CA1063027A - Substituted n-(1-(3,4-methylendioxyphenyl)-propyl(2))-n'-substituted phenylpiperazines - Google Patents
Substituted n-(1-(3,4-methylendioxyphenyl)-propyl(2))-n'-substituted phenylpiperazinesInfo
- Publication number
- CA1063027A CA1063027A CA234,708A CA234708A CA1063027A CA 1063027 A CA1063027 A CA 1063027A CA 234708 A CA234708 A CA 234708A CA 1063027 A CA1063027 A CA 1063027A
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- compositions
- piperazine
- compound
- prop
- methylenedioxyphenyl
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to pharmaceutical compositions comprising as active ingredient N - [1- (3, 4 - methy-lenedioxyphenyl) - prop - 2 - yl] - N'- (2 - chlorophenyl) - piperazine and the physiologically compatible acid addition salts thereof either alone in certain dosage unit ranges or in combination with a coronary dilator.
Pharmaceutical products comprising such compositions are also described and claimed. Pharmaceutical compositions containing N - [1 - (3', 4' - methylenedioxyphenyl) -prop - 2 - yl] - N' - (2 - chlorophenyl) - piperazine and the physiologically compatible acid addition salts are described and exemplified.
The invention relates to pharmaceutical compositions comprising as active ingredient N - [1- (3, 4 - methy-lenedioxyphenyl) - prop - 2 - yl] - N'- (2 - chlorophenyl) - piperazine and the physiologically compatible acid addition salts thereof either alone in certain dosage unit ranges or in combination with a coronary dilator.
Pharmaceutical products comprising such compositions are also described and claimed. Pharmaceutical compositions containing N - [1 - (3', 4' - methylenedioxyphenyl) -prop - 2 - yl] - N' - (2 - chlorophenyl) - piperazine and the physiologically compatible acid addition salts are described and exemplified.
Description
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. - .
' ~,:
The present invention is based upon the discovery that a compound, i.e. N-[1-(3,~.-methylenedioxyphenyl)-prop-
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. - .
' ~,:
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 -~' '.
. - - . ................. ..
, . . . . . .
`~ ~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:
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 -~' '.
. - - . ................. ..
, . . . . . .
`~ ~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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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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.: , . .
,:- ~ ,-., . . - . . .
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 ~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 10 - .
i. -.: . .
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 .
.
.
.. . ... . .. . .. . . .
. . :, , , ~
-~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-~' .
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. . .
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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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 ~ ' ' " .
~ ~ .
~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.
, . ~ . . , . .. . , . . . - .. . . . . . .. . .
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 -- : -~' ~, :
. ': - ' .
~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 . . ~ . . .
.
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; . , ,.' . ,! ~, ' . .: :: !:
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-~ ~~
::
~. .
" .. ., . : : ' : , ' . ! '; ~ , ' . ' . . : , . ' ;
' ' . ' , ' . . '.' , j .: ~ ' ' . ' . . ' . " . ' " " ~ ' ' ' , .. . . . ..
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 :~ . .
~ ; .
. . .
.. . . .
, . . . . ~ . , . ~ .
.. .,:., . i . : . .. .
.: , . .
,:- ~ ,-., . . - . . .
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 ~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.
~, . .: - .
~,~ ~, , .., ~ - .
~ - ' ~ . .. -.. . ..
~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 _ ~, . .
: .
.
: - - . . : ~ ....
. . ' -: -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 10 - .
i. -.: . .
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 .
.
.
.. . ... . .. . .. . . .
. . :, , , ~
-~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-~' .
.:~, .
:
,.: .. ... .. - ,. , .. . .. . - . , ,, . . ,,, ... . , .. . . : .-- .. . . , . . . .: - .
. . .
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:
~ rr~ n~rK
: , ~.
.~. . ., - - . ~ .
',: , . ~
,, . - . . .
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 ~ ' ' " .
~ ~ .
~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.
, . ~ . . , . .. . , . . . - .. . . . . . .. . .
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.
~ :
~, - 17 -, ' , ~ :
. .
' :
.... . . . . . . . .
' ~ : . - . ' ,~
~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 - ~;
~e~rl~ .
~ ~ .
.~; .
. ~ ' : , ., , ~ , . . .
" , i.: : . :.
~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 -- : -~' ~, :
. ': - ' .
~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 . . ~ . . .
.
, ~., ~, . .: , .. , ; .. . ... ,. - -. . . : ,.
; . , ,.' . ,! ~, ' . .: :: !:
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Pharmaceutical compositions comprising as active ingredient N-[1-(3,4-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 sys-tem, together with a pharmaceutical carrier or excipient.
2. Compositions as claimed in claim 1 wherein the compound having a therapeutically useful effect on the cardiac and/or circulatory system is a coronary dilator.
3. Compositions as claimed in claim 2 wherein the coronary dilator comprises 2,6-bis-(diethanolamino)-4,8-dipiperidino-[5,4-d]-pyrimidine.
4. Compositions as claimed in claim 1 in the form of dosage units.
5. Compositions as claimed in claim 4 wherein each dosage unit contains from 5 to 75 mg of N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chloro-phenyl)-piperazine or a physiologically compatible acid addition salt thereof.
6. Compositions as claimed in claim 5 wherein each dosage unit contains greater than 40 but no greater than 60 mg of N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine or a physiologically compatible acid addition salt thereof.
7. Compositions as claimed in claim 4, 5 or 6 wherein each dosage unit contains from 10 to 150 mg of a coronary dilator.
8. Compositions as claimed in claim 1, 3 or 6 in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, suspensions, powders, drops, suppositories or injection solutions.
9. Compositions as claimed in claim 2 wherein the coronary dilator comprises 3-(.beta.-diethylaminoethyl)-4-methyl-7-carbethoxymethyl-2-oxo-2H-chromen; 3,3'-(N,N'-dimethylethylenediamino)-bis-(propyl 3,4,5-trimethoxy-benzoate); N-3'-phenylpropyl-(2')-1,1-diphenyl-(3)-amine; .alpha.-isopropyl-.alpha.-[N-(methyl-N-homoveratryl)-y-aminopropyl]-3,4-dimethoxyphenyl-acetonitrile or L-.omega.-(.beta.-hydroxy-.alpha.-methyl-phenylethylamino)-3-methoxy-propiophenone.
10. Pharmaceutical compositions in the form of dosage units comprising N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine or a physiologically compatible acid addition salt thereof in association with a compound having a therapeutically useful effect on the cardiac system and a pharmaceutical carrier or excipient, each dosage unit containing great-er than 40 mg, but no greater than 60 mg. of said piperazine compound.
11. Pharmaceutical compositions in the form of dosage units comprising N-[1-(3,4-methylenedioxyphenyl)-prop-2-yl]-N'-(2-chlorophenyl)-piperazine or a physiologically compatible acid addition salt thereof in association with a compound having a therapeutically useful effect on the circulatory system and a pharmaceutical carrier or excipient, each dosage unit containing great-er than 40 mg, but no greater than 60 mg. of said piperazine compound.
12. Compositions as claimed in claim 10 or 11 wherein the compound having a therapeutically useful effect on the cardiac or circulatory system is a coronary dilator.
13. Compositions as claimed in claim 10 or 11 wherein the compound having a therapeutically useful effect on the cardiac or circulatory system is 2,6-bis-(diethanolamino)-4,8-dipiperidino-[5,4-d]-pyrimidine.
14. Compositions as claimed in claim 10 or 11 wherein the compound having a therapeutically useful effect on the cardiac or circulatory system is 2,6-bis-(diethanolamino)-4,8-dipiperidino-[5,4-d]-pyrimidine present in an amount of from 10 to 150 mg. per dosage unit.
15. Compositions as claimed in claim 10 or 11 in the form of granules, tablets, coated tablets, capsules, pills, syrups, emulsions, suspensions, powders, drops, suppositories or injection solutions.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2442158A DE2442158C3 (en) | 1974-09-03 | 1974-09-03 | New substituted N- [1 (3,4-methylenedioxyphenyl) propyl (2)] -N'-subst phenylpiperazines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063027A true CA1063027A (en) | 1979-09-25 |
Family
ID=5924765
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,707A Expired CA1061343A (en) | 1974-09-03 | 1975-09-03 | Substituted n-(1-(3,4-methylendioxyphenyl)-propyl(2))-n'-substituted phenylpiperazines |
| CA234,708A Expired CA1063027A (en) | 1974-09-03 | 1975-09-03 | Substituted n-(1-(3,4-methylendioxyphenyl)-propyl(2))-n'-substituted phenylpiperazines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,707A Expired CA1061343A (en) | 1974-09-03 | 1975-09-03 | Substituted n-(1-(3,4-methylendioxyphenyl)-propyl(2))-n'-substituted phenylpiperazines |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS52287A (en) |
| AT (1) | AT344699B (en) |
| BE (2) | BE833003A (en) |
| BG (1) | BG26381A3 (en) |
| CA (2) | CA1061343A (en) |
| CH (1) | CH615174A5 (en) |
| CS (1) | CS192521B2 (en) |
| DD (1) | DD124118A5 (en) |
| DE (1) | DE2442158C3 (en) |
| DK (1) | DK137387C (en) |
| ES (5) | ES440630A1 (en) |
| FI (1) | FI60006C (en) |
| FR (1) | FR2283682A1 (en) |
| GB (3) | GB1514546A (en) |
| HU (1) | HU176754B (en) |
| IE (2) | IE41667B1 (en) |
| IL (2) | IL48033A (en) |
| LU (2) | LU73316A1 (en) |
| NL (1) | NL7510319A (en) |
| NO (1) | NO142911C (en) |
| NZ (1) | NZ178566A (en) |
| PH (1) | PH13631A (en) |
| PL (1) | PL95233B1 (en) |
| RO (1) | RO68380B (en) |
| SE (1) | SE419084B (en) |
| YU (1) | YU37164B (en) |
| ZA (2) | ZA755602B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54109307U (en) * | 1978-01-19 | 1979-08-01 | ||
| US4647606A (en) * | 1982-12-27 | 1987-03-03 | Owens-Corning Fiberglas Corporation | Blend of rapid set asphaltic emulsion with slow set asphalt emulsion |
| HU187229B (en) * | 1983-04-14 | 1985-11-28 | Koezponti Valto Hitelbank | Method for producing fodder increasing yield or additional fodder composition |
| AUPN359095A0 (en) * | 1995-06-19 | 1995-07-13 | Mount Shamrock Pty Ltd | Saw system |
-
1974
- 1974-09-03 DE DE2442158A patent/DE2442158C3/en not_active Expired
-
1975
- 1975-08-13 FI FI752288A patent/FI60006C/en not_active IP Right Cessation
- 1975-08-25 AT AT653875A patent/AT344699B/en not_active IP Right Cessation
- 1975-08-28 RO RO83281A patent/RO68380B/en unknown
- 1975-09-01 CS CS755930A patent/CS192521B2/en unknown
- 1975-09-01 BG BG7530900A patent/BG26381A3/xx unknown
- 1975-09-01 DD DD188118A patent/DD124118A5/xx unknown
- 1975-09-02 DK DK393775A patent/DK137387C/en active
- 1975-09-02 IL IL48033A patent/IL48033A/en unknown
- 1975-09-02 GB GB36152/75A patent/GB1514546A/en not_active Expired
- 1975-09-02 SE SE7509746A patent/SE419084B/en unknown
- 1975-09-02 NL NL7510319A patent/NL7510319A/en not_active Application Discontinuation
- 1975-09-02 GB GB3218/78A patent/GB1521052A/en not_active Expired
- 1975-09-02 JP JP50106441A patent/JPS52287A/en active Pending
- 1975-09-02 BE BE159687A patent/BE833003A/en not_active IP Right Cessation
- 1975-09-02 YU YU2219/75A patent/YU37164B/en unknown
- 1975-09-02 PL PL1975183066A patent/PL95233B1/pl unknown
- 1975-09-02 NO NO753020A patent/NO142911C/en unknown
- 1975-09-02 IL IL48036A patent/IL48036A/en unknown
- 1975-09-02 BE BE159686A patent/BE833002A/en not_active IP Right Cessation
- 1975-09-02 ES ES440630A patent/ES440630A1/en not_active Expired
- 1975-09-02 HU HU75BO1570A patent/HU176754B/en unknown
- 1975-09-02 GB GB36147/75A patent/GB1521051A/en not_active Expired
- 1975-09-03 CA CA234,707A patent/CA1061343A/en not_active Expired
- 1975-09-03 LU LU73316A patent/LU73316A1/xx unknown
- 1975-09-03 ZA ZA755602A patent/ZA755602B/en unknown
- 1975-09-03 PH PH17540A patent/PH13631A/en unknown
- 1975-09-03 ZA ZA755601A patent/ZA755601B/en unknown
- 1975-09-03 LU LU73317A patent/LU73317A1/xx unknown
- 1975-09-03 IE IE1929/75A patent/IE41667B1/en unknown
- 1975-09-03 FR FR7527056A patent/FR2283682A1/en active Granted
- 1975-09-03 NZ NZ178566A patent/NZ178566A/en unknown
- 1975-09-03 IE IE1930/75A patent/IE43338B1/en unknown
- 1975-09-03 CA CA234,708A patent/CA1063027A/en not_active Expired
-
1976
- 1976-12-03 ES ES453933A patent/ES453933A1/en not_active Expired
- 1976-12-03 ES ES453935A patent/ES453935A1/en not_active Expired
- 1976-12-03 ES ES453932A patent/ES453932A1/en not_active Expired
- 1976-12-03 ES ES453934A patent/ES453934A1/en not_active Expired
-
1979
- 1979-05-07 CH CH425779A patent/CH615174A5/en not_active IP Right Cessation
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