Benzothiazinone oxides, processes for their preparation, medicaments containing them and the use thereof, and intermediates for their preparation

Benzothiazinone oxides, processes for their preparation, medicaments 
containing them and the use thereof, and intermediates for their 
preparation 
It is known that compounds which hinder the influx of calcium ions into 
cells can be used as therapeutics for the treatment of various diseases, 
in particular of the cardiovascular system in humans and other 
warm-blooded species. 
Benzothiazinone derivatives having a calcium-antagonist action are 
described in U.S. Pat. No. 4 595 685 and have been proposed in German 
Patent Applications P 36 14 355.3, P 36 14 633.4 and P 37 24 366.7. It has 
now been found, surprisingly, that the 1-oxides and the 1,1-dioxides of 
the compounds described or proposed in the cited patent applications have 
a calciumantagonistic and/or cardiovascular action which is superior in 
some cases. 
Hence have invention is directed at benzothiazinone oxides of the formula I 
##STR2## 
which have a calcium-antagonistic action, and their salts with 
pharmaceutically acceptable acids, in which formula I: 
R(1), R(1)' and R(1)" are identical or different and denote, independently 
of one another, hydrogen, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 
-C.sub.3)-alkoxy, F, Cl, Br, CF.sub.3, nitro, hydroxyl, acetamido or 
amino, 
R(2) denotes hydrogen, (C.sub.1 -C.sub.10)-alkyl, straight-chain or 
branched, (C.sub.3 -C.sub.10)-alkenyl, straight-chain or branched, 
phenyl-(C.sub.1 -C.sub.4)-alkyl, the phenyl ring being unsubstituted or 
substituted by one, two or three substituents from the group comprising 
(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.3)-alkoxy, F, Cl, CF.sub.3, 
(C.sub.1 -C.sub.2)-alkylenedioxy or nitro, 
R(3) denotes hydrogen, (C.sub.1 -C.sub.15)-alkyl, straight-chain or 
branched, (C.sub.3 -C.sub.15)-alkenyl, straight-chain or branched, 
(C.sub.4 -C-.sub.8)-cycloalkyl, (C.sub.4 -C.sub.8)-cycloalkyl-(C.sub.1 
-C.sub.4)-alkyl, phenyl or phenyl-(C.sub.1 -C.sub.4)-alkyl, the phenyl 
radical being unsubstituted or substituted by one, two or three 
substituents from the group comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 
-C.sub.3)-alkoxy, F, Cl, CF.sub.3, (C.sub.1 -C.sub.2)-alkylenedioxy or 
nitro, 
R(4) and R(4)' are identical or different and denote, independently of one 
another, hydrogen, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.3)-alkoxy, F, 
Cl, CF.sub.3, nitro, hydroxyl, acetamido or amino, 
A denotes a CH(OH) group, a C.dbd.0 group, a CH.dbd.CH group, a C.tbd.C 
group, a CH.sub.2 group, oxygen or sulfur, 
m denotes 1 or 2, 
n denotes 1, 2 or 3, 
p denotes zero, 1, 2, 3 or 4; but only 2, 3 or 4 where A is a heteroatom; 
and only 1, 2, 3 or 4 where A is a CH(OH), CH.dbd.CH or C.tbd.C group, 
R(5) denotes one of the following groups 
##STR3## 
in which R(6) and R(7) are identical or different and denote, 
independently of one another, hydrogen, (C.sub.1 -C.sub.10)-alkyl, 
(C.sub.4 -C.sub.8)-cycloalkyl, (C.sub.4 -C.sub.8)-cycloalkyl-(C.sub.1 
-C.sub.4)-alkyl, pyridyl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 
-C.sub.6)-alkyl, benzhydryl or benzhydryl-(C.sub.1 -C.sub.4)-alkyl, each 
of the phenyl radicals being unsubstituted or substituted by one, two or 
three radicals from the group comprising (C.sub.1 -C.sub.4)-alkyl, 
(C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.2)-alkylenedioxy, F, Cl, Br, 
CF.sub.3 or hydroxyl, 
R(.sub.8) denotes hydrogen, (C.sub.1 -C.sub.10)-alkyl, straight-chain or 
branched, (C.sub.1 -C.sub.8 -)-alkanoyl, pyridyl, pyrimidinyl, phenyl, 
phenyl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.3 -C-.sub.5)-alkenyl, 
benzhydryl or benzhydryl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 
-C.sub.4)-alkanoyl or benzoyl, each of the phenyl radicals being 
unsubstituted or substituted by one, two or three radicals from the group 
comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 
-C.sub.2)-alkylenedioxy, F, Cl, Br, CF.sub.3 or hydroxyl, 
R(9) denotes hydrogen, (C.sub.1 -C.sub.10)-alkyl, phenyl, phenyl-(C.sub.1 
-C.sub.4)-alkyl, each of the phenyl radicals being unsubstituted or 
substituted by one, two or three radicals from the group comprising 
(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.2 
-)-alkylenedioxy, F, Cl, Br, CF.sub.3 or hydroxyl, 
R(10) denotes hydrogen, hydroxyl or (C.sub.1 -C.sub.4)-alkoxy, and R(11) 
and R(12) or R(13) and R(14) are identical or different and denote, 
independently of one another, hydrogen, (C.sub.1 -C.sub.10))-alkyl, 
straight-chain or branched, (C.sub.1 -C.sub.6)-alkanoyl, phenyl-(C.sub.1 
-.sub.4)-alkyl, benzhydryl, or benzhydryl-(C.sub.1 -C.sub.4)-alkyl, 
phenyl-(C.sub.1 -C.sub.4)-alkanoyl or benzoyl, each of the phenyl radicals 
being unsubstituted or substituted by one, two or three radicals from the 
group comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, 
(C.sub.1 -C.sub.2)-alkylenedioxy, F, Cl, Br, CF.sub.3 or hydroxyl, 
and the salts of the compounds of the formula I with pharmaceutically 
acceptable acids. 
Preferred compounds of the formula I are those in which at least one of the 
substituents or indices has the following meaning: 
R(1) and R(1)', identical or different and independently of one another, 
hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, CF.sub.3, 
nitro or acetamido, 
R(1)" hydrogen, 
R(2) hydrogen, (C.sub.1 -C.sub.6)-alkyl, straight-chain or branched, allyl, 
methallyl, benzyl, phenethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 
3,4,5-trimethoxybenzyl, 3,4-methylenedioxybenzyl, 
R(3) hydrogen, (C.sub.1 -C.sub.12 -)-alkyl, straight-chain or branched, 
allyl, methallyl, (C.sub.5 -.sub.7)-cycloalkyl, (C.sub.5 
-.sub.7)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, benzyl, methylbenzyl, 
fluorobenzyl, methoxybenzyl, dimethoxybenzyl or phenylethyl, 
R(4) hydrogen, methyl, methoxy, ethoxy, fluorine, chlorine, nitro, 
hydroxyl, acetamido or amino, 
R(4)' hydrogen, 
A a CH(OH) group, a C.dbd.0 group, a CH.dbd.CH group, a C.tbd.C group, a 
CH.sub.2 group, oxygen or sulfur, 
m 1 or 2, 
n 1 or 2, 
p zero, 1, 2 or 3; but only 2 or 3 when A is a heteroatom; and only 1, 2 or 
3 where A is a CH(OH), CH.dbd.CH or C.tbd.C group, 
R(5) one of the following groups 
##STR4## 
in which R(6) denotes hydrogen, methyl, ethyl, propyl or isopropyl, 
R(7) denotes hydrogen, methyl, ethyl, propyl, isopropyl, cyclopentylethyl, 
cyclohexylethyl, phenyl-(C.sub.1 -C.sub.4)-alkyl, benzhydryl or 
benzhydryl-(C.sub.1 -C.sub.4)-alkyl, each of the phenyl radicals being 
unsubstituted or substituted by one, two or three radicals from the group 
comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 
-C.sub.2)-alkylenedioxy, F, Cl, CF.sub.3 or hydroxyl, or denotes 
pyridyl-(C.sub.1 -C.sub.4)-alkyl, 
R(8) denotes hydrogen, (C.sub.1 -C.sub.6)-alkyl, straight-chain or 
branched, (C.sub.1 -C.sub.6)-alkanoyl, phenyl, the phenyl radical being 
unsubstituted or substituted by one or two radicals from the group 
comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 
-C.sub.2)-alkylenedioxy, F, Cl, CF.sub.3 or hydroxyl, or denotes 
phenyl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.3 -.sub.5)-alkenyl, 
benzhydryl or benzhydryl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 
-C.sub.4)-alkanoyl or benzoyl, each of the phenyl radicals being 
unsubstituted or substituted by one, two or three radicals from the group 
comprising methyl, ethyl, methoxy, ethoxy, (C.sub.1 
-C.sub.2)-alkylenedioxy, F, Cl, CF.sub.3 or hydroxyl, 
R(9) denotes phenyl, phenyl-(C.sub.1 -C.sub.4)-alkyl, each of the phenyl 
radicals being unsubstituted or substituted by one, two or three radicals 
from the group comprising (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 
-C.sub.4)-alkoxy, (C.sub.1 -C.sub.2)-alkylenedioxy, F, Cl, CF.sub.3 or 
hydroxyl, 
R(10) denotes hydrogen, hydroxyl or methoxy, R(11), R(12), R(13) and R(14) 
are identical or different and denote hydrogen, (C.sub.1 -C.sub.8)-alkyl, 
(C.sub.1 -C.sub.6)-alkanyl, phenyl-(C.sub.1 -C.sub.4)-alkyl, benzhydryl or 
benzhydryl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 -C.sub.4)-alkanoyl or 
benzoyl, each of the phenyl radicals being unsubstituted or substituted by 
one, two or three radicals from the group comprising methyl, ethyl, 
methoxy, ethoxy, 
(C.sub.1 -C.sub.2)-alkylenedioxy, F, Cl, CF.sub.3 or hydroxyl, and the 
salts of these compounds of the formula I with pharmaceutically acceptable 
acids. 
Particularly preferred compounds of the formula I are those in which at 
least one of the substituents or of the indices has the following meaning: 
R(1) hydrogen, methyl, methoxy, fluorine or chlorine, 
R(1)' hydrogen or methoxy, 
R(1)" hydrogen, 
R(2) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, 
isobutyl, benzyl or phenethyl, 
R(3) hydrogen, (C.sub.1 -C.sub.12)-alkyl, straight-chain or branched, 
cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, allyl, 
methallyl, benzyl, methylbenzyl, fluorobenzyl, methoxybenzyl, 
dimethoxybenzyl or phenylethyl, 
R(4) hydrogen, methoxy, methyl, fluorine, chlorine, nitro or hydroxyl, 
R(4)' hydrogen, 
A a CH(OH) group, a C.dbd.0 group, a CH.dbd.CH group, a C.tbd.C group, a 
CH.sub.2 group or oxygen, 
m 1 or 2, 
n 1 or 2, 
p zero, 1 or 2; but only 2 when A is a heteroatom; and only 1 or 2 where A 
is a CH(OH), CH.dbd.CH or C.tbd.C group, 
R(5) one of the following groups 
##STR5## 
in which R(6) denotes hydrogen or methyl, 
R(7) denotes phenyl-(C.sub.1 -C.sub.4)-alkyl, benzhydryl or 
benzhydryl-(C.sub.1 -C.sub.4)-alkyl, each phenyl radical being 
unsubstituted or substituted by one, two or three radicals from the group 
comprising methyl, methoxy, fluorine, chlorine, methylenedioxy or 
hydroxyl, 
R(8) denotes (C.sub.1 -C.sub.6)-alkyl, straight-chain or branched, (C.sub.1 
-C.sub.6)-alkanoyl, phenyl, phenyl-(C.sub.1 -C.sub.4)-alkyl, benzhydryl or 
benzhydryl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 -.sub.4)-alkanoyl or 
benzoyl, each of the phenyl radicals being unsubstituted or substituted by 
one, two or three radicals from the group comprising methyl, methoxy, 
ethoxy, methylenedioxy, fluorine, chlorine or hydroxyl, 
R(9) denotes phenyl, the phenyl radical being unsubstituted or substituted 
by one, two or three radicals from the group comprising methyl, methoxy, 
fluorine, chlorine, methylenedioxy or hydroxyl, 
R(10) denotes hydrogen, hydroxyl or methoxy, R(11), R(12), R(13) and R(14) 
are identical or different and denote (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 
-C.sub.6)-alkanoyl, phenyl-(C.sub.1 -C.sub.4)-alkyl, benzhydryl or 
benzhydryl-(C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 -C.sub.4)-alkanoyl or 
benzoyl, each of the phenyl radicals being unsubstituted or substituted by 
one, two or three radicals from the group comprising methyl, methoxy, 
methylenedioxy, fluorine, chlorine or hydroxyl, 
and the salts of these compounds of the formula I with pharmaceutically 
acceptable acids. 
The pharmaceutically acceptable acids which are suitable are inorganic 
acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, 
sulfuric acid, phosphoric acid or nitric acid, or organic acids such as 
tartaric acid, malic acid, lactic acid, maleic acid, fumaric acid, malonic 
acid, oxalic acid, gluconic acid, camphorsulfonic acid, benzenesulfonic 
acid, acetic acid, propionic acid or p-toluenesulfonic acid. 
The compounds of the formula I have asymmetric carbon atoms and can thus 
occur as enantiomers or diastereomers. The invention embraces both the 
pure isomers and the mixtures thereof. These mixtures of diastereomers can 
be fractionated into the components by conventional methods, for example 
selective crystallization from suitable solvents or chromatography on 
silica gel or aluminum oxide. Customary methods can be used to fractionate 
the racemates into the individual enantiomers, for example by salt 
formation with optically active acids, such as camphorsulfonic acid or 
dibenzoyltartaric acid, and selective crystallization, or by 
derivatization with suitable optically active reagents, separation of the 
diasteromeric derivatives and cleavage again. 
The invention also relates to processes for the preparation of compounds of 
the formula I, which comprise 
(a) reaction, under conditions of a nucleophilic substitution, of a 
compound of the formula II 
##STR6## 
in which R(1), R(1)', R(1)" , R(2), R(3), R(4), R(4)', A, m, n and p have 
the same meaning as in formula I, and in which Y denotes a leaving group 
which can be displaced nucleophilically, in particular a chlorine, bromine 
or iodine atom, a radical of a sulfonic acid, preferably a 
methanesulfonyloxy radical, a benzenesulfonyloxy radical, a 
toluenesulfonyloxy radical or a trifluoromethanesulfonyloxy radical, with 
one of the compounds of the formulae IIIa, IIIb, IIIc, IIId or IIIe 
##STR7## 
in which R(6), R(7), R(8), R(9), R(10), R(11), R(12), (13) and R(14) have 
the same meaning as in formula I, preferably in a polar organic solvent 
such as an alcohol, preferably methanol, ethanol, propanol or isopropanol, 
or a lower ketone, preferably acetone or methyl ethyl ketone, or 
dimethylformamide, dimethyl sulfoxide or sulfolane, or a hydrocarbon, 
preferably toluene, with or without the presence of an auxiliary base to 
trap the acid which is formed, preferably in the presence of potassium 
carbonate, sodium carbonate, triethylamine, N-ethylmorpholine or pyridine, 
at a temperature between 0 and 160.degree. C., preferably between 
20.degree. and 120.degree. C., or 
(b) reaction of a compound of the formula IV 
##STR8## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)' and m have the same 
meaning as in formula I, with a compound of the formula V 
EQU Z--(CH.sub.2).sub.n --A--(CH.sub.2).sub.p --R(5) (V) 
in which Z is defined in the same way as Y in formula II, and in which R(5) 
and A, n and p have the same meaning as in formula I, either in a polar 
aprotic solvent such as dimethylformamide, dimethyl sulfoxide, 
tetrahydroforan, sulfolane or N-methylpyrrolidone, in the presence of a 
strong base such as sodium hydride, potassium hydride, sodamide, lithium 
diisopropylamide, butyllithium or lithium hexamethyldisilazide, at a 
temperature between -40.degree. and +60.degree. C., preferably between 
-10.degree. and -30.degree. C., or in a protic or aprotic polar organic 
solvent such as a lower alcohol, for example methanol, ethanol or 
isopropanol, or a lower ketone, preferably acetone or methyl ethyl ketone, 
or in dimethylformamide, in the presence of a weak to moderately strong 
base, such as an alkali metal or alkaline earth metal hydroxide or 
carbonate, or an amine such as triethylamine, N-ethylmorpholine, 
N-methyldiisopropylamine or pyridine, at a temperature between 0.degree. 
and 160.degree. C., preferably between 20.degree. and 120.degree. C., or 
(c) reaction of a compound of the formula VI 
##STR9## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)', m and n have the 
same meaning as in formula I, with amines of the formulae IIIa-IIIe 
without solvent or in the presence of a, preferably polar, solvent, such 
as methanol, isopropanol, acetone, THF or dimethylformamide, resulting in 
compounds of the formula I in which A denotes CH(OH) and p denotes 1, or 
(d) reaction, under amide-formation conditions known from the literature, 
of a compound of the formula VII 
##STR10## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)', m and n have the 
same meaning as in formula I, with one of the compounds of the formulae 
IIIa, IIIb, IIIc, IIId or IIIe, resulting in compounds of the formula I in 
which A denotes a C.dbd.0 group and p denotes zero, or 
(e) oxidation of a compound of the formula VIII 
##STR11## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)', R(5), A, n and p 
have the same meaning as in formula I, with oxidizing agents which are 
known to convert thioethers into sulfoxides or sulfones, such as, for 
example, m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, 
potassium permanganate or chromic acid, to give compounds of the formula 
I. 
Compounds of the formula VIII are described, for example, in German 
Offenlegungsschrift 3,347,173 and have been proposed in German Patent 
Applications P 36 14 355.3, P 35 14 363.4 and P 37 24 366.7. 
Compounds of the formula II are obtained from compounds of the formula IX 
##STR12## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)', A, m, n and p have 
the same meaning as in formula I, and in which Y has the same meaning as 
in formula II, with oxidizing agents under the conditions described in 
(e). Compounds of the formula IX have been described or proposed in the 
abovementioned German Offenlegungsschrift 3,347,173 or P 36 14 355.3, P 36 
14 363.4 and P 37 24 366.7, respectively. 
Compounds of the formula II can also be prepared from compounds of the 
formula IV and compounds of the formula X 
EQU Z--(CH.sub.2).sub.n --A--(CH.sub.2).sub.p --Y (X), 
in which A, n and p have the same meaning as in formula I, Y has the same 
meaning as in formula II, and Z has the same meaning as in formula V. 
Compounds of the formula IV are obtained from compounds of the formula XI 
##STR13## 
which R(1), R(1)', R(1)", R(2), R(3), R(4) and R(4)' have the same meaning 
as in formula I, and R(15) represents hydrogen or a protective group which 
can be eliminated under mild conditions, for example a methyl, benzyl or 
acetyl group, with oxidizing agents under the conditions described in e) 
and, where appropriate, subsequent elimination of the protective group 
R(15) under suitable conditions, for example by catalytic hydrogenation 
for the benzyl group, reaction with boron tribromide, boron trichloride, 
trimethyliodosilane or pyridine hydrochloride for the methyl group, or 
potassium carbonate in alcoholic solution for the acetyl group. The 
preparation of the compounds of the formula XI is descr.bed, for example, 
in German Offenlegungsschrift 3,347,173. Compounds of the formula VI are 
obtained from compounds of the formula IV by alkylation using compounds of 
the formula XII 
##STR14## 
in which Z has the same meaning as in formula V, under the conditions 
described for process (b). 
Compounds of the formula VI can also be prepared from compounds of the 
formula XIII 
##STR15## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4).and R(4)' have the same 
meaning as in formula I, by oxidation with oxidizing agents under the 
conditions described in (e). The preparation of compounds of the formula 
XIII is proposed, for example, in German Patent Application P 36 14 355.3: 
A compound of the formula XIII 
##STR16## 
is obtained from compounds of the formula XI 
##STR17## 
with R(15) equal to hydrogen, for example with epichlorohydrin and bases 
(for n=1) by known methods, or by alkylation of compounds of the formula 
XI with compounds of the formula X' 
EQU Z--(CH.sub.2)--CH.dbd.CH.sub.2 (X'), 
in which n has the same meaning as in formula I, and in which Z has the 
same meaning as in formula X, there being formation of compounds of the 
formula XIV 
##STR18## 
Subsequent epoxidation of the compounds by known processes, for example 
with m-chloroperbenzoic acid in methylene chloride yields compounds of the 
formula XIII. 
Compounds of the formula VI can also be prepared from compounds of the 
formula XIV 
##STR19## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)', m and n have the 
same meaning as in formula I, by epoxidation by known processes, for 
example using m-chloroperbenzoic acid or peracetic acid in methylene 
chloride. 
Compounds of the formula XIV are obtained from compounds of the formula IV 
by alkylation using compounds of the formula XV 
EQU Z-(CH.sub.2).sub.n --CH.dbd.CH.sub.2 (XV) 
in which n has the same meaning as in formula I, and Z has the same meaning 
as in formula V. 
Compounds of the formula VII can be prepared from compounds of the formula 
IV by alkylation using compounds of the formula XVI 
EQU Z--(CH.sub.2).sub.n --CO.sub.2 R(16) (XVI), 
in which Z has the same meaning as in formula V, and R(16) denotes hydrogen 
or an alkyl radical, under the conditions described for process (b), or by 
oxidation of compounds of the formula XVII 
##STR20## 
in which R(1), R(1)', R(1)", R(2), R(3), R(4), R(4)' and n have the same 
meaning as in formula I, and R(16) has the same meaning as in formula XVI, 
with oxidizing agents as described under process (e). 
Unless expressly mentioned otherwise, alkyl, alkylene, alkanoyl and alkoxy 
always mean straight or branched chains. 
The compounds of the formula I, according to the invention, have 
pharmacological and biochemical actions, in particular 
calcium-antagonistic and blood-pressure lowering actions, and can thus be 
used for the treatment of all pathological states which derive from 
disturbance of the calcium balance in a warm-blooded animal. 
Their calcium-antagonistic activity can be shown using the biochemical test 
model of the displacement of tritiumlabeled nitrendipine. 
In this test, membrane preparations which contain isolated calcium channels 
are loaded with the labeled substance. After incubation with the test 
substance, the radioactivity which has been released into the supernatant 
solution is determined. The IC.sub.50 values of the compounds of the 
formula I, according to the invention, in this model are from 10.sup.-6 
molar to 10.sup.-10 molar 
Compounds of the formula I are also highly active in other test models with 
which it is possible to detect a calcium-antagonistic action, for example 
on the coronary perfusion in the isolated guinea pig heart, or on the 
action potential of the isolated guinea pig capillary muscle. 
The compounds of the formula I, according to the invention, and their 
pharmacologically tolerated salts diminish the influx of calcium ions into 
cells and are thus suitable for the treatment of the cardiovascular system 
where there are appropriate symptoms, for example for various types of 
angina pectoris, tachycardia, cardiac dysrhythmias and high blood 
pressure. They are active in a wide dose range. The level of the dose 
administered depends on the nature of the desired treatment, on the mode 
of administration, on the condition, on the type and on the size of the 
treated mammal. On oral dosage, satisfactory results are obtained with 
doses of from 0.01, preferably from 0.1, in particular from 0.5, mg and up 
to 100 mg, preferably up to 20 mg, in particular up to 15 mg, of a 
compound of the formula I per kg of body weight. In humans, the daily dose 
varies from at least 10, in particular 20, mg to at most 800 mg, 
preferably 500 mg, it being possible to give single doses of 5 to 200 mg, 
in particular 5 to 100 mg, preferably once to three times a day. These 
data relate to an adult with a body weight of about 75 kg. 
The dose for intravenous and intramuscular administration is at least 1 mg, 
preferarably at least 5 and at most 300 mg, preferably up to 150 mg a day. 
The compounds of the present invention which can be used in pharmacology, 
and their salts, can be used for the preparation of pharmaceutical 
products which contain an effective amount of the active substance 
together with vehicles and which are suitable for enteral and parenteral 
administration. Use is preferably made of tablets or gelatin capsules 
which contain the active substance together with diluents, for example 
lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, 
and lubricants such as diatomaceous earth, talc, stearic acid or its 
salts, such as magnesium or calcium stearate, and/or polyethylene glycol. 
Tablets additionally contain binders such as magnesium aluminum silicate, 
starch, gelatin, tragacanth, methylcellulose, sodium 
carboxymethylcellulose and/or polyvinylpyrrolidone and, if necessary, 
colorants, flavorings and sweeteners. Injectable products are preferably 
isotonic aqueous solutions or suspensions, which can be sterilized and 
contain auxiliaries such as preservatives, stabilizers, wetting agents 
and/or emulsifiers, solubilizers, salts to regulate the osmotic pressure, 
and/or buffer substances. The pharmaceutical products according to the 
invention, which, if desired, can contain. further pharmacologically 
valuable substances, are prepared, for example, by conventional mixing, 
granulating and coating processes, and contain 0.1% to about 75%, 
preferably about 1% to about 50%, of the active substance.