MXPA96006345A - Derivatives of carboestirilo, compositions that contain them and use of them in the preparation of those compositions - Google Patents

Abstract

A method for reducing the size of infarction in a subject suffering from ischemic heart disease is described, said method using as the active agent a derivative of carbostiri

Description

DERIVATIVES OF CARBOESTIRILO, COMPOSITIONS THAT CONTAIN THEM AND USE OF THEM IN THE PREPARATION OF SUCH COMPOSITIONS FIELD OF THE INVENTION The present invention relates to a method for reducing the risk of infarction in a subject suffering from ischemic heart disease, said method used, such as a <) in e active, a derivative of carboes + ir the. THE BACKGROUND OF THE INVENTION I. Carboestip The derivatives of the carbostyril represented by the following general formula (I), and salts thereof, are well known in the art. wherein R is a benzoyl group which can + ener oponalinen + e yru? o (i) alkoxylium Tenorio) in >; 1 n of phenyl as? Bst? ? yen + e () the carbon-carbon bond at positions J and 4 of the carboestiplo skeleton is a single bond or a double enLace; (U.S. Patent No. 4,415,572, which is incorporated in <., Or entirety as referenced herein). It has been found that these carboestipls are oral noopic agents that increase myocardial contractility in model systems, with little effect on heart rate or oxygen consumption in the myocardium. (Feldman and others N. Engl. 3. Med., 329: 149-155 (1993)), and are useful for the treatment of patients with congestive heart failure (US Patent No. 4,415,572; and Hop et al., 3pn. 3., 50: 659-666 (1986) Several studies have shown that the carboest L above improve hernodinal rates, and exercise capacity in patients with congestive heart failure (Inoue and o-tros, Heart vessels 2 : 166-171 (1986), Sasayana et al, Heart Vessels, 2: 23-28 1986), and Feldman and others, Rrn, Heart 3., 116: 771-777 (1988)). In addition, randomized placebo-controlled trials in multiple centers in Japan and the United States have shown that these carboest ip improve quality of life and reduce the risk of death in patients with congestive heart failure (OPC-8212 Mul icenter Research Group , Cardiovasc Drugas Ther., 4: 419-425 (L99Ü), Keldman et al., Arn. J. Cardiol., 68: 1203-1210 (1991), and Feldrnan et al., N. L? Ng. Med., 329: 149-1.55 (1993)). The mechanisms of action associated with the inotropic properties of potassium boosts include a decrease in potassium circulation (Iij ma et al., J.

Pharnacol. Exp. Ther. , 240: 657-662 (1907)), a slight inhibition of fostodiesterase, and an increase in internal calcium circulation (Yatani et al., 3. Cardiovasc. Phar acol., 13: 812-819 (1989); and others, Arzneirmttelforschung, 34: 347-355 (1984)). However, the dose of carotestures that is most effective in reducing mortality (60 gr. Daily) shows a little or no effect, which implies that the drug reduces mortality through another mechanism. , but b in that by its positive inotropic effect (Feidinan et al., N. Engl. 3. Med-, 329: 149-155 (1993), and Pacl > -er, N. Engl. J. Med., 329: 201-202 (1993); . It is known that the above carboes ploe inhibit the production of several cytokines, including íNF-a and 1L-6, by peripheral blood cells stimulated with lipopolysaccharide (PBMC) in a dose-dependent manner.

(Mai uyama and others, T ochern, E ophys, Res. Commu., 195: 1264-1271 (L093), and riatsumop et al., Circuí., 89: 955 -9 ^ 8 (1994)). In addition, they can induce a reversible neuron associated with a decrease in CFU-C (Fel and o + ros, Arn. Heart 3., 116: 771-777 (1988); OPC-82L2 Mui t cen t er Pesearch Group, Cardiovasc. Drugs, Ther. , 4: 4L9-425 (1990); Feldman and others, Arn. 3. Card ol. , 68: 1203-1210 (1991); and Feldrnan and oi ros, N. Cngl. 1. Med., 129: 149-155 (1993)). Adi citonally, carboes ^ i ri Previous ones have found ut ilidad * = > n The regulation of;? pcp + ot; frpuer + < = Programmed metabolic rate), and in the treatment of cancer, inhibition of tumor metastasis and inhibition of replication of RNA viruses (US Patent Application Serial No. 07 / 989,028, filed April 30, 1993 , corresponding to the publication of European Patent 0552373, each of which is incorporated in its entirety as reference in this; Nal-ai and others, Jpn. 3. C ncer Res., Abstract, and Proc. Jpn. Cancer - Assoc. , page 581 (1993); and Maruyarna and others, .Biochem. fliophys. Res. Cornrn., 195: 1264-1271 (1993)). The carboest ips above are also useful for inhibiting the replication of DNA viruses and provide a smergistic effect, when used together with an anti-RNA compound, in the inhibition of the replication of RNA viruses. (U.S. Patent Application Serial No. 08 / 283,707, August 1, 1994; and PCT / US95 / 091 1, filed on July 28, 1995). In addition, it has been found that the above-mentioned carboestipics are useful in the inhibition of nucleoside and nucleobase responses, for example adenosine, in mammalian cells from ror to dependent on the dcsts, and in the increase in phosphorylation of logotypes. nucleoside, particularly AZT (U.S. Patent Application Serial No. 00/203, r'07, IQ August 1994; and PCT / US95 / 09141, filed July 28,? 995). On the other hand, only high concentrations (outside the therapeutic range) of pyridamole (10-L00 μM), another inhibitor le 'transpor +' e nucí > JOI- J do, go to transport of aoenos na (Schol tissel- 'and others, Diochem, Diophys.

Acta, 158: 435-447 (1968) - and PLagemann and others, 3. Membr. Biol., 81: 255-262 (1984)). It is proposed that dipipdamol causes a localized increase in adenosine concentration through its inhibition of adenosine transport to cells (Plagemann et al., Biochem Biophys. Acta, 947: 405-443 (1988)). It is known that adenosm induces an increase in cAMP in myocardial cells either through activation of ddenylate cyclase or through inhibition of tostodiesterase (Fox et al., Ann Pev. Bioche., 47: 655-686 (1978)). : and Takeya et al., Drug Res., 34: 364-370 (1984)), coronary artery dilatation (Fox et al., Ann.Rev. Bioche., 47: 655-686 (1978), an increase in flow cerebral blood (Heis + ad et al., A. 3. Physiol., 240: 775-780 (1981)), a decrease in the production of TNF-a (Parmely et al., 3. Immunol., 151: 389-396 (1993)), and a decrease in platelet aggregation (Dawicki et al., Ipochern, Pharrnacol., 34: 3965-1972 (1985)), strains of their binding to specific adenosine receptors on the surface membranes of cells It is believed that the inhibition of adenosm transport caused by carboetipols provides the relationship with ot or novel aspect of «action. That is, previous carbohydrates could increase blood concentrations of adenosine by inhibiting adenosine transport, thus explaining part of the therapeutic benefit of the vesn pnona < - congestive heart disease (Feldam et al., N. Engl., 3. Med., 329: 149- 155 (1993), and Pac er, N. Engl. J. Med., 329: 201-202 (1993)), or in the reduction of TNF-α production (Maruyama et al., Biochern, Biophys, Res. Cornm., 195: 1264-1271 (1993); and Matsurnori et al., Circuit., 89: 955-958 (1994). )).

II.- Ischemic Cardiac Disease Although ventpcular dysfunction occurs in patients with chronic heart failure and ischemic heart disease, the pathology of these two cardiac diseases is very different. That is, in chronic heart failure, the sensitivity of myofilaments to C 2+ is reduced due to the deterioration of sympathetic nervous regulation, as well as to the deterioration of the renma-angiof ensma and cytocma systems. On the other hand, in ischemic heart disease, anaerobic cell metabolism produces reversible and irreversible cell damage, leading to visual disrusion. The metabolism of the anaerobic myocardium is mainly attributable to the regulation of coronary blood flow. Carbohydrates have been found to increase coronary blood flow in ischemic regions, which is postulated as due to increased aortic blood pressure and the action of coronary dilatation (Maruyama et al., J. Cardiovasc. Phaimacol., 8 : 161- 169, 1986)). However, increases in aortic blood pressure can cause increased coronary blood flow, and can cause increased oxygen demand. This can mitigate the beneficial effects of coronary vasodilation. However, it has also been found that carboetipies enhance improvement in exercise-induced ischemia without change in heart rate or systolic blood pressure, and arrest the progression of ischemia (Kinoshita et al., Respir. Circ, 36). : 1199-1203 (1988)). Although increases in coronary blood flow may involve decreased myocardial ischemia, since the extent of myocardial ischemia depends on blood flow, the size of the infarction is not determined by coronary vasodilator capacity. This is because the coronary artery is completely occluded during myocardial ischemia. The advance of myocardial infarction is attributable to the rate of ATP depletion, and the extent of collateral flux during ischemia, and to platelet and neutrophil activation, Ca + 2 overload and catecholamines, and the generation of free radical derivatives. of oxygen. In this way, the decrease in myocardial ischemia due to coronary vasodiiatation does not necessarily imply the limitation of the risk of infarction. It has also been shown that carbostyrosols improve ST depression during exercise in patients with coronary artery disease (Kinoshita et al., supra). The ST-T level in the electrocardiogram changes due to the intracellular and extracellular balances in C 2+,? +, H + and Na +, heart rotation, movement of the ventricular wall, and the presence of ischemia (Noble et al., Cardiovasc. ., 12: 13-17 (1978)) ,. Thus, there is no indication that carbohydrates can improve myocardial ischemia. Even if the myocardial function of the ischemic area is improved due to coronary vasodilatation caused by carboetypes, the decrease in ischemia does not indicate a reduction in infarct size. This is due to the multiple pathogenesis independent of the coronary blood flow of myocardial necrosis. In the present invention, it has been unexpectedly discovered that carbetinols decrease ischemia of the myocardium and reduce the size of the infarct. This is surprising since carboeetyryls are classified as positive inotropic agents and positive motor agents are known to expand ischemic damage iBlaiklogk et al., J. Mol. Cell. Cardioi., 10: 499-509 (1989)).

BRIEF DESCRIPTION OF THE INVENTION An object of the present invention is to provide a method for reducing the size of the infarct in a subject suffering from ischemic heart disease. These and other objects of the present invention, which will become apparent from the detailed description of the invention provided hereinbefore, are fulfilled by the use of a carboether derivative represented by the invention. • general formula (1) and salts thereof: wherein R is a benzoyl group which may optionally have lower alkoxyl group (s) on the phenyl ring as the substitute (e) and the carbon-aryl bond at positions 3 and 4 of the carbostyril skeleton is a single bond or a double bond.

DETAILED DESCRIPTION OF THE INVENTION In the general formula (1) the benzoyl group which can have lower alkoxyl group (s) as a substituent (s) on the phenyl ring, includes benzoyl groups optionally having from 1 to 3 alkoxy groups of Ci- straight chain or branched chain replacing the phenyl ring, such as benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isobutoxybenzoyl, 4-hexyloxybenzoyl, 3, 4-dimethoxybenzoyl, 3, -dietoxybenzoyl, 3, 4, 5-trimethoxybenzoyl, 2,5-dimethoxybenzoyl, etc. Of the compound (1) of active ingredient according to the invention, 3,4-dihydro-6-LO is most preferable 174- (3,4-di-ethoxy-benzoyl-1) -1-piperaziml-1-2 (LH) -ki- no Lina, ie, vesnapnone. The above carbostyls quickly form a salt with a conventional acid. As such acids, there can be mentioned inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid and bromidic acid; and organic acids such as acetic acid, p-toluensulonic acid, ethane sulphonic acid, oxalic acid, maleic acid, rumapic acid, citric acid, succimic acid and benzoic acid. These salts can also be used as the active ingredient in the present invention, just like the free compound of formula (L). The compounds of general formula (i) and salts thereof may be formulated generally in conventional pharmaceutical preparations per se. These preparations are made using conventional methods, spreading agents, agonizing agents, wetting agents, disintegrating agents, surfactants, lubricants, and similar diluents or excipients. These pharmaceutical preparations may have different dosage forms selected according to the purposes of Therapy, and typical examples thereof are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.). .), and ophthalmic solutions. For the manufacture of tablets, a wide variety of vehicles up to and including well-known ones can be used. Thus, use may be made of for example vehicles or excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binding agents such as water, ethanol, propanol, syrup. simple, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, gum Lacquer, methyl cellulose, potassium phosphate and polyvinylpyridinone; disintegrating agents such as dry cotton, sodium mat, powdered agar, powdered laminate, sodium acid carbonate, calcium carbonate, sorbitan polyoxyethylene fatty acid esters, sodium laupl sulfate, stearic acid monomer, starch lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oils; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; wetting agents or humectants such as gl cerol and .-. Linidon; absorbents, such • starch, lactose, kaolin, bentonite and colloidal silica; and lubricants, such as refined talcum, salts of this rich acid, powdered boric acid and polyethylene glycol. When necessary, the tablets may also be provided with a conventional coating to give for example, sugar-coated tablets, gelatin-coated tallets, enteric-coated tablets, glass-coated wing or double-coated or multi-layer tablets. .

A wide variety of vehicles well known in the art can be used for the delivery of pills. Examples are vehicles or excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and aleo; binding agents such as powdered gum, powdered agacanth gum, gelatin and ethanol; and disintegrating agents such as laminating and agar-. For the manufacture of suppositories, a wide variety of known vehicles can be used. For example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and glyceptides can be mentioned. In the preparation of injections, the solutions or suspensions are preferably Lized and preferably made with the blood and, for the preparation of such dosage forms, all the diluents of conventional use in the field can be used. Thus, for example, water, ethyl alcohol, polyethylene glycol, ethoxylated isostearyl alcohol, isopropyl alcohol, polyethylene oxide and esters of polyoxyethylene sorbitan fatty acids can be mentioned. In this case, the pharmaceutical preparations may contain sodium chloride, glucose or glycerol in an amount sufficient to give solutions to them. It is possible to add conventional solubilization agents, regulating solutions. sedative agents or local anesthetics, etc.

Furthermore, when necessary, the rarinaceutic preparations may contain preservative coloring matters, perfumes, flavoring agents, sweetening agents and the like as well as other drugs. The proportion of the active ingredient compound in these pharmaceutical preparations for use in the present invention is not critical and It can be selected properly on a wide scale. However, generally the proportion is preferably selected within the range of from about 1.0 to about 70% by weight, preferably from about 1.0 to about 30% by weight. The administration route of the pharmaceutical preparations of the present invention is not critical but any is selected according to the dosage form, the age, sex and other factors of the patient, and the severity of the disease to be treated. In this way, for example. < They are provided in the form of tablets, pills, solutions, suspensions, emulsions, granules or capsules. The repairs are administered orally. The injectable solutions are administered intravenously either alone or in admixture with conventional parenteral infusion fluids containing gLucose, amino acids, etc. When necessary, these solutions can also be administered by intramuscular, mtdermic route, subcutaneous or mtrapep toneal. The suppositories are rectally administered, the ophthalmic solutions are Lotions of drops for the eyes.

Although the dosage of the above pharmaceutical preparations depends on the method of administration, the age, sex and other background factors of the patient, the severity of the disease etc., it is generally recommended to administer 0.5 to 30 mg, approximately, of the active ingredient, that is, of the compound (1), per kilogram of body weight per day. The amount of the active ingredient to be contained in each unit of dose is approximately 10 to 1000 rng.

Dosage Form Example 1 3, 4-d? H? Dro-6-r4 - (3, 4-? Rne ox? Benzo? L) -l-piperazinyl] -2 (1 H) ~ quinolma 150 g Avicel (registered trademark of Asahí Chemical Tndustry, Co., Ltd.) 40 g Corn starch 30 g Magnesium stearate 2 g Hi droxi propilmet j lceluiosa 10 g Polyethylene 6000 3 g Castor oil 40 g Methanol 40 g Mix and grind, the previous active ingredient, Avicel, cornstarch and magnesium stearate and The resulting mixture is molded ¡< < ~ > r compression with an i unzr.n ragee RIO rnrn. The tablets thus obtained are covered with a film coating composition consisting of h-dr-oxypropyl Lmethylcellulose, polyethyleneglycol 6000, castor oil and methanol to give film-coated tablets.

Dosisi form Example 2 3, 4-d? H? Dro-6-C4- (3,4-d? Motox? Benzo? L) -l-p? Perazin? L3 -2 (1 H) -qumol ma 150 g Citric acid 1 g Lactose 33.5 g Dihydrogen phosphate 70 g Pluronico F-68 30 g Lauri Lsul ato de sodio 15 g Polyol pyrrol idona 15 g Poliet ílengli col (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45 g Corn starch 30 g Laup 1 dry sodium sulfate 3 g Dry magnesium stearate 3 g Ethanol e.

The active ingredient above is citric acid, lactose, dicalcium phosphate, pluronic r-6 and even sodium sulfate. After size selection using a No. 60 sieve, the mixture is granulated by wet process using an alcoholic solution containing polyvinyl Lpyrrolidone, "arbowax L500 and Carbowax 6000. When necessary, alcohol is added. - to transform the powder into a pastry dough, then corn starch is added, and the mixture is continued until uniform granules are formed.The mixture is then passed through a No. 10 sieve, placed on a tray and dried in an oven maintained at 100 ° C for 12 to 14 hours.The dried granules are screened through a No. 16 sieve, after which dry 1% sodium acetate and dry magnesium stearate are added, after mixing, the mixture is prepared according to the size and shape desired using a tabbing machine. The above cores are treated with a varnish and sprinkled with talcum to prevent absorption of moisture, and then provided with a coating. Repeat varnish coating so many times It's enough for internal use. The tablets are made completely round and smooth by applying an appropriate coating and a smooth coating, the color coating is carried out until a desired color is obtained. After drying, the coated tablets are polished to give uniformly polished tablets. The following examples are provided for illustrative purposes only, and are not intended in any way to limit the scope of the present invention.

L? EXAMPLE 1 EFFECTS OF VESNARINONE ON THE CONCENTRATION OF ADENOSIN IN BLOOD Mongrel dogs weighing 15 to 20 kg were anesthetized by intravenous administration of 30 mg / kg of sodium pentobarbital. Afterwards, his trachea was intubated, and the animals were ventilated with air from the room mixed with oxygen. Then, his thorax was opened through the fifth left intercostal space, and their hearts were suspended in a pericardial splint. The left anterior descending coronary artery (LAD) of each animal was prepared with a cannula and per fused with blood through the left carotid artery through a bypass tube. former accordion. The coronary perfusion pressure fCPP) was followed at the tip of the coronary arterial null. The coronary blood flow (CBF) of the per-fused area was measured with a luxury test ^ Lect romagnet ico attached to the bypass hub. A small short collection bore (L.O.sub.rn diameter and 7.0 crn. Long) was inserted into a small coronary vein near the center of the perfused area for the coronary blood sample. The drained venous blood was collected in a < GJ deposit placed at the level of the left atrium i < , lJ f e regínted to the jugular vein, 10 The concentration of lactate in the blood was determined by an enzymatic analysis (Lergineyer, Methods of Enzirnatic Anaiysis, Acade ic press, He? York (1963), pages 266-270), and the lactate extraction ratio was calculated as the coronary arteriovenous difference in lactate concentration multiplied by -100 and divided by arterial lactate concentration. To follow the conditions of the dogs, my blood pressure was measured using an AP-64LG blood pressure amplifier (Nihon Kodon), and samples of his blood were collected for blood analysis, including pH and blood. 2, using a gas analyzer ABL300 fRadiometer, Copenhagen). With the use of an occlusion that produces a quantitative stenosis of the perfusion tube, the extension of the stenosis fiar i iduci i CDF J3% and 60% of the control flow was defined. After this operation, the union of this occlusion produced a stable nipper fusion for 10 minutes and measurements of all variables were made 20 minutes after the onset of coronary artery clot. After the above measurements, vescarinone vehicle (di-ethyl-ε-phoxide, DMSO 1.0% (v / v)) was emptied in the LAD for 5 minutes, and all previous hernodynamic and metabolic parameters were measured. In this way, using a l mba of? n? fv: n -n, r administered 0.54 rng / rnl of vesarinone towards the LAD, at an infusion rate of 0.2-0.5 ml / rnin. to reach 15 μg / rnl. All previous hernodynamic and metabolic parameters were monitored again at 5 and 10 minutes after infusion. The blood concentration of adenosine was measured by draining 1.0 μl of blood into a syringe containing 0.5 ml dipyridinol 0.02% (w / v) and LOO ul 0.1 μg / rnJ solution 2 '-deoxycophorum in 500 mM EDTA. to obstruct both the uptake of adenosm by red blood cells and the degradation of adenosm. After centrifugation (3000 x g), the supernatant is collected and its adenosine concentration is measured by radiomayayayc. Specifically, adenosine in 100 ul in plasma was succirulated with 100 μl of dioxane containing 40 mg of succinic acid anhydride and 0.4 mg of diethyl in. After incubation for 20 minutes at 4 ° C, the mixture was diluted with 100 μl of diluted anti-adenosine serum i Yarnasa-Shyoyu, Chiba, Jipan) and 100 μl of adenosine methyl ester n- ', 3' -0-d? Succ? N? L-3 [125 i] iodot? rosà na, 0.5 pmol. The mixture is kept in a water bath (3 ° C) for 18 hours, and then 500 μl of the second antibody solution (goat anti-rabbit TgG) is added (Yarnasa-Shyoyu, Chiba, Japan) . After incubation at 4 ° C for 60 minutes, the unreacted material is removed by centrifugation at 3000 rprn (2,500 x g) at 4 ° C for 20 minutes. The radio is removed and the tube is used using a wide range. It has been reported that the degradation of adenosine during this blood sampling procedure is negligible (Yamane, 3. Lminunol., 12: 501-519 (1991); Sato and others, Ann. Biochem. , 121: 409-420 (1982); Hop et al., Am. 3. Physiol. , 250: 14509-14518 (1986); and Kitakaze et al., Circ. Res., 60: 631-630 (1987)),. This method, using the specific antibody was sufficient to detect up to 5.0 pinol is / ml of adenosm. The coefficient of variation of the meta-analysis and the re-analysis was ob- tained from l .. 3 - 3..1% and 'i .1 - 4.9%, respectively. This sensitive radioimmunoassay method for adenosm measurement does not require protein removal, which is usually done in HPLC measurements for adenosine. The results are shown in the following table L for a representative dog. TABLE 1 Time Blood flow Concentration Concentration (nun) coronary adenosine lactate (inl / min) (ng / dl) and mol s / rnL) 0 21 16.4 9.3 Appearance of hypoperfusion 20 12 17.1 15.0 DMSO 25 12 17.0 14.0 Vesnarinone 30 12 L6.7 23. ü Vesnar-í nona 35 12 16..7 l .2 As shown in Table 1. above, when the I-'P decreases from 96 to 53 min Hg so that the CBF decreases to 60 % of the flow of the basal line, the concentrations of lactate and adenosine in the coronary venous blood draw increased. On the other hand, the concentrations of lactate (L9.5 mg / dl) and adenosm (7.2 prnol / l) in coronary arterial blood did not change due to the reduction of CPP throughout the study. Henceforth, the CBF remained constant. The infusion of DMSO during coronary hypoperfusion did not result in any change in CPP or in the concentration of lactate and adenosm in coronary venous blood. However, as shown in Table 1 above, during infusion of vesnapnone, the concentration of adenosine in coronary blood increased despite L5 concentrations of CBF and lactate without change in the venous blood loronapa. Although CPP decreased (from 53 to 51 inrnl-lg) due to adenosm coronary vasodilator effects. These results indicate that vesnapnone increases the release of adenosine in the ischemic myocardium. EXAMPLE 2 EFFECTS OF VESNARINONE ON CORONARY BLOOD FLOW The CPP was reduced with an occluder attached to the tube S of derivation x + racorporeo Jo ic i e n Jiscutidís previously, from node that the CBF decreased to 60% of the control CBF. After having determined low CPP, the occluder was adjusted to keep the CPP constant at a low level. All previous hemodynamic parameters, and venous and coronary arterial blood for the rnetabolic parameters were determined LO minutes after the appearance of hypoperfusion. After these measurements, vesnapnone vehicle (DMSO L .0% (v / v)) was injected in the LAD, and all the melabolic and hernodynamic parameters were measured before 5 minutes after the infusion. Then, using an infusion pump, 0.54 mg / ml of vesnapnone was injected in the LAD, at an infusion rate of 0.2-0.5 ml / min, in order to reach 15 μg / ml. All hernodic and metabolic parameters were measured again at 5 minutes and 10 minutes after infusion. The results are shown in the following table 2 for an experimental dog.

TABLE 2 Lactate concentration (rng / dl) Time Blood flow Blood Venous Blood arterial < rnm) Coronary (rnl / min) Coronary Coronary 0 20 10. ti 13.1 Start of hypoperfusion 10 12 13.8 13. L DMSO 15 12 14.0 12., 9 Vesnar-mona 20 13 11.5 13.2 Vesnap nona 25 14 10.8 13.2 As shown in Table 2 above, when the U > P roduced from 93 to 59 m Hg par to CBF decrease to 00% of the base line flow! The concentration of lactate in the coronary venous blood was increased, but the lactate concentration remained unchanged. Coronary arterial blood. Afterwards, the CPP remained constant. The DMSO does not change the CBF by the concentration of the lac-tato of the coronary arterial blood. However, vesnapnone increased CBF, and decreased the concentration of Lactate from coronary venous blood. These índults > 'ornuestran that La vesn i _ non. * can increase < "•> CBF, that is to say the vasod 1 coronary attack, in ischemic myocardium and decreases the severity of the ischemia.

EXAMPLE 3 EFFECTS OF VESNARINONE ON INFARCTION SIZE Perfusion with adenosm can markedly limit the size of the infarct (Olafsson, Cl re., _76: 1135-1145 (1987)), and as shown in Example 1 above, Vesnarinone may increase- the blood concentration of adenosm. In this way, tests were carried out to determine if vesnapnone also causes a reduction in infarct size. More specifically, the LAD of the previously described lesions was isolated and a strip of moistened umbilical tape was passed around the coronary vessels for occlusion. Coronary occlusion was performed by locating the umbilical cord in a small laryoid tube and applying pressure to the plastic tube. To measure the regional blood flow, a catheter was introduced into the left atrium for injection of feral bacteria, and the regional CBF was determined using a microsphere technique, which uses non-radioactive microspheres (Sel'isui Plástic Co., Ltd ., Tokyo, Japan) made of inert plastic marked with different stable heavy elements as described by Mori, Am "3 - Physiol., 2_6_3: 141946-1 1957 (1992). You have specifi cally used microeras iiu.irc The specific gravity was 1.34 for Br and 1.36 for Zr, the microspheres were suspended in isotonic saline solution with Tween 80 0.01% (v / v). avoid aggregation.The microspheres were subjected to ultrasonication for 5 minutes, followed by 5 minutes of vortex application immediately before injection.10 ml of the microsphere suspension (2-4 x 106 mats) was injected into the left atrium followed for- different rinses sa warm linens (73 ° C) of 5.0 mi. The femurs were administered at 30 minutes after the onset of coronary occlusion. Just before microsphere administration, a reference blood flow sample from the femoral artery was removed at a constant rate of 8.0 rnL / rnin for 2 minutes. The X-ray luorescence of the stable heavy elements was measured with a wavelength and dispersive spectacle of wavelength PW 1480, (PhiLlips Co., Ltd., Almelo, The Netherlands). When the microstrips are irradiated by the beam: >; r im no de r, yos X, The electrons descend to a lower orbit and emit renewable energy with a characteristic X-ray fluorescence energy level for each element. Therefore, it is possible to identify the X-ray fluorescence of different species of labeled microspheres in a single mixture. The regional CBF was calculated according to the formula: flow time - a (tissue count) x (reference flow) / (reference count), and was expressed in ml / rnin / g of net weight. As a control, after 20 minutes of hemodynamic stabilization, the LAD was occluded for 90 minutes and rebutted again for 6 hours. Using an infusion pump, 0.90 mg / ml vesharinone was injected at a fusion rate of 0.2-0.5 ml / min, 20 minutes before coronary occlusion, and for 1 hour of reperfusion after 90 minutes of coronary occlusion, so to achieve 15 μg / rni. After 6 hours of reperfusion, while the LAD was again occluded and perfused with autologous blood, Evans blue dye was injected into a vein if it was tenuous to determine the area of anatomic risk and non-ischemic area in the hearts. Then The hearts were removed immediately, and sliced into cross sections in series of 6 to 7 m in width. The non-ischemic area was identified by the blue dye, and the ischemic region was incubated at 37 ° C for 20 to 30 minutes in 2, 3, 5-tp feni L trazoLio ... 0% chloride (w / v ) (TTC, Sigrna Chemical Co.), in 1 or 0.1 M fate buffer solution (μH 7.4). The TTC stained the non-infarcted myocardium to a brick color and eye indicating the presence of a precipitate of forrnazan, which results from the reduction of TTC by the dehydrogenase enzymes present in the viable tissues. The infarct size was calculated as a percentage of the area at risk. The results are shown in table 3 d below.

TABLE 3 Treatment Blood flow Ark of collateral size risk (%) in farto (v.) DMSO 7.2 i l.l 40.2 + 2.3 43.5 i 3.2 (n = 5) Vesnapnone 7.8 + _ 1.3 41.1 _ | _ 2.4 6.9 _ 3.9? 'n-3) ipypdarnole 6.9 + _ 1.8 40.9 _ • _ 3.3 35.0 + 4.3 in = 5) Salme 8.2 + _ 2.0 41.8 _ 3.3 45.0 + _ 4.2 ln = 5) 0-bPT 7.2 +. L.7 38.9 + _ 2. L 48.1 i «.b I n = 5) As shown in Table 3 above, although the collateral blood flow during ischemia and the risk area in the DMSO and vesnarmone groups did not vary significantly, the infarct size was markedly reduced by admi- vesnapnona. This limiting effect on the size of vesnapnone infarction was completely suppressed 20 minutes after the dogs treated with vesnapnone were submitted to coronary infusion with 25 μg / lg / min of 8-ulphophenylteophylina (S-SPT). 8-SPT is an adenosir receptor antagonist. In this way, the limiting effect of the risk of vesharinone infarction may be mediated by increased release of the pneumonia in an ischemic heart. On the other hand, a significantly smaller decrease in infarct size was observed when 10 μg / kg / mm of the dipyridazole nucleoside transport inhibitor was injected at an infusion rate of 0.2-0.4 nl / rnin, 20 minutes before coronary occlusion and dur-ante one hour of reperfusion after 90 minutes of coronary occlusion. The above results clearly show that the vespharinone motor reduces the size of the heart attack unexpectedly and remarkably. Dipyridamole, which is known to increase the release of adenosine in the ischemic heart, r-educates the size of the infarction less than the vesnar mona. Although dipipdamol is an adenosine nucleoside transport inhibitor as well as vesnapnone, these results seem to indicate that the sites of action and vesicular and dipipdamol tissue affinity are different, which could explain the unexpected differences in potency over the Limit size effect of the mfai to. Although the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that different changes and modifications may be made thereto without departing from the spirit and scope thereof.

Claims (5)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a carbohydrate derivative represented by formula 1. wherein R is a benzoyl group which may optionally have lower alkoxy (s) in the ring of fer as a substitute) and the carbon-carbon bond in the 3-position 15 and 4 of the carboesteryl skeleton is a single bond or a double bond; or a pharmaceutically acceptable salt thereof for the preparation of a medicament for reducing the size of the infarct in a subject suffering from cardiac disease isquein i c. "MI

2. The use of a carbohydrate derivative according to claim 1, further characterized in that in the compounds used R in the formula L is a benzoyl group which may optionally have from 1 to 3 aCoxyl groups of C -6 Straight or branched chain in the ring phen.-

3. The use of a derivative of carboest? P The conformance ion of claim 2, char acterized because in the compounds used said carbostyril is 3,4-dihydro - 6-C4 - (3,4-dimethoxy-1-enzyme) -1- pi perazi n? LH-2 (1H) ~ qumolma, or a pharmaceutically acceptable salt thereof

4. - A pharmaceutical composition for the reduction of infarct size in a subject suffering from ischemic heart disease, comprising a pharmaceutically effective amount of a carboaltyl derivative represented by formula 1 according to claim 1, or a pharmaceutically acceptable salt thereof, and a diluent or excipient 5.- The pharmaceutical composition Pharmacologic according to claim 4 characterized in that R plus formula 1 is a benzoyl group which may optionally have 1 to 3 alkoxy groups C? -6 straight or branched chain in the ring thenyl. The pharmaceutical composition according to claim 4, further characterized in that said carboether is 3,4-dihydro-6- C 4 - (3, 4-d? methox? benzo? l) -1? perazi ni 1] -2 (LH) -quinol or a pharmaceutically acceptable salt thereof. 7. A carboeetyryl derivative represented by the formula L in accordance with the rei indication 1 or a pharmaceutically acceptable salt of the same for the reduction of infarct size in a subject suffering from disease (see here). isquc-rn r ~ 8. The carbostyl derivative according to claim 7 further characterized in that R in formula 1 is a benzoyl group which may optionally have from L to 3 straight chain Ci-β akoxyl groups or branched in the phenyl ring 9. The carbostyril derivative according to claim 7, which is 3, -dihydro-6-C4- (3,4-dirnethoxybenzoyl) -L-piperazinyl] -2 (1H) -quinoline or a pharmaceutically acceptable salt thereof.