Note: Descriptions are shown in the official language in which they were submitted.
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Therapeutic Compositions
This invention relates to therapeutic compositions
containing certain quinolone compounds which we have
found to possess antihypertensive activity. More
particularly, the present invention provides
therapeutic compositions which comprise as an active
ingredient a quinolone of the general formula
' O
Rz ~ S(O)nCH3
wherein n is 0, 1 or 2 and either (a) R2 is hydrogen
and Rl is methyl or ethyl, or (b) R2 is methyl and Rl
is ethyl, provided that, when Rl is ethyl, n is 1 or 2,
together with a pharmaceutically acceptable carrier.
We have found that the compounds of general
formula I have valuable antihypertensive activity.
When administ~red to warm blooded animals in non-toxic
doses the compounds are effective in reducing elevated
blood pressure.
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The compounds of general forn~ula I have been
described in the literature, but no therapeutic
activity has been ascribed to them. Thus, for example,
the individual compounds within the scope of general
5 formula I and methods for their preparation have been
described in one or more of the following publications:
Van Leusen and Taylor, J. Org. Chem., Vol. 33, pp.
66-70 (1968)
Albrecht, Chimie Therapeutique, 1973, No. 1, pp. 45-48.
10 Connor et al., J. Heterocyclic Chem., Vol. 15, pp.
113-114 (1978)
Connor et al., J. Heterocyclic Chem., Vol. 15 pp.
115-117 (1978)
As used hereinafter, the term 'active compound'
15 denotes a quinolone compound of general formula I. In
therapeutic use, the active compound may be
administered orally, rectally or parenterally,
preferably orally. Thus the therapeutic compositions
of the present invention may take the form of any of
20 the known pharmaceutical compositions for oral, rectal
or parenteral administration. Pharmaceutically
acceptable carriers suitable for use in such
compositions are well-known in the art of pharmacy.
The compositions of the invention suitable contain
25 0.1-90% by weight of active compound. The compositions
of the invention are generally prepared in unit dosage
form.
Compositions for oral administration are the
preferred compositions of the invention and these are
30 the known pharmaceutical forms for such administration,
for example tablets, capsules, syrups and aqueous or
oily suspensions. The excipients used in the
preparation of these compounds are the excipients known
in the pharmacists' art. Tablets may be prepared by
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~ixing the active compound with an inert diluent such
as calcium phosphate in the presence of disintegrating
agents, for example maize starch, and lubricating
agents, or example magnesium stearate, and tableting
the mixture by known methods. Such tablets may, if
desired, be provided with enteric coatings by known
methods, for example by the use of cellulose acetate
phthalate. Similarly capsules, for example hard or
soft gelatin capsules, containing the active compound
with or without added excipients, may be prepared by
conventional means and, if desired, provided with
enteric coatings in a known manner. The tablets and
capsules may conveniently each contain 5-500 mg. of the
active compound. Other compositions for oral
administration include, for example, aqueous
suspensions containing the active compound in an
aqueous medium in the presence of a non-toxic
suspending agent such as sodium carboxymethylcellulose,
and oily suspensions containing a compound of the
present invention, in a suitable vegetable oil, for
example arachis oil.
Compositions of the invention suitable for rectal
administration are the known pharmaceutical forms for
such administration, for example suppositories with
cocoa butter or polyethylene glycol bases.
Compositions of the invention suitable for
parenteral administration are the known pharmaceutical
forms for such administration, for example sterile
suspension in aqueous and oily media or sterile
solutions in a suitable solvent.
In some formulations it may be beneficial to use
the compounds of the present invention in the form of
particles of very small size, for example as obtained
by fluid energy milling.
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In the compositions of the present in~ention the
active compound may, if desired, be associated with
other compatible pharmacologically active ingredients.
The therapeutic activity of the quinolones of
general formula I has been demonstrated by tests which
include (A) the oral administration of the compounds to
a strain of spontaneously hypertensive rat and (B) the
intraduodenal administration of the compounds to a
strain of normotensive rat. These tests were carried
out in the following way:
Test A
Female rats weight range 180-240 g., of the
Aoki-Okamoto strain of spontaneously hypertensive rat
were used. The rats in groups of four were fasted
overnight before administration of the test compound.
Blood pressure was determined in the following way.
The rats were placed in a cabinet kept at 38C with
their tails protruding through holes in the cabinet.
After 30 minutes in the cabinet blood pressure was
measured using an inflatable cuff placed round the base
of the tail and arterial pulsations monitored with a
pneumatic pulse transducer. A pressure, greater than
the expected blood pressure, was applied to the cuff,
and this pressure was slowly reduced. The pressure in
the cuff at which arterial pulsations reappeared was
~aken as the blood pressure. The rats were removed
from the cabinet and each group orally dosed with a
given dose of the test compound given as a solution or
suspension in 0.25% aqueous carboxymethylcellulose. In
addition to the pre-dose reading, blood pressure was
measured at 1.5 and 5.0 hours after dosing. A compound
was designated as active if it gave a reduction of
blood pressure of 20% or greater at either of these
time intervals.
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Test B
Male normotensive rats (Wistar strain) of weight
range 210-240 g. were used. The rats were
anaesthetised and cannulae placed in a carotid artery
and in the duodenum. Blood pressure was recorded
electronically by means of a pressure transducer
connected to the arterial cannula. The test compound
was administered into the duodenum as a solution or
suspension in 0.25% aqueous carboxymethylcellulose.
Blood pressure was recorded before dosing and for 30
minutes afterwards. Results were obtained as the mean
of determinations in three rats per dosage level.
Compounds which caused a fall in blood pressure of lO%
or greater during the 30 minute post-dose period were
designated as active.
The following compounds were found to be active in
one or both of the tests at a dosage of 90 mg./kg. or
less.
l-methyl-3-methylsulphinyl-4-quinolone
1-ethyl-3-methylsulphinyl-4-quinolone
l-methyl-3-methylthio-4-quinolone
l-methyl-3-methylsulphonyl-4-quinolone
The present invention provides a method of
reducing blood pressure in a hypertensive warm blooded
animal which comprises the administration of a
quinolone compound of the hereinbefore defined general
formula I. Administration may be enteral or
parenteral; enteral administration, especially oral
administration, is preferred. A suitable dosage for
treating hypertension in warm blooded animals,
including man, is generally within the range 0.1-100
mg./kg./day, more usually 0.5-75 mg./kg./day and
especially 1-50 mg./kg./day, given in single or divided
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doses. Unit dosage forms suitably contain 1-500 mg.,
especially 5-500 mg., of the active compound.
The invention is illustrated by the following
non-limitative Examples.
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Example 1
In the preparation of tablets, the following
mixture is dry granulated and compressed in a tableting
machine to give tablets containing 10 mg. of active
ingredient:
Active Ingredient 10 g.
Lactose 5 g-
Calcium Phosphate 5 g.
Maize Starch 5 g.
In a similar manner tablets are prepared
containing 25 mg. of active ingredient.
Example 2
In a similar manner to that described in Example
1, there are prepared tablets containing 10 mg. or 25
mg. of 1-methyl-3-methylsulphinyl-4-quinolone as the
active ingredient.
Example 3
In the preparation of enteric coated tablets, the
tablets described in Examples 1 and 2 are given a thin
coat of shellac varnish, followed by 20 coats of
cellulose acetate phthalate.
Exam~le 4
In the preparation of capsules, a mixture of equal
parts by weight of active ingredient and calcium
phosphate is encapsulated in hard gelatin capsules,
each capsule containing 10 mg. of active ingredient.
i~
Capsules containing 25 mg. of active ingredient
are prepared in a similar manner.
Example 5
In a similar manner to that described in Example
4, there are prepared capsules containing 10 mg. or 25
mg. of l-methyl-3-methylsulphinyl-4-quinolone as the
active ingredient.
Example 6
In the preparation of enteric coated capsules, the
capsules of Examples 4 and 5 are coated with cellulose
acetate phthalate in a conventional manner.
Example 7
Suppositories weighing 1 g. and containing 25 mg.
active ingredient are prepared in a conventional manner
using a base consisting of:
Polyethylene glycol 4000 33%
Polyethylene glycol 6000 47%
Water 20%
Suitable active ingredients include that listed in
Example 2.
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