
form for use, and in practice the use of the salt form inherently amounts 
to the use of the base form. The acids which can be used to prepare the 
acid-addition salts include preferably those which produce, when combined 
with the free base, medicinally acceptable salts that is, salts whose 
anions are relatively innocuous to the animal organism in medicinal doses 
of the salts so that the benefical properties inherent in the free base 
are not vitiated by side effects ascribable to the anions. In practicing 
the present invention it may be found convenient to form the 
hydrochloride, fumarate, toluenesulfonate, methanesulfonate, or maleate 
salts. However, other appropriate medicinally acceptable salts within the 
scope of 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 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 separates directly, is precipitated with a second organic 
solvent, or can be obtained by concentration of the solution. Although 
medicinally acceptable salts of the basic compounds are preferred, all 
acid-addition salts are within the scope of the invention. All 
acid-addition salts are useful as sources of the free base form even if 
the particular salt per se is desired only as an intermediate product, as, 
for example, when the salt is formed only for purposes of purification or 
identification, or when it is used as an intermediate in preparing a 
medicinally acceptable salt by ion exchange procedures. 
The structures of the compounds of the invention were established by the 
mode of synthesis, by elemental analysis, and by infrared, ultraviolet, 
and nuclear magnetic resonance, spectroscopy. The course of the reactions 
and the identity and homogeneity of the products were assessed by thin 
layer chromatography (TLC). The starting materials are either commercially 
available or may be prepared by procedures well known in the art. 
In the following procedures melting points are given in degrees C and are 
uncorrected. The abbreviation THF stands for tetrahydrofuran, DMF stands 
for N,N-dimethylformamide and Ac stands for the acetyl residue, CH.sub.3 
CO. 
EXAMPLE 1 
Ethyl 4,5-diphenyl-1H-imidazole-1-acetate 
To a stirred suspension of 9.6 (0.24 mol) of 60% sodium hydride-mineral oil 
in 100 mL of DMF under nitrogen at 0.degree. C. was added dropwise 50.0 g 
(0.226 mol) of 4,5-diphenylimidazole in 400 mL DMF. The mixture was 
allowed to warm, stirred at room temperature 1 hr, and 26.6 mL (0.24 mol) 
of ethyl bromoacetate was added. The reaction was stirred 18 hr at room 
temperature, heated on a steam bath 2 hr, cooled, and stripped. The 
residue was partitioned between water and methylene chloride, dried over 
MgSO.sub.4, and filtered through a silica gel column eluting with 
methylene chloride-ethyl acetate to provide 50.1 g of an oil that 
solidified on standing. It may be used in further reactions as is, or it 
may be recrystallized from ether to yield 35.1 g of product mp 
89.degree.-90.degree. C. 
EXAMPLE 2 
Ethyl 4,5-bis(2-methoxyphenyl)-1H-imidazole-1-acetate 
By a process substantially similar to that of example 1, it is contemplated 
that ethyl 4,5-bis(2-methoxyphenyl)-1H-imidazole-1-acetate may be 
synthesized from 4,5-bis(2-methoxyphenyl)-1H-imidazole and ethyl 
bromoacetate. 
EXAMPLE 3 
Ethyl 4-(4-chlorophenyl)-5-phenyl-1H-imidazole-1-acetate 
By a process substantially similar to that of example 1, it is contemplated 
that ethyl 4-(4-chlorophenyl)-5-phenyl-1H-imidazole-1-acetate may be 
synthesized from 4-(4-chlorophenyl)-5-phenyl-1H-imidazole and ethyl 
bromoacetate. 
EXAMPLE 4 
N-[3-(Diethylamino)propyl]-4,5-diphenyl-1H-imidazole-1-acetamide 
A solution of 36.0 g (0.117 mol) of ethyl 4,5-diphenyl-1H-imidazole of 
example 1 in 80 mL of 3-(diethylamino)propanamine was heated at 
100.degree. for 6 hrs, cooled, the excess amine was removed in vacuo, and 
the residue was recrystallized twice from ether to yield 8.0 g of product, 
mp 81.degree.-83.degree. C. 
EXAMPLE 5 
N-[3-(Dimethylamino)propyl]-4,5-diphenyl-1H-imidazole-1-acetamide 
A suspension of 5.0 g (10.3 mmol) of ethyl 4,5-diphenyl-1H-imidazole of 
example 1 in 3.1 mL (24.5 mmol) of 3-(dimethylamino)propanamine was heated 
at 100.degree. C. for 6 hr. The reaction was poured into ice-water and 
held at 0.degree. overnight. The resulting solid was filtered off, dried 
and recrystallized from ether-hexane to yield 4.6 g of product, mp 
92.degree.-94.degree. C. 
EXAMPLE 6 
N-[3-[(1,1-Dimethylethyl)amino]propyl]-4,5-diphenyl-1H-imidazole-1-acetamid 
e 
A mixture of 7.0 g (23 mmol) of ethyl 4,5-diphenyl-1H-imidazole-1-acetate 
of example 1 and 4.5 g (34.6 mmol) of 3-(t-butylamino)propylamine, 
conveniently made by LAH reduction of 3-(t-butylamino)propionitrile in 
THF, was heated at 100.degree. C. for 8 hr. The residue was distributed 
between water and methylene chloride, and the methylene chloride layer was 
dried over MgSO.sub.4 and stripped. The residue was recrystallized from 
ether and then cyclohexane to yield 4.5 g of product, mp 
94.degree.-96.degree. C. 
EXAMPLE 7 
N-[3-(Diethylamino)-2-hydroxypropyl]-4,5-bis(2-methoxyphenyl)-1H-imidazole- 
1-acetamide 
By a procedure substantially similar to that of example 6, it is 
contemplated that 
N-[3-(Diethylamino)-2-hydroxypropyl]4,5-bis(2-methoxyphenyl)-1H-imidazole- 
1-acetamide may be synthesized from ethyl 
4,5-bis(2-methoxyphenyl)-1H-imidazole-1-acetate of example 2 and 
1-amino-3-diethylamino-2-propanol. 
EXAMPLE 8 
4-(4-Chlorophenyl)-5-phenyl-N-[3-(1-pyrrolidinyl)ethyl]-1H-imidazole-1-acet 
amide 
By a procedure substantially similar to that of example 6, it is 
contemplated that 
4-(4-chlorophenyl)-5-phenyl-N-[3-(1-pyrrolidinyl)ethyl]-1H-imidazole-1-ace 
tamide may be synthesized from ethyl 
4-(4-chlorophenyl)-5-phenyl-1H-imidazole-1-acetate of example 3 and 
N-(2-aminoethyl)pyrrolidine. 
The antiarrhythmic activity of compounds of the invention was demonstrated 
by the following procedure. 
Duncan Hartley guinea pigs (600-900 grams) of either sex were anesthetized 
with urethane (1.4 g/kg, i.p.) and supplemented as needed. An intravenous 
route for drug administration was established using microbore tubing 
inserted into the jugular vein. The induction of arrhythmias by aconitine 
hydrochloride (34 g/kg) was evaluated in control guinea pigs given 1 cc 
saline as an intravenous bolus 10 minutes prior to aconitine challenge. 
Compounds to be tested were administered intravenously 10 minutes prior to 
aconitine challenge at an initial dosage of 30 mg/kg. This dosage was 
reduced in subsequent animals if severe cardiac rhythm disturbances 
persisted beyond two minutes after injection in the first guinea pig 
tested. All drugs were tested at the maximally tolerated dose (identified 
by the lack of arrhythmias in the EKG prior to aconitine challenge). 
Compounds were administered in saline as 1 cc bolus injections (n=4-6). 
Time intervals between aconitine injection and the appearance of 
arrhythmias were determined. Specifically noted was the time until the 
onset of (i) the first premature ventricular contraction (PVC); (ii) the 
first sustained run of ventricular tachycardia consisting of 10 or more 
ventricular beats (VTACH); and (iii) the time until the appearance of 
ventricular fibrillation lasting longer than 15 seconds (VFIB). The 
average time and standard error of the mean until the appearance of these 
arrhythmias were calculated for each treatment group and compared to 
concurrent controls using a one-way analysis of variance. Activity was 
defined as a statistically significant delay in the onset of PVC, VTACH 
and VFIB time course compared to control values. 
The following table summarizes the results obtained from the testing of 
representative compounds of the invention. 
______________________________________ 
Example Minutes to 
No. PVC VTACH VFIB 
______________________________________ 
Control 1.0-2.1 1.3-2.5 3.1-6.3 
4 8.1 34.0 60.0 
5 12.3 30.6 60.0 
6 13.5 20.9 45.2 
______________________________________ 
The compounds of the invention can be prepared for use by conventional 
pharmaceutical procedures: that is, by dissolving or suspending them or 
their pharmaceutically acceptable salts in a pharmaceutically acceptable 
vehicle, e.g., water, aqueous alcohol, glycol, oil solution or oil-water 
emulsion, for parenteral or oral administration; or by incorporating them 
in unit dosage form as capsules or tablets for oral administration either 
alone or in combination with conventional adjuvants or excipients, e.g., 
calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, 
and the like. 
The percentage of active component in the composition and method for 
treating or preventing arrhythmia can be varied so that a suitable dosage 
is obtained. The dosage administered to a particular patient is variable 
depending upon the clinician's judgement using as the criteria: the route 
of administration, the duration of treatment, the size and condition of 
the patient, the potency of the active component, and the patient's 
response thereto. An effective dosage amount of active component can thus 
be determined by the clinician considering all criteria and utilizing his 
best judgement on the patient's behalf.