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WO1995014018A1 - New 1,4-dihidropyridine derivatives, process for their preparation and utilization as therapeutic agents - Google Patents

New 1,4-dihidropyridine derivatives, process for their preparation and utilization as therapeutic agents 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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Prior art keywords
morpholinyl
benzisothiazolyl
dihydropyridine
propoxycarbonyl
dioxide
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PCT/ES1994/000116
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Spanish (es)
French (fr)
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
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Laboratorios Alter SA
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Laboratorios Alter SA
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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The 1,4-dihidropyridine derivatives have the formula (I) wherein X is 2-NO2, 3-NO2, 2-Cl, 2-CF3 and 2,3-Cl2 and n is 1, 2 or 3. The process comprises, inter alia, the reaction of the compound having the formula (II) with the compound having the formula (III) in which formulae X and n are as defined hereabove, said reaction being optionally followed by the formation of a pharmaceutically acceptable salt of the compound of formula (I) thus obtained. Said 1,4-dihidropyridine derivatives are useful for the preventive or curative treatment of heart or vascular diseases and for the treatment of spasmodic processes of non vascular smooth fibers.

Description

TITULO DE LA INVENCIÓN  TITLE OF THE INVENTION

NUEVOS DERIVADOS DE 1,4-DIHIDROPIRIDINA, PROCEDIMIENTO PARA SU FABRICACIÓN Y USO COMO AGENTES TERAPÉUTICOS. NEW DERIVATIVES OF 1,4-DIHYDROPIRIDINE, PROCEDURE FOR MANUFACTURING AND USE AS THERAPEUTIC AGENTS.

CAMPO TÉCNICO DE LA INVENCIÓN  TECHNICAL FIELD OF THE INVENTION

La presente invención se encuadra dentro del campo técnico de las 1,4-dihidropiridinas con actividad fariña cológica. De forma mas concreta esta invención se refiere a nuevos derivados de 1,4-dihidropiridina, o sus farmacéuticamente aceptables, al procedimiento para su preparación y a su empleo en composiciones farmacéuticas, en particular para regular la presión sanguínea y actuar sobre el flujo sanguíneo.  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.

ESTADO DE LA TÉCNICA ANTERIOR A LA INVENCIÓN  STATE OF THE PRIOR ART OF THE INVENTION

Ya es sabido que ciertos derivados de 1,4-dihidropiridina poseen propiedades farmacológicas interesantes, - con un amplio espectro de utilidades terapéuticas (F. Bos- sert, W. Vater, Nature wissench. 58, 578 (1971)). Se trata de fármacos utilizados con éxito en el tratamiento de la - h ipertensión arterial, isquemia miocárdica, miocardiopatía hipertrófica y enfermedad de Raynaud entre otras, pero que sin embargo presentan una serie de efectos secundarios que contraindican su utilización en algún tipo de patología.  It is already known that certain 1,4-dihydropyridine derivatives possess interesting pharmacological properties, - with a broad spectrum of therapeutic utilities (F. Bossert, W. Vater, Nature wissench. 58, 578 (1971)). These are drugs used successfully in the treatment of - h ipertension, myocardial ischemia, hypertrophic cardiomyopathy and Raynaud's disease among others, but which nevertheless have a series of side effects that contraindicate their use in some type of pathology.

Los efectos adversos más comunes asociados al tratamiento con estos compuestos lo constituyen la aparición de edemas maleolares, cefaleas y taquicardia refleja, esta última de gran importancia negativa en el caso de la terapéutica antianginosa. The most common adverse effects associated with treatment with these compounds are the appearance of maleolar edema, headache and reflex tachycardia, the latter of great negative importance in the case of antianginal therapy.

La aparición de edema está asociada al efecto vasodilatador periférico que presentan estos compuestos, que conlleva un incremento en la presión hidrostática capilar (mecanismo compensador) y no depende de un efecto depresor sobre el miocardio, ya que las 1,4-dihidropiridinas se caracterizan por una mayor selectividad vascular "versus" car díaca. (Katz, A.M. Pappano, A.J., Messineo, F.C., Smilowitz, H. and Nash-Adler, P., Calcium Channel Blocking Drugs), (The Heart and Cardiovascular System Ed. Fozzard, H.A.; Haber, E., Jennings, R.B., Katz, A.M. and Morgan, H.E.; Raven Press, New York, 2, (1986), 1597-611), (Nayler, W.G.; Calcium Antagonist; Academic Press, (1988), 281-91). The appearance of edema is associated with the peripheral vasodilator effect of these compounds, which leads to an increase in capillary hydrostatic pressure (compensating mechanism) and does not depend on a depressing effect on the myocardium, since 1,4-dihydropyridines are characterized by greater vascular selectivity "versus" car diaca. (Katz, AM Pappano, AJ, Messineo, FC, Smilowitz, H. and Nash-Adler, P., Calcium Channel Blocking Drugs), (The Heart and Cardiovascular System Ed. Fozzard, HA; Haber, E., Jennings, RB, Katz, AM and Morgan, HE; Raven Press, New York, 2, (1986), 1597-611), (Nayler, WG ; Calcium Antagonist; Academic Press, (1988), 281-91).

De la misma forma, las cefaleas y el rubor facial están asociados a la propia acción vasodilatadora y frecuentemente desaparecen después de unos días de tratamiento - (Nayler, W.G.; Calcium Antagonist; Academic Press, 281-91, (1988).  In the same way, 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).

La taquicardia y las palpitaciones asociadas al tratamiento con estos compuestos, son debidas a una activación simpática refleja (reflejo barorreceptor) como respuesta a la caída de las cifras tensionales. Dado que la - frecuencia cardíaca es uno de los principales determinantes del consumo y del aporte de oxígeno al miocardio, la taquicardia refleja inducida por los calcio-antagonistas produce un aumento en la demanda miocárdica de oxígeno y una disminución del aporte de éste al miocardio, que resulta deletéreo en situaciones de isquemia coronaria. La asociación de calcio-antagonistas con beta-bloqueantes en el tratamiento de la cardiopatía isquémica, evita este efecto y conlleva mayores efectos antianginosos. El desarrollo de calcio-antagonistas que no produzcan aumentos - de la frecuencia cardíaca es de una gran importancia, no sólo en el campo de la enfermedad coronaria, sino también en la hipertensión arterial, ya que ésta constituye uno de los factores de riesgo coronario más importante, por lo - que la asociación de ambas patologías no resulta nada excepcional .  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. Since heart rate is one of the main determinants of oxygen consumption and oxygen supply to the myocardium, 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. The development of calcium-antagonists that do not produce increases - of heart rate is of great importance, not only in the field of coronary heart disease, but also in arterial hypertension, since this constitutes one of the most coronary risk factors important, so that the association of both pathologies is not exceptional.

En el caso de la miocardiopatía hipertrófica, en la que también está indicado este tipo de compuestos, la - angina es un síntoma frecuente, por lo que cualquier circunstancia que favorezca la aparición de este síntoma, tal como un aumento de frecuencia cardíaca, tendrá efectos negativos para el paciente. Además, en el caso de la miocar óiopatía hipertrófica obstructiva, la frecuencia cardíaca- aumentada favorece la obstrucción a la salida de la sangre a través del ventrículo izquierdo, empeorándose así la hemodmamia del paciente y favoreciéndose la entrada en insu ficiencia ventricular izquierda. In the case of 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. In addition, in the case of 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.

Es por lo tanto necesario desarrollar nuevos corn puestos con una mayor selectividad vascular frente a la - cardíaca, que sean de lenta instauración y que no produzcan aumento de la frecuencia cardíaca, edemas, cefaleas o taquicardia refleja.  It is therefore necessary to develop new corn stalls with greater vascular selectivity compared to the cardiac, which are of slow establishment and that do not produce an increase in heart rate, edema, headache or reflex tachycardia.

Sorprendentemente, los nuevos derivados de 1,4- dihidropiridinas que se reivindican por los inventores en la presente solicitud, poseen estas propiedades ventajosas. Estas moléculas no producen aumentos de frecuencia cardíaca, e incluso presentan ligeros efectos bradicardizantes, a diferencia de lo que sucede por ejemplo con "Nifedipino" La instauración de la hipotensión lenta y gradual puede - ser la principal causa de la ausencia de taquicardia refleja, ya que dicha instauración lenta favorece el acomodamieii to de los sistemas de control de la presión arterial (ba- rorreceptores, sistema Renina-Angiotensina, etc.) a una - lenta reducción de las cifras tensionales sin la necesidad de poner en marcha mecanismos compensadores que aseguren - la buena perfusión tisular. Esto es lo contrario de lo que ocurriría en casos de una caída brusca de la presión arterial, tal como sucede en la inducida por "Nifedipino" (Burges, R.A.; Review of the Pharmacology of Amlodipine, J. Cardiovasc. Pharmacol. 20 (Suppl. A):S1-S5; 1992).  Surprisingly, 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. This is the opposite of what would happen in cases of a sharp drop in blood pressure, as in the case of "Nifedipine" (Burges, RA; Review of the Pharmacology of Amlodipine, J. Cardiovasc. Pharmacol. 20 (Suppl A): S1-S5; 1992).

Por otra parte, la ausencia de taquicardia refleja tras la administración de los nuevos compuestos reivindicados, no impediría su uso en situaciones de isquemia miocárdica y en la miocardiopatía hipertrófica obstructiva, o bien evitaría el tenerlos que asociar a un beta-bloqueante, además de favorecer su uso en el campo de la hipertensión arterial (Morris, A.D. y Reíd, J.L.; Cardiovas- cular Selectivity and Clmical Applications, of Calcium Antagomsts, J. Cardiovasc. Pharmacol. 20 (Suppl. A):S25-S32; 1992). On the other hand, the absence of reflex tachycardia after the administration of the new claimed compounds, would not prevent its use in situations of myocardial ischemia and in obstructive hypertrophic cardiomyopathy, or avoid having to associate them with a beta-blocker, in addition to favoring its use in the field of arterial hypertension (Morris, AD and Reíd, JL; Cardiovas- cular Selectivity and Clmical Applications, of Calcium Antagomsts, J. Cardiovasc. Pharmacol 20 (Suppl. A): S25-S32; 1992).

Por último, las cefaleas, el rubor facial y los edemas maleolares, se podrían también reducir con un compuesto que ejerza sus efectos vasodilatadores de forma gradual, tal como sucede con los compuestos de la presente solicitud. De la misma forma que ocurre con la frecuencia cardíaca, los mecanismos compensadores del mantenimiento del tono capilar se irían adecuando a la lenta reducción de la tensión arterial (Burges, R.A.; Review of the Pharmacology of Amlodipme, J. Cardiovasc. Pharmacol. 20 (Suppl. A):S1-S5; 1992).  Finally, 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. In the same way as with heart rate, 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).

BREVE DESCRIPCIÓN DE LAS FIGURAS  BRIEF DESCRIPTION OF THE FIGURES

Figura 1: Es una representación gráfica de la presión arterial media (P.A.M.) en SHR conscientes. En abscisas se representa el tiempo en horas y en ordenadas se representa el % P.A.M. Figura 2: Es una representación gráfica de la frecuencia - cardíaca (F.C.) en SHR conscientes. En abscisas se representa el tiempo en horas y en ordenadas en % F . C .  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.

DESCRIPCIÓN DETALLADA DE LA INVENCIÓN  DETAILED DESCRIPTION OF THE INVENTION

Los compuestos de la presente invención son nuevos esteres de 1,4-dιhιdroριrιdmas, de fórmula general (I):  The compounds of the present invention are new esters of 1,4-dιhιdroριrιdmas, of general formula (I):

Figure imgf000006_0001
Figure imgf000006_0001

o una sal farmacéuticamente aceptable, en la cual or a pharmaceutically acceptable salt, in which

X representa un grupo 2-NO2, 3-NO2, 2-Cl, 2-CF3 y 2,3-Cl2; n es un número igual a 1, 2 o 3. 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.

Algunos ejemplos epecíficos de los compuestos de la presente invención, sin por ello limitarla, son los siguientes:  Some specific examples of the compounds of the present invention, without limiting it, are the following:

2,6-Dιmetιl-5-[1,3-di(N-morfolinil)-2-propoxιcarbonil]-4-(2-nιtrofenil)-1,4-dιhιdropιrιdma-3-carboxιlato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo · (Diclorhidrato). 2,6-Dιmetιl-5- [1,3-di (N-morpholinyl) -2-propoxyιcarbonyl] -4- (2-nιtrophenyl) -1,4-dιhιdropιrιdma-3-carboxylate of 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl · (Hydrochloride).

4-(2,3-Diclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3-(2H)ona-1,1-dióxi¬do)]etilo (Diclorhidrato).  2- [N-4- (2,3-Dichlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N - (1,2-benzisothiazolyl-3- (2H) one-1,1-dioxyl)] ethyl (Hydrochloride).

4-(2,3-Diclorofenil)-2,6-dimetil-5-A,3-di-(N-morfolinil)-2-propoxicarbonil7-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3-(2H)ona-1,1-dióxido)]propilo (Diclorhidrato).  3- [N- (4- (2,3-Dichlorophenyl) -2,6-dimethyl-5-A, 3-di- (N-morpholinyl) -2-propoxycarbonyl7-1,4-dihydropyridine-3-carboxylate 1,2-benzisothiazolyl-3- (2H) one-1,1-dioxide)] propyl (Hydrochloride).

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxi¬carbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3-(2H)ona-1,1-dioxido)]etilo.  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxy¬carbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate 2- [N - (1,2-benzisothiazolyl-3- (2H) one-1,1-dioxide)] ethyl.

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxi¬carbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-diòxido)]propilo.  3- [N-2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxy¬carbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

2,6-Dimetil-5-[1 ,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo.  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 2- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl.

4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-pr,opoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)7etilo.  2- [N-4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-pr, opoxycarbonyl] -1,4-dihydropyridine-3-carboxylate - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide) 7-ethyl.

4-(2,3-Diclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo.  4- (2,3-Dichlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl-2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate of [N- (1 , 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl.

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido) ]propilo. 2 ,6-Dimetil-5-/l,3-di-(N-morfolinil)-2-propoxicar¬bonil]-4-(3-nitrofenil)-l,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo. 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl. 2,6-Dimethyl-5- / l, 3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -l, 4-dihydropyridine-3-carboxylate of [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl.

4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N- (1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo .  [N- (1, Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N- (1, 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl.

2,6-Dimeti1-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo.  2,6-Dimeti1-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo .  3- [N- (4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

Los nuevos compuestos se pueden obtener de acuerdo con métodos ya descritos en la literatura.  The new compounds can be obtained according to methods already described in the literature.

Así,  So,

a) Un compuesto de fórmula (II)  a) A compound of formula (II)

Figure imgf000008_0001
Figure imgf000008_0001

en la cual X y n están definidos anteriormente, se hace reaccionar con un compuesto de fórmula (III) in which X and n are defined above, it is reacted with a compound of formula (III)

Figure imgf000008_0002
para dar un compuesto de fórmula (I); o
Figure imgf000008_0002
to give a compound of formula (I); or

b) Un compuesto de fórmula (IV)  b) A compound of formula (IV)

Figure imgf000009_0001
Figure imgf000009_0001

en la cual X está definida anteriormente, se hace reaccionar con un compuesto de fórmula (V) in which X is defined above, it is reacted with a compound of formula (V)

Figure imgf000009_0002
Figure imgf000009_0002

en la cual n ya está definido anteriormente, para dar un compuesto de fórmula (I); o in which n is already defined above, to give a compound of formula (I); or

c) Un compuesto de fórmula (VI)  c) A compound of formula (VI)

Figure imgf000009_0003
Figure imgf000009_0003

en la cual n está definido anteriormente, se hace reaccionar con un compuesto de fórmula (III) y un compuesto de fórmula (VII) in which n is defined above, it is reacted with a compound of formula (III) and a compound of formula (VII)

Figure imgf000009_0004
en la cual X se ha definido anteriormente, para dar un compuesto de fórmula (I); o
Figure imgf000009_0004
in which X has been defined above, to give a compound of formula (I); or

d) Un compuesto de fórmula (VIII)  d) A compound of formula (VIII)

Figure imgf000010_0001
Figure imgf000010_0001

se hace reaccionar con un compuesto de fórmula (V) en la cual n está definida anteriormente, y un compuesto de fórmuía (VII) en la cual X está definida anteriormente, para dar un compuesto de fórmula (I); o it is reacted with a compound of formula (V) in which n is defined above, and a compound of formmuia (VII) in which X is defined above, to give a compound of formula (I); or

e) Un compuesto de fórmula (VI), en la cual n está anteriormente definido, se hace reaccionar con un compuesto de fórmula (VIII) y con un compuesto de fórmula (VII), en la cual X se ha definido anteriormente, en presencia de amoníaco, para dar un compuesto de fórmula (I).  e) A compound of formula (VI), in which n is previously defined, is reacted with a compound of formula (VIII) and with a compound of formula (VII), in which X is defined above, in the presence of ammonia, to give a compound of formula (I).

Las condiciones de reacción empleadas en las variantes (a) a (e), son las siguientes:  The reaction conditions used in variants (a) to (e) are the following:

Se consideran como disolventes el agua y todos los disolventes orgánicos inertes. Se emplean preferentemente alcoholes, como por ejemplo metanol, etanol, isopropanol y n-butanol; éteres, como por ejemplo éteres dialquí^ lieos inferiores tales como el éter etílico el terc-butilmetiléter y el éter isopropílico o éteres cíclicos tales como tetrahidrofurano y dioxano; ácidos carboxílicos alifáticos inferiores tales como los ácidos acético y propiónico; dialquilformamidas inferiores tales como la dimetilformamida; alquilnitrilos inferiores tales como acetonitrilo; el dimetilsulfóxido; bases heteroaromáticas líquidas - tales como piridina. También se pueden emplear mezclas de estos disolventes, incluido el agua. En caso necesario, también se pueden hacer reaccionar los reactivos sin disol vente. Water and all inert organic solvents are considered as solvents. Alcohols are preferably used, such as methanol, ethanol, isopropanol and n-butanol; ethers, such as lower ethers dialquí ^ 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.

Las temperaturas de reacción pueden variar aproxi madamente entre 20ºC y 150ºC, preferentemente entre 50ºC y Reaction temperatures may vary approximately between 20 ° C and 150 ° C, preferably between 50 ° C and

100ºC. Normalmente, la reacción se lleva a cabo a la tempe_ ratura de ebullición del disolvente utilizado. 100 ° C Normally, the reaction is carried out at the boiling temperature of the solvent used.

La reacción se puede llevar a cabo a presión atmos férica y también bajo presión elevada. Generalmente se trabaja a la presión atmosférica.  The reaction can be carried out at atmospheric pressure and also under elevated pressure. Generally work at atmospheric pressure.

Los agentes reaccionantes se utilizan preferentemente en cantidades 'equimoleculares aproximadamente. El amo níaco utilizado se añade en un exceso de 1 a 2 moles preferentemente para obtener resultados ventajosos. Las relaciones molares pueden variar entre grandes límites, sin per judicar al resultado.  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.

El tiempo de reacción oscila entre 2 y 20 horas. De acuerdo con la invención, el producto formado en el cur so de la reacción se separa y se aisla mediante técnicas - que se utilizan expresamente para este fin y se puede some ter a una purificación clásica tal como, por ejemplo, recristalización en un disolvente apropiado o en una mezcla de tales disolventes, destilación o cromatografía.  The reaction time ranges from 2 to 20 hours. According to the invention, 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.

La caracterización de las estructuras de los diferentes compuestos de fórmula general (I), se realiza mediante los análisis elementales cuantitativos y los espectros IR, 1H-RMN y 13C-RMN.  The characterization of the structures of the different compounds of the general formula (I) is carried out by means of quantitative elemental analyzes and the IR, 1 H-NMR and 13 C-NMR spectra.

Los compuestos de partida son conocidos o, en caso de ser nuevos, se pueden obtener de acuerdo con métodos estándar descritos en la bibliografía.  The starting compounds are known or, if new, can be obtained according to standard methods described in the literature.

La invención se refiere también a aquellas formas de realización del procedimiento según las cuales se - parte de un compuesto obtenible como intermedio en cualquier etapa del procedimiento y se realizan las etapas - del proceso que falten, o el procedimiento se interrumpe en cualquier etapa, o en las cuales un producto de parti da se forma bajo las condiciones de reacción o en las cuales un componente de reacción se presenta en forma de sus sales. 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.

Las sales farmacéuticamente aceptables de adición con ácidos de los compuestos (I) se preparan de forma convencional, mediante tratamiento de una solución o - suspensión de la base libre I con un equivalente químico o dos de un ácido orgánico o inorgánico farmacéuticamente - aceptable. Ejemplos de ácidos son clorhídrico, sulfúrico, fosfórico, acético, cítrico, oxálico. malónico, salicílico. málico, láctico, p-toluensulfónico, glucónico, fumárico, succínico, ascórbico, maléico, metanosulfónico y bencenosulfónico. Las sales de adición dobles con ácidos pueden presentar ventajas, merced a alguna de sus propiedades físicas tales como la alta solubilidad en disolventes polares como por ejemplo el agua. Esto facilitaría la obtención de formas galénicas que incluyesen la administración del produto disuelto en agua, como por ejemplo en ampollas para administración oral o intravenosa en pacientes con venoclisis o ingresados en unidades de cuidados - intensivos.  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. Examples of 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.

Las mezclas de diastereoisómeros o enantiómeros obtenidas, se pueden separar merced a las diferentes propiedades fisicoquímicas de los componentes por medio de métodos conocidos, como por ejemplo recristalización fracciona da y/o cromatografía, por reacciones de inducción asimétrica o mediante el empleo de microorganismos.  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.

Los compuestos de la presente invención pueden ser administrados solos, pero generalmente serán administrados mezclados con un vehículo farmacéutico seleccionado de acuerdo con la vía de administración y la práctica farmacéutica estándar. Por ejemplo, pueden ser administrados oralmente bien en forma de comprimidos que contengan excipientes tales como almidón o lactosa, o en cápsulas bien solos o mezclados con excipientes, o en forma de jarabes o suspensiones que contengan agentes colorantes o aromati- . zantes. También pueden ser inyectados vía parenteral, como por ejemplo intramuscularmente, intravenosamente o subcutáneamente. En la administración parenteral, pueden ser - empleados preferentemente en forma de solución acuosa estè ril que puede contener otros solutos, como por ejemplo cualquier sal o glucosa para hacer isotónica la solución. 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. For example, 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. In 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.

Las composiciones farmacéuticas podrán contener una cantidad de alguno de los compuestos de fórmula general (I), de forma tal que el nivel de dosis administrado esté comprendido entre 0,001-10 mg/kg. La cantidad de prin_ cipio activo que podrán contener cada una de las formas de dosis podrá estar comprendida aproximadamente entre 0,05-1 mg o entre 0,1 y 99% en peso de la preparación, preferentemente entre 2 y 50% en peso en preparaciones orales. La dosis diaria de la sustancia activa depende del tipo de administración. En general, se administran oralmente de 50 a 100 mg/día.  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.

Mientras que la administración intramuscular puede ser dada en una sola dosis o dividida hasta en 3 dosis, la administración intravenosa puede incluir un gotero para su dosificación en continuo. Necesariamente, tendrán lugar variaciones que dependerán del peso y condiciones del sujeto a ser tratado y de la vía particular de administración elegida.  While intramuscular administration may be given in a single dose or divided up to 3 doses, 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.

Las actividades farmacológicas de los nuevos compuestos de fórmula (I) han sido comprobadas mediante - los siguientes tests biológicos:  The pharmacological activities of the new compounds of formula (I) have been verified by - the following biological tests:

1- Inhibición de la contracción producida por d,-espol .arizacion con K+ en aorta de conejo. 1- Inhibition of the contraction produced by d, -espol .arizacion with K + in rabbit aorta.

2- Presión arterial y frecuencia cardíaca en SHR anestesiada.  2- Blood pressure and heart rate in anesthetized SHR.

3- Presión arterial y frecuencia cardíaca en 3- Blood pressure and heart rate in

SH.R consciente. Tal como puede deducirse de los resultados de los diferentes tests farmacológicos, los compuestos de fórmuía general (I) de la presente invención exhiben una marcada acción hipotensora y relajante de la fibra lisa vascu lar, pudiendo ser empleados en la terapia o prevención de enfermedades del sistema cardiovascular. Su administración no va acompañada de un aumento de la frecuencia cardíaca o taquicardia refleja, lo cual les hace especialmente ιnteresantes. Entre las enfermedades en las que están indicados se incluyen por ejemplo la hipertensión arterial, la ιsquemía miocárdica y la miocardiopatía hipertrófica obstructiva entre otras. Otra propiedad importante de estos compuestos, ya mencionada anteriormente, la constituye la posibilidad de obtener sales con una elevada solubilidad acuosa (10-20%), lo cual podría ser una herramienta estratégica básica para el tratamiento de pacientes con venoclisis o ingresados en unidades de cuidados intensivos. SH.R conscious. As can be deduced from the results of the different pharmacological tests, 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. Among the diseases in which they are indicated include, for example, arterial hypertension, myocardial ιschemia, 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

MODOS DE REALIZACIÓN DE LA INVENCIÓN  EMBODIMENTS OF THE INVENTION

Los siguientes ejemplos ilustran la presente invención sin, por ello, limitarla:  The following examples illustrate the present invention without, therefore, limiting it:

EJEMPLO 1  EXAMPLE 1

2,6-Dιmetιl-5-[1,3-di-(N-morfolinil)-2-propoxιcarbonil]-4-(2-nιtrofenil)-1,4-dιhιdropιrιdιna-3-carboxιlato de 2-[N-(1,2-benzιsotιazolil-3(2H)ona-1,1-dióxido)]etilo (Diclorhidrato). 2,6-Dιmetιl-5- [1,3-di- (N-morpholinyl) -2-propoxyιcarbonyl] -4- (2-nιtrophenyl) -1,4-dιhιdropιrιdιna-3-carboxylate 2- [N- ( 1,2-benzotsotιazolyl-3 (2H) one-1,1-dioxide)] ethyl (Hydrochloride).

Figure imgf000014_0001
Figure imgf000014_0001

Una solución constituida por 90 g (0,2 mol) del 2-(2-nιtrobencιlιdén) acetilacetato de 2-[N-(1,2-benzιsotιa zolιl-3(2H)ona-l,l-dιóxιdo)7etιlo y 63,47 g (0,2 mol) del 3-amιnocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 240 mL de isopropanol anhidro, se calienta a reflujo con agιtación durante 18 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10ºC, se decanta el disolvente y el aceite residual se cristaliza en 50mL de acetato de eti lo. La base libre así obtenida se transforma en el correspondiente diclorhidrato mediante disolución de la misma en etanol absoluto y adición de otra solución de éter previamente saturada de ácido clorhídrico gas. De esta forma resulta finalmente un sólido amarillo de P.Fus.: 221-42C (recristalizado en etanol), con un rendimiento del 82%. A solution consisting of 90 g (0.2 mol) of 2- (2-nιtrobencιlιdén) acetylacetate 2- [N- (1,2-benzιsotιa zolιl-3 (2H) ona-l, l-dιóxιdo) 7etιlo and 63 , 47 g (0.2 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-amynocrotonate in 240 mL of anhydrous isopropanol, heated under reflux with agitation for 18 hours. After this time, the reaction mixture is cooled to -10 ° C, the solvent is decanted and the residual oil is crystallized from 50 ml of ethyl acetate. The free base thus obtained is transformed into the corresponding dihydrochloride by dissolving it in absolute ethanol and adding another solution of previously saturated ether of gas hydrochloric acid. This finally results in a yellow solid of P.Fus .: 221-42C (recrystallized from ethanol), with a yield of 82%.

EJEMPLO 2  EXAMPLE 2

4-(2,3-Dιclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dιhιdropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo (Diclorhidrato). 4- (2,3-Dιchlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dιhιdropiridine-3-carboxylate [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl (Hydrochloride).

Figure imgf000015_0001
Figure imgf000015_0001

Una solución constituida por 60 g (0,13 mol) del 2-(2,3-dιclorobencιlιdén)acetilacetato de 2-[N-(1,2-benzi¬sotiazolil-3 (2H)ona-1,1-dióxido)]etilo y 40,15 g (0,13 mol) del 3-amιnocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 140 mL de isopropanol anhidro, se calienta a reflujo con - agitación durante 16 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10ºC, se decanta el disolvente y el aceite residual se cristaliza en 50 mL de acetato de etilo. La base libre así obtenida se transforma en el correspondiente diclorhidrato mediante disolución de la - misma en etanol absoluto y adición de otra solución de éter previamente saturada de ácido clorhídrico gas. De esta for ma resulta finalmente un sólido amarillo de O. Fus.: A solution consisting of 60 g (0.13 mol) of 2- (2,3-dιchlorobenzιlιdén) 2- [N- (1,2-benzi¬sothiazolyl-3 (2H) one-1,1-dioxide) acetylacetate ] ethyl and 40.15 g (0.13 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-amynocrotonate in 140 mL of anhydrous isopropanol, heated under reflux with - stirring for 16 hours . After this time, the reaction mixture is cooled to -10 ° C, the solvent is decanted and the residual oil is crystallized from 50 mL of ethyl acetate. The free base thus obtained is transformed into the corresponding dihydrochloride by dissolving it in absolute ethanol and adding another solution of previously saturated ether of gas hydrochloric acid. This way ma is finally a yellow solid of O. Fus .:

219-239C con descomposición, con un rendimiento del 61%. 219-239C with decomposition, with a yield of 61%.

EJEMPLO 3  EXAMPLE 3

4-(2,3-Diclorofenil)-2,6-dimeti1-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo(Diclorhidrato). 3- [N-4- (2,3-Dichlorophenyl) -2,6-dimeti1-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl (Hydrochloride).

Figure imgf000016_0001
Figure imgf000016_0001

Una solución constituida por 15 g (0,03 mol) del 2-(2,3-diclorobencilidén)acetilacetato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo y 9,75 g (0,03 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 40 mL de isopropanol anhidro, se calienta a reflu_ jo con agitación durante 16 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10⍛C, se decanta el disolvente y el aceite residual se cristaliza en 15 mL de acetato de etilo. La base libre así obtenida se purifica mediante recristalización en metanol y se transforma en el correspondiente diclorhidrato mediante disolución de la misma en etanol absoluto y adición de otra solución de éter previamente saturada de ácido clorhídrico gas. De esta forma resulta finalmente un sólido amarillo de P.Fus.: 195-92C con descomposición, con un rendimiento del 51%.  A solution consisting of 15 g (0.03 mol) of 3- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl 2- (2,3-dichlorobenzylidene) acetylacetate and 9.75 g (0.03 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 40 mL of anhydrous isopropanol, is refluxed with stirring for 16 hours. After this time, the reaction mixture is cooled to -10⍛C, the solvent is decanted and the residual oil is crystallized from 15 mL of ethyl acetate. The free base thus obtained is purified by recrystallization from methanol and transformed into the corresponding dihydrochloride by dissolving it in absolute ethanol and adding another solution of previously saturated ether of gas hydrochloric acid. This finally results in a yellow solid of P.Fus .: 195-92C with decomposition, with a yield of 51%.

EJEMPLO 4  EXAMPLE 4

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato - de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo.

Figure imgf000017_0001
2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate - 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl.
Figure imgf000017_0001

Una solución constituida por 15 g (0,03 mol) del 2-(2-trifluormetilbencilidén)acetilacetato de 2-[N-(1,2-benzisotiazolil-3-(2H)ona-1,1-dióxido)]etilo y 10,06 g (0,03 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 35 mL de isopropanol anhidro, se calienta a reflujo con agitación durante 18 horas. Al cabo de dicho tiempo, se evaporan a presión reducida 15 mi del disolvente y la solución resultante se enfría a -10⍛C, con lo que resulta un producto que se purifica mediante cromatografía en columna de Silicagel (eluyente: cloruro de metileno/me- tanol (10:0,5). De esta forma se obtiene un sólido amarillo de P .Fus.: 101-3⍛C, con un rendimiento del 43%. A solution consisting of 15 g (0.03 mol) of 2- [N- (1,2-benzisothiazolyl-3- (2H) one-1,1-dioxide)] ethyl 2- (2-trifluoromethylbenzylidene) acetyl acetate and 10.06 g (0.03 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 35 mL of anhydrous isopropanol, heated under reflux with stirring for 18 hours. After this time, 15 ml of the solvent is evaporated under reduced pressure and the resulting solution is cooled to -10⍛C, resulting in a product that is purified by Silicagel column chromatography (eluent: methylene chloride / me - tanol (10: 0.5) In this way a yellow solid of P. Fus .: 101-3⍛C is obtained, with a yield of 43%.

EJEMPLO 5  EXAMPLE 5

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato -de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo. 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate -de 3- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

Figure imgf000017_0002
Figure imgf000017_0002

Una solución constituida por 15 g (0,03 mol) del 2-(2-trifluormetilbencilidén)acetilacetato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo y 9,77 g (0,03 mol) del 3-aminocrotonato de 1 , 3-di- (N-morfolinil ) -2-propilo en 35 mL de isopropanol anhidro, se calienta a reflujo con agitación durante 16 horas. Al cabo de dicho tiempo, se evaporan a presión reducida 15 mi del disolvente y la solución resultante se enfría a -10⍛C, con lo que resulta un producto que se purifica mediante cromatografía en columna de Silicagel (eluyente: cloruro de metileno/metanol (10:0,5). De esta forma se obtiene un sólido amarillo de P.Fus.: 82-4⍛C, con un rendimiento del 45%. A solution consisting of 15 g (0.03 mol) of 3- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl and 9.77 g (0.03 mol) of 3- (2-trifluoromethylbenzylidene) acetylacetate 1,3-di- (N-morpholinyl) -2-propyl aminocrotonate in 35 mL of anhydrous isopropanol, heated under reflux with stirring for 16 hours. After this time, 15 ml of the solvent is evaporated under reduced pressure and the resulting solution is cooled to -10⍛C, resulting in a product that is purified by Silicagel column chromatography (eluent: methylene chloride / methanol (10: 0.5) In this way a yellow solid of P.Fus .: 82-4⍛C is obtained, with a yield of 45%.

EJEMPLO 6  EXAMPLE 6

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido Metilo. 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 2- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-methyl dioxide.

Figure imgf000018_0001
Figure imgf000018_0001

Una solución constituida por 15 g (0,03 mol) del 2-(3-nitrobencilidén)acetilacetato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo y 10,58 g (0,03 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 35 mL de isopropanol anhidro, se calienta a reflujo con agitación durante 14 horas. Al cabo de dicho tiempo, se evaporan a presión reducida 15 mi del disolvente y la solución resultante se enfría a -10⍛C, con lo que resulta un producto que se purifica mediante cromatografía en columna de Silicagel (eluyente: cloruro de metileno/metanol (10:0,5). De esta forma se obtiene un sólido amarillo de P.Fus.: 92-5⍛C, con un rendimiento del 40%. EJEMPLO 7 A solution consisting of 15 g (0.03 mol) of 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl 2- (3-nitrobenzylidene) acetylacetate 58 g (0.03 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 35 mL of anhydrous isopropanol is heated under reflux with stirring for 14 hours. After this time, 15 ml of the solvent is evaporated under reduced pressure and the resulting solution is cooled to -10⍛C, resulting in a product that is purified by Silicagel column chromatography (eluent: methylene chloride / methanol (10: 0.5) In this way a yellow solid of P.Fus .: 92-5⍛C is obtained, with a yield of 40%. EXAMPLE 7

4- ( 2-Clorofenil ) -2 , 6-dimetil-5- [1 , 3-di- ( N-morfolinil ) -2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 2- [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo.  2- (N- (4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl.

Figure imgf000019_0002
Figure imgf000019_0002

Una solución constituida por 15 g (0,03 mol) del 2-(2-clorobencilidén)acetilacetato de 2-[N-(1,2-benzιsotiazolil-3(2H)ona-1,1-dióxido)]etilo y 10,48 g (0,03 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 40 mL de isopropanol anhidro, se palienta a reflujo con agitación durante 18 horas. Al cabo de dicho tiempo, se evaporan a presión reducida 15 mi del disolvente y la solución resultante se enfría a -10⍛C, con lo que resulta un producto que se purifica mediante cromatografía en columna de Silicagel (eluyente: cloruro de metileno/metanol (10:0,5). De esta forma se obtiene un sólido amarillo de P.Fus.: 100-3⍛C, con un rendimiento del 44%.  A solution consisting of 15 g (0.03 mol) of 2- [N- (1,2-benzιsothiazolyl-3 (2H) one-1,1-dioxide)] ethyl 2- (2-chlorobenzylidene) acetylacetate , 48 g (0.03 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 40 mL of anhydrous isopropanol, is refluxed with stirring for 18 hours. After this time, 15 ml of the solvent is evaporated under reduced pressure and the resulting solution is cooled to -10⍛C, resulting in a product that is purified by Silicagel column chromatography (eluent: methylene chloride / methanol (10: 0.5) In this way a yellow solid of P.Fus .: 100-3⍛C is obtained, with a yield of 44%.

EJEMPLO 8  EXAMPLE 8

4-('2,3-Diclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)7metilo. [N- [2,3-] Dichlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide) 7methyl.

Figure imgf000019_0001
Una solución constituida por 3 g (7 mmol) del _ 2- ( 2, 3-diclorobencilidén) acetilacetato de [N-(1,2-benzisotiazolil-3(2H) ona-1,1-dióxido)/metilo y 2,2 g (7 mmol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 10 mL de etanol absoluto, se calienta a reflujo con agitación durante 16 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción -10⍛C, se filtra el sólido resultante y se purifica mediante recristalización en metanol. De esta forma resulta finalmente un sólido amarillo de P.Fus.: 252-32C, con un rendimiento del 60%.
Figure imgf000019_0001
A solution consisting of 3 g (7 mmol) of _ 2- (2, 3-dichlorobenzylidene) [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide) / methyl acetylacetate and 2, 2 g (7 mmol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 10 mL of absolute ethanol is heated under reflux with stirring for 16 hours. After this time, the reaction mixture is cooled -10⍛C, the resulting solid is filtered and purified by recrystallization from methanol. This finally results in a yellow solid of P.Fus .: 252-32C, with a yield of 60%.

EJEMPLO 9  EXAMPLE 9

2,6-Dimetil-5-[1 ,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo. 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

Figure imgf000020_0001
Figure imgf000020_0001

Una solución constituida por 4,5 g (0,01 mol) del 2-(2-nitrobencilidén)acetilacetato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo y 3,1 g (0,01 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 10 mL de etanol absoluto, se calienta a reflujo con agitación durante 12 horas. Al cabo de dicho tiempo, se evapora el disolvente a presión reducida y el residuo se cristaliza en 5 mL de acetato de etilo. De esta forma se obtiene un sólido amarillo de P.Fus.: 105-7⍛C, con un rendimiento del 69%. EJEMPLO 10 A solution consisting of 4.5 g (0.01 mol) of 3- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl 2- (2-nitrobenzylidene) acetylacetate and 3.1 g (0.01 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 10 mL of absolute ethanol, heated under reflux with stirring for 12 hours. After this time, the solvent is evaporated under reduced pressure and the residue is crystallized from 5 mL of ethyl acetate. In this way a yellow solid of P.Fus .: 105-7⍛C is obtained, with a yield of 69%. EXAMPLE 10

2,6-Dimeti1-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2,6-Dimeti1-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate

[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo. [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl.

Figure imgf000021_0002
Figure imgf000021_0002

Una solución constituida por 3,2 g (7,5 mmol) del 2-(3-nitrobencilidén)acetilacetato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo y 2,3 g (7,5 mmol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 10 mL de etanol absoluto, se calienta a reflujo con agi_ tación durante 4 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10⍛C, se filtra el sólido resultante y se purifica mediante recristalización en - etanol. De esta forma resulta finalmente un sólido amarillo de P.Fus.: 190-2⍛C, con un rendimiento del 76% .  A solution consisting of 3.2 g (7.5 mmol) of [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl 2- and 3 (nitrobenzylidene) acetylacetate , 3 g (7.5 mmol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 10 mL of absolute ethanol is heated under reflux with stirring for 4 hours. After this time, the reaction mixture is cooled to -10⍛C, the resulting solid is filtered and purified by recrystallization from ethanol. This finally results in a yellow solid of P.Fus .: 190-2⍛C, with a yield of 76%.

EJEMPLO 11  EXAMPLE 11

4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2- propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de  4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate

[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dioxido)]metilo.  [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl.

Figure imgf000021_0001
Una solución constituida por 3,5 g (0,025 mol) . de 2-clorobenzaldehído, 7,4 g (0,025 mol) de acetilacetato de [N-(l,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo y 7,8 g (0,025 mol) del 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 25 mL de etanol absoluto, se calienta a reflujo con agitación durante 4 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10⍛C, se filtra el sólico resultante y se purifica mediante recristalización en metanol. De esta forma resulta finalmente un sólido amarillo de P. Fus.: 230-2⍛C, con un rendimiento del 66%.
Figure imgf000021_0001
A solution consisting of 3.5 g (0.025 mol). of 2-chlorobenzaldehyde, 7.4 g (0.025 mol) of [N- (l, 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl acetylacetate and 7.8 g (0.025 mol) of 1,3-di- (N-morpholinyl) -2-propyl 3-aminocrotonate in 25 mL of absolute ethanol, heated under reflux with stirring for 4 hours. After this time, the reaction mixture is cooled to -10⍛C, the resulting solic acid is filtered and purified by recrystallization from methanol. This finally results in a yellow solid of P. Fus .: 230-2⍛C, with a yield of 66%.

EJEMPLO 12  EXAMPLE 12

2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo. 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl.

Figure imgf000022_0001
Figure imgf000022_0001

Una solución constituida por 2,8 g (6 mmol) del A solution consisting of 2.8 g (6 mmol) of the

2-(3-nitrobencilidén)acetilacetato de 3-[N-(1,2-benzisotÍazolil-3(2H)ona-1,1-dióxido)]propilo y 1,9 g (6 mmol) del - 3-aminocrotonato de 1,3-di-(N-morfolinil)-2-propilo en 10 mL de etanol absoluto, se calienta a reflujo con agitación durante 4 horas. Al cabo de dicho tiempo, se enfría la mezcía de reacción a -10⍛C, se decanta el disolvente y el residuo obtenido se cristaliza en 10 mL de acetato de etilo y después se purifica mediante cromatografía en columna de Silicagel (eluyente: cloruro de metileno/metanol (10:0,5). De esta forma se obtiene un sólido de P.Fus.: 155-6⍛C, con un rendimiento del 49%. EJEMPLO 13 2- (3-Nitrobenzylidene) 3- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl acetylacetate acetate and 1.9 g (6 mmol) of the - 3-aminocrotonate of 1,3-di- (N-morpholinyl) -2-propyl in 10 mL of absolute ethanol is heated under reflux with stirring for 4 hours. After this time, the reaction mixture is cooled to -10⍛C, the solvent is decanted and the residue obtained is crystallized from 10 mL of ethyl acetate and then purified by Silicagel column chromatography (eluent: chloride methylene / methanol (10: 0.5), thus obtaining a solid of P.Fus .: 155-6⍛C, with a yield of 49%. EXAMPLE 13

4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiπdina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)ypropilo  3- [N- (4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyπdine-3-carboxylate [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide) and propyl

Figure imgf000023_0001
Figure imgf000023_0001

Una solución constituida por 15 g (0,03 mol) del 2-(2-clorobencιlιdén)acetιlacetato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dιóxιdo)]propilo y 10,5 g (0,03 mol) del 3-aminocrotonato de 1,3-di-(N-morfolmil)-2-propilo en 40 mL de isopropanol anhidro, se calienta a reflujo con agitación durante 20 horas. Al cabo de dicho tiempo, se enfría la mezcla de reacción a -10⍛C, se decanta el disolveri te y el residuo obtenido se cristaliza en 15 mL de acetato de etilo. Por último, el producto así obtenido se purifica mediante recristalización en etanol, con lo que resulta un sólido amarillo de P.Fus.: 162-4 C, con un rendimiento del 70%.  A solution consisting of 15 g (0.03 mol) of 3- (N- (1,2-benzisothiazolyl-3 (2H) ona-1,1-dioxide)] propyl and 10 (2-chlorobenzylbenden) acetyl acetate 5 g (0.03 mol) of 1,3-di- (N-morpholmil) -2-propyl 3-aminocrotonate in 40 mL of anhydrous isopropanol is heated under reflux with stirring for 20 hours. After this time, the reaction mixture is cooled to -10⍛C, the solvent is decanted and the residue obtained is crystallized from 15 mL of ethyl acetate. Finally, the product thus obtained is purified by recrystallization from ethanol, resulting in a yellow solid of P.Fus .: 162-4 C, with a yield of 70%.

ESTUDIOS BIOLÓGICOS  BIOLOGICAL STUDIES

1. - Aorta aislada de Conejo  1. - Rabbit isolated aorta

Se han utilizado conejos machos albinos NZ con un peso medio de 2,5 kg.  Albino male rabbits NZ with an average weight of 2.5 kg have been used.

Tras disección de la aorta torácica, se corta en espirales de 15 mm que se montan en un baño de 40 ml, con una tensión inicial de 1 gramo. El líquido nutricio utilizado ha sido Krebs-Henseleit con una concentración de Ca de 1,5 mM y burbujeado con Carbógeno.  After dissection of the thoracic aorta, it is cut into 15 mm spirals that are mounted in a 40 ml bath, with an initial tension of 1 gram. The nutritional liquid used has been Krebs-Henseleit with a concentration of Ca of 1.5 mM and bubbled with Carbogen.

Tras la estabilización de la preparación se provo ca la contracción de la aorta con un pulso depolarizante . de K 35 mM. La contracción se mantiene durante 2-3 horas y posteriormente se añade al baño el producto a estudiar registrándose el efecto durante 4 horas o hasta alcanzar el estado estable. After stabilization of the preparation caused Ca contraction of the aorta with a depolarizing pulse. of K 35 mM. The contraction is maintained for 2-3 hours and subsequently the product to be studied is added to the bath, registering the effect for 4 hours or until the stable state is reached.

Se ensayaron las concentraciones de los produc- Product concentrations were tested

_9 tos y el estándar (nifedipino) en el rango molar de 10 a 10-7. _9 cough and the standard (nifedipine) in the molar range of 10 to 10 -7 .

Excepto los productos que constituyen los Ejemplos 1 y 2, que son solubles en agua, el resto de los productos fueron disueltos en DMSO con una concentración final en el baño de 40 μl/40 ml.  Except for the products constituting Examples 1 and 2, which are soluble in water, the rest of the products were dissolved in DMSO with a final concentration in the bath of 40 μl / 40 ml.

2. - Registros de Presión arterial y Frecuencia Cardiaca en SHR Anestesia.  2. - Records of Blood Pressure and Heart Rate in SHR Anesthesia.

Se han utilizado ratas espontáneamente hipertensas (SHR) machos de pesos comprendidos entre 285-320 gr.  Spontaneously hypertensive (SHR) male rats weighing between 285-320 gr have been used.

Previa anestesia con Pentobarbital sódico (70 mg/kg í.p. en un volumen de 1ml/kg) se cánula la tráquea y la arteria femoral izquierda para el registro de la Presión - arterial y la vena femoral derecha para la administración intravenosa de los productos.  Prior anesthesia with sodium pentobarbital (70 mg / kg í.p. in a volume of 1ml / kg) the trachea and the left femoral artery cannula for the pressure - arterial and right femoral vein for intravenous administration of the products.

El electrocardiograma periférico, derivación D11, se obtuvo mediante electrodos subcutáneos localizados en la raíz de las extremidades. The peripheral electrocardiogram, lead D 11 , was obtained by subcutaneous electrodes located at the root of the extremities.

Los parámetros estudiados fueron: Presión arterial media (P.A.M.) y frecuencia cardiaca (F.C.).  The parameters studied were: Average blood pressure (P.A.M.) and heart rate (F.C.).

Todas las señales se registraron en un polígrafo PH 7758 B y se almacenaron en un sistema computarizado Scroll-Monitor (Buxco) del que se obtienen los valores de cada parámetro cada 20 segundos.  All signals were recorded on a PH 7758 B polygraph and stored in a Scroll-Monitor (Buxco) computer system from which the values of each parameter are obtained every 20 seconds.

Una vez estabilizado el animal, se obtiene el va lor control y se comienza la administración intravenosa del compuesto a estudiar, mediante bomba de infusión, en un tiempo de 1 minuto.  Once the animal is stabilized, 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.

Los productos que constituyen los Ejemplos 1 y 2 fueron disueltos en suero salino fisiológico, mientras que el resto de los compuestos se disolvieron en PEG-400. El volumen de administración fue de 0,1 ml/animal. The products constituting Examples 1 and 2 they were dissolved in physiological saline, while the rest of the compounds were dissolved in PEG-400. The administration volume was 0.1 ml / animal.

Se registraron los efectos para cada una de las dosis a los 5, 15, 30, 60 y 120 minutos tras infusión, utilizándose 1 animal por dosis.  The effects for each of the doses were recorded at 5, 15, 30, 60 and 120 minutes after infusion, using 1 animal per dose.

3. - Registro de Presión Arterial y Frecuencia Cardíaca en SHR consciente.  3. - Record of Blood Pressure and Heart Rate in conscious SHR.

Se han utilizado SHR machos de pesos comprendidos entre 290-350 gr.  SHR males weighing between 290-350 gr have been used.

Previa anestesia con Pentobarbital sódico (40 mg/kg i.p. en 1ml/kg) se cánula la aorta abdominal a través de la arteria femoral i zquierda con un catéter de polietileno que posteriormente se exterioriza a través de la nuca del animal y se fija a un muelle convencional a la tapa de la jaula de tal manera que por deslizamiento permite el movimiento del animal en todas las direcciones.  After anesthesia with sodium pentobarbital (40 mg / kg ip in 1ml / kg), the abdominal aorta cannula through the femoral artery and left with a polyethylene catheter that is subsequently externalized through the nape of the animal and fixed to a Conventional spring to the cage lid in such a way that by sliding allows the movement of the animal in all directions.

Los catéteres deben lavarse diariamente introduciendo 0,2 mi. de solución salina fisiológica heparinizada.  Catheters should be washed daily by introducing 0.2 ml. of heparinized physiological saline.

Después de 48 horas del procedimiento quirúrgico se conecta el animal a un transductor de presión HP conectado a un polígrafo HP 7758 B y a un sistema computarizado Scroll-Monitor (Buxco) del que se obtienen los valores de cada parámetro cada 20 segundos.  After 48 hours of the surgical procedure, 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.

Los parámetros estudiados fueron: Presión arterial media y frecuencia cardíaca, calculada a través de la onda de presión arterial.  The parameters studied were: Average blood pressure and heart rate, calculated through the blood pressure wave.

Tras estabilizar el animal durante 1 hora, se obtiene el valor control y se administra vía oral el compuesto a estudiar mediante sonda esofágica.  After stabilizing the animal for 1 hour, the control value is obtained and the compound to be studied orally is administered by esophageal probe.

Los productos que constituyen los Ejemplos 1 y 2 fueron disueltos en suero salino fisiológico, mientras que el resto de los compuestos se disolvieron en una mezcla de Tween 80 y Metilcelulosa al 0,5%. El volumen de administración fué de 10 ml/Kg. Se registraron los efectos para cada una de las. dosis a los 15, 30, 60, 120, 180 y 240 minutos tras administración, utilizándose 1 animal por dosis. The products constituting 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.

TABLA 1.- Efecto relajante de los distintos compuestos de la serie versus nifedipino en espirales de aorta de conejo contraída con 35 mM de K . La dosis elegida de cada uno de los compuestos fue la más próxima a su CI50. TABLE 1.- Relaxing effect of the different compounds of the series versus nifedipine in spirals of rabbit aorta contracted with 35 mM K. The chosen dose of each of the compounds was the closest to its IC 50 .

Figure imgf000026_0001
Figure imgf000026_0001

Como puede observarse en la tabla 1, todos los compuestos de la serie, excepto los Ejemplos 5, 10, 11 y 12 presentan una lenta instauración de acción, existiendo grandes diferencias entre el efecto relajante obtenido tras 1 hora de incubación con el obtenido después de 4 horas. Por el contrario, el efecto de nifedipino resulta de rápida instauración, obteniéndose el efecto máximo en la primera hora de incubación y manteniéndose este des pues de 4 horas. Los compuestos de la serie con mayor actividad a la vez que con una más lenta instauración del efecto son los constituidos por los Ejemplos 1, 2, 3, 4 y 7. As can be seen in Table 1, all the compounds in the series, except for Examples 5, 10, 11 and 12 have a slow action, with large differences between the relaxing effect obtained after 1 hour of incubation with that obtained after 4 hours. On the contrary, the effect of nifedipine results from rapid establishment, obtaining the maximum effect in the first hour of incubation and maintaining this des of 4 hours. The compounds of the series with greater activity while having a slower establishment of the effect are those constituted by Examples 1, 2, 3, 4 and 7.

TABLA 2.- Dosis que produce el 50% de inhibición de la contracción (CI50) inducida por 35 mM de K+ en aorta a: lada de conejo, después de 4 horas de incubación. TABLE 2.- Dose that produces 50% inhibition of contraction (IC 50 ) induced by 35 mM K + in aorta a: rabbit side, after 4 hours of incubation.

Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Los efectos, de los compuestos estudiados, sobre la PAM y FC se muestran en las tablas 3 y 4, respectivamente.
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
The effects of the compounds studied on PAM and FC are shown in Tables 3 and 4, respectively.

Todos los productos ensayados disminuyeron los valores de PAM y FC de forma dosis-dependiente con una duración de acción superior a nifedipmo.  All products tested decreased the PAM and FC values in a dose-dependent manner with a duration of action greater than nifedipmo.

De los 10 compuestos estudiados, 6 resultaron más activos que nifedipino en el efecto hipotensor y sobre la frecuencia cardíaca con una duración de acción del efecto máximo de 30-60 minutos. Estos 6 productos fueron, en - orden decreciente de actividad: Ejemplo 7 ≥ Ejemplo 4 > Ejemplo 2 > Ejemplo 3 ≥ Ejemplo 1 > Ejemplo 9.  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.

La cinética de instauración del efecto nipotensor resultó muy diferente entre estos compuestos y Nifedipino así, mientras esta ultima reduce los valores tensiona les de forma muy acusada durante los 5 primeros minutos - postmfusión para posteriormente comenzar a revertir, nuestros compuestos disminuyen la presión arterial y frecuencia cardíaca de forma lenta y paulatina alcanzándose el - efecto máximo, en la mayoría de los casos, entre los 15-30 y entre los 30-60 minutos postinfusión para los compuestos Ejemplos 1 y 2.  The kinetics of the nipotensor effect were very different between these compounds and Nifedipine as well, while the latter reduces the stress values very sharply during the first 5 minutes - post-fusion to later begin to reverse, our compounds decrease blood pressure and frequency cardiac slowly and gradually reaching the maximum effect, in most cases, between 15-30 and between 30-60 minutes post-infusion for the compounds Examples 1 and 2.

Sobre la frecuencia cardíaca, nifedipino no modifica ó incrementa este parámetro mientras que la mayoría de nuestros compuestos presentan un efecto bradicardizante que resulta claramente dosisdependiente .  On heart rate, nifedipine does not modify or increase this parameter while most of our compounds have a bradycardiating effect that is clearly dose dependent.

Corroborando el efecto hipotensor de instalación lenta y mantenida junto a la ausencia de taquicardia refleja, en las Figuras 1 y 2 se representan los efectos hιpoten_ sores y sobre frecuencia cardíaca del Ejemplo 1 (elegido - de la serie) versus nifedipmo en ratas espontáneamente hipertensas conscientes, tras administración oral. Como se - observa en ambas figuras, el Ejemplo 1 (10 mg/kg) presenta un efecto hipotensor semejante a nifedipino (1 mg/kg), pero que a diferencia de este no produce aumento de la fre cuencia cardíaca. Corroborating the hypotensive effect of slow and sustained installation together with the absence of reflex tachycardia, Figures 1 and 2 represent the effects hιpoten_ sores and on heart rate of Example 1 (chosen - from the series) versus nifedipmo in spontaneously hypertensive conscious rats , after oral administration. As can be seen in both figures, 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

La cinética del efecto hipotensor es muy diferente entre ambos compuestos, mientras que nifedipino disminuye las cifras tensionales de forma rápida y muy acusada durante la primera hora de la administración para después comenzar a revertir, el Ejemplo 1 mantiene su efecto hipotensor después de 4 horas postadministración.  The kinetics of the hypotensive effect is very different between the two compounds, while nifedipine decreases blood pressure levels rapidly and strongly during the first hour of administration and then begins to reverse, Example 1 maintains its hypotensive effect after 4 hours post-administration. .

Claims

REIVINDICACIONES 1.- Nuevos derivados de 1,4-dιhιdropιrιdιna de fórmula general (I):  1.- New derivatives of 1,4-dιhιdropιrιdιna of general formula (I):
Figure imgf000032_0001
o una sal farmacéuticamente aceptable de los mismos, en la cual
Figure imgf000032_0001
or a pharmaceutically acceptable salt thereof, in which X representa un grupo 2-NO2, 3-NO2, 2-Cl, 2-CF3 y 2,3-Cl2; X represents a group 2-NO 2 , 3-NO 2 , 2-Cl, 2-CF 3 and 2,3-Cl 2 ; n es un número igual a 1, 2 ó 3.  n is a number equal to 1, 2 or 3. 2.- Un compuesto según la reivindicación 1, caracterizado porque está seleccionado entre los siguientes:  2. A compound according to claim 1, characterized in that it is selected from the following: 2 ,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidropiridina-3-carboxila to de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]eti¬lo (Diclorhidrato);  2, 6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxy to 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] eti¬lo (Dihydrochloride); 4-(2,3-Diclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxi¬lato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo (Diclorhidrato);  4- (2,3-Dichlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl (Hydrochloride); 4-(2,3-Diclorofeml)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo (Diclorhidrato);  4- (2,3-Dichlorofeml) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 3- [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl (Hydrochloride); 2,6-Dimetil-5-[1,3-di-(N-morfolmil)-2-propoxicarbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carbo xilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)] etilo; 2,6-Dimethyl-5- [1,3-di- (N-morpholmil) -2-propoxycarbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carbo 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl xylate; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)=-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido) etilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) = -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 2- [N- (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide) ethyl; 4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfo¬linil)-2-propoxicarbónil]-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo;  4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl; 4-(2,3-Diclorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo;  [N- (4- (2,3-Dichlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidroporidina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydroporidine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]metilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate [N- (1, 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl; 4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]meti¬lo;  [N- (1, Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N- (1, 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo; 4-(2-Clorofenil)-2,6-dimetil-5-/Í,3-di-(N-morfolinil)-2-propoxicarbonily-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo; 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 4- (2-Chlorophenyl) -2,6-dimethyl-5- / Í, 3-di- (N-morpholinyl) -2-propoxycarbonily-1,4-dihydropyridine-3-carboxylate 3- [N- (1 , 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 3.- Un procedimiento para la preparación de compuestos de fórmula (I):  3.- A process for the preparation of compounds of formula (I):
Figure imgf000034_0002
Figure imgf000034_0002
 o una sal farmacéuticamente aceptable de los mismos , en la cual or a pharmaceutically acceptable salt thereof, in which X representa un grupo 2-NO2, 3-NO2, 2-Cl, X represents a group 2-NO 2 , 3-NO 2 , 2-Cl, 2-CF3 y 2,3-Cl2; 2-CF 3 and 2,3-Cl 2 ; n es un número igual a 1, 2 o 3;  n is a number equal to 1, 2 or 3; cuyo procedimiento se caracteriza por estar seleccionado entre los siguientes: whose procedure is characterized by being selected from the following: a) hacer reaccionar un compuesto de fórmula (II):  a) reacting a compound of formula (II):
Figure imgf000034_0001
Figure imgf000034_0001
 en la cual X y n son los definidos anteriormente, con un compuesto de fórmula (III) in which X and n are those defined above, with a compound of formula (III)
Figure imgf000035_0001
Figure imgf000035_0001
 para dar un compuesto de fórmula (I); o to give a compound of formula (I); or b) hacer reaccionar un compuesto de fórmula (IV)  b) react a compound of formula (IV)
Figure imgf000035_0002
en la cual X es la definida anteriormente, con un compuesto de fórmula (V)
Figure imgf000035_0002
in which X is defined above, with a compound of formula (V)
Figure imgf000035_0003
en la cual n es el definido anteriormente, para dar un compuesto de fórmula (I); o
Figure imgf000035_0003
in which n is the one defined above, to give a compound of formula (I); or c) hacer reaccionar un compuesto de fórmula (VI)  c) reacting a compound of formula (VI)
Figure imgf000036_0001
Figure imgf000036_0001
 en la cual n es el definido anteriormente, con un compuesto de fórmula (III) y un compuesto de fórmula (VII) in which n is defined above, with a compound of formula (III) and a compound of formula (VII)
Figure imgf000036_0002
Figure imgf000036_0002
 en la cual X es el definido anteriormente, para dar un compuesto de fórmula (I); o in which X is as defined above, to give a compound of formula (I); or d) hacer reaccionar un compuesto de fórmula (VIII)  d) reacting a compound of formula (VIII)
Figure imgf000036_0003
con un compuesto de fórmula (V) en la cual n es la definida anteriormente, y un compuesto de fórmula (VII) en - la cual X es la definida anteriormente, para dar un com •puesto de fórmula (I); o
Figure imgf000036_0003
with a compound of formula (V) in which n is the one defined above, and a compound of formula (VII) in - which X is the one defined above, to give a com • position of formula (I); or e) hacer reaccionar un compuesto de fórmula e) reacting a compound of formula (VI), en la cual n es la definida anteriormente, con un compuesto de fórmula (VIII) y con un compuesto de fórmula(VI), in which n is defined above, with a compound of formula (VIII) and with a compound of formula (VII), en la cual X es la definida anteriormente, en presencia de amoníaco, para dar un compuesto de fórmula (I); y opcionalmente, después de cualquiera de los procedimientos (a) a (e) anteriores, formar una sal farmacéuticamente aceptable del compuesto de fórmula (I) obtenido. (VII), in which X is the one defined above, in the presence of ammonia, to give a compound of formula (I); and optionally, after any of the procedures (a) to (e) above, form a pharmaceutically acceptable salt of the compound of formula (I) obtained. 4.- Medicamentos destinados al tratamiento preventivo o curativo de enfermedades del corazón o vasculares y al tratamiento de procesos espasmódicos de la fibra lisa no vascular, caracterizados porque contienen como componente activo al menos un compuesto de fórmula (I):  4.- Medicines intended for preventive or curative treatment of heart or vascular diseases and for the treatment of spasmodic processes of non-vascular smooth fiber, characterized in that they contain at least one compound of formula (I) as active component:
Figure imgf000037_0001
o una sal farmacéuticamente aceptable, en la cual
Figure imgf000037_0001
or a pharmaceutically acceptable salt, in which X representa un grupo 2-NO2, 3-NO2, 2-Cl, 2-CF3 y 2,3-Cl2; X represents a group 2-NO 2 , 3-NO 2 , 2-Cl, 2-CF 3 and 2,3-Cl 2 ; n es un número igual a 1, 2 ó 3.  n is a number equal to 1, 2 or 3. 5.- Medicamentos según la reivindicación 4, caracterizados porque el componente activo está seleccionado entre los siguientes compuestos:  5. Medicaments according to claim 4, characterized in that the active component is selected from the following compounds: 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)] etilo (Diclorhidrato); 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 2- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl (hydrochloride); 4-(2,3-Diclorofenil)-2,6-dimeti1-5-[1,3-di- (N-morfoliml)-2-propoxicarbónil]-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1- dióxido)]etilo (Diclorhidrato);  2- [N-4- (2,3-Dichlorophenyl) -2,6-dimeti1-5- [1,3-di- (N-morpholiml) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl (Hydrochloride); 4-(2,3-Diclorofeml)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo (Diclorhidrato);  4- (2,3-Dichlorofeml) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 3- [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl (Hydrochloride); 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxi¬carbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxy¬carbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate 2- [N - (1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl; 2,6-Dimeti1-5-/1,3-di-(N-morfolinil )-2-propoxicarbonil]-4-(2-trifluormetilfenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo;  2,6-Dimeti1-5- / 1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 2-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido))]etilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 2- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide))] ethyl; 4-(2-Clorofenil)-2,6-dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de 2-[N-1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]etilo;  2- [N-1 4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate , 2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] ethyl; 4-(2,3-Diclorofenil)-2,6-dimetil-5-[l,3-di-(N-morfolinil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)] metilo;  [N- (4- (2,3-Dichlorophenyl) -2,6-dimethyl-5- [l, 3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] methyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(2-nitrofenil)-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzisotiazolil-3(2H)ona-1,1-dióxido)]propilo;  2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (2-nitrophenyl) -1,4-dihydropyridine-3-carboxylate 3- [N- ( 1,2-benzisothiazolyl-3 (2H) one-1,1-dioxide)] propyl; 2,6-Dimetil-5-[1,3-di-(N-morfolinil)-2-propoxicarbonil]-4-(3-nitrofenil)-1,4-dihidropiridina-3-carboxila to de [N-(l,2-benzιsotιazolιl-3(2H)ona-l,1-dιóxιdo)]meti¬lo; 2,6-Dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxyla to of [N- (l, 2-benzιsotιazolιl-3 (2H) ona-l, 1-dιóxιdo)] put it; 4-(2-Clorofenιl)-2,6-dιmetil-5-[1,3-di-(N-morfo¬linil)-2-propoxicarbonil]-1,4-dihidropiridina-3-carboxilato de [N-(1,2-benzιsotιazolil-3(2H)ona-1,1-dιóxιdo)]meti¬lo;  [N- (4- (2-Chlorophenyl) -2,6-dιmethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzιsotιazolyl-3 (2H) one-1,1-dioxod)] meti¬lo; 2,6-Dιmetιl-5-A,3-dι-(N-morfolinil)-2-propoxicarbonil]-4-(3-nιtrofenil)-1,4-dιhιdropiridina-3-carboxilato de 3-[N-(1,2-benzιsotiazolil-3(2H)ona-1,1-dιóxιdo)]propilo;  2,6-Dιmetιl-5-A, 3-dι- (N-morpholinyl) -2-propoxycarbonyl] -4- (3-nιtrophenyl) -1,4-dιhιdropiridine-3-carboxylate 3- [N- (1 , 2-benzisothiazolyl-3 (2H) one-1,1-dioxido)] propyl; 4-(2-Clorofenil)-2,6-dimetιl-5-[1,3-di-(N-morfolinil)-2-propoxιcarbonil]-1,4-dihidropiridina-3-carboxilato de 3-[N-(1,2-benzιsotιazolil-3(2H)ona-1,1-dιóxιdo)]propilo.  3- [N- (4- (2-Chlorophenyl) -2,6-dimethyl-5- [1,3-di- (N-morpholinyl) -2-propoxycarbonyl] -1,4-dihydropyridine-3-carboxylate 1,2-benzιsotιazolyl-3 (2H) one-1,1-dioxyl)] propyl. 6.- Medicamentos según las reivindicaciones 4 y 5, caracterizados porque, además del componente activo, contienen excipientes farmacéuticamente aceptables.  6. Medicaments according to claims 4 and 5, characterized in that, in addition to the active component, they contain pharmaceutically acceptable excipients. 7.- Aplicación en el tratamiento preventivo o - curativo de enfermedades del corazón o vasculares y en el tratamiento de procesos espasmódicos de la fibra lisa no vascular , de compuestos representados por la siguiente - fórmula (I):  7.- Application in the preventive or curative treatment of heart or vascular diseases and in the treatment of spasmodic processes of non-vascular smooth fiber, of compounds represented by the following - formula (I):
Figure imgf000039_0001
Figure imgf000039_0001
 o una sal farmacéuticamente aceptable, en la cual or a pharmaceutically acceptable salt, in which X representa un grupo 2-NO2 3-NO2, 2-Cl, X represents a group 2-NO 2 3-NO 2 , 2-Cl, 2-CF3 y 2,3-Cl2; 2-CF 3 and 2,3-Cl 2 ; n es un número igual a 1, 2 ó 3.  n is a number equal to 1, 2 or 3.
PCT/ES1994/000116 1993-11-19 1994-11-11 New 1,4-dihidropyridine derivatives, process for their preparation and utilization as therapeutic agents Ceased WO1995014018A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253092A1 (en) * 1986-05-28 1988-01-20 Alter, S.A. 1,4-Dihydropyridines, processes for their preparation and their use as antithrombotic drugs
EP0441736A2 (en) * 1990-02-06 1991-08-14 Alter, S.A. New 1,4-dihydropyridine derivatives, a process for their preparation and their use for influencing the blood flow

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253092A1 (en) * 1986-05-28 1988-01-20 Alter, S.A. 1,4-Dihydropyridines, processes for their preparation and their use as antithrombotic drugs
EP0441736A2 (en) * 1990-02-06 1991-08-14 Alter, S.A. New 1,4-dihydropyridine derivatives, a process for their preparation and their use for influencing the blood flow

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