CH628889A5 - Substituted propylamine, process for its preparation and pharmaceutical composition containing this compound - Google Patents
Substituted propylamine, process for its preparation and pharmaceutical composition containing this compound Download PDFInfo
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- CH628889A5 CH628889A5 CH27378A CH27378A CH628889A5 CH 628889 A5 CH628889 A5 CH 628889A5 CH 27378 A CH27378 A CH 27378A CH 27378 A CH27378 A CH 27378A CH 628889 A5 CH628889 A5 CH 628889A5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Description
L'invention concerne également un procédé pour l'obtention du (j) composé de formule I à partir d'un ester de l'acide dibromopropioni-que. The invention also relates to a process for obtaining (j) compound of formula I from an ester of dibromopropionic acid.
io Les esters de l'acide dibromopropionique, et notamment l'ester éthylique de l'acide dibromopropionique, sont des composés connus, dont la préparation peut être effectuée par des procédés à la portée de l'homme de l'art. The esters of dibromopropionic acid, and in particular the ethyl ester of dibromopropionic acid, are known compounds, the preparation of which can be carried out by methods within the reach of those skilled in the art.
Dans une première étape, on traite un ester 2,3-dibromopropionique par de l'isobutanol en présence de sodium. In a first step, a 2,3-dibromopropionic ester is treated with isobutanol in the presence of sodium.
Dans une deuxième étape, on traite par un excès de Pyrrolidine le produit de l'étape 1. In a second step, the product from step 1 is treated with an excess of Pyrrolidine.
Dans une troisième étape, on traite par du bromure de N-benzyl-aniline-magnésium l'ester d'acide 3-isobutoxy-2-pyrrolidino-propionique obtenu dans l'étape 2. In a third step, the 3-isobutoxy-2-pyrrolidino-propionic acid ester obtained in step 2 is treated with N-benzyl-aniline-magnesium bromide.
Dans une quatrième étape, on réduit, notamment par du LiAlH4 dans de l'éther, la fonction amide du produit de l'étape 3, obtenant ainsi la 3-isobutoxy-2-pyrrolidino-N-phényl-N-benzylpropylamine. In a fourth step, the amide function of the product of step 3 is reduced, in particular with LiAlH4 in ether, thereby obtaining 3-isobutoxy-2-pyrrolidino-N-phenyl-N-benzylpropylamine.
Si on le désire, on peut, par traitement avec de l'acide chlorhydri-que dilué, obtenir le monochlorhydrate-monohydrate de ce dernier composé. If desired, it is possible, by treatment with dilute hydrochloric acid, to obtain the monohydrochloride-monohydrate of the latter compound.
D'une manière générale, les sels d'addition du composé de formule I avec des acides organiques ou inorganiques pharmaceutiquement acceptables font également partie de l'invention. In general, the addition salts of the compound of formula I with pharmaceutically acceptable organic or inorganic acids are also part of the invention.
A titre d'exemple, on décrit ci-dessous, après en avoir rappelé brièvement le schéma réactionnel, la synthèse du composé selon la présente invention. By way of example, the synthesis of the compound according to the present invention is described below, after having briefly recalled the reaction scheme.
35 35
La présente invention concerne une nouvelle propylamine substituée et un procédé pour son obtention, ainsi que son utilisation en thérapeutique, notamment dans le domaine cardio-vasculaire, en particulier pour le traitement de l'angor. 40 The present invention relates to a new substituted propylamine and a process for obtaining it, as well as its use in therapy, in particular in the cardiovascular field, in particular for the treatment of angina. 40
Le composé selon l'invention est la 3-isobutoxy-2-pyrrolidino-N-phényl-N-benzylpropylamine, répondant à la formule générale: The compound according to the invention is 3-isobutoxy-2-pyrrolidino-N-phenyl-N-benzylpropylamine, corresponding to the general formula:
lre étape: 1st step:
Br - ch2 - ch - c02c2h5 Br Br - ch2 - ch - c02c2h5 Br
Na ch, Na ch,
CH, CH,
\ \
i i
/ /
ch-ch2oh ch3 ch-ch2oh ch3
ch, ch,
CH3 CH3
\ \
/ /
ch-ch2-o-ch2-ch-ch2-n ch-ch2-o-ch2-ch-ch2-n
45 45
ch ch
\ / \ /
ch-ch2-o-ch2-ch-co2c2h5 ch-ch2-o-ch2-ch-co2c2h5
Br Br
(D (D
2e étape: 2nd step:
ch ch. ch ch.
CH CH
\ / \ /
ch - ch2 - o - ch2 - ch - c02c2h, ch - ch2 - o - ch2 - ch - c02c2h,
CH, CH,
Br toluène Br toluene
Les caractéristiques physico-chimiques du composé de formule I sont indiquées plus loin. The physicochemical characteristics of the compound of formula I are indicated below.
Ce nouveau composé trouve son application à titre de médicament, et notamment à titre de principe actif dans le traitement des affections cardio-vasculaires, en particulier dans le traitement de l'angor. This new compound finds its application as a medicament, and in particular as an active principle in the treatment of cardiovascular affections, in particular in the treatment of angina.
On connaît déjà des composés répondant à la formule générale: 3e étape: Ar—CH, Compounds corresponding to the general formula are already known: 3rd step: Ar — CH,
ch. ch.
\ / \ /
ch- ch, - o -ch, -ch- c02c2h5 ch- ch, - o -ch, -ch- c02c2h5
M M
Ar' Ar '
\ / \ /
ch, ch,
n-ch2-ch2-a, n-ch2-ch2-a,
\ \
65 / 65 /
ch3 ch3
ch-ch2-o-ch2-ch-co2c2h5 ch-ch2-o-ch2-ch-co2c2h5
où A représente un reste aminé, tandis que Ar et Ar' représentent chacun un reste aromatique. Mais ces composés, qui sont les plus where A represents an amino residue, while Ar and Ar 'each represent an aromatic residue. But these compounds, which are the most
■N, ■ N,
3 3
628889 628889
<0>n-c„;-<0> <0> n-c „; - <0>
MgX MgX
éther ether
CH\ CH \
,ch-ch2-o-ch2-ch-co-n / Il ch, ^ c^sy/\ , ch-ch2-o-ch2-ch-co-n / Il ch, ^ c ^ sy / \
\OI \ OI
(II) N/ (II) N /
4' étape: 4th step:
Réduction de la fonction amide du composé II par LiAlH4 dans l'éther, pour donner le composé de formule I. Reduction of the amide function of compound II by LiAlH4 in ether, to give the compound of formula I.
On reprend maintenant plus en détail chacune de ces étapes. We now repeat each of these steps in more detail.
1" étape: 1 "step:
On a introduit 5,1 g de Na en morceaux dans 150 ml d'isobuta-nol. On a agité, en chauffant si nécessaire, jusqu'à dissolution. 5.1 g of Na in pieces were introduced into 150 ml of isobuta-nol. Stirred, heating if necessary, until dissolved.
On a ensuite refroidi à — 5°C, afin d'ajouter goutte à goutte et à cette température 0,2 mol (52 g) d'ester éthylique de l'acide dibromopropionique: Then cooled to −5 ° C., in order to add dropwise and at this temperature 0.2 mol (52 g) of ethyl ester of dibromopropionic acid:
(Br- CH2 - CH - C02C2H5). (Br- CH2 - CH - C02C2H5).
Br Br
On a agité pendant 2 à 3 h à température ambiante. The mixture was stirred for 2 to 3 h at room temperature.
On a filtré le sel NaBr formé en cours de réaction. On a évaporé l'isobutanol. On a repris le résidu par 200 ml de CHC13 et on a lavé à l'eau. The NaBr salt formed during the reaction was filtered. The isobutanol was evaporated. The residue was taken up in 200 ml of CHCl3 and washed with water.
On a séché la phase organique sur du sulfate de sodium et on a concentré sous vide. The organic phase was dried over sodium sulfate and concentrated in vacuo.
Après distillation, on a obtenu 32 g de produit ayant pour masse moléculaire M = 253, et pour point d'ébullition sous 15 mm de mercure Ej 5 = 120°C, de formule: After distillation, 32 g of product were obtained having the molecular mass M = 253, and the boiling point under 15 mm of mercury Ej 5 = 120 ° C, of formula:
ch, ch,
CH., CH.,
\ / \ /
ch-ch2-o-ch. ch-ch2-o-ch.
-ch-co2c2h5. -ch-co2c2h5.
Br Br
2' étape: 2nd step:
On a ajouté un excès triple de Pyrrolidine au produit de l'étape 1, en solution dans le toluène à 25° C. A triple excess of Pyrrolidine was added to the product of step 1, dissolved in toluene at 25 ° C.
On a chauffé pendant 2 à 3 h. It was heated for 2 to 3 hours.
On a évaporé le toluène sous vide, on a repris le résidu par CHCI3, on a lavé la phase organique à l'eau, on a séché sur du sulfate de sodium et on a évaporé. The toluene was evaporated in vacuo, the residue was taken up in CHCl 3, the organic phase was washed with water, dried over sodium sulfate and evaporated.
Après distillation du produit brut, on a obtenu le produit de formule: After distillation of the crude product, the product of formula was obtained:
CH, CH,
\ / \ /
CH, CH,
M = 243 M = 243
EIS = 130°C;ng ch - ch2 - o - ch2 - ch - c02c2h5 EIS = 130 ° C; ng ch - ch2 - o - ch2 - ch - c02c2h5
1,4485. 1.4485.
3e étape: 3rd step:
A 0,15 atome-gramme de magnésium dans 10 ml d'éther anhydre, on a ajouté goutte à goutte 0,15 mol de bromure d'éthyle. Après dissolution totale du magnésium, on a ajouté goutte à goutte 0,15 mol de N-benzylaniline dans 50 ml d'éther. On a maintenu le reflux pendant 1 à 2 h. On a ensuite ajouté 0,1 mol de l'aminoester obtenu dans l'étape 2 et on a porté à reflux pendant 6 h. Après hydrolyse par 10 ml d'eau saturée en NH4CI, on a filtré et décanté. On a lavé le précipité par de l'éther et on a ensuite séché les phases éthérées sur du sulfate de sodium et on a concentré sous vide. To 0.15 gram atom of magnesium in 10 ml of anhydrous ether, 0.15 mol of ethyl bromide was added dropwise. After the magnesium had completely dissolved, 0.15 mol of N-benzylaniline in 50 ml of ether was added dropwise. The reflux was maintained for 1 to 2 h. Then 0.1 mol of the aminoester obtained in step 2 was added and the mixture was brought to reflux for 6 h. After hydrolysis with 10 ml of water saturated with NH4Cl, it was filtered and decanted. The precipitate was washed with ether and the ethereal phases were then dried over sodium sulfate and concentrated in vacuo.
On a distillé l'extrait sec et on a obtenu le composé de formule: The dry extract was distilled and the compound of formula:
ch, ch,
CH, CH,
\ / \ /
ch-ch2-o-ch2-ch-co-n n ch-ch2-o-ch2-ch-co-n n
E05 = 182°C M = 380. E05 = 182 ° C M = 380.
4e étape: 4th step:
20 A 0,05 mol d'hydrure de lithium aluminium dans 200 ml d'éther anhydre, on a ajouté 0,025 mol de l'amide obtenu dans l'étape 3. To 0.05 mol of lithium aluminum hydride in 200 ml of anhydrous ether, 0.025 mol of the amide obtained in step 3 was added.
On a poursuivi la réaction pendant 30 h après avoir chauffé à reflux. The reaction was continued for 30 h after heating to reflux.
Après hydrolyse à 0°C par un minimum d'eau saturée en NH4C1, 25 on a filtré et on a décanté la phase éthérée, on a séché sur du sulfate de sodium et on a concentré sous vide. La distillation de l'extrait sec a donné le produit de formule I. After hydrolysis at 0 ° C with a minimum of water saturated with NH4Cl, it was filtered and the ethereal phase was decanted, dried over sodium sulfate and concentrated in vacuo. The distillation of the dry extract gave the product of formula I.
(E0i5 = 192°C.) (E0i5 = 192 ° C.)
30 Préparation du chlorhydrate: 30 Preparation of the hydrochloride:
On a traité le produit I sous forme de base, dans l'eau, par de l'acide chlorhydrique dilué, jusqu'à acidité. The product I was treated as a base, in water, with dilute hydrochloric acid, until acidity.
On a filtré le précipité, on a lavé à l'eau et on a séché. The precipitate was filtered, washed with water and dried.
Le sel obtenu était un monochlorhydrate-monohydrate de for-35 mule brute C24H34N20, HCl, H20. The salt obtained was a crude monohydrochloride monohydrate of formula C24H34N20, HCl, H2O.
M = 421,03. M = 421.03.
Point de fusion, F = 91 ± 2°C. Melting point, F = 91 ± 2 ° C.
Analyse élémentaire: Elementary analysis:
m Calculé: C 68,46 H 8,86 N6,65 Cl 8,42% m Calculated: C 68.46 H 8.86 N6.65 Cl 8.42%
Trouvé: C 68,39 H 8,82 N6,72 Cl 8,36% Found: C 68.39 H 8.82 N 6.72 Cl 8.36%
Propriétés pharmacologiques et applications thérapeutiques: Pharmacological properties and therapeutic applications:
Les études effectuées dans le domaine cardio-vasculaire ont 45 montré que le composé de l'invention avait de remarquables propriétés pharmacologiques qu'on peut expliquer par le fait qu'il s'est avéré posséder, en plus des propriétés communes aux coronaro-dilatateurs, des propriétés ß-frenatrices, sans toutefois posséder les effets indésirables des ß-bloquants, notamment au niveau pulmonaire et au 50 niveau de la contractilité myocardique. The studies carried out in the cardiovascular field have shown that the compound of the invention has remarkable pharmacological properties which can be explained by the fact that it has been found to possess, in addition to the properties common to coronary dilators. , ß-frenatory properties, without however possessing the undesirable effects of ß-blockers, in particular on the pulmonary level and on the level of myocardial contractility.
Grâce à ces propriétés, qui sont illustrées ci-après par quelques tests pharmacologiques, une application thérapeutique du composé de l'invention réside dans le traitement de l'angor. Thanks to these properties, which are illustrated below by a few pharmacological tests, a therapeutic application of the compound of the invention lies in the treatment of angina.
On a mesuré la toxicité aiguë DL50 du composé de l'invention 55 chez la souris: The acute LD50 toxicity of the compound of invention 55 was measured in mice:
— par voie orale, DL50 = 1955 mg/kg (±200), - by oral route, LD50 = 1955 mg / kg (± 200),
— par voie intraveineuse, DL50 = 23,5 mg/kg(± 1,3). Administré en une seule fois (1,25 mg/kg i.V.), le composé de l'invention a provoqué chez le chien anesthésié, dont le thorax avait 60 été ouvert pour mettre en place des appareils de mesure, les variations de paramètres hémodynamiques suivantes (moyenne sur 6 animaux): - intravenously, LD50 = 23.5 mg / kg (± 1.3). Administered at one time (1.25 mg / kg iV), the compound of the invention caused, in the anesthetized dog, the chest of which had been opened to set up measuring devices, the following variations in hemodynamic parameters (average on 6 animals):
— augmentation du débit coronaire sinusal: +49,7% ±16%, - increased sinus coronary flow: + 49.7% ± 16%,
— augmentation de la Pv02 coronaire sinusale: +77,4% 65 ±17,7%, - increase in coronary sinus Pv02: + 77.4% 65 ± 17.7%,
— légère augmentation de l'amplitude des contractions du ventricule droit : +11,8 % ± 2%, - slight increase in the amplitude of the contractions of the right ventricle: + 11.8% ± 2%,
— ralentissement de la fréquence cardiaque: —13,6% ±2,6%, - slower heart rate: —13.6% ± 2.6%,
628889 628889
4 4
— abaissement de la pression artérielle systémique: —20,1% ± 2,4%, pendant un court laps de temps. - lowering of systemic blood pressure: —20.1% ± 2.4%, for a short period of time.
On a approfondi cette étude par une expérimentation sur des chiens consistant à stimuler les récepteurs cardio-vasculaires ß-adre-nergiques par administration d'isoprénaline, et à antagoniser les effets tachycardisant, hypotenseur et inotrope positif de ce profit par administration en perfusion continue (0,75 mg/kg/min) du produit de l'invention et, d'autre part, de l'amiodarone pris pour référence. Le tableau ci-après donne les pourcentages d'inhibition observés lorsque 5 la quantité totale administrée avait atteint 16,875 mg/kg. We deepened this study by an experiment on dogs consisting in stimulating the cardiovascular ß-adrenergic receptors by administration of isoprenaline, and in antagonizing the tachycardising, hypotensive and inotropic effects of this profit by administration in continuous infusion ( 0.75 mg / kg / min) of the product of the invention and, on the other hand, of the amiodarone taken for reference. The table below gives the percentages of inhibition observed when the total amount administered had reached 16.875 mg / kg.
Pourcentage d'inhibition Inhibition percentage
Composé administré ' - Administered compound '-
Tachycardie Tachycardia
Hypotension diastolique Diastolic hypotension
Effet inotrope positif Positive inotropic effect
Composé de l'invention Compound of the invention
76,4 ± 5,9 (significatif à l%o) 76.4 ± 5.9 (significant at 1% o)
60,9 ± 8,7 (significatif à 1 %) 60.9 ± 8.7 (significant at 1%)
38,5 ± 7,4 (significatif à 1 %) 38.5 ± 7.4 (significant at 1%)
Amiodarone Amiodarone
73,1 ± 4,7 (significatif à l%o) 73.1 ± 4.7 (significant at 1% o)
16,2 + 6,1 (N.S.) 16.2 + 6.1 (N.S.)
12,5 + 23,2 (N.S.) 12.5 + 23.2 (N.S.)
On constate que le composé de l'invention est plus actif que l'amiodarone sur deux des trois paramètres retenus. It is found that the compound of the invention is more active than amiodarone on two of the three parameters selected.
De même, dans le test modifié de Bergamashi et Longoni [«Am. Heart. J.», 86(3), 385-394 (1973)], concernant le déclenchement d'une crise d'angor chez le coronarien par stress émotionnel, on a constaté que l'indice de Robinson [«Chartier, Antianginal Drug», p. 29, Springer Verlag (1971)] était plus favorable pour le composé de l'invention que pour l'amiodarone. Similarly, in the modified test of Bergamashi and Longoni ["Am. Heart. J. ", 86 (3), 385-394 (1973)], concerning the triggering of an angina attack in the coronary by emotional stress, it was found that the Robinson index [" Chartier, Antianginal Drug " , p. 29, Springer Verlag (1971)] was more favorable for the compound of the invention than for amiodarone.
Au niveau pulmonaire, on a observé que le composé de l'invention était sans action sur le bronchospasme histaminique chez le cobaye, alors que le propanolol et le practolol, ß-bloquants bien connus, potentialisent ce bronchospasme. At the pulmonary level, it has been observed that the compound of the invention has no action on the histamine bronchospasm in guinea pigs, while propanolol and practolol, well-known β-blockers, potentiate this bronchospasm.
Exemple de présentation galênique et de posologie: Example of galenic presentation and dosage:
20 Comprimés à 100 mg Composé de l'invention Silice colloïdale Cellulose microcristalline Amidon de blé Polyvinylpyrrolidone (PVP) Méthylcellulose Talc officinal Stéarate de magnésium 20 100 mg tablets Compound of the invention Colloidal silica Microcrystalline cellulose Wheat starch Polyvinylpyrrolidone (PVP) Methylcellulose Talc officinal Magnesium stearate
100 mg 100 mg
8 mg 85 mg 8 mg 85 mg
110 mg 10 mg 110 mg 10 mg
9 mg 15mg 9 mg 15mg
3 mg 3 mg
340 mg 340 mg
On mélange le composé de l'invention et les trois premiers exci- Posologie: pients,puisonmouilleavecunempoisdePVPdansdel'éthanolà75%. 1 à 3 comprimés dosés à lOOmg/d. The compound of the invention and the first three excipients are mixed: dosages, then wetted with a paste of PVP in 75% ethanol. 1 to 3 tablets dosed at 100 mg / d.
On granule et on sèche, puis on introduit les trois derniers excipients, on 35 De manière générale, le composé de l'invention, associé aux exci-mélange et on peut alors comprimer la poudre obtenue pour obtenir des pients et/ou supports habituels, peut être administré par voie orale ou comprimés de poids moyen 340 mg. intraveineuse à une dose quotidienne del00à300 mg environ. The last three excipients are granulated and dried, the compound of the invention is generally combined with the exci-mix and the powder obtained can then be compressed to obtain the usual pients and / or supports, can be administered orally or medium weight tablets 340 mg. intravenously at a daily dose of approximately 300 to 300 mg.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7702058A FR2378024A1 (en) | 1977-01-25 | 1977-01-25 | NEW SUBSTITUTED PROPYLAMINE, OBTAINING AND APPLYING |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH628889A5 true CH628889A5 (en) | 1982-03-31 |
Family
ID=9185890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH27378A CH628889A5 (en) | 1977-01-25 | 1978-01-11 | Substituted propylamine, process for its preparation and pharmaceutical composition containing this compound |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5392764A (en) |
| AU (1) | AU516479B2 (en) |
| BE (1) | BE863214A (en) |
| CH (1) | CH628889A5 (en) |
| DE (1) | DE2802864C2 (en) |
| ES (1) | ES466237A1 (en) |
| FR (1) | FR2378024A1 (en) |
| GB (1) | GB1595031A (en) |
| IL (1) | IL53816A0 (en) |
| NL (1) | NL189258C (en) |
| PT (1) | PT67556B (en) |
| ZA (1) | ZA78426B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3278160D1 (en) * | 1981-12-28 | 1988-04-07 | Carter Wallace | Process for the preparation of b-û(2-methylpropoxy)-methyl¨-n-phenyl-n-(phenylmethyl)-1-pyrrolidineethanamine |
| DK156396C (en) * | 1983-09-27 | 1990-01-08 | Cerm Cent Europ Rech Mauvernay | 2- (N-PYRROLIDINO) -3-ISOBUTOXY-N-SUBSTITUTED PHENYL-N-BENZYL-PROPYLAMINE COMPOUNDS AND PHARMACEUTICAL AGENTS CONTAINING THESE |
| EP0146159B1 (en) * | 1983-11-11 | 1988-01-13 | Akzo N.V. | Ether of n-propanolamine derivative |
| GB8330197D0 (en) * | 1983-11-11 | 1983-12-21 | Akzo Nv | Ether of n-propanolamine derivative |
| FR2558161B1 (en) * | 1984-01-18 | 1987-01-23 | Cerm Cent Europ Rech Mauvernay | 3-ALKOXY 2- (N-PYRROLIDINO) N-FURYLMETHYL OR N-THIENYLMETHYL N-PYRIDYL PROPYLAMINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2558160B1 (en) * | 1984-01-18 | 1986-05-30 | Cerm Cent Europ Rech Mauvernay | 3-ALKOXY 2- (N-PYRROLIDINO) -N-PYRIMIDINYL OR -PYRAZINYL PROPYLAMINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2558159B1 (en) * | 1984-01-18 | 1986-06-13 | Cerm Cent Europ Rech Mauvernay | 3-ALKOXY 2- (N-PYRROLIDINO) -N-PYRIDYL-N-ARYLMETHYL-PROPYLAMINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| DE3726632A1 (en) * | 1987-08-11 | 1989-05-18 | Boehringer Mannheim Gmbh | 1,2-DIAMINO COMPOUNDS, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DE3726633A1 (en) * | 1987-08-11 | 1989-02-23 | Boehringer Mannheim Gmbh | NEW 1,2-DIAMINO COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| JP2678758B2 (en) * | 1988-02-16 | 1997-11-17 | 興和株式会社 | Novel propane derivative |
| WO2016098128A1 (en) * | 2014-12-16 | 2016-06-23 | Council Of Scientific & Industrial Research | Process for the preparation of bepridil |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE795735A (en) * | 1972-03-06 | 1973-06-18 | Cerm Cent Europ Rech Mauvernay | NEW ETHYLENEDIAMINES SUBSTITUTES WITH CARDIOVASCULAR ACTIVITY |
-
1977
- 1977-01-25 FR FR7702058A patent/FR2378024A1/en active Granted
- 1977-10-03 JP JP11797777A patent/JPS5392764A/en active Granted
-
1978
- 1978-01-11 CH CH27378A patent/CH628889A5/en not_active IP Right Cessation
- 1978-01-13 GB GB1506/78A patent/GB1595031A/en not_active Expired
- 1978-01-16 IL IL53816A patent/IL53816A0/en not_active IP Right Cessation
- 1978-01-20 NL NLAANVRAGE7800753,A patent/NL189258C/en not_active IP Right Cessation
- 1978-01-20 PT PT67556A patent/PT67556B/en unknown
- 1978-01-21 ES ES466237A patent/ES466237A1/en not_active Expired
- 1978-01-23 BE BE184554A patent/BE863214A/en not_active IP Right Cessation
- 1978-01-23 AU AU32660/78A patent/AU516479B2/en not_active Expired
- 1978-01-24 ZA ZA00780426A patent/ZA78426B/en unknown
- 1978-01-24 DE DE2802864A patent/DE2802864C2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BE863214A (en) | 1978-07-24 |
| FR2378024A1 (en) | 1978-08-18 |
| GB1595031A (en) | 1981-08-05 |
| JPS5429493B2 (en) | 1979-09-25 |
| DE2802864A1 (en) | 1978-07-27 |
| JPS5392764A (en) | 1978-08-15 |
| IL53816A0 (en) | 1978-04-30 |
| DE2802864C2 (en) | 1982-12-09 |
| NL189258B (en) | 1992-09-16 |
| NL189258C (en) | 1993-02-16 |
| ZA78426B (en) | 1979-01-31 |
| PT67556A (en) | 1978-02-01 |
| NL7800753A (en) | 1978-07-27 |
| AU516479B2 (en) | 1981-06-04 |
| PT67556B (en) | 1979-06-18 |
| AU3266078A (en) | 1979-08-02 |
| ES466237A1 (en) | 1978-10-16 |
| FR2378024B1 (en) | 1979-05-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PFA | Name/firm changed |
Owner name: RIOM LABORATOIRES-C.E.R.M. |
|
| PL | Patent ceased |