MXPA01003568A - Derivatives of isosorbid mononitrate, utilization as vasodilator agents with reduced tolerance - Google Patents

Abstract

Disclosed are derivatives of isosorbid mononitrate and pharmaceutically acceptable salts thereof which have a vasodilator activity with a reduced tolerance effect, having the general formula (I) wherein A and B represent independently any of the groups NO2 and-CO-R, Z being an atom of oxygen or sulfur, and R being optionally substituted C1-C4 alkyl, aryl or aralkyl group or the group (a) wherein R1 is hydrogen or optionally substituted C1-C4 alkyl, aryl or aralkyl group,so that always either A or B is NO2 but never both at the same time, when Z is a sulfur atom R is optionally substituted C1-C4 alkyl, aryl or aralkyl group, and when Z is an oxygen atom R is the group (a).

Description

DERIVATIVES OF ISOSORBID MONONITRATE AND ITS EMPLOYMENT AS VASODILATOR AGENTS WITH DECREASED TOLERANCE.

Field of the art The present invention relates to new isosorbide mononitrate derivatives which possess a potent vasodilating activity and which, at the same time, exhibit a significantly reduced tolerance.

STATE OF THE PRIOR ART Nitric acid esters with organic compounds, commonly known as organic nitrates, have been known and used for a long time as vasodilating agents. Among them, the usefulness of isosorbide nitrates, mononitrate and dinitrate is well known, and compounds with vascular and coronary activity based on substitution reactions in the free hydroxyl of isosorbide mononitrate have also been described. For example, US-A-4891373 discloses 2-inpropanol derivatives corresponding to the formulas indicated for the treatment of angina pectoris and systemic and pulmonary hypertension. For its part, US-A-5665766 discloses the 5-mononitrate of isosorbide 2-acetylsalicylate, of the formula Ref: 128211 as well as its platelet antiaggregant activity. One of the main drawbacks of the organic nitrates mentioned lies in the fact that they are quite sensitive to the phenomenon known as ta-quifilaxia or tolerance, which means that the body's response to its effect decreases during a prolonged treatment, which requires gradually increasing the doses supplied, or performing a pharmacological wash. It is also known that one way to reduce the tolerance in organic nitrates is to introduce thiol groups into the molecule, for example by means of sulfur-containing amino acids. Thus, in European patent EP-B-0362575 organic nitrates are described that incorporate molecules of cysteine, especially, and methionine. Patent application WO-A-92/04337 discloses organic nitrates derived from the thiazolidine ring with vasodilating activity and a decreased tolerance. Patent application WO-A-93/03037 discloses a huge variety of organic nitrates vasodilators, with diminished tolerance, of very variable structures, among which is included in a generic manner, ie without specifying or describing a single product assignable to it, to isosorbide mononitrate derivatives assignable to the chemical structure wherein Rs represents a hydrogen atom, a C-C6 alkyl group, a phenyl, etc. The organic nitrates described in the aforementioned documents alone do not solve the problems caused by the tolerance of organic nitrates, since they still manifest problems related to low vasodilator activity, intensity in the reduction of tolerance > etc., so there is a need to have new organic nitrates that, maintaining a high vasodilatory activity, show a tolerance degree that is even more diminished and more persistent.

OBJECT OF THE INVENTION The object of the invention is a new type of compounds derived from isosorbide mononitrate capable of provoking a potent vasodilator effect, and which show little or no effect of tolerance. Another object of the present invention is the use of the new isosorbide mononitrate derivatives in the preparation of medicaments for the treatment of disorders related to dysfunctions of the circulatory system, especially at the level of the coronary system.

DESCRIPTION OF THE INVENTION The new derivatives of isosorbide mononitrate, and their pharmaceutically acceptable salts, object of the invention correspond to the general formula (I) where A and B indistinctly represent any of the groups -ONO 2 •, Z being an oxygen or sulfur atom, and R represents an optionally substituted aryl or aralkyl alkyl group, or the group wherein R 1 is hydrogen or an optionally substituted C 1, aryl or aralkyl alkyl group. All this in such a way that: a) always one of A or B is -0N02, but never both at the same time; b) when Z is a sulfur atom R is an optionally substituted Ci-C, aryl or aralkyl alkyl group; and c) when Z is an oxygen atom R is the group wherein R1 represents the groups indicated above. Among the new derivatives object of the invention, those in which, when S is a sulfur atom, R is a short chain alkyl group and, when Z is an oxygen atom, R 1 is a hydrogen atom are preferred. or a Cj-C4 short chain alkyl group, with those in which B is the group -0N02, ie those in which the nitrate ester group is in the 5-position, being especially preferred within the mentioned criteria. of the ring system of the isosorbide. The preferences indicated should not be considered, in any case, as limiting the scope of the object of the present invention. In the case that R1 is hydrogen, the compounds object of the present invention can be represented as any of their two tautomers and both tautomeric structures should be considered within the object of the present invention. As concrete examples of compounds forming part of the object of the present invention, the following may be mentioned: isosorbide 2- (2'-ethylthio) nicotinate 5-mononitrate, 2- (2'-ethylthio) mononitrate ) isosorbide nicotinate, of formula -mononitrate of isosorbide 2- (2'-mercaptone) nicotinate, of formula 2 - . 2 - . 2-isosorbide 5- (2'-mercapto) nicotinate monomitrate, of formula 2-acetylmercaptoisosorbide 5-mononitrate, of formula -isosorbide 2- (2'-methylthio) nicotinate mononitrate, of formula 2-isosorbide 5- (2'-methylthio) nicotinate mononitrate, of formula , as well as its pharmaceutically acceptable salts, especially its hydrochlorides. Compound i and its hydrochloride and compound 5 are especially preferred. The compounds of the present invention can be obtained by esterification techniques, from products known and / or accessible to the expert in the fundamental literature on organic chemistry, by Examples are the Chemical Abstracts Service publications or the Beilstein encyclopedia on organic products, or any other appropriate publication that can be accessed in university libraries. Thus, for example, when Z is an oxygen atom the compounds can be obtained from the isosorbide or the corresponding isosorbide mononitrate by reaction of esterification thereof with the corresponding carboxylic acid or an activated derivative thereof, for example a chloride of acid, an acid anhydride, an active ester, etc. If part of the isosorbide it is necessary to proceed, subsequently, to the formation of the nitrate ester of the free hydroxyl thereof, which is not necessary if starting from either of the two mononitrates of the isosorbide, either in position 5 or in position 2 of the annular structure of said compound. These compounds, when R1 is a hydrogen atom, that is to say when they possess a free thiol group, can be oxidized to disulfides forming dimers. The corresponding monomers are obtained by treating said dimers with triphenylphosphine in water, as described in R. Humphrey (1964), Analytical Chem, 36.1812 and LEOver an (1974), Synthesis, 59. When Z is a sulfur atom the situation turns out to be very similar since it suffices to start from the corresponding thiocarboxylic acid instead of the aforementioned carboxylic acid and use the techniques, well known to the expert, for the formation of the thioester bond. On the other hand, if any of the reactions involve epimerization of a chiral center, the appropriate enantiomer of isosorbide can be used as starting material., for example isomanide. The tests carried out show that the new isosorbide mononitrate derivatives object of the invention possess a vasodilator activity comparable, at least, with that of isosorbide mononitrate itself, and in some cases much higher, but they show a tolerance significantly lower than that observed in said compound, which in some cases becomes practically nil. This means that the compounds of the pre-senté invention can be used very effectively in the preparation of drugs with vasodilator effect for the treatment of dysfunctions of the circulatory system, especially at the cardiovascular and coronary level. Therefore, the compounds of the general formula (I), as well as their pharmaceutically acceptable salts, can be used, by using conventional galenic techniques, to prepare drugs that can be administered by different routes. By way of example it can be noted that orally they can be administered in the form of pharmaceutical preparations such as tablets, capsules, syrups and suspensions. Parenterally in the form of solutions or emulsions, etc. They can also be administered topically in the form of creams, ointments, ointments, etc., and also transdermally, for example by means of par-ches and dressings. They can also be applied directly to the rectum, in the form of suppositories. The preparations may contain physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers, etc. In the case of injectables, physiologically acceptable buffers, solubilizing or isotonic agents can be incorporated. The daily dose may vary depending on the symptomatology, age, body weight of the patients, the mode of administration, etc., and the normal daily dose for an adult may be between 1 and 500 mg. be administered in a single dose or divided into several doses per day. In the examples that are set forth in this description, the appropriate procedures for obtaining several of the compounds assignable to the general formula (I) are detailed. In view of said examples, for the person skilled in the art, the way to obtain the compounds not expressly exemplified is evident and direct, through the application of modifications of the exposed methods, typical of the general common knowledge of those skilled in the art. . Thus, the examples set forth below should not be construed as limiting the scope of the present invention, but as an additional, more detailed explanation facilitating the former. I have a better understanding of the subject.

Examples The compounds obtained in the following examples are identified by their spectroscopic infrared (IR) and / or proton nuclear magnetic resonance (H-NMR) and carbon 13 ("C-NMR") spectra. of IR have been made in evaporated film of CHC13 or in tablet KBr, in a device PER-KIN-ELMER FTIR model 1700. The position of the most significant bands in cm "1 is indicated. The nuclear magnetic resonance spectra were performed on a Varian Gemini-200 device. The frequency of work and the solvent used to carry out the spectrum are indicated in the XH-NMR spectra. The position of the signals is indicated in d (ppm), using as a reference the signal of the solvent protons. 7.24 ppm for chloroform and 2.49 ppm for deuterated dimethylsulfoxide are taken as reference values. Parentheses indicate the number of protons corresponding to each signal measured by electronic integration and the type of signal using the following abbreviations: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), sa ( wide signal), sc (complex signal), D20 (disappears when performing the spectrum after adding a few drops of deuterated water). The working frequency and the solvent used in each spectrum are indicated in the 13 C-NMR spectra. The position of the signals is indicated in d (ppm), using as a reference the signal of the solvent protons. The reference values are 77.00 ppm for chloroform and 39.50 ppm for deuterated dimethylsulfoxide. Nuclear magnetic resonance experiments have also been performed using the pulse sequence APT (Attached Proton Test). In the experimental part of the examples the following abbreviations are used: AcOEt ethyl acetate DMS0-d6 hexadeuterated dimethylsulfoxide EtOEt diethyl ether Example 1 Obtaining the hydrochloride of 5- (2'-ethylthio) nicotinate monositrate of isosorbide (1).

Stage 1.- In a 50 mL flask, fitted with a reflux condenser capped with a CaCl2 tube and magnetic stirring, 4.25 g (23.2 mmol) of 2-ethythionicotinic acid are dissolved in 20 mL of sodium chloride. thionyl (1.64 g / ml, 275.6 mmol). The reaction mixture is refluxed for 3.5 h. After this time, the mixture is cooled and the excess of thionyl chloride is removed under reduced pressure, adding portions of toluene. 4.67 g of a yellowish solid corresponding to the acid chloride product of interest are obtained after drying under reduced pressure. Performance: 100%. Step 2. - In a 50 ml flask, provided with magnetic stirring and reflux condenser, 4.67 g (23.2 mmol) of the acid chloride obtained in the previous step are dissolved in Ar-atmosphere. 25 mL of pyridine. Cool with an ice bath and add 4.44 g (23.2 mmol) of isosorbide mononitrate. The reaction mixture is left stirring at room temperature and in Ar atmosphere for 19 h. After this time, the solvent is removed under reduced pressure. The residue is dissolved in 50 mL of CHCl3 and washed: first with 50 mL of water, secondly with 50 mL of 5% aqueous HCl solution and again with 50 mL of water. The organic phase is dried over anhydrous MgSO 3, filtered and the solvent is removed under reduced pressure. 7.25 g of the product of interest are obtained after drying under reduced pressure. Yield: 88%. Step 3. - 6.0 g (16.85 mmol) are dissolved in a 250 ml 3-neck flask equipped with magnetic stirring, reflux condenser capped with a CaCl2 tube and a pressure-compensated addition funnel. of the product obtained in the previous step in 150 mL of EtOEt. The mixture is stirred at room temperature and 30 mL of EtOEt solution saturated with HCl (previously prepared solution by bubbling gas HCl directly into the EtOEt until saturation thereof) is added dropwise, producing precipitation of a white solid. . Filter and wash the solid with abundant EtOEt and dry under reduced pressure. 6.55 g of the product of interest are obtained. Performance: 99%. 'H-NMR (200 MHz. DMSO-d,): 10.26 (1H, s, of D20, HCl), 8.60 (1H, dd, J = 5 Hz, J = 1.8 Hz, CHar), 8.20 (1H , dd, J = 7.7 Hz, J = 2 Hz, CHar), 7.22 (1H, dd, J = 3 Hz, J = 8 Hz, CHar), 5.43 (1H, sc, CH-ON02), 5.30 (1 H , d, J = 3 Hz, CH-O-CO), 5.05 (1H, t, J = 5.5 Hz, CH), 4.65 (1H, d, J = 5 Hz, CH), 4.20-3.80 (4H, sc , CH2), 3.17 (2H, q, J = 7.6 Hz, CH2 -S), 1.23 (3H, t, J = 7.6 Hz, CH3). "C-NMR (50 MHz. DMSO-d,): 164.06 (C = 0), 161.34 (Car-COO), 152.88 (CHar), 139.63 (C ar), 122.48 (Car-S), 119.13 (C ar), 86.19 (CH-ON02), 82.64 (CH), 81.78 (CH), 78.10 (CH-O-CO), 72.90 (CH2), 69.33 (CH2), 23.84 (CH2-S), 14.31 (CH3).

E g 2 Obtaining 2- (2'-ethylthio) nicotinate isosorbide 2- (2) mononitrate hydrochloride.

Step 1.- The same method used in stage 2 of example 1 is used, using as starting material the 2-isosorbide mononitrate. The product of interest is obtained with a chemical yield of 88%. Step 2. - In a 500 ml 3-neck flask, fitted with magnetic stirring, reflux condenser capped with a CaCl 2 tube and a pressure-compensated addition funnel, 7.0 g (19.66 mmol) of the product obtained in the previous stage in a mixture of 200 mL of EtOEt + 100 mL of CH2C12. HE. stir at room temperature and add dropwise 30 mL of EtOEt solution saturated with HCl (previously prepared solution by bubbling HCl gas directly into the EtOEt until saturation thereof), producing precipitation of a white solid. Filter and wash the solid with abundant EtOEt and dry under reduced pressure. 7.05 g of the product of interest are obtained. Yield: 91%.

'H-NMR (200 MHz. DMSO-d £): 8.63 (1H, dd, J = 5 Hz, J = 1.8 Hz, CHar), 8.33 (1H, sa, of D20, HCl), 8.23 (1H, dd , J = 8 Hz, J = 1.8 Hz, CHar), 7.24 (1H, dd, J = 3 Hz, J = 7.8 Hz, CHar), 5.44 (1H, d, J = 3.2 Hz, CH-O-CO), 5.33 (1H, sc, CHONO), 4.91 (1H, t, J = 5.6 Hz, CH), 4.67 (1H, d, J = 5.4 Hz, CH), 4.20-3.80 (4H, sc, CH2), 3.08 (2H, q, J = 7.2 Hz, CH.-S), 1.20 (3H, t J = 7.2 Hz CH3) "C-NMR (50 MHz, DMSO-d¿): 163.74 (C = 0), 161.53 (Car-COO), 152.77 (CHar), 139.24 (CHar), 122.05 (Car- bide). S), 119.01 (CHar), 86.65 (CH-ONO-), 84.13 (CH), 80.79 (CH), 74.48 (CH-O-CO), 70.78 (CH2-0), 70.70 (CH.-O), 23.67 (CH2), 14.14 (CH3).

Example 3. - Obtaining isosorbide 2- (2-mercapto) nicotinate 5-mononitrate (3.).

Step 1. - In a 100 ml flask, fitted with a reflux condenser capped with a CaCl2 tube and magnetic stirring, suspend 3.0 g (19.35 mmol) of 2-mercaptonicotinic acid in 30 mL of sodium chloride. thionyl (1.64 g / ml; 413.4 mmol). The reaction mixture is brought to re-flow for 2 h, observing the dissolution of the solid during this period. The reaction is cooled and the excess of thionyl chloride is removed under reduced pressure by adding portions of toluene. Obtained after drying under reduced pressure, 3.35 g of a yellow-orange solid corresponding to the acid chloride of interest. Performance, 100%. Step 2. - In a 250 ml flask, provided with magnetic stirring and reflux condenser, 3.0 g (17.29 mmol) of the acid chloride obtained in the previous step in 75 mL are suspended under Ar atmosphere. of pyridine. Cool with an ice bath and add 3.30 g (17.29 mmol) of 5-isosorbide mononitrate. The reaction mixture is allowed to stir at room temperature and under Ar atmosphere for 19 h, during which time the mixture darkens. After the reaction is complete, the solvent is removed under reduced pressure. The residue is dissolved in 250 mL of CHC13 and washed: first with 250 mL of water, second with 250 mL of aqueous solution of 5% HCl and again with 250 'mL of water. The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is removed under reduced pressure. 5.45 g of a yellow solid is obtained after drying under reduced pressure. It is recrystallized from isopropyl alcohol to obtain 4.83 g of a white solid, which is subsequently treated in an acid medium with triphenylphosphine (1: 1.25 molar) in methanol, with 10% water, for 20 min. The solvent is removed under reduced pressure and the residue is dissolved in AcOEt which is washed with water. The organic phase is dried and the solvent is removed under reduced pressure, the product of interest being isolated by preparative chromatography. Yield: 35.7% 'H-NMR (200 MHz, Cd3COCd3): 7.90 (1H, dd, J = 6.1 Hz, J = 1.6 Hz, CHar), 7.70 (1H, dd, J = 7.2 Hz, J = l .6 Hz, CHar), 6. 97 (1H, dd, J = 6.4 Hz, J = 7.2 Hz, CHar), 5.63-5.55 (1H, sc, CH-ON02), 5.38 (1H, d, J = 3.4 Hz, CH-O-CO), 5.09 (1H, t, J = 5.1 Hz, CH), 4.75 (1H, d, J = 4.8 Hz, CH), 4.20-3.85 (4H, sc, CH2). IR (p.KBr): 3438.2925, 1735, 1639, 1571, 1281, 1095.

Example 4.- Obtaining 2- (2'-mercapto) nicotinate isosorbide 2-msnonitrate (4.).

In a 250 ml flask, provided with magnetic stirring and reflux condenser, 3.0 g (17.29 mmol) of the acid chloride obtained in step 1 of example 3 are suspended in an Ar atmosphere under an Ar atmosphere. 50 mL of pyridine and 25 L of CHC13. Cool with an ice bath and add 3.30 g (17.29 mmol) of 2-isosorbide mononitrate. The reaction mixture is allowed to stir at room temperature and under Ar atmosphere for 19 h, during which time the mixture darkens. When the reaction is finished, the solvent is removed at re-ducted pressure. The residue is dissolved in 300 mL of CHC13 and washed: first with 300 mL of water, second with 300 mL of 5% aqueous HCl solution and again with 300 mL of water. The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is removed under reduced pressure. 5.10 g of a yellowish-white solid is obtained after drying under reduced pressure. It is recrystallized from isopropyl alcohol to obtain 4.55 g of a white solid, which is subsequently treated in an acid medium with triphenylphosphine (1: 1.25 molar) in methanol, with 10% water, for 20 min. The solvent is removed under reduced pressure and the residue is dissolved in AcOEt which is washed with water. The organic phase is dried and the solvent is removed under reduced pressure, the product of interest being isolated by preparative chromatography. Yield: 37.6%. 'H-NMR (200 MHz, Cd3COCd3): 7.98 (1H, dd, J = 4.2 Hz, J = 1.0 Hz, CHar), 7.76 (1H, dd, J = 4.9 Hz, J = 1.0 Hz, CHar ), 7.34 (1H, dd, J = 4.5 Hz, J = 4.8 Hz, CH «), 5.50-5.36 (2H, sc, CH-ON02 + CH-0-CO), 5.02 (1H, t, J = 3.7 Hz, CH), 4.74 (1H, d, J = 3.4 Hz, CH), 4.20-3.90 (4H, sc, CH2). IR (p.KBr): 3395, 2876, 1727, 1653, 1631, 1593, 1291, 1276.

Example 5.- Obtaining 2-acetylmer-captoisosorbide 5-mononitrate (5).

Step 1. - In a 1 L flask equipped with reflux condenser, compensated pressure addition funnel and magnetic stirring, 60 g (411 mmol) of isomannide, 88 g (461 mmol) of paratoluensulfonyl chloride, 296 mL are mixed. of CC14, 33 mL of CH2Cl2 and 247 mL of H2O. An atmosphere of Ar is created and a solution of 29.9 g (453 mmol) of 85% KOH is added dropwise and keeping the reaction temperature at 5 ° C. The addition time is 1 h 20 min. The resulting mixture is stirred at 5 ° C for 7 h. The solid is filtered and washed with 2 x 125 mL portions of H20 and dried under reduced pressure. The solid obtained is recrystallized from 1200 mL of CC14, filtering hot and allowing the filtrate to cool. The crystals obtained are filtered and washed yielding 54.5 g of a fraction A of the product of interest, isomanide monotosylate. The solid resulting from the hot filtration is recrystallized from 1000 mL of CC14 obtaining 29.5 g of a B fraction of the product of interest. Step 2. - In a 500 L flask equipped with reflux condenser and magnetic stirring, 22.7 g (76 mmol) of isomanide monotosylate and 13.0 g (113 mmol) of potassium thioacetate are mixed in 113 mL of n. -butanol. An atmosphere of Ar is created and brought to reflux for 1 h. Cool, filter, wash with 200 mL of ethanol and remove the solvents under reduced pressure. 20 g of a solid are obtained. Analysis by thin-layer chromatography with an independent sample indicates that the product of interest is not predominant in crude oil. The crude obtained is treated with 300 mL of n-butanol and 40 mL of thioacetic acid at reflux for 1 h. Allow to cool and filter on a layer of Si02. The solvents of the filtrate are evaporated under reduced pressure to obtain a crude product which is subjected to Flash chromatography. For the chromatographic separation, a CHCl3 / Ac0Et 4: 1 mixture is used as the eluent. A fraction of 4.14 g of product of interest, 2-acetyl mercapto isosorbide sufficiently pure to be used in the next synthesis step is obtained. Various fractions of the product of interest are obtained with enough impurities. These latter fractions are subjected to preparative reverse phase chromatography obtaining the purification of the desired product. Stage 3. - Prepare a nitrating mixture by adding, slowly and with caution, 2.4 ml of 60% HN03 on one. mixture of 10 mL of acetic anhydride and 10 mL of acetic acid. The preparation is carried out at 0 ° C. In a 100 mL flask equipped with a reflux condenser and magnetic stirring, 2.51 g (12.3 mmol) of the product obtained in the previous step are dissolved in 14.5 mL of water at 0 ° C. acetic acid and, after stirring for a few instants, the previously prepared nitrating mixture is added dropwise, for 20 minutes, keeping the temperature at 0 ° C. It is stirred for 2 h at 0 ° C, the crude oil is poured on 200 mL of water and portions of AcOEt are extracted with 3 x 200 mL. Each of the three portions is washed separately with 2 x 220 mL portions of a saturated solution of NaHCO 3 and 200 mL of water. Dry over Na 2 SO 4, filter and remove the solvents under reduced pressure. 2.4 g of a crude product is obtained which is subjected to Flash chromatography using a CHCl 3 / AcOEt 25: 1 mixture as eluent. 2.08 g of the product of inserts are obtained. Performance 68%. 'H-NMR (200 MHz. CDC1: 5.36-5.24 (1H, sc, CH-0N02), 4.90-4.80 (1H, SC, CH), 4.44-4.37 (1H, sc, CH), 4.22-4.10 (1H , sc, CH), 4.10-3.98 (2H, sc, CH2), 3.92-3.78 (2H, sc, CH2), 2.33 (3H, s, CH3). 13C-NMR (50 MHz, CDC1: 194.48 (C = 0), 86.50 (CH- ON02), 81.44 (CH), 81.22 (CH), 78.48 (CH2), 69.25 (CH2), 45.92 (CH-S), 30.48 (CH3).

IR (ctn "'): 300-2800, 1700, 1650, 1630, 1280, 1080, 960.

Example 6 Obtaining isosorbide 2- (2'-methylthio) nicotinate 5-mononitrate (6.).

In a 50 mL flask, provided with magnetic stirring and reflux condenser, 2.00 g (10.7 mmol) of 2-methyl-thienicotinic acid chloride in 12 mL of pyridine are suspended in Ar-atmosphere. Cool with an ice bath and add 2.04 g (10.7 mmol) of 5-isossrbide mononitrate. The reaction mixture is allowed to stir at room temperature and under Ar atmosphere for 15 h. After this time, the solvent is removed under reduced pressure. The residue is dissolved in 50 mL of CHC13 and washed: first with 50 L of water, second with 50 mL of aqueous solution of 5% HCl and again with 50 mL of water. The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is removed under reduced pressure. 2.80 g of the product of interest are obtained after drying under reduced pressure. Performance: 77%.

'H-NMR (200 MHz, DMS0-d6): 8.68 (lH, dd, J = 5 Hz, J = 1.8 Hz, CHar), 8.22 (lH, dd, J = 7.7 Hz, J = 2 Hz, CHar) , 7.26 (lH, dd, J = 3 Hz, J = 8 Hz, CH "), 5.54 (1H, td, J = 2 Hz, J = 6 Hz, CH-0N02), 5.34 (lH, d, J = 3 Hz, CH-O-CO), 5.06 (1H, t, J = 5.5Hz, CH), 4.58 (1H, d, J = 5 Hz, CH), 4.18-3.82 (4H, sc, CH2), 2.45 (3H, s, CH3-S).

"C-NMR (50 MHz, DMS0-dβ): 163.191 (C = 0), 161.64 (Car-COO), 152.80 (Carar), 139.27 (Carar), 122.20 (C) ? rS), 118.83 (CHar), 85.97 (CH-ON02), 82.41 (CH), 81.53 (CH), 77.87 (CH-O-CO), 72.67 (CH2), 69.07 (CH.), 13.34 ( CH,).

Example 7 Obtaining isosorbide 5- (2'-methylthio) nicotinate 2-mononitrate (7).

In a 50 mL flask, provided with magnetic stirring and. reflux condenser, 2.00 g (10.7 mmol) of 2-methylthionicotinic acid chloride in 12 mL of pyridine are suspended under an Ar atmosphere. Cool with an ice bath and add 2.04 g (10.7 mmol) of 2-isosorbide mononitrate. The reaction mixture is allowed to stir at room temperature and under Ar atmosphere for 15 h. After this time, the solvent is eliminated under reduced pressure. The residue is dissolved in 50 mL of CHC13 and washed: first with 50 mL of water, secondly with 50 mL of 5% aqueous HCl solution and again with 50 mL of water. The organic phase is dried over anhydrous MgSO 4, filtered and the solvent is removed. at reduced pressure. 2.75 g of the product of interest are obtained after drying under reduced pressure. Performance: 75%.

'H-NMR (200 MHz, DMS0-ds): 8.90 (lH, dd, J = 5 Hz, J = 1.8 Hz, CHar), 8.27 (lH, dd, J = 7.7 Hz, J = 2 Hz, CHar), 7.27 (lH, dd, J = 3 Hz, J = 7.8 Hz, CHar), 5.42-5.31 (1H, SC, J = 2 Hz, J = 6 Hz, CH-ON02), 5.60 (lH, d , J = 3.2 Hz, CH-O-CO), 5.06 (1H, t, J = 5.5Hz, CH), 4.92 (1H, d, J = 5.6 Hz, CH), 4.10-3.88 (4H, sc, CH2 ), 1.24 (3H, s, CH3-S). 13 C-NMR (50 MHz, DMS0-ds): 163.71 (C = 0), 161.89 (Car-COO), 152.77 (CHar), 139.04 (C ar), 121.92 (Car-S), 118.87 (C ar), 86.56 ( CH-ON02), 84.05 (CH), 80.69 (CH) 74.41 (CH-O-CO), 70.69 (CH2), 70.61 (CH2), 13.37 (CH3).

Example 8.- Vasodilation assays. The methodology followed in the trials is substantially coincident with that described in the following bibliographical references: * Furchgot, R.F. "Methods in nitric oxide research". Feelisch & Stamler eds. John Wiley £ Sons, Chichester, England, pp 567-581. * Trongvanichnam, K, et al. Jpn J. Pharmacol. nineteen ninety six; 71: 167-173. * Salas, E., et al. Eur. J. Pharmacol. 1994; 258: 47-55. The different compounds are tested at five different concentrations, in a range of concentrations between 0.001 and 10 mM, using 6 to 9 arterial rings for each compound. The results obtained are compared with those provided by 5-isosorbide mononitrate, used as a reference product. The results are shown below in Table 1, and are expressed in CES0 (effective concentration 50), ie the concentration of each compound tested that produces a 50% vasodilation in the arterial ring previously contracted with 1 μM of norepinephrine.

As observed in the table, the two compounds tested show a potent vasodilator activity, at least similar to that of the reference product, being noteworthy that compound 1 shows a vasodilatory activity superior to that of the reference product.

Example 9.- Tolerance tests. The different tested compounds are administered subcutaneously to rats at doses of 10 mg / kg, every eight hours, for three days, and are tested ex vivo to check their ability to vasodilate rat arterial segments after subcutaneous administration of the compound. The methodology followed is substantially coincident with that described in the following bibliographical references: * De Garavilla, L., et al. Eur. J. Pharmacol. nineteen ninety six; 313: 89-96. * Keith, R.A., et al. J. Pharmacol. Exp. Ther. 1982; 221: 525-531. The different compounds are tested at five different concentrations, in a range of concentrations between 0.001 and 10 mM, using 6 to 9 arterial rings for each compound. The results obtained are compared with those provided by 5-isosorbide mononitrate, used as a reference product, and those obtained with animals that have not been administered the compound. The results obtained are shown in table 2, also expressed in CES0.

Table 2. Tolerance tests It is understood that a compound has developed tolerance when the CESO of the product in the vascular rings of the animals subjected to the administration of the compound, as specified, is higher than the CESO of the compound in the vascular rings of the animals that have not been submitted to the administration of the compound. The CE5o of 5-isosorbide mononitrate in the group of animals to which said compound was administered was seven times higher than that obtained in the animals to which they had not been supplied.

EC50 Group B = 7 EC50 Group A which indicates a strong development of tolerance for the reference product. In contrast, for the two compounds tested, 1 and 5., which form part of the object of the present invention, the ratio of CES0 obtained for both groups is significantly lower, which indicates a development of tolerance much lower than the reference product. cia, being of note that in the case of compound 5 the development of tolerance is practically nil under the conditions of the test. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds derived from isosorbide mononitrate, and their pharmaceutically acceptable salts, which correspond to the general formula (I) cscB? sUeácß because A and B represent irrllstiptarente any of the groups O -ON02; -z A. Z being an oxygen or sulfur atom, and R represents an optionally substituted Cj-C4, aryl or aralkyl alkenyl group, or the group wherein R1 is hydrogen or a Cj-C4 alkyl, aryl or aralkyl group, optionally substituted; all this in such a way that: a) always one of A or B is -0N02, but never both at the same time; b) when Z is a sulfur atom R is an optionally substituted Cj-C, aryl or aralkyl alkyl group; and c) when Z is an oxygen atom R is the group where R 'represents the groups indicated above.

2. Compounds, according to claim 1, characterized in that when S is a sulfur atom, R is a short chain alkyl group ^ C. and, when Z is an oxygen atom, R1 is a hydrogen atom or a short chain alkyl group Ca-C4.

3. Compounds, according to claims 1 or 2, characterized in that the substituent B is the group -0NO2.

4. The isosorbide 2- (2'-ethylthio) nicotinate 5-mononitrate compound and its pharmaceutically acceptable salts.

5. The compound, 2 -mononi time of 5- (2'-ethylthio) nicotinate of isosorbide and its pharmaceutically acceptable salts.

6. The compound 5-mononitrate of isosorbide 2- (2'-mercapto) icotinate and its pharmaceutically acceptable salts.

7. The compound 2-mononitrate of isosorbide 5- (2'-ercapto) nicotinate and its pharmaceutically acceptable salts.

8. The compound 5-mononitrate 2-acetylmer-captoisosorbide.

9. The use of the compounds of claims 1 to 8 to prepare drugs with vasodilator effect for the treatment of dysfunctions of the circulatory system.

10. The use, according to claim 9 < of the compounds of claims 1 to 8 for preparing medicaments for the treatment of cardiovascular and coronary dysfunctions.