WO1995014018A1 - Nouveaux derives de 1,4-dihidropyridine, procede pour leur preparation et utilisation en tant qu'agents therapeutiques - Google Patents

Nouveaux derives de 1,4-dihidropyridine, procede pour leur preparation et utilisation en tant qu'agents therapeutiques Download PDF

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Publication number
WO1995014018A1
WO1995014018A1 PCT/ES1994/000116 ES9400116W WO9514018A1 WO 1995014018 A1 WO1995014018 A1 WO 1995014018A1 ES 9400116 W ES9400116 W ES 9400116W WO 9514018 A1 WO9514018 A1 WO 9514018A1
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WO
WIPO (PCT)
Prior art keywords
morpholinyl
benzisothiazolyl
dihydropyridine
propoxycarbonyl
dioxide
Prior art date
Application number
PCT/ES1994/000116
Other languages
English (en)
Spanish (es)
Inventor
Miguel Fau De Casa-Juana Muñoz
Luis Rafael Santos Gil
Carlos Sunkel Letelier
Francisco Javier Cillero Corral
Antonio Garcia Garcia
María Antonia GONZALES MORALES
Jaime Priego Fernandez Del Campo
Original Assignee
Laboratorios Alter, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Alter, S.A. filed Critical Laboratorios Alter, S.A.
Publication of WO1995014018A1 publication Critical patent/WO1995014018A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention falls within the technical field of 1,4-dihydropyridines with phalogenic pharyngeal activity. More specifically, this invention relates to new 1,4-dihydropyridine derivatives, or their pharmaceutically acceptable ones, to the process for their preparation and their use in pharmaceutical compositions, in particular to regulate blood pressure and act on blood flow.
  • headaches and facial flushing are associated with the vasodilator action itself and often disappear after a few days of treatment - (Nayler, W.G .; Calcium Antagonist; Academic Press, 281-91, (1988).
  • the tachycardia and the palpitations associated with the treatment with these compounds are due to a reflex sympathetic activation (baroreceptor reflex) in response to the drop in blood pressure.
  • reflex tachycardia induced by calcium-antagonists produces an increase in myocardial oxygen demand and a decrease in its contribution to the myocardium, which is deleterious in situations of coronary ischemia.
  • the association of calcium-antagonists with beta-blockers in the treatment of ischemic heart disease avoids this effect and leads to greater antianginal effects.
  • hypertrophic cardiomyopathy in which this type of compounds is also indicated, la-angina is a frequent symptom, so any circumstance that favors the appearance of this symptom, such as an increase in heart rate, will have effects Negative for the patient.
  • myocar obstructive hypertrophic oriopathy the increased heart rate favors the obstruction at the outflow of blood through the left ventricle, thus worsening the hemodynamics of the patient and favoring the entry into left ventricular insufficiency.
  • the new 1,4-dihydropyridine derivatives claimed by the inventors in the present application possess these advantageous properties. These molecules do not produce increases in heart rate, and even have slight bradycardiating effects, unlike what happens, for example, with "Nifedipine.”
  • the establishment of slow and gradual hypotension may be the main cause of the absence of reflex tachycardia, since that such slow installation favors the adjustment of blood pressure control systems (barreceptors, Renina-Angiotensin system, etc.) to a slow reduction in blood pressure levels without the need to set up compensatory mechanisms to ensure - good tissue perfusion.
  • headaches, facial flushing and maleolar edema may also be reduced with a compound that exerts its vasodilator effects gradually, as is the case with the compounds of the present application.
  • the compensatory mechanisms of capillary tone maintenance would adapt to the slow reduction of blood pressure (Burges, RA; Review of the Pharmacology of Amlodipme, J. Cardiovasc. Pharmacol. 20 ( Suppl. A): S1-S5; 1992).
  • Figure 1 It is a graphic representation of the mean arterial pressure (P.A.M.) in conscious SHR. In abscissa the time is represented in hours and in ordinates the% P.A.M.
  • Figure 2 It is a graphical representation of heart rate (F.C.) in conscious SHR. In abscissa the time is represented in hours and in ordinates in% F. C.
  • the compounds of the present invention are new esters of 1,4-d ⁇ h ⁇ dro ⁇ r ⁇ dmas, of general formula (I):
  • X represents a group 2-NO 2 , 3-NO 2 , 2-Cl, 2-CF 3 and 2,3-Cl 2 ; n is a number equal to 1, 2 or 3.
  • the new compounds can be obtained according to methods already described in the literature.
  • reaction conditions used in variants (a) to (e) are the following:
  • Alcohols are preferably used, such as methanol, ethanol, isopropanol and n-butanol; ethers, such as lower ethers dialqu ⁇ ⁇ lieos such as ethyl ether tert-butyl methyl ether and isopropyl ether cyclic ethers or such as tetrahydrofuran and dioxane; lower aliphatic carboxylic acids such as acetic and propionic acids; lower dialkylformamides such as dimethylformamide; lower alkyl nitriles such as acetonitrile; dimethylsulfoxide; liquid heteroaromatic bases - such as pyridine. Mixtures of these solvents, including water, can also be used. If necessary, the reagents can also be reacted without dissolving come.
  • Reaction temperatures may vary approximately between 20 ° C and 150 ° C, preferably between 50 ° C and
  • reaction is carried out at the boiling temperature of the solvent used.
  • the reaction can be carried out at atmospheric pressure and also under elevated pressure. Generally work at atmospheric pressure.
  • the reactants are preferably used in approximately equimolecular amounts.
  • the niaco master used is added in an excess of 1 to 2 moles preferably to obtain advantageous results. Molar relationships can vary between large limits, without prejudicing the outcome.
  • reaction time ranges from 2 to 20 hours.
  • the product formed in the course of the reaction is separated and isolated by techniques - which are expressly used for this purpose and can be subjected to a classical purification such as, for example, recrystallization from a solvent. appropriate or in a mixture of such solvents, distillation or chromatography.
  • the starting compounds are known or, if new, can be obtained according to standard methods described in the literature.
  • the invention also relates to those embodiments of the process according to which - part of a compound obtainable as an intermediate at any stage of the process and the steps - of the missing process are performed, or the process is interrupted at any stage, or in which a product of parti It is formed under the reaction conditions or in which a reaction component is presented in the form of its salts.
  • the pharmaceutically acceptable acid addition salts of the compounds (I) are prepared in a conventional manner, by treating a solution or - suspension of the free base I with a chemical equivalent or two of a pharmaceutically acceptable inorganic or organic acid.
  • acids are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic. Malonic, salicylic. malic, lactic, p-toluenesulfonic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic and benzenesulfonic.
  • Double acid addition salts may have advantages, thanks to some of their physical properties such as high solubility in polar solvents such as water. This would facilitate obtaining galenic forms that included the administration of the product dissolved in water, such as in ampoules for oral or intravenous administration in patients with venoclysis or admitted to intensive care units.
  • the mixtures of diastereoisomers or enantiomers obtained can be separated thanks to the different physicochemical properties of the components by means of known methods, such as fractional recrystallization and / or chromatography, by asymmetric induction reactions or by the use of microorganisms.
  • the compounds of the present invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected in accordance with the route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected in accordance with the route of administration and standard pharmaceutical practice.
  • they can be administered orally either in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or mixed with excipients, or in the form of syrups or suspensions containing coloring agents or aromati-. zantes.
  • They can also be injected parenterally, such as intramuscularly, intravenously or subcutaneously.
  • parenteral administration they may preferably be used in the form of a sterile aqueous solution that may contain other solutes, such as any salt or glucose to make the solution isotonic.
  • the pharmaceutical compositions may contain an amount of any of the compounds of general formula (I), such that the dose level administered is between 0.001-10 mg / kg.
  • the amount of active ingredient that each of the dosage forms may contain may be between approximately 0.05-1 mg or between 0.1 and 99% by weight of the preparation, preferably between 2 and 50% by weight in oral preparations
  • the daily dose of the active substance depends on the type of administration. In general, they are administered orally from 50 to 100 mg / day.
  • intravenous administration may include a dropper for continuous dosing. Necessarily, variations will take place that will depend on the weight and conditions of the subject to be treated and the particular route of administration chosen.
  • the compounds of general formula (I) of the present invention exhibit a marked hypotensive and relaxing action of vascular smooth fiber, and can be used in the therapy or prevention of diseases of the Cardiovascular system. Its administration is not accompanied by an increase in heart rate or reflex tachycardia, which makes them especially interesting.
  • diseases in which they are indicated include, for example, arterial hypertension, myocardial ⁇ schemia, and obstructive hypertrophic cardiomyopathy, among others.
  • Another important property of these compounds, already mentioned above, is the possibility of obtaining salts with a high aqueous solubility (10-20%), which could be a basic strategic tool for the treatment of patients with venoclysis or admitted to units of intensive care
  • the nutritional liquid used has been Krebs-Henseleit with a concentration of Ca of 1.5 mM and bubbled with Carbogen.
  • Spontaneously hypertensive (SHR) male rats weighing between 285-320 gr have been used.
  • the peripheral electrocardiogram, lead D 11 was obtained by subcutaneous electrodes located at the root of the extremities.
  • the control value is obtained and the intravenous administration of the compound to be studied is started, by means of an infusion pump, in a time of 1 minute.
  • Catheters should be washed daily by introducing 0.2 ml. of heparinized physiological saline.
  • the animal is connected to an HP pressure transducer connected to an HP 7758 B polygraph and to a Scroll-Monitor (Buxco) computer system from which the values of each parameter are obtained every 20 seconds.
  • HP pressure transducer connected to an HP 7758 B polygraph and to a Scroll-Monitor (Buxco) computer system from which the values of each parameter are obtained every 20 seconds.
  • the control value is obtained and the compound to be studied orally is administered by esophageal probe.
  • Examples 1 and 2 were dissolved in physiological saline, while the rest of the compounds were dissolved in a mixture of Tween 80 and 0.5% Methylcellulose.
  • the administration volume was 10 ml / kg.
  • the effects were recorded for each of the. dose at 15, 30, 60, 120, 180 and 240 minutes after administration, using 1 animal per dose.
  • Example 7 Of the 10 compounds studied, 6 were more active than nifedipine in the hypotensive effect and on heart rate with a maximum duration of action of 30-60 minutes. These 6 products were, in decreasing order of activity: Example 7 ⁇ Example 4> Example 2> Example 3 ⁇ Example 1> Example 9.
  • nifedipine does not modify or increase this parameter while most of our compounds have a bradycardiating effect that is clearly dose dependent.
  • Figures 1 and 2 represent the effects h ⁇ poten_ sores and on heart rate of Example 1 (chosen - from the series) versus nifedipmo in spontaneously hypertensive conscious rats , after oral administration.
  • Example 1 (10 mg / kg) has a hypotensive effect similar to nifedipine (1 mg / kg), but unlike this it does not cause increased fre heart count
  • Example 1 maintains its hypotensive effect after 4 hours post-administration.

Abstract

Les dérivés 1,4-dihidropyridine ont la formula (I) dans laquelle X représente 2-NO2, 3-NO2, 2-Cl, 2-CF3 et 2,3-Cl2 et n vaut 1, 2 ou 3. Le procédé comprend, entre autre, la réaction du composé de formule (II) avec le composé de la formule (III) dans lesquelles X et n sont tels que définis antérieurement, cette réaction étant éventuellement suivie de la formation d'un sel pharmaceutiquement acceptable du composé de la formule (I) ainsi obtenu. Les dérivés de 1,4-dihidropyridine sont utiles pour le traitement préventif ou curatif de maladies du c÷ur ou vasculaires et pour le traitement de processus spasmodiques de la fibre lisse non vasculaire.
PCT/ES1994/000116 1993-11-19 1994-11-11 Nouveaux derives de 1,4-dihidropyridine, procede pour leur preparation et utilisation en tant qu'agents therapeutiques WO1995014018A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP9302422 1993-11-19
ES9302422 1993-11-19

Publications (1)

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WO1995014018A1 true WO1995014018A1 (fr) 1995-05-26

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PCT/ES1994/000116 WO1995014018A1 (fr) 1993-11-19 1994-11-11 Nouveaux derives de 1,4-dihidropyridine, procede pour leur preparation et utilisation en tant qu'agents therapeutiques

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253092A1 (fr) * 1986-05-28 1988-01-20 Alter, S.A. 1,4-Dihydropyridines, leurs procédés de préparation et leur utilisation comme médicaments antithrombotiques
EP0441736A2 (fr) * 1990-02-06 1991-08-14 Alter, S.A. Dérivés de la 1,4-dihydropyridine, procédé pour leur préparation et utilisation comme agents actifs sur la circulation du sang

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253092A1 (fr) * 1986-05-28 1988-01-20 Alter, S.A. 1,4-Dihydropyridines, leurs procédés de préparation et leur utilisation comme médicaments antithrombotiques
EP0441736A2 (fr) * 1990-02-06 1991-08-14 Alter, S.A. Dérivés de la 1,4-dihydropyridine, procédé pour leur préparation et utilisation comme agents actifs sur la circulation du sang

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