Note: Descriptions are shown in the official language in which they were submitted.
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Etozolin, i.e. 2-ethoxycarbonylmethylene-3-methyl-5-piperidino-4-
thiazolidone, is an outstandingly compatible and potent diuretic disclosed
in our United States Patent Specification No. 3,072,653, granted January 8th,
1963. Investigations on humans have shown that 400 mg. thereof have
about the same diuretic effectiveness as 40 mg. of the known diuretic furo-
semide, i.e. 4-chloro-N-furfuryl-5-sulphamoyl-anthranilic acid.
It is kno~n that all potent diuretics, such as furosemide and
othacrynic acid, i.e. 2,3-dichloro-4-(2-methylene-butyryl)-phenoxyacetic acid,
also excrt a considerable influence on the excretion of electrolytes. For
1~ this reason, that is in order to prevent an impoverishment in the organism of
certain electrolytes and especially of potassium ions, strongly effective
diuretics are used in dosages which are as low as possible. Thus, the usual
furosemide dosage at the commencement of a diuretic treatment is 40 mg. once
or twice daily. Subsequently, this dosage is adminis~ered only every other
day (see Rote Liste, 1975; Editio Cantor, Aulendorf/Wurtt., No. 37038B). If,
however, strongly effective diuretics are used for the treatment of high blood
pressure, then these must be administered at high dosage levels over a com-
paratively long period of time. Thus, the antihypertensively effective daily
dosage for furosemide is about two to four times higher than the diuretically
2~ e~fective dosage. Prolonged use at such a high dosage level is undesirable
bec~use of the danger of too great a loss of electrolytes and fluids and, in
the case of patients with normal or only slightly reduced kidney function is
contraindicated under many circumstances.
Since etozolin belongs to the group of potent diuretics, it would
be e~pected that it would behave in an analogous manner and that its prolonged
use as an anti-hypertensive would, because of the influencing of the electro-
lytes connected th~rewith and initiated by the high dosage, not result in any
ad~antage as compared with the already known diuretics. For this reason, in
United States Patent Specification No. 3,072,653, the therapeutic utilization
3~ of the anti-hypertensive side effect, brought about in the case of potent
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diuretics inter alia by increased water excretion, was not considered.
According to the present invention there is provided an anti-
hypertonic composition in oral dosage unit form comprising etozolin and/or at
least one pharmacologically acceptable salt thereof and a carrier, the amount
of etozolin present being from 30 to 100 mg per dosage unit. Preferably
etozolin is present in an amount between 40 and 90 mg per dosage unit. Dosage
units containing from 50 to 75 mg of etozolin are particularly preferred.
Tllus, we have now found that etozolin is a highly effective anti-
hyp~rtensive sgent and that this anti-hypertensive action is unexpectedly found
1~ 8t a dosage level which brings about practically no diuresis. The anti-
hypcrtensive action of etozolin is completely new and unexpectedO Consequent-
ly, in the 12 years which have elapsed since the publication of United States
Patent Specification No. 3,072,653, during which etozolin has been extensively
investigated, the valuable and important anti-hypertensive effectiveness of
etozolin was not discovered and there has been no teaching of a pharmaceutical
with this effectiveness Csee Arzneimittelforschung, 14 ~11), 1242/1964; Arch.
Exptl~ Pathol. Pharmacol., 249 (5), 432/1964; Klin. Wochenschr., 42 ~24),
1236/1964; Rev. Can. Biol., 23 ~2), 197/1964).
The results initially obtained from animal experiments have been
~0 confirmed on humans. According to these results, etozolin ac~s in an unfore-
seeably low sub-diuretic dosage of 200 mg. per day, in an outstandingly anti-
hypertensive manner. The blood pressure is significantly lowered and a
diminution of the action was not found, even after several weeks of therapy.
Thus, eto201in behaves in a completely different manner from the previously
known diuretics, the anti-hypertensive effect of which comes about essentially
via the kidneys, i.e. by an increased excretion of electrolytes and water.
This can be seen from the fact that, with the previously known diuretics, an
anti-hypertensive effect can only be achieved at all by the administration of
high, strongly diuretically-effective dosages and that with the reduction of
the extracellular volume of fluid, diuresis decreases correspondingly.
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In contradistinction thereto, the findings with etozolin indicate
that this substance acts not only by renal action but also, surprisingly,
by peripheral mechanisms which are more comparable with those of diazoxide,
i.e. 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine l,l-dioxide (commercially
available under the Trade Mark "hyperstat"; Physicians' Desk Reference, 29th
edn., 1975, p. 1327). Therefore, it is to be assumed that etozolin, as com-
parcd to the conventional diuretics, is also useul in the case of hyper-
tensivc crises as a blood pressure lowering agent.
Thus, etozolin is a completely new type of anti-hypertensively
ln Q~ective pharmaceutical. It acts in low dosages almost exclusively as an
anti-hypertensive and manifests, in higher dosages, an additional diuretic
e~ectiveness. There is thus provided the possibility, if desired, of combin-
ing these two properties by a simple increase of the dosage. Thus, etozolin
permits a departure from the previously conventional method of treatment,
which consisted of a combination of a diuretic with an anti-hypertensive. This
constitutes a considerable technical advance since, in modern therapy, the
efort is increasingly made to achieve certain complex pharmaceutical effects
by single substances with a suitable spec~rum of activity and thus to avoid
the combination of several active materials in a single pharmaceutical com-
position.
Furthermore, etozolin is characterized by a prolonged anti-
l~pertensive action, an extraordinarily good compatibility and an extremely
lo~ toxicity~ This also represents a technical advance since it is well
documented that previously used anti-hypertensivespossess more or less marked
side e~ects, some of which are of a serious nature~
Etozolin is, even in sub-diuretic dosages, an effective and non-
toxic anti-hypertensive which is superior to the previously known substances
having the same type of effect and thus represents a substantial improvement
o~ the pharmacological art, which was previously unknown.
High blood pressure therapy is planned for years ahead and any
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interruption, brought about by side effects, must be avoided, in order to
avoid the dan~r of resistance (see, for example, Deutsche Med. Wochenschrift,
90, 549/1965). It is clear what importance is to be attributed to an anti-
hypertensive therapy by means of a sin~Le substance without substantial side
effects, especially without a ha~ul action upon the electrolyte and water
metabolism of the body, and one which also has a low toxicity.
An anti-hypertensi.ve action can be achieved even with a dosage
which is only 25% of the dluretically effective dosage, i.e. in a normal case
with a dosage oE 100 mg. per day. me usual anti-hypertensive dosage is
100 - 200 mg. etozolin per day. In the case of 400 mg. etozolin per day,
the anti-hypertensive effect is superimposed by a marked diuretic action.
me preparation of etozolin is achieved by reaction of 2-ethoxy-
carbonyl~rethylene-3-nE?thyl-5-bro~4-thiazolidinone with piperidine and is
described in ExaTple 4 of United States Patent Specification No. 3,072,653.
Etozolin is adm~nistered orally as an anti-hypertonic. As oral
forms of a~ninistration, there can be used, for example, tablets, dragees,
capsules and granulates. In the production of oral forms of administration,
conventional, adauvant and carrier materials are employed in the usual man-
ner, such as starch, lactose, m~nitol, methyl cellulose, talc, hi hly dis-
20 persed silicic acids, high molecular wei~ht fatty acids (such as stearicacid),
--4--
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gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and veget-
able fats and solid high molecular weight polymers (such as polyethylene
glycol). If desired, the compositions can also contain additional flavoring
materials as well as sweetening materials.
By pharmacologically compatible salts, is meant conventionally
recognized salts of inorganic or organic acids which are nontoxic in the
~nounts administered, for example, hydrochloric acid, sulphuric acid, phos-
plloric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid,
salicylic acid~ malonic acid, maleic acid, succinic acid or ascorbic acid.
1~ Thc salts can be prepared in the usual manner by neutralization of the free
etozolin base with the desired acid in an appropriate solvent. The preferred
salt is the hydrochloride, which has a melting point of 158 - 159C.
The following Example is given for the purpose of illustrating the
present invention:
EXAMPLE
Hard gelatine capsule with a dosagè of`lOO`mg.`etozolin
The following powdered active and adjuvant materials are homo-
geneously mixed in the given amounts and placed in hard gelatine capsules of
size ~:
~o etozolin 30 g.
lactose 31 g.
maize starch 31 g.
talc 1 g.
The weight of filling per capsule is 310 mg.
