10,11-dihydro-5H-dibenzo[a,d]cycloheptadiene derivatives in a method for treating cardiac arrhythmia

10,11-Dihydro-5H-dibenzo[a,d]cycloheptadiene derivatives of the formula I ##STR1## where R.sup.1 and R.sup.2 have the meanings stated in the description, and their preparation are described. The novel substances are useful for the treatment of disorders.

The present invention relates to novel 
10,11-dihydro-5H-dibenzo[a,d]cycloheptadiene derivatives, a process for 
their preparation and their use in the treatment of disorders. 
German Laid-Open Application No. DOS 2,328,758 discloses diphenylmethyl 
derivatives of the formula (C.sub.6 H.sub.5).sub.2 CH--CH.sub.2 
--COH(CH.sub.3)--CH.sub.2 --NH--alkyl which act on the central nervous 
system and have a spasmolytic action as well as an antiarrhythmic action. 
We have found that 10,11-dihydro-5H-dibenzo[a,d]cycloheptadiene derivatives 
of the formula I 
##STR2## 
where R.sup.1 is hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 
-alkenyl, C.sub.2 -C.sub.6 -alkynyl, C.sub.1 -C.sub.6 -hydroxyalkyl or 
C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl and R.sub.2 is hydrogen, 
or R.sup.1 and R.sup.2, together with the nitrogen atom which connects 
them to one another, form a morpholine ring or a piperidine ring which may 
be substituted in the 4-position by hydroxyl and/or by unsubstituted or 
halogen-substituted phenyl, and their salts with physiologically tolerated 
acids are useful for the therapy of arrhythmias. 
Preferred acids for the formation of physiologically tolerated salts are 
hydrohalic acids, such as hydrobromic acid and in particular hydrochloric 
acid, with which the novel compounds form salts which crystallize 
particularly readily. Other examples are phosphoric acid, nitric acid, 
sulfuric acid, monofunctional and bifunctional carboxylic acids and 
hydroxycarboxylic acids, such as acetic acid, oxalic acid, maleic acid, 
succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, 
sorbic acid or lactic acid, and sulfonic acids, such as p-toluenesulfonic 
acid and naphthalene-1,5-disulfonic acid. 
The novel compounds can be prepared by a method in which 
2-[(10,11-dihydro-5H-dibenzocycloheptadienyl)methyl]-2-methyloxirane is 
reacted with an amine of the formula HNR.sup.1 R.sup.2, where R.sup.1 and 
R.sup.2 have the stated meanings, and, if required, the resulting compound 
is converted to its salts with physiologically tolerated acids. 
As a rule, the solvent used is a lower alcohol, preferably ethanol or 
n-propanol, and the reaction is advantageously carried out at the boiling 
point of the alcohol used. However, it is also possible to use other 
solvents, such as tetrahydrofuran, dioxane, acetonitrile or 
dimethylformamide. 
When the reaction is complete, the compound obtained is advantageously 
purified by distillation, or by conversion to an addition salt with an 
acid followed by recrystallization. 
The 2-[(10,11-dihydro-5H-dibenzocycloheptadienyl)methyl]-2-methyloxirane 
required for the preparation of the novel substances can be obtained by 
reacting (10,11-dihydro-5H-dibenzocycloheptadienyl)-acetone with 
trimethylsulfoxonium iodide in the presence of sodium hydroxide in 
dimethyl sulfoxide (cf. J. Amer. Chem. Soc. 84, (1962) 3782). 
The preparation gives the novel compounds in the form of racemates, which, 
if desired, can be separated into the optical antipodes by fractional 
crystallization of suitable salts of optically active acids by a 
conventional method. 
The compounds according to the invention and their physiologically 
tolerated addition salts with acids possess antiarrhythmic properties and 
are therefore particularly useful for the treatment of cardiac 
arrhythmias, for the prophylaxis of sudden heart death and for the 
treatment of coronary heart disease. To investigate the pharmacodynamic 
properties of the novel products, the following method was used: 
The substances were administered orally to Sprague-Dawley rats weighing 
200-250 g. 45 minutes thereafter, the animals were anesthetized with 100 
mg/kg of thiobutabarbital Na, administered intraperitoneally. Aconitine, 
as an arrhythmogenic substance, was infused intravenously into the jugular 
vein 60 minutes after administration of the substance (dosage rate: 0.005 
mg per kg per min). In the case of untreated animals (N=52), arrhythmias 
appeared in the ECG after 2.74.+-.0.07 minutes, the appearance of these 
arrhythmias being delayed by antiarrhythmic agents in a dose-dependent 
manner. 
The dose which prolongs the duration of aconitine infusion by 50%, ie. the 
ED 50%, was determined from the linear relationship between log dose 
(mg/kg) of the test substances and the relative prolongation of aconitine 
infusion duration (.DELTA.%). 
Furthermore, the dose at which toxic symptoms (change in the initial ECG, 
cyanosis or cramp) occur was determined from the geometric progression of 
doses (factor 2.154) used in the experiments. 
The quotient of acute toxic dose to antiarrhythmic ED 50% was determined as 
a measure of the therapeutic index of the novel compounds. 
The novel compounds have an antiarrhythmic action when administered orally 
in doses of less than 43.5 mg/kg and are therefore clearly superior to the 
comparative substance quinidine. They also possess a greater therapeutic 
index than the comparative compound. 
TABLE 1 
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Antiarrhythmic action 
Rat, oral administration 
Example ED 50% (mg/kg).sup.1 
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1 6.51 
9 2.57 
3 3.11 
4 6.47 
6 6.83 
5 7.78 
Quinidine 43.5 
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.sup.1 Dose (mg/kg) which prolongs the aconitine infusion duration by 50% 
TABLE 2 
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Antiarrhythmic action and toxicity 
Rat, oral administration 
Example ED 50%.sup.1 Toxic dose 
No. (mg/kg) (mg/kg.sup.2) 
Q.sup.3 
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3 3.11 100 32 
4 6.47 215 33 
Quinidine 
43.5 464 11 
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.sup.1 Dose which prolongs the aconitine infusion duration by 50%. 
.sup.2 Dose (mg/kg) at which the first toxic symptoms are observed. 
##STR3## 
The novel compounds can be administered orally or parenterally 
(intravenously, intramuscularly) in a conventional manner. 
The dosage depends on the age, condition and weight of the patient and on 
the route of administration. As a rule, the daily dose of active compound 
is from about 0.5 to 15 mg/kg of body weight in the case of oral 
administration and from about 0.005 to 0.1 mg/kg of body weight in the 
case of parenteral administration. 
The novel compounds may be employed in the conventional solid or liquid 
pharmaceutical forms, such as tablets, film tablets, capsules, powders, 
granules, coated tablets, suppositories or solutions. These are prepared 
in a conventional manner, and to do so the active compounds can be mixed 
with the conventional pharmaceutical auxiliaries, such as tablet binders, 
fillers, preservatives, tablet disintegrating agents, flow regulators, 
plasticizers, wetting agents, dispersants, emulsifiers, solvents, 
retarding agents, antioxidants and/or propellants (cf. H. Sucker et al., 
Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The 
administration forms thus obtained normally contain from 0.1 to 99% by 
weight of the active compound.

The Examples which follow illustrate the invention. 
A. 
Preparation of the starting compound 
4 g (0.133 mole) of sodium hydride (80% strength in liquid paraffin) are 
suspended in 175 ml of anhydrous dimethyl sulfoxide, and 28.5 g (0.133 
mole) of trimethyl sulfoxonium iodide are added a little at a time, at 
from 15.degree. to 20.degree. C., to the stirred and cooled suspension. 
When evolution of hydrogen is complete, cooling is discontinued and 25 g 
(0.1 mole) of (10,11-dihydro-5H-dibenzocycloheptadienyl)-acetone, 
dissolved in 80 ml of anhydrous dimethyl sulfoxide, are introduced in the 
course of 1 hour, after which stirring is continued for a further 2 hours 
at 40.degree. C. The reaction solution is poured onto 2 l of ice water, 
stirred for 2 hours, while cooling, and then extracted with diethyl ether, 
and the extracting agent is distilled off. 
25.9 g of 
2-[10,11-dihydro-5H-dibenzocycloheptadienyl)-methyl]-2-methyloxirane are 
isolated as a crude product, which can be used without further 
purification. 
B. 
Preparation of the end products 
Example 1 
7 g (0.027 mole) of 
2-[10,11-dihydro-5H-dibenzocycloheptadienyl)-methyl]-2-methyloxirane and 4 
ml of isopropylamine in 50 ml of isopropanol are refluxed for 8 hours. 
The solvent is distilled off under reduced pressure, the residue is taken 
up in ether, the ether solution is washed with water and then dried with 
Na.sub.2 SO.sub.4, and HCl gas is passed in until the solution gives a 
neutral reaction. The precipitate formed is filtered off and 
recrystallized from acetone/ether. 
3.6 g (37%) of 
N-[2-hydroxy-2-methyl-3-(10,11-dihydro-5H-dibenzocycloheptadienyl)-propyl] 
-N-isopropylamine hydrochloride of melting point 158.degree. C. are 
isolated in this manner. 
The compounds below were prepared, or can be prepared, by a similar method. 
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mp. [.degree.C.] 
Example 
R.sup.1 R.sup.2 
hydrochloride 
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2 H H 192 
3 CH.sub.3 H 207 
4 C(CH.sub.3).sub.3 H 211 
5 CH.sub.2CH.sub.2CH.sub.3 
H 169 
6 C(CH.sub.3)CH.sub.2 OCH.sub.3 
H 136 
7 (CH.sub.2).sub.5 195 
8 (CH.sub.2).sub.2O(CH.sub.2).sub.2 
157 
9 
##STR4## 161 
10 C(CH.sub.3).sub.2CCH H 232 
11 CH.sub.2CH.sub.3 H 
12 CH.sub.2(CH.sub.2).sub.2CH.sub.3 
H 
13 CH.sub.2CH(CH.sub.3)CH.sub.3 
H 
14 CH.sub.2(CH.sub.2).sub.4CH.sub.3 
H 
15 CH.sub.2CH(CH.sub.3)(CH.sub.2).sub.2CH.sub.3 
H 
16 CH.sub.2 CCH H 
17 CH(CH.sub.3)CCH H 
18 CH.sub.2CH.sub.2 OH H 
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