WO2000004015A1 - 1-4-dihydropyridines with benzodioxo carbonyl group as calcium blockers - Google Patents

1-4-dihydropyridines with benzodioxo carbonyl group as calcium blockers Download PDF

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Publication number
WO2000004015A1
WO2000004015A1 PCT/FR1999/001749 FR9901749W WO0004015A1 WO 2000004015 A1 WO2000004015 A1 WO 2000004015A1 FR 9901749 W FR9901749 W FR 9901749W WO 0004015 A1 WO0004015 A1 WO 0004015A1
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mult
benzodioxane
methoxycarbonyl
nitrophenyl
compound
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PCT/FR1999/001749
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French (fr)
Inventor
Gérard DURET
Gérard GLAUERT
Marguerite Henry
André PESSONNIER
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Laboratoire L. Lafon
PESSONNIER, Alain, Marcel
PESSONNIER, Jeanne
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Priority to AU46292/99A priority Critical patent/AU4629299A/en
Publication of WO2000004015A1 publication Critical patent/WO2000004015A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel 1,4-dihydropyridine derivatives which are calcium channel blockers useful in therapy in the treatment of angina.
  • the triple combination beta blocker + nitro derivative (trinitrine or isosorbide dinitrate or isosorbide mononitrate) + nifedipine (first generation calcium antagonist) has been shown to be able to control attacks of unstable angina, at least at short term, in 80% of cases.
  • this triple association did not bring, in the medium term, the hoped-for progress: indeed, after one year, nearly 30% of angina patients are victims of a very serious accident (death, myocardial infarction or relapse of stable angina).
  • death myocardial infarction or relapse of stable angina
  • calcium channel blockers should remain the effective therapy for stable angina and unstable angina and especially the treatment of choice for angina patients who do not tolerate ⁇ -adrenergic antagonists and nitrates.
  • 1,4-dihydropyridine have already been described, described in addition to nifedipine.
  • esters of 2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4- have already been described.
  • A represents a group chosen from the groups of formula:
  • R 2 represents a group chosen from the 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl groups.
  • the present invention aims to provide new 1,4-dihydropyridine derivatives which are calcium channel blockers and which have improved properties compared to those of compounds corresponding to the formula described in EP-A-0 494 816.
  • the “addition salts with pharmaceutically acceptable acids” designate the salts which give the biological properties of the free bases, without having an undesirable effect.
  • These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
  • the compounds of formula I can be obtained by the reaction of the acid of formula:
  • addition salts are obtained conventionally by reaction of the compound of formula I with a pharmaceutically acceptable acid in an appropriate solvent.
  • the bases can be obtained from the addition salts by treatment with a strong base.
  • the acid of formula II can be prepared as described in EP-A-0 494 816 or as described in EP-A-0 680 952.
  • the alcohols of formula III can be obtained by reaction of a compound of formula: with a chlorine derivative of formula
  • the reaction medium is diluted with 800 ml of dichloromethane and, in 15 min, 1 mol of 1- (1, 4-benzodioxane-6-yl) -4- (3-hydroxypiperidino) -1 -butanone is introduced (fractions) 21-) in the form of the hydrochloride and then stirred under a stream of nitrogen for one hour.
  • the reaction medium is washed successively with water and 2N sodium hydroxide, the organic phase, dried over dry sodium sulphate and the solvent evaporated to give an orange oil. After purification of this product is obtained by passing through a silica column and eluting with the mixture [dichloromethane-99 / isopropanol-1], 0.57 mole of a yellow powder.
  • the affinity of the compounds for the DHP sites of the cardiac ventricles is measured from a membrane preparation of the receptors, preparation obtained after dissection of the ventricles, homogenization then double centrifugation (48000 g; 15 min., 4 ° C).
  • the intensity of the binding to membrane receptors is defined by the concentration (molar) of the test compound which is necessary to displace 50% of the amount of the specific ligand (+) [ 3 H] -PN 200-110 previously linked to the sites DHH. This concentration is the Cl 50 concentration.
  • the results expressed as Cl 50 are given in the summary table of the pharmacological and hemodynamic results.
  • the technique used uses a ring of arterial vascular tissue taken from the thoracic aorta of the rat and then kept alive in aerated Krebs bicarbonate buffer, and subjected to an initial tension of 2.0 g.
  • the introduction of potassium chloride (in a volume of 300 ⁇ l) at the concentration of 5.10 2 mol.l "1 into the Krebs buffer bath generates a sustained contraction whose amplitude (isometric tension) is antagonized by the addition of a solution of the studied compound of increasing concentrations, each addition being carried out every 5 min, then the molar concentration of the studied compound is calculated which decreases by 50% the maximum contraction observed under KCI This concentration is the inhibitory concentration 50% (or Cl 50 ).
  • the animals receive increasing doses of each compound studied by the IV route every 30 min.
  • the effect on coronary flow is evaluated by its maximum percentage change after each dose.
  • the minimum active dose on coronary flow is the dose which increases the basal coronary onset by 50%.
  • the therapeutic margin is defined as the ratio between the minimum arrhythmogenic dose and the dose which increases basal coronary flow (DC) by 50% (this dose is called “minimum active dose on coronary flow”).
  • the minimum arrhythmogenic doses by IV route were determined for each compound in the anesthetized dog (see summary table) and the arrhythmogenic dose / active dose ratio on the coronary flow rate (therapeutic margin) was determined.
  • the compounds of the invention allow an effective treatment of stable angina since they improve the supply of oxygen to the myocardium (by the specific increase in coronary flow), reduce the myocardial consumption of oxygen by reducing contractility. that they induce. These compounds therefore represent a significant therapeutic advance thanks to better control of the factors which exacerbate the ischemic process which they induce.
  • the present invention therefore also relates to pharmaceutical compositions comprising, as active principles, one of the compounds of formula I or one of their pharmaceutically acceptable salts.
  • the active substance is mixed with one or more pharmaceutical excipients, the nature and the relative proportion of which depends on the route of administration chosen.
  • the compounds of formula I can be used in solutes allowing an intravenous infusion at constant flow or combining a loading dose (accelerated flow or bolus) and a maintenance dose delivered for several hours under electrocardiographic control (Holter recording of blood pressure and ECG).
  • the compounds of formula I can be used at variable doses depending on the severity of the episode of angina pectoris, the presence or not of an attack of unstable angina or simultaneous vasospastic angina pectoris.
  • the effective dosage may be between 0.01 and 1.0 mg / kg / day as a continuous intravenous infusion, preferably being a dose of the order of 0.02 to 0.5 mg / kg / day.
  • the intravenous infusion may be continued for a few days at a dose of the order of 0.05 to 0.3 mg / kg / day.
  • the doses will be chosen between 0.05 and 2.0 mg / kg / day.
  • the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers compatible with human therapy.
  • suitable unit dosage forms include oral forms such as tablets, possibly scored or capsules and intravenous dosage forms allowing the use of a syringe or an electric infusion pump with controlled flow rates.
  • a wetting agent such as sodium lauryl sulfate
  • a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
  • a preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
  • the active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives, the modification of dissolution kinetics of which will make it possible to obtain a "delay" effect (prolongation of the duration of action) desired sustained release pharmaceutical forms.
  • the active principle can also be presented in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ - cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ - cyclodextrin or methyl- ⁇ -cyclodextrin.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or polyethylene glycol.
  • a cosolvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as Tween® 80.

Abstract

The invention concerns compounds of formula (I) wherein: n = 1 or 2; m = 3 or 4; p = 1 or 2; and their addition salts with pharmaceutically acceptable acids.

Description

-4-DIHYDR0PYRIDINES A GROUPE CARBONYL BENZODIOXO COMME INHIBITEURS CALCIQUES-4-DIHYDR0PYRIDINES WITH CARBONYL BENZODIOXO GROUP AS CALCIUM INHIBITORS
La présente invention concerne de nouveaux dérivés de la 1 ,4- dihydropyridine qui sont des inhibiteurs calciques utilisables en thérapeutique dans le traitement de l'angor.The present invention relates to novel 1,4-dihydropyridine derivatives which are calcium channel blockers useful in therapy in the treatment of angina.
Avant 1970, le traitement médical de l'angor stable reposait uniquement sur l'association alitement et trinitrine. De ce fait, quatre mois après le déclenchement de la crise, la mortalité était de 17 % et le taux d'infarctus du myocarde de 40 %. C'est l'invention du blocage des récepteurs β-adrénergiques (souvent associé au traitement anticoagulant) qui a permis, à partir de 1970, de faire baisser la morbi-mortalité (ex : à 1 an, taux de mortalité abaissé à 8 - 18 % ; fréquence de l'infarctus du myocarde abaissé à 14 - 22 %). C'est ensuite l'introduction des bloqueurs des canaux calciques qui est à l'origine des progrès thérapeutiques que nous connaissons aujourd'hui. En effet, la triple association bêta bloquant + dérivé nitré (trinitrine ou dinitrate d'isosorbide ou mononitrate d'isosorbide) + nifédipine (antagoniste calcique de première génération) s'est avérée capable de maîtriser les crises d'angor instable, au moins à court terme, dans 80 % des cas. Cependant, cette triple association n'a pas apporté, à moyen terme, le progrès espéré : en effet, au bout d'un an, près de 30 % des patients angoreux sont victimes d'un accident très grave (décès, infarctus du myocarde ou récidive d'angor stable). Aujourd'hui, il s'avère encore nécessaire d'améliorer le traitement de la phase ischémique de l'angor stable. A cet égard, Il est important de pouvoir mieux diminuer la consommation d'oxygène myocardique tout en obtenant une vasodilatation coronaire et une réduction des résistances vasculaires périphériques, sans tachycardie réflexe et, mieux encore, associée à une réduction contrôlée de la fréquence cardiaque et de la postcharge.Before 1970, medical treatment for stable angina was based solely on the combination of bed rest and trinitrine. As a result, four months after the onset of the crisis, mortality was 17% and the rate of myocardial infarction 40%. It was the invention of the blocking of β-adrenergic receptors (often associated with anticoagulant treatment) which made it possible, from 1970, to lower morbidity and mortality (eg at 1 year, mortality rate lowered to 8 - 18%; frequency of myocardial infarction lowered to 14 - 22%). It is then the introduction of calcium channel blockers which is at the origin of the therapeutic progress that we know today. Indeed, the triple combination beta blocker + nitro derivative (trinitrine or isosorbide dinitrate or isosorbide mononitrate) + nifedipine (first generation calcium antagonist) has been shown to be able to control attacks of unstable angina, at least at short term, in 80% of cases. However, this triple association did not bring, in the medium term, the hoped-for progress: indeed, after one year, nearly 30% of angina patients are victims of a very serious accident (death, myocardial infarction or relapse of stable angina). Today, it is still necessary to improve the treatment of the ischemic phase of stable angina. In this regard, it is important to be able to better reduce myocardial oxygen consumption while obtaining coronary vasodilation and a reduction in peripheral vascular resistance, without reflex tachycardia and, better still, associated with a controlled reduction in heart rate and afterload.
Dans ce cadre, les inhibiteurs calciques devraient rester la thérapeutique efficace de l'angor stable et de l'angor instable et surtout le traitement de choix pour les patients angoreux qui ne tolèrent pas les antagonistes β-adrénergiques et les dérivés nitrés. Différents dérivés de 1 ,4-dihydropyridine ont déjà été décrits décrits en plus de la nifédipine. Ainsi, notamment, dans FR 2 218 107, on a déjà décrit différents esters de l'acide 2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydropyridine-3-carboxylique et notamment l'ester 2[méthyl(phényl-méthyl) aminojéthylique connu sous le nom de nicardipine.In this context, calcium channel blockers should remain the effective therapy for stable angina and unstable angina and especially the treatment of choice for angina patients who do not tolerate β-adrenergic antagonists and nitrates. Various derivatives of 1,4-dihydropyridine have already been described, described in addition to nifedipine. Thus, in particular, in FR 2 218 107, various esters of 2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4- have already been described. dihydropyridine-3-carboxylic acid and in particular ester 2 [methyl (phenyl-methyl) aminojethyl known under the name of nicardipine.
On a par ailleurs décrit dans EP-A-0494 816 d'autres dérivés de 1 ,4- dihydropyridine présentant en position 3 une chaîne du type :We have also described in EP-A-0494 816 other derivatives of 1,4-dihydropyridine having in position 3 a chain of the type:
-COO - A - (CH2)3 - C - R2 -COO - A - (CH 2 ) 3 - C - R 2
O dans laquelle :O in which:
A représente un groupe choisi parmi les groupes de formule:A represents a group chosen from the groups of formula:
Figure imgf000004_0001
et R2 représente un groupe choisi parmi les groupes 2,4,6-triméthoxyphényle, 2- thiényle et phényle.
Figure imgf000004_0001
and R 2 represents a group chosen from the 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl groups.
La présente invention vise à fournir de nouveaux dérivés de 1 ,4- dihydropyridine qui sont des inhibiteurs calciques et qui présentent des propriétés améliorées par rapport à celles de composés répondant à la formule décrite dans EP-A-0 494 816.The present invention aims to provide new 1,4-dihydropyridine derivatives which are calcium channel blockers and which have improved properties compared to those of compounds corresponding to the formula described in EP-A-0 494 816.
La présente invention a ainsi pour objet des composés de formule :The subject of the present invention is therefore compounds of formula:
Figure imgf000004_0002
Figure imgf000004_0002
dans laquelle : n = 1 ou 2 m = 3 ou 4 p = 1 ou 2 et leurs sels d'addition avec des acides pharmaceutiquement acceptables. Les « sels d'addition avec des acides pharmaceutiquement acceptables » désignent les sels qui donnent les propriétés biologiques des bases libres, sans avoir d'effet indésirable. Ces sels peuvent être notamment ceux formés avec des acides minéraux, tels que l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique, l'acide nitrique, l'acide phosphorique; des sels métalliques acides, tels que l'orthophosphate disodique et le sulfate monopotassique, et des acides organiques.in which: n = 1 or 2 m = 3 or 4 p = 1 or 2 and their addition salts with pharmaceutically acceptable acids. The “addition salts with pharmaceutically acceptable acids” designate the salts which give the biological properties of the free bases, without having an undesirable effect. These salts can be in particular those formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acidic metal salts, such as disodium orthophosphate and monopotassium sulfate, and organic acids.
Les composés de formule I peuvent être obtenus par la réaction de l'acide de formule :The compounds of formula I can be obtained by the reaction of the acid of formula:
Figure imgf000005_0001
Figure imgf000005_0001
avec un alcool de formulewith an alcohol of formula
Figure imgf000005_0002
dans laquelle n, m et p ont la signification donnée précédemment. Les sels d'addition s'obtiennent de façon classique par réaction du composé de formule I avec un acide pharmaceutiquement acceptable dans un solvant approprié. Inversement, les bases peuvent être obtenues à partir des sels d'addition par traitement par une base forte.
Figure imgf000005_0002
in which n, m and p have the meaning given above. The addition salts are obtained conventionally by reaction of the compound of formula I with a pharmaceutically acceptable acid in an appropriate solvent. Conversely, the bases can be obtained from the addition salts by treatment with a strong base.
L'acide de formule II peut être préparé comme décrit dans EP-A-0 494 816 ou comme décrit dans EP-A-0 680 952.The acid of formula II can be prepared as described in EP-A-0 494 816 or as described in EP-A-0 680 952.
Les alcools de formule III peuvent être obtenus par réaction d'un composé de formule :
Figure imgf000006_0001
avec un dérivé chloré de formuleThe alcohols of formula III can be obtained by reaction of a compound of formula:
Figure imgf000006_0001
with a chlorine derivative of formula
Figure imgf000006_0002
Figure imgf000006_0002
Les dérivés chlorés de formule (V) peuvent eux-mêmes être préparés selon le schéma suivant :The chlorinated derivatives of formula (V) can themselves be prepared according to the following scheme:
SnCV benzène
Figure imgf000006_0003
Figure imgf000006_0004
SnCV benzene
Figure imgf000006_0003
Figure imgf000006_0004
Les exemples suivants illustrent la préparation des composés selon l'invention.The following examples illustrate the preparation of the compounds according to the invention.
1 - Préparation des dérivés chlorés de formule V1 - Preparation of chlorinated derivatives of formula V
11-) Préparation de la 4-chloro-1-(1,4-benzodioxanne-6-yl)-1- butanone.11-) Preparation of 4-chloro-1- (1,4-benzodioxane-6-yl) -1-butanone.
Au sein d'une solution maintenue vers +5° de 1 mole de 1 ,4- benzodioxanne et de 1 ,08 moles de chlorure de 4-chlorobutyryle dans 750 ml de benzène sec, on coule en 1h30min, une solution de 1 ,16 moles de tétrachlorure d'étain dans 400 ml de benzène sec. On agite en laissant revenir à la température ambiante pendant 3h et on jette le milieu réactionnel sur 1500 ml d'acide chlorhydrique 2N. On agite une heure et on décante la phase organique que l'on lave par de l'eau. Après séchage sur sulfate de sodium sec et évaporation du solvant on purifie le résidu par une cristallisation dans le mélange: cyclohexane-5 : benzène-1 pour donner 0,81 mole d'une poudre jaune. Fjnst(Kofler) = 72° Rendement = 81 %In a solution maintained at + 5 ° of 1 mole of 1, 4-benzodioxane and 1, 08 moles of 4-chlorobutyryl chloride in 750 ml of dry benzene, a solution of 1, 16 is poured in 1 h 30 min. moles of tin tetrachloride in 400 ml of dry benzene. The mixture is stirred while allowing to return to ambient temperature for 3 h and the reaction medium is thrown onto 1500 ml of 2N hydrochloric acid. The mixture is stirred for one hour and the organic phase is decanted, which is washed with water. After drying over dry sodium sulfate and evaporation of the solvent, the residue is purified by crystallization from the mixture: cyclohexane-5: benzene-1 to give 0.81 mole of a yellow powder. F jnst (Kofler) = 72 ° Yield = 81%
Les produits suivants sont préparés selon cette méthode:The following products are prepared using this method:
12-) 5-chloro-1 -(-1 ,4-benzodioxanne-6-yl)-1 -pentanone à partir du 1 ,4- benzodioxanne et du chlorure de 5-chlorovaléryle. Rendement - 100 %.12-) 5-chloro-1 - (- 1, 4-benzodioxanne-6-yl) -1 -pentanone from 1,4-benzodioxane and 5-chlorovaleryl chloride. Yield - 100%.
13-) 4-chloro-1-(1 ,3-benzodioxole-5-yl)-1-butanone à partir du 1 ,3- benzodioxole et du chlorure de 4-chlorobutyryle (Rdt = 95%).13-) 4-chloro-1- (1, 3-benzodioxole-5-yl) -1-butanone from 1,3-benzodioxole and 4-chlorobutyryl chloride (Yield = 95%).
2- Préparation des aminoalcools de formule III2- Preparation of the amino alcohols of formula III
21-) Préparation de la 1 -(1 ,4-benzodioxanne-6-yl)-4-(3- hydroxypipéridino)-1 -butanone.21-) Preparation of 1 - (1, 4-benzodioxane-6-yl) -4- (3-hydroxypiperidino) -1 -butanone.
Au sein d'une suspension au reflux de 1 mole de 3-hydroxy pipéridine, de 1 ,5 moles de carbonate de potassium et en présence de 0,15 mole d'iodure de potassium dans 600 ml d'acétonitrile, on introduit par fractions en 30 min, 1 mole de 4-chloro-1-(1 ,4-benzodioxanne-6-yl)-1 -butanone (composé -1 1-). On maintient le reflux 4 h, on reprend le milieu réactionnel par de l'acétate d'éthyle et on lave par de l'eau. La phase organique est traitée par un passage acide / base et après séchage sur sulfate de sodium sec et évaporation du solvant, le résidu est purifié par un lavage dans l'éther diisopropylique pour donner 0,52 mole d'une poudre beige. Rendement = 52% Fιnst(Kofler) = 1 10°Into a reflux suspension of 1 mole of 3-hydroxy piperidine, 1.5 moles of potassium carbonate and in the presence of 0.15 mole of potassium iodide in 600 ml of acetonitrile, are introduced in portions in 30 min, 1 mole of 4-chloro-1- (1, 4-benzodioxane-6-yl) -1 -butanone (compound -1 1-). The reflux is maintained for 4 h, the reaction medium is taken up in ethyl acetate and washed with water. The organic phase is treated with an acid / base passage and after drying over dry sodium sulfate and evaporation of the solvent, the residue is purified by washing in diisopropyl ether to give 0.52 mole of a beige powder. Efficiency = 52% F ιnst (Kofler) = 1 10 °
Les produits suivant sont préparés selon cette méthode:The following products are prepared using this method:
22-) 1 -(1 ,4-benzodioxanne-6-yl)-5-(3-hydroxypipéridino)-1 -pentanone à partir du composé -12- et de la 3-hydroxy pipéridine. Rendement = 45 %.22-) 1 - (1,4-benzodioxane-6-yl) -5- (3-hydroxypiperidino) -1 -pentanone from compound -12- and 3-hydroxy piperidine. Yield = 45%.
23-) 1 -(1 ,4-benzodioxanne-6-yl)-5-[(3S)(3-hydroxypipéridino)]-1 - pentanone à partir du composé -12- et de la (S)3-hydroxy pipéridine.23-) 1 - (1, 4-benzodioxane-6-yl) -5 - [(3S) (3-hydroxypiperidino)] - 1 - pentanone from compound -12- and (S) 3-hydroxy piperidine .
24-) 1 -(1 ,4-benzodioxanne-6-yl)-5-[(3R)(3-hydroxypipéridino)]-1 - pentanone à partir du composé -12- et de la (R)3-hydroxy pipéridine.24-) 1 - (1, 4-benzodioxane-6-yl) -5 - [(3R) (3-hydroxypiperidino)] - 1 - pentanone from compound -12- and (R) 3-hydroxy piperidine .
25-) 1 -(1 ,4-benzodioxanne-6-yl)-4-[(3S)(3-hydroxypipéridino)]-1 - butanone à partir du composé -11- et de la (S)3-hydroxy pipéridine. Rendement =50%; Finst(Kofler) = 105°.25-) 1 - (1, 4-benzodioxane-6-yl) -4 - [(3S) (3-hydroxypiperidino)] - 1 - butanone from compound -11- and (S) 3-hydroxy piperidine . Yield = 50%; F inst (Kofler) = 105 °.
26-) 1 -(1 ,4-benzodioxanne-6-yl)-4-[(3R)(3-hydroxypipéridino)]-1 - butanone à partir du composé -11- et de la (R)3-hydroxy pipéridine. Rendement =53%; Finst(Kofler) = 105°.26-) 1 - (1, 4-benzodioxane-6-yl) -4 - [(3R) (3-hydroxypiperidino)] - 1 - butanone from compound -11- and (R) 3-hydroxy piperidine . Yield = 53%; F inst (Kofler) = 105 °.
27-) 1 -(1 ,4-benzodioxanne-6-yl)-5-(3-hydroxypyrrolidino)-1 -pentanone à partir du composé -12- et de la 3-hydroxy pyrrolidine. Rendement = 35 %.27-) 1 - (1,4-benzodioxane-6-yl) -5- (3-hydroxypyrrolidino) -1 -pentanone from compound -12- and 3-hydroxy pyrrolidine. Yield = 35%.
28-) 1 -(1 ,4-benzodioxanne-6-yl)-5-[(3S)(3-hydroxypyrrolidino)]-1 - pentanone à partir du composé -12- et de la (S)3-hydroxy pyrrolidine.28-) 1 - (1, 4-benzodioxane-6-yl) -5 - [(3S) (3-hydroxypyrrolidino)] - 1 - pentanone from compound -12- and (S) 3-hydroxy pyrrolidine .
29-) 1 -(1 ,4-benzodioxanne-6-yl)-5-[(3R)(3-hydroxypyrrolidino)]-1 - pentanone à partir du composé -12- et de la (R)3-hydroxy pyrrolidine.29-) 1 - (1, 4-benzodioxane-6-yl) -5 - [(3R) (3-hydroxypyrrolidino)] - 1 - pentanone from compound -12- and (R) 3-hydroxy pyrrolidine .
210-) 1 -(1 ,4-benzodioxanne-6-yl)-4-(3-hydroxypyrrolidino)-1 -butanone à partir du composé -11- et de la 3-hydroxy pyrrolidine. Rendement =44%; Finst(Kofler) = 76°.210-) 1 - (1, 4-benzodioxane-6-yl) -4- (3-hydroxypyrrolidino) -1 -butanone from the compound -11- and 3-hydroxy pyrrolidine. Yield = 44%; F inst (Kofler) = 76 °.
211 -) 1 -(1 ,4-benzodioxanne-6-yl)-4-[(3S)(3-hydroxypyrrolidino)]-1 - butanone à partir du composé -11- et de la (S)3-hydroxy pyrrolidine. Rendement =37 %; Finst(Kofler) = 66°. 212-) 1-(1,4-benzodioxanne-6-yl)-4-[(3R)(3-hydroxypyrrolidino)]-1- butanone à partir du composé -11- et de la (R)3-hydroxy pyrrolidine. Rendement =39%; Finst(Kofler) = 72°.211 -) 1 - (1, 4-benzodioxane-6-yl) -4 - [(3S) (3-hydroxypyrrolidino)] - 1 - butanone from compound -11- and (S) 3-hydroxy pyrrolidine . Yield = 37%; F inst (Kofler) = 66 °. 212-) 1- (1,4-benzodioxane-6-yl) -4 - [(3R) (3-hydroxypyrrolidino)] - 1- butanone from compound -11- and (R) 3-hydroxy pyrrolidine . Yield = 39%; F inst (Kofler) = 72 °.
213-) 1 -(1 ,3-benzodioxole-5-yl)-4-(3-hydroxypipéridino)-1 -butanone à partir du composé -13- et de la 3-hydroxy pipéridine. Rendement = 22%.213-) 1 - (1, 3-benzodioxole-5-yl) -4- (3-hydroxypiperidino) -1 -butanone from compound -13- and 3-hydroxy piperidine. Yield = 22%.
214-) 1-(1,3-benzodioxole-5-yl)-4-[(3S)(3-hydroxypipéridino)]-1- butanone à partir du composé -13- et de la (S)3-hydroxy pipéridine. Rendement =27%; Finst(Kofler) = 102°.214-) 1- (1,3-benzodioxole-5-yl) -4 - [(3S) (3-hydroxypiperidino)] - 1- butanone from compound -13- and (S) 3-hydroxy piperidine . Yield = 27%; F inst (Kofler) = 102 °.
215-) 1 -(1 ,3-benzodioxole-5-yl)-4-[(3R)(3-hydroxypipéridino)]-1 - butanone à partir du composé -13- et de la (R)3-hydroxy pipéridine. Rendement =33%; Finst(Kofler) = 105°.215-) 1 - (1, 3-benzodioxole-5-yl) -4 - [(3R) (3-hydroxypiperidino)] - 1 - butanone from compound -13- and (R) 3-hydroxy piperidine . Yield = 33%; F inst (Kofler) = 105 °.
3- Préparation des dihydropyridines de formule I3- Preparation of dihydropyridines of formula I
31-) Préparation de la (4S)-2,6-diméthyl-4-(3-nitrophényl)-5- méthoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate de N-[4-(1,4- benzodioxanne-6-yl)-4-oxobutyl]pipéridine-3'-yle (CRL 42816)31-) Preparation of (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5- methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate of N- [4- (1,4- benzodioxane- 6-yl) -4-oxobutyl] piperidine-3'-yl (CRL 42816)
Au sein d'une solution de 1 ,10 moles de chlorure d'oxalyle dans 1000 ml de dichlorométhane, on introduit, par fractions, 1 mole de 4-(R) acide 5- méthoxycarbonyl-2,6-diméthyl-4-(3-nitrophényl)-1 ,4-dihydropyridine-3- carboxylique et on agite à la température ambiante pendant 3h sous courant d'azote. On dilue le milieu réactionnel par 800 ml de dichlorométhane et on introduit par fractions en 15 min, 1 mole de 1-(1 ,4-benzodioxanne-6-yl)-4-(3- hydroxypipéridino)-1 -butanone (composé -21-) sous forme de chlorhydrate puis on agite sous courant d'azote une heure. Le milieu réactionnel est lavé successivement par de l'eau et de la soude 2N, la phase organique, séchée sur sulfate de sodium sec et le solvant évaporé pour donner une huile orangée. On obtient après purification de ce produit par un passage sur colonne de silice et en éluant par le mélange [dichlorométhane-99 / isopropanol-1], 0.57 mole d'une poudre jaune.Into a solution of 1.10 moles of oxalyl chloride in 1000 ml of dichloromethane, 1 mole of 4- (R) 5-methoxycarbonyl-2,6-dimethyl-4- ( 3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid and the mixture is stirred at room temperature for 3 h under a stream of nitrogen. The reaction medium is diluted with 800 ml of dichloromethane and, in 15 min, 1 mol of 1- (1, 4-benzodioxane-6-yl) -4- (3-hydroxypiperidino) -1 -butanone is introduced (fractions) 21-) in the form of the hydrochloride and then stirred under a stream of nitrogen for one hour. The reaction medium is washed successively with water and 2N sodium hydroxide, the organic phase, dried over dry sodium sulphate and the solvent evaporated to give an orange oil. After purification of this product is obtained by passing through a silica column and eluting with the mixture [dichloromethane-99 / isopropanol-1], 0.57 mole of a yellow powder.
Rendement = 57%, [α]D = +14(c=1 ,25;MeOH) MS (Cl) M+1 = 620Yield = 57%, [α] D = +14 (c = 1.25; MeOH) MS (Cl) M + 1 = 620
Η RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique)Η NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic)
6 (singulet élargi, 1 H, NH), 5,05 (s, 1 H, 4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3- piperidinyl-H), 4,28 (2 mult., 4H, CH2 dioxannyl), 3,6 (s, 3H, COOCH3), 2,3 (2 singulets, 6H, 2-6 CH3), 1 ,2-3 (série de mult., 14H, CH2)6 (widened singlet, 1 H, NH), 5.05 (s, 1 H, 4-dihydropyridinyl-H), 4.75 (mult., 1 H, 3-piperidinyl-H), 4.28 (2 mult ., 4H, CH 2 dioxannyl), 3.6 (s, 3H, COOCH 3 ), 2.3 (2 singlets, 6H, 2-6 CH 3 ), 1, 2-3 (mult. Series, 14H, CH 2 )
Les produits suivants sont préparés selon cette méthode:The following products are prepared using this method:
32-) (4S, 3'R)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxylate de N-[4-(1,4-benzodioxanne-6-yl)-4-oxobutyl] pipéridine-3'-yle (CRL 42925) à partir du composé -26- et du 4(R)acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine- 3-carboxylique.32-) (4S, 3'R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4- dihydro-3-pyridinecarboxylate of N- [4- (1,4-benzodioxane -6-yl) -4-oxobutyl] piperidine-3'-yl (CRL 42925) from compound -26- and 4 (R) 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) acid ) -1,4-dihydropyridine-3-carboxylic.
Rendement = 60%; [α]D = -23 (c=1 ,25; MeOH). MS (EI) M+ = 619Yield = 60%; [α] D = -23 (c = 1.25; MeOH). MS (EI) M + = 619
Η RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique)Η NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic)
6 (singulet élargi, 1 H, NH), 5,05 (s, 1 H, 4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3- piperidinyl-H), 4,28 (2 mult., 4H, CH2 dioxannyl), 3,6 (s, 3H, COOCH3), 2,9 (dt, 2H, CH2CO), 2,35 (2 singulets, 6H, 2-6 CH3), 1 ,2-2,7 (série de mult., 12H, CH2)6 (widened singlet, 1 H, NH), 5.05 (s, 1 H, 4-dihydropyridinyl-H), 4.75 (mult., 1 H, 3-piperidinyl-H), 4.28 (2 mult ., 4H, CH 2 dioxannyl), 3.6 (s, 3H, COOCH 3 ), 2.9 (dt, 2H, CH 2 CO), 2.35 (2 singlets, 6H, 2-6 CH 3 ), 1, 2-2,7 (mult. Series, 12H, CH 2 )
33-) (4S, 3'S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxylate de N-[4-(1 ,4-benzodioxanne-6-yl)-4- oxobutyl]pipéridine-3'-yle (CRL 42943) à partir du composé -25- et du 4(R) acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique. Rendement = 57%; [α]D = +66 (c=1 ,26; MeOH). MS (EI) M+ = 619 1H RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique)33-) (4S, 3'S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate N- [4- (1, 4-benzodioxane-6 -yl) -4- oxobutyl] piperidine-3'-yl (CRL 42943) from compound -25- and 4 (R) 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) acid - 1, 4-dihydropyridine-3-carboxylic. Yield = 57%; [α] D = +66 (c = 1.26; MeOH). MS (EI) M + = 619 1 H NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic)
6,05 (singulet élargi, 1 H, NH), 5,05 (s, 1 H, 4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3-piperidinyl-H), 4,28 (2 mult., 4H, CH2 dioxannyl), 3,6 (s, 3H, COOCH3), 2,9 (t, 2H, CH2CO), 2,4 (2 singulets, 6H, 2-6 CH3), 1 ,2-2,8 (série de mult., 12H, CH2)6.05 (widened singlet, 1 H, NH), 5.05 (s, 1 H, 4-dihydropyridinyl-H), 4.75 (mult., 1 H, 3-piperidinyl-H), 4.28 ( 2 mult., 4H, CH 2 dioxannyl), 3.6 (s, 3H, COOCH 3 ), 2.9 (t, 2H, CH 2 CO), 2.4 (2 singlets, 6H, 2-6 CH 3 ), 1, 2-2.8 (mult. Series, 12H, CH 2 )
34-) (4S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinedicarboxylate de N-[4-(1 ,3-benzodioxole-5-yl)-4- oxobutyl]pipéridine-3'-yle (CRL 42820) à partir du composé -213- et du 4(R) acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique.34-) (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4- dihydro-3-pyridinedicarboxylate of N- [4- (1, 3-benzodioxole-5-yl ) -4- oxobutyl] piperidine-3'-yl (CRL 42820) from the compound -213- and 4 (R) acid 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic.
Rendement = 31 %; [α]D = +14 (c=1 ,24; MeOH).Yield = 31%; [α] D = +14 (c = 1.24; MeOH).
MS (Cl) M+1 = 606MS (Cl) M + 1 = 606
1H RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique) 1 H NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic)
6,05 (s, 2H, methylenedioxolyl), 5,8 (singulet élargi, 1 H, NH), 5,1 (2 singulets,6.05 (s, 2H, methylenedioxolyl), 5.8 (enlarged singlet, 1H, NH), 5.1 (2 singlets,
1 H, 4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3-piperidinyl-H), 3,6 (s, 3H, COOCH3),1 H, 4-dihydropyridinyl-H), 4.75 (mult., 1 H, 3-piperidinyl-H), 3.6 (s, 3H, COOCH 3 ),
2.4 (2 singulets, 6H, 2-6 CH3), 1 ,2-2,9 (série de mult., 14H, CH2)2.4 (2 singlets, 6H, 2-6 CH 3 ), 1, 2-2.9 (mult. Series, 14H, CH 2 )
35-) (4S, 3'R)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxyiate de N-[4-(1 ,3-benzodioxole-5-yl)-4- oxobutyl]pipéridine-3'-yle (CRL 42944) à partir du composé -215- et du 4(R) acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique. Rendement = 59%; [α]D = -22 (c=1 ,26; MeOH). MS (El) M+1 = 606, M+ = 605 1H RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique)35-) (4S, 3'R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4- dihydro-3-pyridinecarboxyiate of N- [4- (1, 3-benzodioxole -5-yl) -4- oxobutyl] piperidine-3'-yl (CRL 42944) from compound -215- and 4 (R) 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) acid ) -1,4-dihydropyridine-3-carboxylic. Yield = 59%; [α] D = -22 (c = 1.26; MeOH). MS (El) M + 1 = 606, M + = 605 1 H NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic)
6.05 (s, 2H, methylenedioxolyl), 5,8 (singulet élargi, 1 H, NH), 5,05 (singulet, 1 H, 4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3-piperidinyl-H), 3,6 (s, 3H, COOCH3), 2,96.05 (s, 2H, methylenedioxolyl), 5.8 (widened singlet, 1 H, NH), 5.05 (singlet, 1 H, 4-dihydropyridinyl-H), 4.75 (mult., 1 H, 3- piperidinyl-H), 3.6 (s, 3H, COOCH 3 ), 2.9
(dt, 2H, CH2CO), 2,35 (2 singulets, 6H, 2-6 CH3), 1 ,3-2,7 (série de mult, 12H, CH2) 36-) (4S, S'S^e-diméthyM-β-nitrophény -S-méthoxycarbonyM ,4- dihydro-3-pyridinecarboxylate de N-[4-(1,3-benzodioxole-5-yl)-4- oxobutyl]pipéridine-3'-yle (CRL 42949) à partir du composé -214- et du 4(R) acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique.(dt, 2H, CH 2 CO), 2.35 (2 singlets, 6H, 2-6 CH 3 ), 1, 3-2.7 (mult series, 12H, CH 2 ) 36-) (4S, S'S ^ e-dimethyM-β-nitrophény -S-methoxycarbonyM, 4- dihydro-3-pyridinecarboxylate N- [4- (1,3-benzodioxole-5-yl) -4- oxobutyl] piperidine -3'-yl (CRL 42949) from the compound -214- and 4 (R) 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid .
Rendement = 26%; [α]D = +57 (c=1 ,21 ; MeOH).Yield = 26%; [α] D = +57 (c = 1.21; MeOH).
MS (El) M+1 = 606MS (El) M + 1 = 606
1H RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique) 6,05 (s, 2H, methylenedioxolyl), 5,8 (singulet élargi 1 H, NH), 5,05 (singulet, 1 H, 1 H NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic) 6.05 (s, 2H, methylenedioxolyl), 5.8 (widened singlet 1 H, NH), 5.05 (singlet, 1 Hr,
4-dihydropyridinyl-H), 4,75 (mult., 1 H, 3-piperidinyl-H), 3,65 (s, 3H, COOCH3), 2,94-dihydropyridinyl-H), 4.75 (mult., 1 H, 3-piperidinyl-H), 3.65 (s, 3H, COOCH 3 ), 2.9
(t, 2H, CH2CO), 2,4 (s, 6H, 2-6 CH3), 1 ,2-2,85 (série de mult., 12H, CH2)(t, 2H, CH 2 CO), 2.4 (s, 6H, 2-6 CH 3 ), 1, 2-2.85 (mult. series, 12H, CH 2 )
37-) (4S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxylate de N-[4-(1 ,4-benzodioxanne-6-yl)-4- oxobutyl]pyrrolidine-3'-yle (CRL 42962) à partir du composé -210- et du 4-(R),acide 5-méthoxycarbonyl-2,6-diméthyl-4-37-) (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate of N- [4- (1,4-benzodioxane-6-yl ) -4- oxobutyl] pyrrolidine-3'-yl (CRL 42962) from the compound -210- and 4- (R), 5-methoxycarbonyl-2,6-dimethyl-4- acid
(3-nitrophényl)-1 ,4-dihydropyridine-3-carboxylique. Rendement = 58% ; [α]D = + 56,8(c=1 ,25; MeOH).(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic. Yield = 58%; [α] D = + 56.8 (c = 1.25; MeOH).
MS (Cl) M+1 = 606MS (Cl) M + 1 = 606
Η RMN 400 MHz (CDCI3) δ = 6,9-8,1 (série de mult., 8H, 7H aromatique + NH)Η NMR 400 MHz (CDCI 3 ) δ = 6.9-8.1 (mult. Series, 8H, 7H aromatic + NH)
5,3 (mult, 1 H, 3-pyrrolidinyl), 5,05 (d, 1 H, 4-dihydropyridinyl-H), 4,3 (2 mult, 4H, CH2 dioxannyl), 3,65 (2 singulets, 3H, COOCH3), 2,45 (2 singulets, 3H, CH3),5.3 (mult, 1 H, 3-pyrrolidinyl), 5.05 (d, 1 H, 4-dihydropyridinyl-H), 4.3 (2 mult, 4H, CH 2 dioxannyl), 3.65 (2 singlets , 3H, COOCH 3 ), 2.45 (2 singlets, 3H, CH 3 ),
2,35 (singulet, 3H, CH3), 2-3,2 (série de mult, 12H, CH2)2.35 (singlet, 3H, CH 3 ), 2-3.2 (mult series, 12H, CH 2 )
38-) (4S,3,S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1,4- dihydro-3-pyridinecarboxylate de N-[4-(1 ,4-benzodioxanne-6-yl)-4- oxobutyl]pyrrolidine-3'-yle (CRL 42967) à partir du composé -211- et du 4-(R),acide 5-méthoxycarbonyl-2,6-diméthyl-4-38-) (4S, 3 , S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4- dihydro-3-pyridinecarboxylate of N- [4- (1, 4-benzodioxane -6-yl) -4- oxobutyl] pyrrolidine-3'-yl (CRL 42967) from the compound -211- and 4- (R), 5-methoxycarbonyl-2,6-dimethyl-4- acid
(3-nitrophényl)-1 ,4-dihydropyridine-3-carboxylique.(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic.
Rendement = 17,5% ; [α]D = +77,8(c=1 ,25; MeOH). MS (El) M+1 = 606 Η RMN 400 MHz (CDCI3) δ = 6,8-8,05 (série de mult, 7H aromatique)Yield = 17.5%; [α] D = +77.8 (c = 1.25; MeOH). MS (El) M + 1 = 606 Η NMR 400 MHz (CDCI 3 ) δ = 6.8-8.05 (mult series, 7H aromatic)
7 (singulet élargi, 1 H, NH), 5,25 (mult., 1 H, 3-pyrrolidinyl-H), 5,05 (s, 1 H, 4- dihydro-pyridinyl-H), 4,3 (2 mult, 4H, CH2 dioxannyl), 3,65 (s, 3H, COOCH3), 2,45 (s, 3H, CH3), 2,37 (s, 3H, CH3), 1 ,9-3,2 (série de mult., 12H, CH2)7 (widened singlet, 1 H, NH), 5.25 (mult., 1 H, 3-pyrrolidinyl-H), 5.05 (s, 1 H, 4-dihydro-pyridinyl-H), 4.3 ( 2 mult, 4H, CH 2 dioxannyl), 3.65 (s, 3H, COOCH 3 ), 2.45 (s, 3H, CH 3 ), 2.37 (s, 3H, CH 3 ), 1, 9- 3.2 (mult. Series, 12H, CH 2 )
39-) (4S,3,R)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1,4- dihydro-3-pyridinecarboxylate de N-[4-(1 ,4-benzodioxanne-6-yl)-4- oxobutyl]pyrrolidine-3'-yle (CRL 42970) à partir du composé -212- et du 4-(R),acide 5-méthoxycarbonyl-2,6-diméthyl-4-39-) (4S, 3 , R) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4- dihydro-3-pyridinecarboxylate of N- [4- (1,4-benzodioxane -6-yl) -4- oxobutyl] pyrrolidine-3'-yl (CRL 42970) from the compound -212- and 4- (R), 5-methoxycarbonyl-2,6-dimethyl-4- acid
(3-nitrophényl)-1 ,4-dihydropyridine-3-carboxylique.(3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic.
Rendement = 47% ; [α]D = +27,8(c=1 ,26; MeOH).Yield = 47%; [α] D = +27.8 (c = 1.26; MeOH).
MS (El) M+1 = 606 1H RMN 400 MHz (CDCI3) δ = 6,9-8,1 (série de mult, 7H aromatique)MS (El) M + 1 = 606 1 H NMR 400 MHz (CDCI 3 ) δ = 6.9-8.1 (mult series, 7H aromatic)
6,75 (singulet élargi, 1 H, NH), 5,25 (mult, 1 H, 3-pyrrolidinyl-H), 5 (s, 1 H, 4- dihydro-pyridinyl-H), 4,3 (2 mult., 4H, CH2 dioxannyl), 3,7 (s, 3H, COOCH3), 3,056.75 (widened singlet, 1 H, NH), 5.25 (mult, 1 H, 3-pyrrolidinyl-H), 5 (s, 1 H, 4-dihydro-pyridinyl-H), 4.3 (2 mult., 4H, CH 2 dioxannyl), 3.7 (s, 3H, COOCH 3 ), 3.05
(t, 2H, CH2-CO), 2,45 (s, 3H, CH3), 2,35 (s, 3H, CH3), 2-2,95 (série de mult., 10H, CH2).(t, 2H, CH 2 -CO), 2.45 (s, 3H, CH 3 ), 2.35 (s, 3H, CH 3 ), 2-2.95 (mult. series, 10H, CH 2 ).
40-) (4S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxylate de N-[5-(1 ,4-benzodioxanne-6-yl)-5- oxopentyl]pipéridine-3'-yle (CRL 42979)40-) (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate N- [5- (1, 4-benzodioxane-6-yl ) -5- oxopentyl] piperidine-3'-yl (CRL 42979)
à partir du composé -22- et du 4-(R), acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique. Rendement = 21% ; [α]D = +19,3(c=1 ,27; MeOH). MS (El) M+1 = 634 1H RMN 400 MHz (CDCI3) δ = 6,8-8,1 (série de mult., 7H aromatique) 6,1 (s, 1 H, NH), 5,1 (2 singulets, 4-dihydropyridinyl-H), 4,75 (mult., 3-piperidinyl- H), 4,3 (2 mult, 4H, CH2 dioxannyl), 3,67 (s, 3H, COOCH3), 2,3 (singulet élargi, 6H, 2-6 CH3), 1 ,3-2,9 (série de mult, 14H, CH2)from compound -22- and 4- (R), 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid. Yield = 21%; [α] D = +19.3 (c = 1.27; MeOH). MS (El) M + 1 = 634 1 H NMR 400 MHz (CDCI 3 ) δ = 6.8-8.1 (mult. Series, 7H aromatic) 6.1 (s, 1H, NH), 5.1 (2 singlets, 4-dihydropyridinyl-H), 4.75 (mult., 3-piperidinyl- H), 4.3 (2 mult, 4H, CH 2 dioxannyl), 3.67 (s, 3H, COOCH 3 ), 2.3 (widened singlet, 6H, 2-6 CH 3 ), 1, 3-2.9 (mult series, 14H, CH 2 )
41 -) (4S)-2,6-diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4- dihydro-3-pyridinecarboxylate de N-[5-(1 ,4-benzodioxanne-6-yl)-5- oxopentyl]pyrrolidine-3'-yle (CRL 42980) à partir du composé -27- et du 4-(R),acide 5-méthoxycarbonyl-2,6-diméthyl-4-(3- nitrophényl)-1 ,4-dihydropyridine-3-carboxylique. Rendement = 45% ; [α]D = +30,5(c=1 ,25; MeOH). MS (El) M+1 = 62041 -) (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1,4-dihydro-3-pyridinecarboxylate of N- [5- (1, 4-benzodioxane-6-yl ) -5- oxopentyl] pyrrolidine-3'-yl (CRL 42980) from compound -27- and 4- (R), 5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl) acid - 1, 4-dihydropyridine-3-carboxylic. Yield = 45%; [α] D = +30.5 (c = 1.25; MeOH). MS (El) M + 1 = 620
On donnera ci-après des résultats pharmacologiques mettant en évidence les propriétés avantageuses des composés de l'invention.Pharmacological results will be given below showing the advantageous properties of the compounds of the invention.
1) Activité anticalcique par mesure de l'affinité pour les sites DHP des ventricules cardiaques de rat1) Anticalcic activity by measurement of the affinity for the DHP sites of the rat cardiac ventricles
L'affinité des composés pour les sites DHP des ventricules cardiaques est mesurée à partir d'une préparation membranaire des récepteurs, préparation obtenue après dissection des ventricules, homogénéisation puis double centrifugation (48000 g ; 15 min., 4° C).The affinity of the compounds for the DHP sites of the cardiac ventricles is measured from a membrane preparation of the receptors, preparation obtained after dissection of the ventricles, homogenization then double centrifugation (48000 g; 15 min., 4 ° C).
Ces préparations membranaires sont mises en contact avec le ligand radioactif spécifique (+) [3H]-PN 200-110 et le composé à étudier, à différentes concentrations. La suspension est agitée 30 min à la température de 30° C. La réaction est alors arrêtée par filtration à l'aide d'un système type Harvester. Le filtre est introduit dans une fiole de comptage contenant du liquide scintillant. La radioactivité présente sur chaque filtre est alors mesurée par comptage dans un compteur β à scintillation liquide.These membrane preparations are brought into contact with the specific radioactive ligand (+) [ 3 H] -PN 200-110 and the compound to be studied, at different concentrations. The suspension is stirred for 30 min at a temperature of 30 ° C. The reaction is then stopped by filtration using a Harvester type system. The filter is introduced into a counting flask containing scintillating liquid. The radioactivity present on each filter is then measured by counting in a liquid scintillation β counter.
L'intensité de la liaison aux récepteurs membranaires est définie par la concentration (molaire) du composé à tester qui est nécessaire pour déplacer 50 % de la quantité du ligand spécifique (+)[3H]-PN 200-110 préalablement lié aux sites DHP. Cette concentration est la concentration Cl50. Les résultats exprimés en Cl50 sont donnés dans le tableau récapitulatif des résultats pharmacologiques et hémodynamiques.The intensity of the binding to membrane receptors is defined by the concentration (molar) of the test compound which is necessary to displace 50% of the amount of the specific ligand (+) [ 3 H] -PN 200-110 previously linked to the sites DHH. This concentration is the Cl 50 concentration. The results expressed as Cl 50 are given in the summary table of the pharmacological and hemodynamic results.
2) Activité anticalcique par mesure de l'antagonisme de la contraction de l'aorte isolée de rat par le chlorure de potassium (KCI)2) Anticalcic activity by measuring the antagonism of the contraction of the isolated aorta of rat by potassium chloride (KCI)
La technique mise en oeuvre utilise un anneau de tissu vasculaire artériel prélevé sur l'aorte thoracique du rat puis maintenu en survie dans du tampon Krebs bicarbonate aéré, et soumis à une tension initiale de 2,0 g. L'introduction de chlorure de potassium (sous un volume de 300 μl) à la concentration de 5.102 mol.l"1 dans le bain de tampon de Krebs génère une contraction soutenue dont l'amplitude (tension isométrique) est antagonisée par l'addition d'une solution du composé étudié de concentrations croissantes, chaque addition étant pratiquée toutes les 5 min. On calcule ensuite la concentration molaire du composé étudié qui diminue de 50% la contraction maximale observée sous KCI. Cette concentration est la concentration inhibitrice 50% (ou Cl50).The technique used uses a ring of arterial vascular tissue taken from the thoracic aorta of the rat and then kept alive in aerated Krebs bicarbonate buffer, and subjected to an initial tension of 2.0 g. The introduction of potassium chloride (in a volume of 300 μl) at the concentration of 5.10 2 mol.l "1 into the Krebs buffer bath generates a sustained contraction whose amplitude (isometric tension) is antagonized by the addition of a solution of the studied compound of increasing concentrations, each addition being carried out every 5 min, then the molar concentration of the studied compound is calculated which decreases by 50% the maximum contraction observed under KCI This concentration is the inhibitory concentration 50% (or Cl 50 ).
Les résultats exprimés en Cl50 sont donnés dans le tableau récapitulatif des résultats pharmacologiques et hémodynamiques.The results expressed as Cl 50 are given in the summary table of the pharmacological and hemodynamic results.
3) Effet sur le débit coronaire du chien anesthésié3) Effect on the coronary flow of the anesthetized dog
Les animaux reçoivent par voie IV des doses croissantes de chaque composé étudié toutes les 30 min. L'effet sur le débit coronaire est évalué par son pourcentage de variation maximum après chaque dose.The animals receive increasing doses of each compound studied by the IV route every 30 min. The effect on coronary flow is evaluated by its maximum percentage change after each dose.
La dose minimale active sur le débit coronaire est la dose qui augmente de 50% le début coronaire basai.The minimum active dose on coronary flow is the dose which increases the basal coronary onset by 50%.
Les résultats sont présentés dans le tableau récapitulatif ci-après. 4) Marge thérapeutiqueThe results are presented in the summary table below. 4) Therapeutic margin
La marge thérapeutique est définie comme étant le rapport entre la dose minimale arythmogène et la dose qui augmente de 50% le débit coronaire (DC) basai (cette dose est appelée "dose minimale active sur le débit coronaire").The therapeutic margin is defined as the ratio between the minimum arrhythmogenic dose and the dose which increases basal coronary flow (DC) by 50% (this dose is called "minimum active dose on coronary flow").
On a déterminé pour chaque composé chez le chien anesthésié les doses minimales arythmogenes par voie IV (cf. tableau récapitulatif) et on a déterminé le rapport dose arythmogène/dose active sur le débit coronaire (marge thérapeutique).The minimum arrhythmogenic doses by IV route were determined for each compound in the anesthetized dog (see summary table) and the arrhythmogenic dose / active dose ratio on the coronary flow rate (therapeutic margin) was determined.
TABLEAUBOARD
Figure imgf000016_0001
Figure imgf000016_0001
Les composés de l'invention permettent un traitement efficace de l'angor stable puisqu'ils améliorent l'apport d'oxygène au myocarde (par l'augmentation spécifique du débit coronaire), réduisent la consommation myocardique en oxygène par la diminution de la contractilité qu'ils induisent. Ces composés représentent donc une avancée thérapeutique significative grâce au meilleur contrôle des facteurs qui exacerbent le processus ischémique qu'ils induisent. La présente invention concerne donc également des compositions pharmaceutiques comprenant, en tant que principes actifs, un des composés de formule I ou un de leurs sels pharmaceutiquement acceptables. Dans ces compositions pharmaceutiques, la substance active est mélangée avec un ou plusieurs excipients pharmaceutiques dont la nature et la proportion relative dépend de la voie d'administration choisie.The compounds of the invention allow an effective treatment of stable angina since they improve the supply of oxygen to the myocardium (by the specific increase in coronary flow), reduce the myocardial consumption of oxygen by reducing contractility. that they induce. These compounds therefore represent a significant therapeutic advance thanks to better control of the factors which exacerbate the ischemic process which they induce. The present invention therefore also relates to pharmaceutical compositions comprising, as active principles, one of the compounds of formula I or one of their pharmaceutically acceptable salts. In these pharmaceutical compositions, the active substance is mixed with one or more pharmaceutical excipients, the nature and the relative proportion of which depends on the route of administration chosen.
Pour traiter la crise aiguë d'angor stable, les composés de formule I peuvent être utilisés en solutés permettant une perfusion intraveineuse à débit constant ou combinant une dose de charge (débit accéléré ou bolus) et une dose d'entretien délivrée pendant plusieurs heures sous contrôle électrocardiographique (enregistrement Holter de la pression artérielle et de l'ECG).To treat the acute attack of stable angina, the compounds of formula I can be used in solutes allowing an intravenous infusion at constant flow or combining a loading dose (accelerated flow or bolus) and a maintenance dose delivered for several hours under electrocardiographic control (Holter recording of blood pressure and ECG).
Les composés de formule I peuvent être utilisés à des doses variables selon la gravité de l'épisode d'angine de poitrine, la présence ou non d'une crise d'angor instable ou d'angor vasospastique simultanée. Ainsi, la posologie efficace pourra être comprise entre 0,01 et 1 ,0 mg/kg/jour en perfusion intraveineuse continue, être de préférence, une dose de l'ordre de 0,02 à 0,5 mg/kg/jour. Une fois la crise aiguë jugulée, la perfusion intraveineuse pourra être poursuivie quelques jours à une dose de l'ordre de 0,05 à 0,3 mg/kg/jour. Lorsque le traitement fera appel à la voie orale, pour un traitement prophylactique de longue durée, les doses seront choisies entre 0,05 et 2,0 mg/kg/jour.The compounds of formula I can be used at variable doses depending on the severity of the episode of angina pectoris, the presence or not of an attack of unstable angina or simultaneous vasospastic angina pectoris. Thus, the effective dosage may be between 0.01 and 1.0 mg / kg / day as a continuous intravenous infusion, preferably being a dose of the order of 0.02 to 0.5 mg / kg / day. Once the acute attack has been stopped, the intravenous infusion may be continued for a few days at a dose of the order of 0.05 to 0.3 mg / kg / day. When the treatment will use the oral route, for a long-term prophylactic treatment, the doses will be chosen between 0.05 and 2.0 mg / kg / day.
Dans les compositions pharmaceutiques de la présente invention pour l'administration par voie orale ou intraveineuse, les principes actifs peuvent être administrés sous formes unitaires d'administration, en mélange avec des supports pharmaceutiques classiques compatibles avec la thérapeutique humaine. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, éventuellement sécables ou les gélules et les formes d'administration intraveineuse permettant l'usage d'une seringue ou d'une pompe à perfusion électrique à débits contrôlés.In the pharmaceutical compositions of the present invention for oral or intravenous administration, the active ingredients can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers compatible with human therapy. Suitable unit dosage forms include oral forms such as tablets, possibly scored or capsules and intravenous dosage forms allowing the use of a syringe or an electric infusion pump with controlled flow rates.
Lorsque l'on prépare une composition solide sous forme de comprimés, on peut ajouter au principe actif, micronisé ou non, un agent mouillant (tel que le laurylsulfate de sodium) et on mélange le tout avec un véhicule pharmaceutique (tel que la silice, la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou des analogues). On peut enrober les comprimés de saccharose, de divers polymères ou d'autres matières appropriées ou encore les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.When a solid composition is prepared in the form of tablets, a wetting agent (such as sodium lauryl sulfate) can be added to the active principle, micronized or not, and the whole is mixed with a pharmaceutical vehicle. (such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like). The tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
On obtient une préparation en gélules en mélangeant le principe actif avec un diluant tel qu'un glycol ou un ester de glycérol et en incorporant le mélange obtenu dans des gélules molles ou dures. Le principe actif peut être formulé également sous forme de microcapsules ou microsphères, éventuellement avec un ou plusieurs supports ou additifs, dont la modification de cinétique de dissolution permettra d'obtenir un effet "retard" (prolongation de la durée d'action) recherché avec les formes pharmaceutiques à libération prolongée.A preparation in capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules. The active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives, the modification of dissolution kinetics of which will make it possible to obtain a "delay" effect (prolongation of the duration of action) desired sustained release pharmaceutical forms.
Le principe actif peut être également présenté sous forme de complexe avec une cyclodextrine, par exemple α-, β- ou γ-cyclodextrine, 2-hydroxypropyl-β- cyclodextrine ou méthyl-β-cyclodextrine.The active principle can also be presented in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β- cyclodextrin or methyl-β-cyclodextrin.
Pour une administration parentérale, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des agents solubilisants pharmacologiquement compatibles, par exemple le propylèneglycol ou le polyéthylèneglycol. Ainsi, pour préparer une solution aqueuse injectable par voie intraveineuse, on peut utiliser un cosolvant : un alcool tel que l'éthanol, un glycol tel que le polyéthylèneglycol ou le propylèneglycol et un tensioactif hydrophile tel que le Tween® 80. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or polyethylene glycol. Thus, to prepare an aqueous solution for intravenous injection, a cosolvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as Tween® 80.

Claims

REVENDICATIONS
Composés de formuleFormula compounds
Figure imgf000019_0001
Figure imgf000019_0001
(I) dans laquelle : n = 1 ou 2 m = 3 ou 4 p = 1 ou 2, et leurs sels d'addition avec des acides pharmaceutiquement acceptables.(I) in which: n = 1 or 2 m = 3 or 4 p = 1 or 2, and their addition salts with pharmaceutically acceptable acids.
2. Composé selon la revendication 1 qui est le (4S)-2,6-diméthyl-4-(3- nitrophényl)-5-méthoxycarbonyl-1 ,4-dihydro-3-pyridinecarboxylate de N-[4-(1 ,4- benzodioxanne-6-yl)-4-oxobutyl]pyrrolidine-3'-yle, et ses sels d'addition avec des acides pharmaceutiquement acceptables.2. Compound according to claim 1 which is (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4-dihydro-3-pyridinecarboxylate of N- [4- (1, 4- benzodioxane-6-yl) -4-oxobutyl] pyrrolidine-3'-yl, and its addition salts with pharmaceutically acceptable acids.
3. Composés selon la revendication 1 qui sont le (4S,3'R) et le (4S,3'S) -2,6- diméthyl-4-(3-nitrophényl)-5-méthoxycarbonyl-1 ,4-dihydro-3-pyridinecarboxylate de N-[4-(1 ^-benzodioxanne-ô-ylH-oxobutyljpipéridine-S'-yle, et leurs sels d'addition avec des acides pharmaceutiquement acceptables.3. Compounds according to claim 1 which are (4S, 3'R) and (4S, 3'S) -2,6- dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4-dihydro-3 N- [4- (1 ^ -benzodioxane--ylH-oxobutyljpiperidine-S'-yl-pyridinecarboxylate), and their addition salts with pharmaceutically acceptable acids.
4. Composé selon la revendication 1 qui est le (4S)-2,6-diméthyl-4-(3- nitrophényl)-5-méthoxycarbonyl-1 ,4-dihydro-3-pyridinecarboxylate de N-[5-(1 ,4- benzodioxanne-6-yl)-5-oxopentyl]pipéridine-3'-yle , et ses sels d'addition avec des acides pharmaceutiquement acceptables.4. Compound according to claim 1 which is (4S) -2,6-dimethyl-4- (3-nitrophenyl) -5-methoxycarbonyl-1, 4-dihydro-3-pyridinecarboxylate of N- [5- (1, 4- benzodioxane-6-yl) -5-oxopentyl] piperidine-3'-yl, and its addition salts with pharmaceutically acceptable acids.
5. Procédé de préparation d'un composé selon la revendication 1 , comprenant la réaction de l'acide de formule :
Figure imgf000020_0001
avec un alcool de formule :5. Process for the preparation of a compound according to claim 1, comprising the reaction of the acid of formula:
Figure imgf000020_0001
with an alcohol of formula:
Figure imgf000020_0002
dans laquelle n, m et p ont la signification donnée à la revendication 1.
Figure imgf000020_0002
in which n, m and p have the meaning given to claim 1.
6. Composition thérapeutique comprenant, à titre de principe actif, un composé selon l'une quelconque des revendications 1 , 2, 3 ou 4.6. Therapeutic composition comprising, as active principle, a compound according to any one of claims 1, 2, 3 or 4.
7. Composés de formule7. Formula compounds
Figure imgf000020_0003
dans laquelle n, m et p ont la signification donnée à la revendication 1.
Figure imgf000020_0003
in which n, m and p have the meaning given to claim 1.
8. Utilisation des composés selon les revendications 1 , 2, 3 ou 4 pour la fabrication d'un médicament antiangoreux.8. Use of the compounds according to claims 1, 2, 3 or 4 for the manufacture of an antianginal drug.
9. Procédé de traitement d'un patient souffrant d'angor, qui comprend l'administration au patient d'une quantité efficace d'un composé selon la revendication 1. 9. A method of treating a patient suffering from angina, which comprises administering to the patient an effective amount of a compound according to claim 1.
PCT/FR1999/001749 1998-07-17 1999-07-16 1-4-dihydropyridines with benzodioxo carbonyl group as calcium blockers WO2000004015A1 (en)

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US7430780B2 (en) 2002-08-09 2008-10-07 Colgate-Palmolive Company Toothbrush

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EP0494816A1 (en) * 1991-01-09 1992-07-15 Laboratoire L. Lafon 1,4-Dihydropyridine derivatives, process for their preparation and therapeutical composition containing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0494816A1 (en) * 1991-01-09 1992-07-15 Laboratoire L. Lafon 1,4-Dihydropyridine derivatives, process for their preparation and therapeutical composition containing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7430780B2 (en) 2002-08-09 2008-10-07 Colgate-Palmolive Company Toothbrush

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