BACKGROUND OF THE INVENTION 
Pharmacological agents possessing the ability to block cellular 
transmembrane influx of calcium are capable of suppressing that portion of 
myocardial or vascular smooth muscle contractility which is dependent upon 
extracellular calcium. Church et al., Can. J. Physiol. Pharmacol., 58, 254 
(1980); Fleckenstein, Calcium and the Heart, P. Harris and L. Opie, eds., 
Academic Press (1971); Nayler et al., Bas. Res. Cardiol., 76, 1 (1981); 
Calcium Blockers, S. Flaim and R. Zelis, eds., Urban and Schwartzenberg, 
(1982). 
These pharmacological agents, termed calcium entry blockers, have been 
proven to be useful in the treatment of hypertension, cardiac arrhythmias, 
angina pectoris, and coronary artery vasospasm (a possible cause of sudden 
cardiac death syndrome). Circ. Res., 52, Suppl. I, (1983); Hypertension 5, 
Suppl. II, (1983). In theory, calcium entry blockers are thought to act by 
blocking calcium influx through discrete calcium channels (slow channels) 
in cell membranes. Various tissues exhibit relative differences in 
sensitivity toward the calcium blocking effect achieved by certain calcium 
antagonists, theoretically as a result of tissue specific differences in 
the calcium channels. Acta Pharmacol. Toxicol., 43, 5 (1978); loc. cit. 
291 (1978); Microvascular Res., 5, 73 (1973); Am. Rev. Pharmacol. 
Toxicol., 17, 149 (1977). It is believed that the slow calcium current is 
responsible for activation of pacemaker cells in the sinoatrial node and 
the atrioventricular node of the heart. Verapamil, a known calcium channel 
blocking agent, is believed to slow conduction velocity through the 
atrio-ventricular node of the heart, in explanation of the mechanism of 
its anti-arrhythmic activity. 
DESCRIPTION OF THE INVENTION 
In accordance with this invention there is provided a group of compounds of 
the formula: 
##STR3## 
in which Z is 
##STR4## 
where R is hydrogen, alkyl of 1-6 carbon atoms, polyfluorinated alkyl of 
1 to 6 carbon atoms, --CN, cyanoalkyl in which the alkyl moiety contains 1 
to 3 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or cycloalkylalkyl of 
4 to 8 carbon atoms; 
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7, independently, are 
hydrogen, alkoxy of 1-3 carbon atoms, trifluoromethyl, --Cl, --Br or --F; 
R.sup.8 is hydrogen or alkyl of 1 to 6 carbon atoms; 
or a pharmaceutically acceptable salt thereof. 
The compounds of this invention represent analogues of the compounds 
disclosed and claimed in my co-pending application Ser. No. 609,151, filed 
May 11, 1984, now U.S. Pat. No. 4,539,426, issued Sept. 3, 1985, which 
have surprisingly been found to be as potent as the most potent compound 
of my copending application. 
The pharmaceutically acceptable salts of the anti-arrhythmic agents of this 
invention are prepared directly by neutralization of the free base or by 
metathetical displacement. The physiologically acceptable salts may be 
formed with organic or inorganic acids such as hydrochloric, hydrobromic, 
phosphoric, sulfuric, sulfonic, nitric, methylsulfonic, acetic, maleic, 
succinic, fumaric, tartaric, citric, salicylic, lactic, 
naphthalenesulfonic acid, and the like. 
The compounds of this invention are prepared by several stage processes 
involving alkylation reactions performed on amines or sulfonamides or 
both. Briefly, an appropriately substituted aromatic amine 
##STR5## 
in which R.sup.2, R.sup.3, R.sup.4 and R are as defined above, is reacted 
with CISO.sub.2 -(CH.sub.2).sub.4 -Cl, and the product is employed to 
alkylate an aralkylamine of the formula 
##STR6## 
where R.sup.5-8 are as defined, supra. This reaction sequence affords the 
N-aromatic-propanesulfonamide type compounds of this series. The 
benzenesulfonamide type compounds of this series are produced in analogous 
manner by reaction of an appropriately substituted aromatic sulfonamide 
##STR7## 
or by reaction of an aromatic sulfonyl halide with an omegahydroxy 
alkylamine followed by N-alkylation and replacement of the hydroxyl group 
with a halogen, and alkylation of the appropriate aralkylamine. Similarly, 
the hydroxyl group may be oxidized to an aldehyde which may be reacted 
with an appropriately substituted aralkylamine by reductive amination. The 
intermediates employed are either known compounds or are prepared from 
literature compounds by procedures well within the skill of the medicinal 
chemist. 
The compounds of this invention exhibit Ca.sup.+2 antagonism in rabbit 
aortic smooth muscle when tested by a modified procedure from that 
described by Brockaert et al., Eur. J. Pharmacol., 53, 281 (1979). Here, 
transverse strips (10 mm.times.2.5 mm) from the thoracic aorta were cut 
and suspended vertically in a jacketed (37.degree. C.-50 ml volume) organ 
bath in physiological saline solution (PSS) aerated with 95% O.sub.2 /5% 
CO.sub.2. The composition of PSS was as follows (mM): NaCl 112, KCl 5, 
NaHCO.sub.3 25, KH.sub.2 PO.sub.4 1, MgSO.sub.4 1.2, CaCl.sub.2 2.5, 
dextrose 10. The lower end of each tissue strip was attached to a fixed 
post and the upper end to a Statham UC-4 transducer. Changes in force 
development were recorded on a Beckman Dynograph Polygraphic Recorder. 
Following equilibration, the muscles were contracted in a depolarizing 
solution of PSS in which 100 mM KCl was substituted for an equimolar 
concentration of NaCl. Following attainment of steady-state isometric 
force (20 min.), the test compound was added to afford a final 
concentration of 1.times.10.sup.-5 M. The inhibitory effect, expressed as 
percent relaxation, was determined from the mean of two experiments twenty 
minutes after the addition of the compound being tested. 
In addition, the compounds of this invention demonstrate an inhibitory 
influence on arterial Ca.sup.+2 -calmodulin dependent myosin light chain 
phosphorylation and subsequent contractile protein function when tested in 
standard experimental procedures for these inhibitory properties. 
As such, the compounds of the invention present an activity profile 
consistent with that of anti-arrhythmic agents, which utility was proven 
by in vivo experiments in the standard experimental animal as follows: 
Rats weighing between 400-500 gms were anesthetized with 35-40 mg/kg Na 
pentobarbital i.p. Rats were close-clipped on the neck and left side prior 
to cannulation of the jugular vein and tracheotomy. In some experiments, a 
catheter was introduced into the carotid artery for measurement of 
arterial blood pressure. Respiration was provided by a Harvard Model 681 
respirator at a rate of approximately 55/min and a volume of 4 cc per 
cycle. The rat was then placed upon its right side and the heart was 
exposed by making an incision and separating the ribs. 4-0 silk on taper 
RB-1 needle was passed under the left anterior descending coronary artery 
(LAD) at a location just under the tip of the left atrial appendage. The 
suture was left to be tied upon occlusion. Lead II ECG and 
cardiotachometer output were recorded on a Beckman R612. 
The rat was allowed to stabilize for several minutes before the 
administration (1 mg/kg) of drug via the cannulated jugular vein. 
Compounds were suspended in carbowax, with total dose volumes kept below 
0.20-0.25 ml. Fifteen minutes after dosing, the LAD was occluded by tying 
the suture. This procedure provokes severe ventricular arrhythmias, 
terminating in ventricular fibrillation and death in approximately 73 
percent of animals given vehicle only. Data were analyzed based on 
statistical analysis of heart rate fluctuations. Output from a Beckman 
cardiotachometer was digitized at 200 msec/pt using a Nicolet 3091 digital 
oscilloscope, and the data analyzed to yield mean.+-.variance of the rate 
for each 1 minute period (300 points). The measured variance for the 
period 5-11 minutes post-occlusion was well correlated with the severity 
of the observed ventricular arrhythmias, and provided a quantitative 
measure for the relative antiarrhythmic effectiveness of the compound 
being tested. 
For the purpose of these coronary ligation (C.L.) experiments, the actual 
mortality rate, expressed as a percentage of the animals employed, was 
obtained for purpose of comparison with the mortality rate of 73 percent 
in vehicle-treated animals. 
Thus, these data establish the compounds of this invention as Ca.sup.+2 
antagonists which are useful as anti-arrhythmic agents functioning more at 
the vascular level than other known Ca.sup.+2 entry blockers. It has been 
observed that compounds of this invention inhibit arterial Ca.sup.+2 
-calmodulin dependent myosin light chain phosphorylation and subsequent 
contractile protein function. 
Based upon the activity profile elicited by the compounds of this invention 
in the above-described standard scientifically recognized test models, the 
compounds are established as anti-arrhythmic agents useful in the 
treatment of cardiac arrhythmias and conditions characterized by coronary 
arteries vasospasm. For that purpose, the compounds may be administered 
orally or parenterally in suitable dosage forms compatable with the route 
of administration, whether oral, intraperitoneal, intramuscular, 
intravenous, intranasal, buccal, etc. The effective dose range determined 
in the animal test models has been established at from 1 to about 50 
milligrams per kilogram host body weight to be administered in single or 
plural doses as needed to relieve the arrhythmatic dysfunction. The 
specific dosage regimen for a given patient will depend upon age, 
pathological state, severity of dysfunction, size of the patient, etc. 
Oral administration is performed with either a liquid or solid dosage unit 
in any conventional form such as tablets, capsules, solutions, etc., which 
comprise a unit dose (e.g. from about 25 milligrams to about 4 grams) of 
the active ingredient alone or in combination with adjuvants needed for 
conventional coating, tableting, solubilizing, flavoring or coloring. 
Parenteral administration with liquid unit dosage forms may be via sterile 
solutions or suspensions in aqueous or oleagenous medium. Isotonic aqueous 
vehicle for injection is preferred with or without stabilizers, 
preservatives and emulsifiers. 
The following example illustrates the preparation of a representative 
compound of this invention. After the example, the Ca.sup.+2 antagonist 
activity of the compound is presented in terms of percent relaxation 
(P.R.) at 10.sup.-5 M concentration unless indicated otherwise. Similarly, 
the percentage mortality of standard experimental test animals upon 
coronary ligation (C.L.) is presented for comparison with the control 
mortality rate of 73 percent of animals receiving vehicle alone.

EXAMPLE 1 
3,4-Dichloro-N-[4-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]butyl]-N-(1-me 
thylethyl)benzenesulfonamide 
3,4-Dichlorobenzene sulfonyl chloride (98.3 g, 0.4 m) in methylene chloride 
(200 ml) was added dropwise to 4-amino-1-butanol (35.69 g, 0.4 m) and 
diisopropyl ethylamine (51.75 g, 0.4 m) in methylene chloride (500 ml). 
After workup the crude product, 
N-(4-hydroxybutyl)-3,4-dichlorobenzenesulfonamide, was obtained as a gummy 
white crystalline solid, m.p. 78.degree.-80.degree. C., identified by 
combustion and spectral data. 
The product of the preceding paragraph (40.10 g, 0.134 m) in dry 
dimethylformamide (400 ml) was treated with NaH/mineral oil 60% (5.38 g, 
0.134 m) and the reaction stirred one hour at room temperature. Then 
2-bromopropane (16.5 g, 0.134 m) was added and the reaction heated at a 
temperature of 35.degree. to 50.degree. C. over the weekend. The reaction 
was worked up and the crude product chromatographed on dry column alumina 
(1 kg) with 1:1 ethyl acetate/hexane to provide the N-isopropylated 
product (16.09 g) as a light yellow oil. 
Pyridine-chromic acid complex was prepared by adding chromium trioxide 
(26.4 g, 94 m. moles) to pyridine (41.76 g) in methylene chloride (660 
ml). The reaction mixture was stirred at room temperature for 3/4 hours. 
Then N-isopropyl-N-(4-hydroxybutyl)-3,4-dichlorobenzenesulfonamide 
prepared in the preceding paragraph (15.01 g) in methylene chloride (150 
ml) was added all at once. After 1/2 hour the liquid was decanted and 
washed with 5% aqueous NaOH, 5% aqueous HCl, 5% aqueous NaHCO.sub.3 and 
finally brine. After removal of solvent there was obtained 
N-isopropyl-N-(4-oxobutyl)-3,4-dichlorobenzenesulfonamide as a dark oil 
(9.01 g) which started to nicely crystallize but was used below without 
further purification. 
The aldehyde prepared in the preceding paragraph (8.90 g, 0.027 m) and 
N-methyl-homoveratrylamine (5.29 g, 0.027 m) in absolute ethanol (100 ml) 
containing PtO.sub.2 (0.6 g) was shaken under hydrogen (7 hours) and the 
reaction filtered and stripped to provide the crude product (13.32 g) as a 
dark greenish gum. This material was chromatographed, after removal of a 
small amount of insoluble solid, on dry column silica gel (500 g) with 30% 
methanol/70% ethyl acetate to provide the title compound (7.26 g) as a 
clear white gum. 
Analysis for: C.sub.24 H.sub.34 N.sub.2 Cl.sub.2 O.sub.4 S: Calculated: C, 
55.70; H, 6.62; N, 5.41. Found: C, 55.63; H, 6.59; N, 5.29. 
P.R.=68%. 
C.I.=0%.