Note: Descriptions are shown in the official language in which they were submitted.
iO630Z7
The present invention relates to pharmaceutical
compositions comprising N-[1-(3,~.-methylenedioxyphenyl)-
prop-2-yl]-N'-(2-chlorophenyr~piperazine and acid addition
salts thereof.
It is known from Genman Offenlegungsschrift No.
1 670 1~. that compounds of general formula
Ar-CHj-CH~~~
(wherein Ar represents a fused bicyclic aromatic group -
in which the ring remote from the remainder of the
molecule may, if desired, be a carbo- or heterocyclically ~ -
saturated or aromatic ring; and Rl and R2, which may
`~ be the same or different, each represents a hydrogen
or halogen atom or a trifluoromethyl group or an alkyl
or alkoxy group with 1 to b~ carbon atoms) and acid
~:~ addition salts thereof, possess a depressant activity
on the central nervous system and, therefore, appear
. - to :be suitable or use as sedatives, neuroleptics or
ma~or tranquilizers. - .
- - 2 -
'
~,:
1063027
The present invention is based upon the discovery
that a compound, i.e. N-[1-(3,~.-methylenedioxyphenyl)-prop-
2-yl~-N'-(2-chlorophenyl)-piperazine and the physiologically
compatible acid addition salts thereof, possess the
property of decreasing the level of lipids and the
cholesterol level in the blood.
In particular tests which have been conducted show
that N-[1-(3,6-methylenedioxyphenyl)-prop-2-yl]-N'-(2-
chlorophenyl)-piperazine and its physiologically compatible
acid addition salts are even superior to the compounds
disclosed in German Offenlegungschrift No. 2,136,929. -
Furthermore, the toxicity of the compounds of the present
invention is low, so that these compounds are suitable
for therapeutic use.
Thus according to one feature of the present invention
there are provided pharmaceutical compositions comprising
as active ingredient N-[1-(3,~-methylenedioxyphenyl)-prop-
2-yl]-N'-(2-chlorophenyl)-piperazine or a physiologically
compatible acid addition salt thereof and a compound having
a therapeutically useful effect on the cardiac and/or
circulatory system, together with a pharmaceutical carrier
or excipient.
According to a further feature of the present
_ 3 -
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. - - . ................. ..
, . . . . . .
`~ ~0630Z7
invention there are provided pharmaceutical compositions
comprising as active ingredient N-[1-(3,4-methylenedioxy-
phenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine or a
physiologically compatible acid addition salt thereof in
association with a pharmaceutical carrier or excipient
when used for decreasing the blood lipid level and the
blood cholesterol level. The composition advantageously
also contains a compound having a therapeutically useful
effect on the cardiac and/or circulatory system, prefer-
ably a coronary dilator.
The coror.ary dilator to be employed in the pharma-
ceutical compositions of the present invention may, for
example, include any of the following:
3~ diethylaminoethyl)-~1-methyl-7-carbethoxymethyl-2-
oxo-2H-chromen; 3,3'-(N,N'-dimethylethylenediamino)-bis-
(propyl 3,~,s-trimethoxybenzoate); N-3'-phenylpropyl-
(2')-1,1-diphenyl-(3)-amine; a-isopropyl-~-[N-(methyl-
N-homoveratryl)-~-aminopropyl]-3,4-dimethoxyphenyl-
acetonitrile and L-~ -hydroxy-a-m~thyl-phenylethylamino~
3-metho~-propiophenone, but is preferably 'dipyridamol'.
Thus, for example, for the prophylactic treatment of
coronary thromboses, compositions according to the inven- -
tion contain N-[1-(3,~-methylenedioxyphenyl)-prop-2-yl]-
N'-~2-chlorophenyl)-piperazine or a physiologically
compatible acid addition salt thereof and a coronary
dilator such as 'dipyridàmol~ ~i.e. 2,6-bis-(diethanol-
amino)-~,8-dipiperidino-(5,4-d)-pyrimidine].
The pharmaceutical compositions of the present
invention are preferably in dosage unit form, each dosage
unit preferably containing from 5 to 75 mg of N-[1-(3,L-
~ ~~
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.. . . . ..
1063027
methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-
piperazine or a physiologically compatible acid addition
salt thereof. This latter mentioned compound may be
conveniently administered in a daily dosage of from
25 to 75, preferably 40 to 60 mg., the compound being
administered, for example, 1 to 5 times daily.
Where the compositions according to the invention
are in the form of dosage units containing a coronary
dilator each dosage unit preferably contains from 10 to
150 mg of the coronary dilator. The daily dose of
coronary dilator is advantageously from 50 to 150 mg.
According to a still further feature of the present
invention there are provided pharmaceutical compositions
in the form of dosage units comprising as active ingredient
N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chloro-
phenyl)-piperazine or a physiologically compatible acid
addition salt thereof in association with a pharmaceutical
carrier or excipient, each dosage unit containing greater
than ~0 mg, but no greater than 60 mg, of active ingredient.
The composition may, if desired, further contain a compound
h~ving a therapeutically useful effect on the cardiac and/
r circ~latory system conveniently a coronary dilator
~ 5
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. . .
.. . . .
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.: , . .
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10 63U~z~7
preferably 2,6-bis-(diethanolamino)-6,8-dipiperidino-[s,4-
d]-pyrimidine.
Pharmaceutical compositions in the form of dosage
units, each dosage unit containing greater than ~0, but
no greater than 60 mg of N-[1-(3,4-methylenedioxyphenyl)-
prop-2-yl]-N'-(2-chlorophenyl)-piperazine and the
physiologically compatible acid addition salts thereof,
are used, for example, as the single daily dosage,~0 to
60 mg being the preferred daily dosage of N-[1-(3,4-methy-
lenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine
and the physiologically compatible acid addition salts
thereof. :~
According to a further feature of the present
invention there are provided pharmaceutical compositions
~ in the form of dosage units comprising as active ingredient
N-[1-(3,~-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chloro-
.~ phenyl)-piperazine or a physiologically compat~.ble acid
. àddition salt thereof in association with a pharmaceutical
carrièr or excipient, each dosage unit containing from
to less than 15 mg of active ingredient.
: N-~1-(3,6-methylenedioxyphenyl)-prop-2-yl]-N!-(2-
. . . . ..... .. . . .. . . .
-
; ~0630Z7
chlorophenyl)-piperazine contains an asymmetric carbon
atom and thus exists not only in racemic form but also
in the form of optically active isomers. It will be
appreciated that pharmaceutical compositions containing
any or all such forms of this compound (and physiologically
compatible acid addition salts thereof) are within the
scope of the present invention.
N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-
chlorophenyl)-piperazine,in either rac~mic or opticalIy active
form,and its physiologically compatible acid addition
salts thereof may, for example, be prepared as described
in German Offenlegungs chrift No. 1,670,144. ~ -
According to a still further feature of the present
invention there are provided pharmaceutical products for
decreasing the blood lipid level and the blood cholesterol
level comprising a container having therein a phanmaceutical
composition , which composition comprises N-[1-(3,4-
methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-
piperazine or a physiologically compatible acid addition
salt thereof as active ingredient, the said container being
in association with written or printed directions for the
- 7
~0630Z7
use of the composition for clinical treatment of
conditions in which decreasing the blood lipid level
and the blood cholesterol level is therapeutically
useful.
The compositions may be presented in a package
in association with instructions for the use thereof.
Such directions may be written or printed and may,
for example, be physically attached to a container
for the composition or the package may comprise a
container for the compositions and separate instructions.
Pharmaceutical products are conventionally marketed in
for example, a bottle (e.g. containing tablets or
capsules), ampoules or vials, the container bearing ~ - -
,~ . , .
itself printed or written instructions for the
intended use of the product and/or being accompanied
by separate printed or written instructions for such
us~. Phanmaceutical products are thus commonly marketed
- together with a leaflet, often called a "package insert" -
e'~,; ~ ;.: . : -
which describes the intended medical use of the product
concerned and may, for example, recommend daily doses,
possible side effects (if any~ and provide other useful
medical information to the medical practitioner.
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~0630Z7
In the pharmaceutical products of the present
invention the pharmaceutical composition is preferably
present in the container in the form of a plurality of
dosage units.
It will be appreciated that the pharmaceutical
products of the present invention may comprise any of the
pharmaceutical compositions of the present invention, such
compositions are thus preferably in the form of dosage
units as hereinbefore described and advantageously further
contain a compound having a therapeutically useful effect
on the cardiac and circulatory system e.g. a coronary
dilator as hereinbefore described.
According to a yet still further feature of the
present invention there is provided a method of treating
patients to decrease the blood lipid level and the blood -
cholesterol level which method comprises administering to
the patient an effective amount of N-[1-(3,4-methylene-
dioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine
or a physiologically compatible acid addition salt thereof.
The method is conveniently effected using any of the above
described compositions of the present invention. The
_ 9 _
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10 6 ~ 2~7
composition is preferably administered in a daily dosage
of from 25 to 75 mg, especially ~.0 to 60 mg, of N-[1-(3,4-
methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine.
Where the composition employed contains in addition a com-
pound having a therapeutically useful effect on the
cardiac and/or circulatory system e.g. a coronary dilator,
the composition is preferably administered in a daily
dosage of 50 to 150 mg of the coronary dilator e.g.
..
Z,6-bis-(diethanolamino)-b~,8-dipiperidino [s,4-d]-
pyrimidine.
;~ The pharmaceutical compositions may be presented,
; for example, in a form suitable for oral, parenteral or
rectal administration. Thus the compositions may, for ~ -
example, be presented in the conventional pharmacological
forms of administration such as, for example, tablets,
~ ~ . . .. .
coated tablets, emulsions, powders, capsules or in a form
suitable for obtaining sustained release. These compositions
may, for example, be produced by the use of conventional
.. . .. .
~^ ~ pharmaceutical excipients employing the conventional
` methods of perparation.
Tablets may be produced, for example, by mixing the
~ . . . . ... ..
~ active ingredients with known excipients, such as inert
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1063027
diluents e.g. calcium carbonate, calcium phosphate or
lactose, disintegrants such as corn starch or alginic
acid, binders such as starch or gelatin, lubricants such
as magnesium stearate or talcum and/or agents for obtaining
a sustained release such as carboxypolymethylene, carboxy-
methylcellulose, cellulose acetatephthalate or polyvinyl
acetate. The tablets may, if desired, also consist of
several layers.
Coated tablets e.g. sugar-coated tablets may be
produced in a similar manner by coating cores, produced
in a similar manner to the tablets, with agents generally
used for tablet coatings, such as polyvinylpyrrolidone,
shellac, gum arabic, talcum, titanium dioxide or sugar.
In order to obtain sustained release effects or in order
to avoid incompatibilities, the core may consist of several
layers. The tablet coat may also consist of several layers
in order to obtain a sustained release, in which case the
excipients mentioned above for tablets may be used.
Syrups of the active ingredient or active ingredient
co~binations according to the invention may, if desired,
additionally contain a sweetener, such as saccharin,
cyclamate, glycerin or sugar, and/or a taste improving
.
.
.
.. . ... . .. . .. . . .
. . :, , , ~
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~0 63UDZ~7
agent such as flavourings, e.g. vanillin or orange extract.
They may also contain suspension agents or thickeners
such as sodium carboxymethylcellulose, wetting agents
such as condensation products of fatty alcohols with
ethylene oxide, or preservatives such as p-hydroxy-
benæoates.
Capsules containing an active ingredient or active
ingredient combination may, for example, be produced by
mixing the active ingredients with inert carriers, such
as lactose or sorbitol, and filling the mixture into
gelatine capsules.
Suitable suppositories may be produced, for example,
by mixing the active ingredient or active ingredient
combinations with the conventional carriers envisaged
for this purpose such as neutral fats or polyethylene glycol
of derivatives thereof. -
~ For parenteral administration, the carrier may be
;~ a sterile, parenterally compatible liquid such as sterile
water, or a parenterally compatible oil e.g. arachis oil,
contained in ampoules.
The cholesterol decreasing action of N-[1-(3,4-
- 12
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- .. . . , . . . .: - .
. . .
1063027
methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-
piperazine and the physiologically compatible acid
addition salts thereof was examined in a trial lasting
18 days and involving rats of the FW L9 strain. The
compound was administered perorally, once daily by stomach-
probe, in emulsion form together with the solubilizer
Tween 80. The controls received physiological, common
salt solution together with Tween 80.
The serum-cholesterol was determined according to the
methods of Levine, and J. and B. Zak in Clin. Chem.
Acta 10, pages 381-38h (1964). The doses of "Clofibrate",
a preparation at present on the market, were 6 times
higher than the doses of the other substances. The
results are presented in the following table:
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10630Z7
Compound Da~ 0 DaY 4 Dav 8 Day 18
A. Comparison Compounds
Clofibrate 93.3 72.8 65.6 78.1
(-22%) (-30%) (-16%)
N-[1-(3,~-Methylene-
dioxyphenyl~prop-2-yl]-
N'-phenylpiperazine. HCl 89.9 70.8 55-7 51.3
(-21%) (-38%) (-43%)
... . . _ _
B. Compound employed in ~ -
the compositions of the
present invention -
N-[1-(3,6-Methylenedioxy-
phenyl~prop-2-yl~-N'-(2- 75.0 33.7 20.4 5~9
chlorophenyl)piperazine. (-55%) (-73%) (-92%) -
HCl
The total cholesterol content (average over 10
animals) in mg per 100 ml of serum and the percentage
.
decrease over the course of the examination is stated
in each case together with the final value for each
group (Day 0 z 100%).
The following non-limiting Examples serve to illustrate
the invention. In each case the compositions were packaged
- together with printed directions for the use of the
. .
compositions in reducing the blood lipid level and the
blood cholesterol level.
~ 14
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~063027
Example 1 (Tablets)
N-[1-(3',~1'-methylenedioxyphenyl)-
prop-2-yl]-N'-(2-chlorophenyl)-
piperazine. HCl 5o mg
lactose 5o mg
corn starch 93 mg
sec. calcium phosphate 67 mg
soluble starch 3 mg
magnesium stearate 3 mg
colloidal silicic acid 4 mg
250 mg
Production:
The active ingredient is mixed with part of the
excipients, thoroughly kneaded with an aqueous solution
of the starch and granulated with the aid of a screen
in the conventional way. The granulate is mixed with
the remaining excipients and pressed into tablets each
weighing 250 mg.
ExamPle 2 (Coated Tablets)
N~ ( 3 ~, L I -methylenedioxyphenyl)- -~
prop-2-yl~-N'-(2-~hlorophenyl)-
piperazine. HCl 40 mg
~,6-bis-(diethanolamino)-4,8-di-
piperidino [s,4-d]pyrimidine 70 mg
. - , , . . . . . - - . -
.
- . - ~ ..
.
~0630Z7
corn starch 60 mg
sec. calcium phosphate 50 mg
magnesium stearate 3 mg
soluble starch 3 mg
colloidal silicic acid 4 mg
280 mg
Production:
The active ingredients are mixet with part of the
excipients, thoroughly kneaded with an aqueous solution
of the soluble starch and then granulatet in the
conventional manner. The granulate mixed with the remain-
ing excipients and pressed into tablet cores each weighing
380 mg of weight. The cores are coated with the aid of tal-
cum, sugar and gum arabic in the conventional way.
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10630Z7
Example 3 (Coated Tablets)
-
1 core contains:
N-3'-Phenylpropyl(2)-1,1-diphenyl(3)-amine
lactate ~5.0 mg.
N-C1-(3,4-methylenedioxyphenyl)-prop-2-yl]-
N'-(2-chlorophenyl)-piperazine 25.0 mg.
Lactose 20.0 mg.
Potato starch 16.0 mg.
Polyvinylpyrrolidone 3.0 mg.
Magnesium stearate 1.0 m~
, 110.0 mg.
Preparation: The mixture-of the active substances
lactose and potato starch is moistened with a 25% ';' '
ethanolic solution of polyvinylpyrrolidone, granulated
thwugh a sieve with a 1.5 mm. mesh and dried at bsC.
The dried granulate is again granulated through a-sieve
of 1 mm. mesh and mixed with the magnesium stearate.
The cores thus obtained are coated ''in conventional
manner with a coat which consists substantially of sugar
and talc. The coated tablets thus obtained are polished
'with beeswax. Final weight = 150 mg.
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~0630Z7
Example /. (Suppositories)
1 Suppository contains:
3-(~-Diethylaminoethyl)-tl-methyl-7-
carbethoxymethoxy-2-oxo-2H-chromen
hydrochloride 125.0 mg
N-[l-t3,4-methylenedioxyphenyl)prop-
A~ 2-yl]-N'-(2-chlorophenyl)-piperazine 75.0 mg. -
,.
Suppository base e.g. Witepsol H 12 1600.0 mg
. _ . .
~ 1800.0 mg.
~ ~ .. . ..
~ The finely divided active substance is stirred into the
, ~ ,
melted suppository base at ~0C. The mixture is homo-
genised and poured at about 3sC into slightly pre-cooléd
moulds.
Suppository weight : 1.7 g.
Example ~ (Tablets)
N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-
N'-(2-chlorophenyl)-piperazine. HCl 50 mg
.
;~ 3,3'-(N,N'-dimethylethylenediamino)-bis-
(propyl-3,6,s-trimetho~y benzoate) 45 mg
- ~18 - ~;
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~0630Z7
lactose 5o mg
corn starch 93 mg
sec. calcium phosphate 47 mg
soluble starch . 3 mg
magnesium stearate 3 mg
colloidal silicic acid . 4 mg -
295 mg
Production: . :
As described in Example 1 ~
Example 6 (Coated Tablets) ~ :
1 core contains~
N-[1-(3,4-methylenedioxyphenyl)-prop-2-`
yl]-N'-(2-chlorophenyl)-piperazine HCl.LO mg
a-isopropyl-a-[N-(methyl-N-bromoveratryl)-
~, .
-a-aminopropyl]-3,6-dimethoxyphenyl-
. ~ ~ . . . .
acetonitrile 70 mg
corn starch 60 mg
lactose 50 mg ~ : .
- ~ ~ sec. calcium phosphate 50 mg
~: ~ magnesium stearate 3 mg --
,~ ~
-- 19 -- : -
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~0630Z7
soluble starch 3 mg
colloidal silicic acid 4 mg
280 mg
Production: As described in Example 2
Example 7 (Coated Tablets)
.: '
1 core contains:-
N-[l-(3~rl-methylenedioxyphenyl)-prop-
.....
2-yl]-N'-(2-chlorophenyl)-piperazine HCL Lo mg -~
L-~-(~-hydroxy-a-methyl-phenylethyl- - -:
amino)-3-methoxy-propiophenone 70 mg
lactose 50 mg -~:~
corn starch . 60 mg ~
sec. calcium phosphate 50 mg :: :
~ .
.
;: magnesium stearate 3 ~g . .
. ~ . soluble starch 3 mg ~.
colloidal silicic acid ~ mg
280 mg
Production: As described in Example 2
20 -
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