MXPA97001527A - Procedure to reduce tissue damage associated with isque - Google Patents

Abstract

The present invention relates to the use of an inhibitor of sorbitol dehydrogenase in the preparation of compositions to prevent tissue damage resulting from ischemia in a patient in need of such treatment.

Description

PROCEDURE TO REDUCE FLUID DAMAGES ASSOCIATED WITH ISCHEMIA FIELD OF THE INVENTION The invention relates to the use of sorhitol dehydrogenase inhibitors to reduce tissue damage resulting from ischemia in mammals, including human patients.

BACKGROUND OF THE INVENTION The inhibitors of sorbitol deshi rogenaba constitute a class of compounds that have recently become known for their utility in preventing and treating conditions derived from complications of diabetes, such as diabetic neuropathy. Such compounds are well known to those skilled in the art and are easily identified by standard biological assays. For example, PCT Publication UO 94/07867 describes methods of inhibiting oorbitol dehydrogenase and thereby reducing fructose levels. The procedures use certain substituted pindiinidms, for the control of diabetic complications such as diabetic diabetic and diabetic macroangiopathy. In addition, the United States patents number1. .., 215,990 and 5,138,058 disclose certain pyrunidine compounds having accumulative activity 1e sorbitol deshihydrogenase, which are useful as reagents for a pharmacological research model of aldose reductase inhibitor assays. In particular, US Pat. No. 5,215,990 describes, as Example 2, the compound 4 ~ r - (N, Nd? Met? Lsulfamo? L) p? Era?? No] -2-h? Drox? me? lp? r? rn? -d? na. Joseph R. Uilliamson and others »," Perspect i ves m Diabetes, Hyperglycernic Pseudohypoxia and Diabetic Corn iícations'P Diabetes, Vol. 42, B01-813, Jumo 1993, describes (figure 2) "parallels between functional consequences of an increased NADH / NPD + cystolic system, linked to hyperglyceric pseudohypoxia in diabetic tissues, and hypoxia or ischemia in myocardial tissue BRIEF DESCRIPTION OF THE INVENTION This invention is directed to a method of reducing tissue damage (for example, by substantially avoiding tissue damage or inducing tissue protection) resulting from ischemia. The method comprises administering to a mammal, including a human patient, in need of such treatment an amount, effective to reduce tissue damage, of an inhibitor of sorbitol dehydrogenase. A preferred aspect of this invention is a method of reducing damage to the heart resulting from iocardial ischemia.

Also another preferred aspect of this invention is a method of reducing damage to the brain resulting from cerebral burns. Also another preferred aspect of this invention is a method of reducing liver damage resulting from hepatic ischemia. Also another preferred aspect of this invention is a method of reducing damage to the kidneys resulting from renal ischemia. Also another preferred aspect of this invention is a method of reducing damage to the lungs resulting from pulmonary ischemia. Also another preferred aspect of this invention is a method of reducing stomach damage resulting from gastric ischemia. Also another preferred aspect of this invention is a methods of reducing damage to the intestine resulting from intestinal ischemia. Also another preferred aspect of this invention is a method of reducing damage to skeletal muscles resulting from musculoskeletal ischemia. Another preferred aspect of this invention is a method of reducing damage to the spleen resulting from splenic ischemia. Also another preferred aspect of this invention is a method of reducing damage to the pancreas resulting from pancreatic ischemia. Also another preterm aspect of this invention e < , a procedure to reduce damage to the retina resulting from ischemia and malignancy. The term "reduction" is intended to include partial prevention or prevention, which, although higher than that which would result from not taking a drug or taking a placebo, is less than 100%., of the substantial prevention total entity. The term "data resulting from ischemia [...]" as used herein, refers to conditions directly associated with reduced blood flow to the tissue, for example due to a clot or blockage of blood vessels that impart blood to the tissue of the body. patient, and that originate, inter alia, a reduced transport of oxygen to said tissue, deteriorated tissue behavior, tissue dysfunction and necrosis. Those skilled in the art should recognize that this invention also includes improved tissue performance (eg, during ischemia the ability to maintain normal muscle function is improved). For example, a person can walk a greater distance before having to stop for pain.

DETAILED DESCRIPTION OF THE INVENTION Compound (active agent) of this invention? > Any oorbitol deshi drogenase inhibitor can be used. FL term "inhibitor of sorbitol dehydrogenase" or refers to compounds that inhibit the bioconversion of sorbitol to D-α-tructuosa, catalyzed by the enzyme sorbitol dehydrogenase. The experts in the technique can easily determine such inhibition according to standard assays (NE Carneron, MD l eonard, I. -, Ross and P .. H. Uhiting, "The Effects of '- Orbinil on Peppheral Herve Conducton Velocity, Pol yol Concent rations and Morphology the treptozotoom-Diabetic Ra ", Diabetologia, 29, 168-174, 1986). Hereafter, oorbitol dehydrogenase inhibitors are described and referenced, although other orthbitol dehydrogenase inhibitors may be known to those skilled in the art. The patent of F.U.A. No. 5,138,058 (the disclosure of which is incorporated herein by reference) discloses certain substituted pipines with piperazine, which have accumulative activity of sodium. The patent of E.U.A. No. 5,215,990 (the disclosure of which is incorporated herein by reference) discloses certain pyrirnidine deposits having a sorbitol accumulating activity. In addition, PCT publication No. UO 994/07867 discloses certain substituted pinnidines as inhibitors of sorbitol dehydrogenase. The compounds have the formula wherein R 1 are prodrugs of hydroxycarbonylalkyl Ci -C & , (C 1 -C 4) alkoxy, C 1 -C 6 -alkyl, (C 1 -C 4 alkyl) - (C 1 -C 4 alkyl). (Ci-C-alkyl) -SO- (to Ci-C-cycloalkyl), (Ci-C-alkyl-O 2 - (Ci-C-alkyl), Ci-C-dihydroxyalkyl, aryl, hetero-heteroaryl, Ci-C-heteroarylalkyl, Ci-arylalkyl -Ce (alkoxy Ci-Ce) -carbomlaplo, aplalkyloxy Ci-Ce or heteroaplalkyloxy Ci-Cs, in which those mentioned by ryl and aryl residues of the aforementioned Ci-C-alkyl are independently selected from phenyl and naphthyl, and in wherein said heteroapels and heteroaryl moieties of said heteroepyl Ci-C-alkyl and heteroerylalkyl-Ci-C are independently selected from pipdyl, furyl, tetrahydrofuplo, thienyl, imidazolyl, pyrazolyl, tpazolyl, thiazole, oxazolyl and benzothiazolyl, and in which the aforementioned aplo and heteroaryl and these aplo and heteroala of the said heteroerylalkyl Ci-C and heteroeplaxykyloxy Ci-Ce can optionally be substituted with one or more substituents independently selected from chlorine, bromine, Ci-C6 alkyl, Ci-Ci alkoxy. S- (alkyl C? -C6), -SO- (al Ci-Ce), SO2- (Ci-C-alkyl). h droxialqui lo CiCe and t rif 1 or or 1 lo; or R1 is a group of formula wherein the dotted line represents an optional double bond, and U, 0 and Z are independently selected from hydrogen, Ci-Cβ alkyl, rif luoro and ilo, phenyl, furyl, triazolyl, thiazolyl and timly, wherein said phenyl, furyl, triazolyl, thiazolyl and thienyl can optionally be substituted with one or more susti uyent.es, preferably with zero to two substituents, selected from alkyl Ci-C, akoxy Ci-C, tpfl uoromethyl at rox17 0 I or R 1 is a group of formula -C-R 6, wherein R 6 is hydrogen, C 1 -C 4 alkyl, selected from phenyl and naphthyl, or heteroaryl selected from pindyl, furyl, thienyl, irnidazolyl, pyrazolyl, fupol, t enyl , irnidazole .1 lo, pyrazolyl, tpazolyl, oxazolyl, benzofuranyl and benzothie it, wherein said aryl and heteroaryl groups may be optionally substituted with one or more ingredients, preferably with zero to two substituents, selected independently from chlorine , bromine, nitro, t rit luoromethyl, alkoxy C _ .- Ce, -s- (C? -Ce alkyl) m -SO- (to the Ci-C? chl) and -SO2- (Ci-C e alkyl) I or Rl is a group of formula YO-CH-P7, wherein R7 is selected from phenyl and naphthyl, or heterocycle selected from pyridyl, fuplo, timme, irnidazole lyo, pyrazole Lio, triazolyl, thiazolyl, oxazolyl, benzot lazolyl, benzofarranyl, benzot e lo and qumolilo, in which the said ap lo and heteroaryl groups may be optionally substituted with one or more substituents, preferably with zero to two substituents, independently selected from chloro, bromo, Ci-C alkyl, Ci-C alkoxy , -S- (Ci-Ce alkyl), -SO- (Ci-Ce), -SO2- (Ci-Ce alkyl) and rif loromethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, selected phenyl and naphthyl, selected heteroyl of fupyl, tiely, thiazole, lyso and oxaolyl, in which the said aplo and heteroaplo groups may be optionally substituted with one or more radicals. Examples, preferably with zero to two substituents, independently selected from chlorine, bromine, nitro, tpfluoromethyl, alkyl Ci-Cß, alkoxy Ci-Ce, -S- (Ci-Cß alkyl), ~ S0- (Ci-C alkyl) and -SO 2 - (C 1 -C 6 alkyl) 7 R 2 R 3 are selected from hydrogen, alkyl Ci -Ce. femlo and femlalkyl Ci-C in which the said fem and the phenyl residue of said ferulalkyl -Ce may be optionally substituted with one or more ".uotit.uyent.es independently selected from Ci-Ce alkyl. Ci-Ce alkoxy, chlorine, bromine and tri luoro.net i lo; and R2 and R3 form, together with the nitrogen to which they are attached, a cyclic group selected from aze-tidy, pyrrolidino, piperidy, piperazine and rnorfolm, wherein said cyclic group may be optionally substituted with zero to two independently selected substituents. The alkyl is Ci-C, -CONH2, -SO2NH2, N- (C1-C'-alkylo) sulo famo, N, N ~ d? (a-C? -C4) sulfamoyl, (Ci-alkoxy) Ce) carbon 1 Lo, N, N-di (alkyl Ci -CA) carbamo? N, (C 1 -C 4 alkyl) carbaryl 1, N- (- "and ilcarbamoyl, (Ci-C) carbonyl, phenylcarbomyl, (Ci-Cß alkyl) -sulfoyl, (Ci-alkyl) Ce) sulphonyl, femlsulphonyl, heteroarylsulphyl and heteroarylcarbonyl, femlsulphonyl and heteroaryl of the aforementioned heterocyclics 1 carbon and heteroarylsulphonyl, and heteroanyl sulphide are selected from furyl, thienyl, thiazolyl and oxazolyl, and in which the Femlo of the aforementioned femcarbonyl, N-phenylcarbamoyl, phenylcarbonyl and femlsulfonyl may be optionally substituted with one or more substituents independently selected from C 1 -C 4 alkyl, CI-CA alkoxy, chlorine, bromine, nitro, mood, cyano and trifluoromethyl; hydrogen, chlorine, bromine, cyano, nitro, trifluoro etiio, ino, Ci-Ce alkyl, hydroxyCi-C, alkoxy Ci-Ce, femlo, naphthyl or furyl, wherein said phenyl, naphthyl and furyl can be substituted optionally with one or more substituents independently selected from chlorine, brom or, t-rifluoromethyl, Ci-C-alkyl, Ci-C-alkoxy, -S- (Ci-C e alkyl), -S0- (Ci-C e alkyl), -SO 2 - (Ci-C e alkyl). and hydroxy; and RS is hydrogen, Ci-Cß alkyl, Ci-C alkoxy, t-trifluoro ethyl, hydroxy-Ci-Ce, -S- (Ci-C alkyl) -SO- (Ci-Ce alkyl), -SO 2 - (Ci alkyl) -Ce), phenyl or fuplo, in which the mentioned femlo and fuplo may optionally be substituted with one or more substituents independently selected from chloro, bromo, tp fluoromethyl, Ci-Cβ alkyl, Ci-Ce alkoxy. -S0- ( Ci-Cß alkyl), S 2 2- (Ci-Ce alkyl) and hydroxy 7 or a pharmaceutically acceptable salt of said compound.Other inhibitors of sorbitol dehydrogenase decipher by PCT publication No. UO 94/07867 include Formula compounds R \ / R 3 wherein R is hydrogen, CF3, Ci-Cß alkyl, (Ci-Cß alkyl) -S- (Ci-Cß alkyl), (Ci-Ce alkyl) -SO- (Ci-Cß alkyl), (alkyl) Ci -Ce) - 02- (Ci-Ce alkyl), Ci-Cß hydroxy-alkyl, Ci-C-dihydroxy-Ci, Ci-C alco alkoxy, (Ci-C) -koxy) -C1- (Ci-Cß alkyl), selected aryl of phenyl and naphthyl, arylalkyl Ci-Cd in which the aplo moiety is selected from phenyl and naphthyl, (Ci-Ce alkoxy) carbonylayl in which the aplo moiety is selected from phenyl and nephthyl, arylalkyl Ci-C in which the Aryl residue is selected from femlo and naphthyl, aplalkyloxy Ci-Ce wherein the aplo moiety is selected from phenyl and naphthyl, heteroaryl selected from pipdoyl, furyl, terehydrofuryl, thienyl, irnidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl and benzothienyl; Ci-Cß heteroaryl-alkyl in which heteroaryl as defined above or Ci-heteroalkylkyloxy, Ce in which heteroaryl is as defined above, and wherein said aryl and heteroaryl groups, the aryl moieties of the said aryl-Ci-Cß), (Ci-C-carbylaryloyl) and erylylkyloxy Ci-C, and the heteroeryl moiety of the heteroeryloyl-Ci-C ecyl ester may optionally be substituted. with one or more sustituyent.es independently selected from chlorine, bromine, alkyl Ci -Ce. -S- (Ci-Cß alkyl) -SO- (Ci-Cß alkyl), -SO2 - (Ci-C alkyl) hydroxy- C 1 -Ce alkyl and trifluoromethyl, or R 1 is a group of formula 0 > / \ z " wherein the dotted line represents an optional double bond and U, Q and Z are independently selected from hydrogen, alkyl Ci-Cé, t nfluororneti lo, femlo, furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl, fupol, triazolyl and thienyl may optionally be substituted with one or more of their ingredients independently selected from Ci-Cß alkyl. Ci-Cβ alkoxy, trifluoro-rnetium and hydroxy, - II or Rl is a group of formula-C-R6, wherein R * is hydrogen, Ci-C alkyl, aryl selected from phenyl and naphthyl, or selected heteroaryl of pipdyl, fuplo, thienyl, irnidazolyl, pyrazolyl, tpezolyl, tlazolyl, oxazolyl, henzothiezolyl, benzofurazyl and benzothiemyl, wherein said aplo and heteroaryl groups may be optionally substituted with one or more substituents independently selected from chlorine, bromine, nitro, tpfluorornetiio,, Ci-Cβ alkoxy. -S- (Ci-Cß alkyl), -90- (alkyl C? ~ Ce) and -SO2- (Ci-Ce alkyl); I or R1 is a group of formula Y-0-CH-R, wherein R7 is selected from femto and naphthyl, or heteroethyl selected from pyridyl, fungal, time, imidozol, pyrazolyl, tpazolyl, thiazolyl, oxazolyl, benzothiezolyl , benzofuremlo, benzotiemlo and quinolilo, in which the cited groups aplo and heteroaryl may be optionally substituted with one or more substituents, preferably with zero to two substituents, independently selected from chlorine, bromine, Ci-C alkyl, alkoxy Ci -Ce, -S- (the CiC & amp;), -SO- (the Ci-Cß chyle), -SO2 - (CiCe alky) and tpfluoromethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, selected phenyl and nephthyl group, selected heteroyl of furyl, time, thiazolyl and oxazolyl, wherein said aplo and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chlorine, bromine, nitro, trifluoromethyl, Ci-C6 alkyl Ci-C6, -SO- (Ci- Ce) and -SO2- (Ci-Ce alkyl); R2 and R3 is independently selected from hydrogen, Ci-Ce alkyl, femlo and ialkyl Ci-Ce. wherein said phenyl moiety and phenyl moiety of said phenylalkyl Ci-C may be optionally substituted with one or more substituents. The components selected independently from Ci-C, Ci-C6 alkoxy, chlorine, bromine and trifororornet 1107 or R2 and R3 form, together with the nitrogen to which they are attached, a selected cyclic group of ezetidm, pyrrolidino, piperidm, piperazmo and orfolin , in which the cyclic cyclic group can optionally be substituted with zero to two substituents independently selected from C 1 -C 6 alkyl -CONH 2, - 2 H 2, N- (C 1 -C 4 alkylo) fernoyl sulph, N, Nd? (Ci-alkyl Jsulfa oyl, (C1-C4 -coxy) carbonyl, N, Nd? (Ci-C alkyl) cerbemoyl, N- (the Ci-C *) cerbemoyl, N-phenylcerbemoyl, ( Ci-Ce alkyl) cerboml, femylcarbonyl, (Ci-Cé) alkyl sulfonyl, (Ci-Cβ alkyl) sulfinyl, phenylsulfonyl, heteroarylsulphonyl and heteroarylcarbonyl, in which the heteroeryl residues of the said heteroarylcarbonyl and heteroerysulfonyl are selected from furyl , thienyl, thiazolyl and oxazolyl, and wherein the phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl, phenylcarbonyl and phenylsulfonyl may optionally be substituted with one or more substituents independently selected from C 1 -C 4 alkyl, C 1 -C 6 alkoxy, chlorine, bromine, nitro, amino, cyano and trifluoromethyl; R * is hydrogen, chlorine, bromine, cyano, nitro, trifluoromethyl, amino, Ci-Cß alkyl, hydroxy alkyl Ci-C, alkoxy C?-C phenyl, naphthyl or furyl, wherein said phenyl, nephthyl and furyl can optionally be substituted optionally n one or more substituents independently selected from chloro, bromo, trifluoromethyl, Ci-C & , alkoxy Ci-Ce -S- (C1-C6 alkyl), -SO- (Ci-Ce alkyl). -SO2- (Ci-Ce alkyl) and hydroxy 7 and RS is hydrogen, Ci-Ce alkylco-Ci-C, trifluoromethyl, hydroxy alkyl Ci-Cß, -S- (alkylene Ci-Ce), -SO- (Ci-Cß alkyl), -SO 2 - (Ci-C e alkyl) -. phenyl or furyl, in which the phenyl and furyl compounds may be optionally substituted with one or more substituents independently selected from chlorine, bromine, trifluoromethyl, Ci-Ce alkyl, Ci-C-alkoxy-SO- (Ci-C-alkyl) , -S0- (Ci-Cß alkyl), -S02- (Ci-Cß alkyl) and hydroxy, - or a pharmaceutically acceptable salt thereof. The compounds described above are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis, particularly taking into account the descriptions of the relevant patent and patent application specifications. Some sorbitol dehydrogenase inhibitors have asymmetric carbon atoms and, therefore, are enantiomers or distereomers. The diastereomeric mixtures can be separated into their individual distereomers, the differences in their physical and chemical properties being tolerated by methods known per se, for example, by cross-linking and / or frequent crystallization. Some inhibitors of sorbitol dehydrogenase are acidic and form a fermaceutically acceptable cephecyl ester. All these salts are within the scope of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities, usually in a stoichiometric ratio in an aqueous, non-aqueous or aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a solvent followed by filtration, by evaporation of the solvent or, in the course of aqueous solutions, by lyophilization, as appropriate. Some inhibitors of sorbitol dehydrogenase are basic and form a salt with a pharmaceutically acceptable anion. All of these salts are within the scope of this invention and can be prepared by conventional methods. For example, they can be prepared by simply contacting the acidic and basic entities, usually in an equiometric relation, in an ecuous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the course of equitable solutions, by lyophilization, as deemed appropriate. In addition, some of the compounds of this invention form hydrates or solvates and these are also within the scope of the invention. The activity and, therefore, the utility of the compounds of the present invention as medicinal agents that provide protection from tissue damage to tissues in a mammal can be demonstrated by the activity of the compounds in the vitro assay described hereinafter. This teaching is directed more particularly to providing protection from ischemic damage to iocardial tissue (for example, by inducing cardioprotection). The teaching also provides means by which the activities of the compounds of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful in determining dosage levels in mammals, including humans, that induce protection from ischemia, particularly in the myocardium. Cardioprotection, indicated by an infarcted myocardial reduction, can be induced pharmacologically using receptor agonists. adenosine in hearts of rabbits isolated and inversely perfused, as in vitro model of iocardial ischemic precondition (Liu et al., Cardiovasc. Pes., 28: 1,057-1,061, 1994). The assay described below demonstrates that a test compound (ie, a compound claimed herein) can also pharmacologically induce cardioprotection, that is, reduced degree of myocardial infarction, when administered to an isolated rabbit heart. The effects of the compound of the study are compared with the ischemic precondition and with the adenosine A1 / A3 agonist., N6-C2- (4-am? Nofen? DetilHadenosina (formerly APNEA), which I have induced to pharmacologically induce cerdioprotection in the rabbit isolated corezon (Liu et al., Cardiovasc. Res., 28: 1.057-1.061, 1994). The concrete methodology is described and continued The protocol used for these experiments faithfully follows that described by Liu et al., Cardiovasc. Res., 28: 1,057-1,061, 1994. Male New Zealand white rabbits are anesthetized (3-4 kg). ) with sodium pentobarbital (30 mg / kg intravenously) After deep anesthesia is obtained (determined by the absence of ocular flicker reflex), the animal is intubated and ventilated with 100% O2 using a positive pressure ventilator. a left thoracotonia, the heart is discovered and a loop (2-0 silk) is placed loosely around a branch of the left anterior descending coronary artery, approximately 2/3 of the distance to the apex of the heart. extracted from the chest and installed quickly (<30 seconds) on a Langendorff device. The heart is perfused inversely through the aorta in a non-recirculating manner with a modified Krebs solution (NaCl 118.5 thousand, KC1 4.7 mi, flgSO * 1.2 thousand, NeHC03 24.8 thousand, CeCl2 2.5 rnM and glucose 10 thousand), at a constant pressure of 80 rnm Hg and at a temperature of 37 ° C. The pH of the melt is maintained at 7.4-7.5 by bubbling a mixture of O2 / CO2 95/5%. The temperature of the heart is strictly controlled by using heated containers for the physiological solution and water-wrapped around both the perfusion tube and the isolated heart. The heart rate and left ventricular pressures are determined by a latex balloon that is inserted into the left ventricle and connected by a stainless steel tube to a pressure transducer. The straventricular balloon is inflated to provide a systolic pressure of 80-100 m Hg and a diastolic pressure equal to or less than 10 rnm of Hg. Throughout the experimental period, perfusate flow rates are routinely determined. The heart is balanced for 30 minutes, at which time the heart must show stable left ventricular pressures within the parameters defined above. If the heart rate falls below 180 beats per minute at any time before the 30-minute period of regional ischemia, the heart normalizes to -200 beats per minute for the remainder of the experiment. Ischemic preconditioning is induced by total cessation of cardiac perfusion (general ischemia) for 5 minutes, followed by reperfusion for 10 minutes. Once again, general ischemia / reperfusion is repeated, followed by a 30-minute regional ischemia. Regional ischemia is produced by tightening the loop around the coronary artery branch. After the 30-minute refinal ischemia, the loop is loosened and the heart is perfused for 120 additional minutes. Pharmacological cerdioprotection is induced by infusing the test compound at predetermined concentrations, for 30 minutes before the regional ischemia of 30 minutes and continuing until the end of the reperfusion period of 120 minutes. The hearts receiving test compounds do not suffer the two periods of ischemic precondition. The reference compound, APNEA (500 nM), is perfused to hearts (which do not receive the test compound) for a period of 5 minutes ending 10 minutes before regional ischemia of 30 minutes. At the end of the 120-minute reperfusion period, the coronary artery loop is tightened and a 0.5% suspension of fluorescent particles of zinc sulfate and cadmium (1-10 uM) is perfused into the heart, this stains the entire myocardium except the surface risk of infarct development (risk area). The heart is removed from the Langendorff apparatus, dried, weighed, wrapped in aluminum foil and altered overnight at -20 ° C. The next day, the heart is divided into trensverseles of 2 nm from the vertex to just above the coronary artery loop. The slices are stained for 20 minutes at 37 ° C with 1% RI enyltetyl chloride LO (TTC) in phosphate tarninated saline solution. Since TTC reacts with living tissue (containing NAD-dependent dehydrogenases), this staining differentiates between living tissue (stained red) and dead tissue (infarcted, non-stained tissue). In the left ventricle, the infarcted surface (not stained) and the risk surface (without fluorescent particles) are stored, using a pre-calibrated image analyzer. To normalize the ischemic damage to the difference of the risk surfaces between hearts, the data are expressed as surface ratio fartede to surface risk of infarction (SI / SRI,%). The activity and, therefore, the usefulness of the compounds of the present invention as medicinal agents that provide protection from schistosic damage to tissues in a mammal can be further demonstrated by the activity of the compounds in the vitro assay described hereinafter. The assay also provides means by which the activities of the compounds of this invention can be comped with the activities of other known compounds. The results of these comparisons are useful to determine dosage levels in mammals, including humans, that induce protection from ischemia. The activity of a sorbitol dehydrogenase inhibitor in a tissue can be determined by assaying the amount of sorbitol dehydrogenase inhibitor required to increase the level of oorbitol in the tissue (i.e., by inhibiting the additional metabolism of sorbitol consequent to blockage of the sorbitol. sorbitol dehydrogenase) or to decrease the level of fructose in the tissue (inhibiting its production from sorbitol consequent to blockade of sorbitol dehydrogenase). Although not wishing to be bound by any particular theory or mechanism, it is believed that an inhibitor of sorbitol dehydrogenase, by inhibiting sorbitol dehydrogenase, prevents or reduces the ischemic damage described below in the following paragraph and scheme. When the supply of oxygenated blood to a tissue is interrupted or reduced (ischemia), the oxygen deficient tissue cells produce their energy (ATP) of glucose by glycolysis (which does not require the presence of oxygen). Glucolysis also requires a NAD + contribution and, in an ischemic tissue, the time in which glycolysis can be maintained is sensitive to the contribution of NAD +. However, sorbitol dehydrogenase (SDH) also uses NAD * but does not produce an increase in ATP. Therefore, it follows that 00 avoiding or delaying the use of NAD + by SDH with inhibitors of sorbitol dehydrogenase (SDI), will increase or prolong the capecity of an ischemic tissue to perform glycolysis, that is, to produce energy in the absence of oxygen, and in turn it will increase and prolong the survival of tissue cells. Since the inhibition of SDH delayed the reaction of NAD + in tissues, a sorbitol dehydrogenase is an effective antuskemic agent. G s Also the activity of a sorbitol dehydrogenase inhibitor can be determined by the amount of sorbitol dehydrogenase inhibitor required to increase the level of sorbitol in the tissues or to decrease the level of fructose in the tissues. Rates Sprague-Dawley are made diabetic by intravenous injection of streptozocin, at a dose of 55 mg / kg in citrate buffer pH 4.5. They are given food ed libitum under controlled conditions of accommodation, temperature and lighting. After five sernanes of dibetes, the retes are anesthetized with an overdose of pentoberbitel, tissues are quickly extracted and the levels of sorbitol and fructose are analyzed. Sorbitol levels are aligned according to the procedure of Doneld M. Eedes et al., "Repid Analysis of Sorbitol, Gelectitol, flannitol end Myoinositol Mix tures From Biologicel Sources ", Journel of Chrometography, 490, 1-8 (1989). The level of fructose in rat tissues is determined enzymatically using a modification of the Arneyema procedure (rtethods Enzy ology, 89, 20-29, 1982), in which ferrocyanide is replaced by resazupna, a dye that is reduced to highly fluorescent resorufme. . The fluorescence ratio due to resorumph is ethic acid with the amount of fructose oxide dehydrogenated by the fructose. The assay contains 0.1 rnl of nerve extract neutralized with 6% perchloric acid, in a final volume of 1.5 ml. After incubating for 60 minutes at room temperature in a cerrado cedar. the fluorescence of the sample was determined at 560 nrn of excitation and 580 nm of emission, with slits of 5 mm each, in a spectrophotometer of fluorescence Per in-Elmer model 650-40. Fructose concentrations are calculated by comparing with a series of known fructose standards. The sorbitol dehydrogenase inhibitor compounds of this invention are, therefore, useful in reducing or minimizing damage directly to any tissue that may be exposed to damage by ischemia / reperfusion (eg, heart, brain, lung, kidney, liver, digestive tract, skeletal muscle, retina) as a result of an ischemic event (for example, myocardial infarction). The active compound is, therefore, useful when pere eviter is used prophylactically, that is, to mitigate or counteract (prospectively or prophylactically) tissue damage (eg, iocardial tissue) in patients at risk of ischemia (eg, ischemia). m-toc. The dehydrogenase inhibitor compounds of this invention are particularly suitable for the treatment of diabetic patients due to ß bol i srno increased by sorbitol dehydrogenase in the diabetic steth. The compounds of this invention are also suitable for prophylactic use in non-diabetic patients who have actually suffered or are considered to be at risk of suffering from ischemic events (e.g., rhinocardial ischemia). The administration of the compounds of this invention can be by any method that provides the inhibitors of sorbitol dehydrogenase the desired tissue. These procedures include: topical, orel, perenteral, intreductive, etc. Thus, for example, in a mode of administration, the sorbitol dehydrogenase inhibitor of this invention can be administered just before cardiac surgery (for example, within twenty-four hours before surgery) when there is a risk of myocardial ischemia. In an example of an alternative ear, the compounds can be administered after cardiac surgery (for example, within twenty-four hours after surgery) when there is a risk of rhinocardial ischemia. The compounds of this invention can also be administered in a chronic daily mode. In any case, the amount and time of administration of the compound (s) will of course depend on the patient to be treated, serious of the disease, administration time and judgment of the prescribing physician. Therefore, due to the variability from patient to patient, the doses indicated below are an operative step and the doctor can assess the dose of the drug to achieve the effect that the patient considers appropriate. When considering the degree of activity of the sorbitol dehydrogenase inhibitor, the physician must balance various factors, such as target tissue, greveded from the diseased / condition and eded of the patient. An amount of the sorbitol dehydrogenase inhibitor of this invention that is effective in providing ischemic protection is used. Typically, an effective dose for the sorbitol dehydrogenase inhibitors of this invention is in the range of 0.1 mg / kg. at 100 mg / kg. day, in a single dose or in divided doses, preferably 0.1 mg / kg.day and 20 mg / kg. in a single dose or in divided doses. Generally, the compounds of the invention are administered orally, although parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used, for example, when oral administration is unsuitable for the instant target or when the is unable to ingest the drug (for example, due to age or surgical status). In certain tissues, such as the eye, topical administration may also be suitable. The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one inhibitor of sorbitol dehydrogenase together with a ferrneceutically acceptable carrier or diluent. Therefore, the compounds can be individually or jointly squeezed, in any form of oral dosing, either directly or through conventional means. For oral administration, a pharmaceutical composition may take the form of solutions, suspensions, tablets, pills, capsules, powders and similar forms. Tablets containing various excipients, such as sodium chloride, calcium carbonate and calcium phosphite, are used together with various disintegrants such as starch and preferably the potato or tapioce dressing, and certain complex silicones, together with binding agents such as co. polyvinylpyrrolidone, sacerose, gelatin and gum arabic. In addition, for the manufacture of tablets, lubricating agents such as magnesium stearate, sodium lauryl-cethate and talc are often very useful. Solid compositions of similar type are also used as fillers in soft and hard gelatin capsules; Preferred materials in this regard also include lactose or milk milk esi as high molecular weight polyethylene glycols. When ecuous suspensions and / or elixirs are desired for oral administration, the compound of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as with diluents such as water, ethanol , propylene glycol, glycerol and various similar combinations thereof. For parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts may be employed. Said aqueous solutions can be suitably buffered, if necessary, and first the liquid diluent should be made isotonic with sufficient saline or glucose. These aqueous solutions are specifically evecuedes for intravenous, intramuscular, subcutaneous or intraperitoneal injection. In this regard, the sterile equitable media employed can be obtained by standard procedures well known to those skilled in the art. Also transdermal or trecreneal compositions (for example, clichés) can be prepared by those skilled in the art. The methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or may be apparent in light of this description, by those skilled in the art. For examples, see Phar eceuticel Sciences, by Remington, Riack Publishing Co peny, Eester, Pe., 15th edition (1975). The ferrneceutical compositions according to the invention may contain 0.01% ~ 95% of the compound (s) of this invention, preferably l% -70%. In any case, the composition or formulation to be administered must contain a compound (s) according to the invention in an amount effective to treat the symptoms of the patient to be treated, that is, to provide protection from ischemic damage.

EXAMPLE 1 They were anesthetized with sodium pentobarbital (30mg / kg per intravenous vie) male New Zealand white rabbits (3-4 kg) (control group, n = 6, - preconditioned group, n = 6, - group treated with APNEA, n = 9; group treated with 4-C4- (N, N-di-rnetisulfemoyl)? Iperezinol] -2-hydroxymethylpyrirnidine, n = 8 e 5 ufl, n = 6 at 50 μn and n = 7 to 200 pfu). After obtaining deep anesthesia (determined by the euphemising reflex of parpedoe reflex), the enimal was intubated and ventilated with 100% O2 using a positive pressure ventilator. A left thoracotomy was performed, the heart was discovered and a loop (2-0 silk) was placed loosely around the left anterior descending coronary artery, approximately 2/3 of the distance to the heart's vortex. . The heart was removed from the chest and quickly installed (<30 seconds) in a Langendorff apar-ato. The heart was perfused inversely through the aorta in a non-recirculating manner with a solution of reconstituted Krebs (NaCl 118.5 ml, KC1 4.7 M, MgSO / i 1.2 rnM, KH2PO4 1.2 thousand, NaHC03 24.8 thousand, CaCl2 2.5 thousand and glucose 10 mi), hereinafter denoted Krebs solution, e a constant pressure of 80 mm Hg and a temperature of 37 ° C. The pH of the penfundido was maintained at 7.4-7.5 by bubbling a mixture of O2 / CO2 95% / 5%. The temperature of the dressing was rigorously controlled using heated containers of the physiological solution and water jacket around both the perfusion tube and the isolated heart. The pigment rhythm and left ventricular pressure were determined by a latex balloon that was inserted into the left ventricle and connected by a stainless steel tube to a pressure transducer. The raventricular balloon was inflated to provide a systolic pressure of 80-100 mm Hg and a diestolic pressure equal to or less than 10 mrn Hg. During the entire experimental period, the flow rates of the perfusate were routinely determined. The hearts were allowed to equilibrate for 30 minutes before any other manipulation, during which time they showed the left ventricular pressures previously measured. The hearts that were preconditioned underwent a period of five minutes of global ischemia (achieved by aortic stroke) followed by ten minutes of reuse. This procedure was repeated a second time, after which the seizure was subjected to 30 minutes of regional ischemia (provided by tightening the loop around the branch of the coronary artery) and a period of 120 minutes of reperfusion (performed by loosening the loop of the coronary artery). In hearts that were treated with the A1 / A3 APNEA agonist, the drug was perfused (500 nM in Krebs solution) to the heart by the aorta for five minutes, followed by 10 minutes of perfusion with Krebs solution without drug. The hearts were then subjected to 30 minutes of ischemia and a 120 minutes of reperfusion, as described above. In hearts that were treated with the test compound, 4- [4 (N, Nd? Met? Lsulfamo? L) p? Peraz? No] -2-h? Drox? Rnet? L-pirinidma (5.50 and 200 μM in Krebs solution), the drug was perfused to the heart by the aorta during a period that began minutes before the regional ischemia of 30 minutes and continued during all periods of ischemia and reperfusion described above (total perfusion time: 3 hours). The control hearts were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion, without any other treatment.

At the end of the 120-minute roperfusion period, the coronary artery loop was again squeezed and the heart was perfused with a 0.5% suspension of lumenscent zinc sulphate particles and cadmium in Krebs solution (1-L0). μM). The heart was removed after the appearance of Langendorff, dried, weighed, wrapped in aluminum foil and almelanised overnight at -20 ° C. The next day, each heart was sectioned into 5-7 transverse 2 mm sheaths from the apex to the coronary artery loop. The slices were stained for 20 minutes at 37 ° C. with 1% triphenyltetrazolium chloride (TTC) in phosphate buffered saline. When the left ventricle was surrounded, the infarcted (unstained) surface and the risk surface (without fluorescent particles) were calculated, using a precelibredo image analyzer. To normalize the ischemic damage a The risk surface differences between hearts were expressed as the ratio of infarct surface to infarct risk area (SR / SRI,%). The results of the above in vitro test are detailed in the following Table 1. The results show that the test compound induced significant cardioprotection with respect to the control group.

TABLE 1 Error. SI / SRI treatment (%) 10 typical with role 14 63.5 4.1 Pre-conditioned 10 11.3 2.7 APNEA (500nM) 9 19.0 3.6 4 - . 4 - C 4 - (, N- dirnet 11 - (5-sul f a-rnoyl) p? Peraz? No] -2- hydroxy-rnetylpyridine (5 μM) 48.5 4.2 4-C4- (N, N-d? Met? L- (5-sulfe-rnoyl) ??? erez? No3 ~ 2-h droxi-rnetilpipopdine (50 μM) 39.0 2.7 4-C - (N, N-d? Met? L- (5-sulfe-rnoyl) ?? perez? Nol-2-hydroxy-rnetylpipepdi a (200 μM) 38.7 5.9 SI / SRI = ratio "infarct area / infarct risk area" E3EMPL0 2 Rates Sprague-Dewley were made by intravenous injection of streptozocine at a dose of 55 mg / kg in citrate buffer pH 4.5. They were given comide ad libitum under controlled housing, temperature and lighting conditions. After five years of diets, the rats were anesthetized with an overdose of pentobarbital and very rapidly tissue was detached and the content of sorbitol and fructose was elevated by the aforementioned procedures. The sorbitol levels were analyzed according to the procedure of Doneld M. Eedes et al., "Repid Analysis of Sorbitol, Galactitol, Menthol and Myoinositol Mixtures From Biologi el So? Rces'P Journal of Chrornatography, 490 1-8 (1989 The fructose in rat tissues was determined enzymatically using a modification of the Ameyarna method (Methods Enzymology, 89, 1982), in which ferricyanide was replaced by resazupna, a dye that is reduced to highly fluorescent resorumph. Due to resorumate and stoichiometry with the amount of fructose oxidized by the fructose dehydrogenate, the sample contained 0.1 ml of neutralized nerve extract with 6% percropic acid, in a final volume of 1.5 ml, after incubation for 60 minutes at room temperature. environment in a closed drawer, the fluorescence of the sample was determined at 560 nn of excitation and 580 n of emission, with slits of 5 rnm yields one, in a fluorescent photometer spectrum. Encia Perr Elrner model 650-40. Fructose concentrations were calculated by comparing with a series of known standards containing 0 to 200 ng of fructose per test. Table 2 details the increase in sorbitol in various tissues and, therefore, the inhibition of sorbitol dehydrogenase and, consequently, the antifungal activity of the sorbitol dehydrogenase inhibitor 4-r - (N, Nd? -met? Lsulfem ?) l? peraz? no] -2-h? drox? met? l? pm? d? na. Table 3 shows the decrease in fructose in various tissues, and, therefore, the inhibition of eorbitol dehydrogenase and, consequently, the antisqueal activity of the inhibitor of sorbitol dehydrogenase 4- [4- (N, N- dimethylsulfamoyl) pipera-zi no 3 - 2 - hi drox irnet i 1 pi rirni di na .. w J¡- * - í-ü? r-o .o or p or U. or < J or J? TABLE 2 Effects of 4- [4 (N, N-dimethylsulfamoyl) piperazino-2-hydroxymethylpyrimidine (SDI), administered at a dose of 200 mg / kg. day, on sorbitol levels (nanomoles / g) in rats with diabetes for 5 weeks duration UA UP RET CER NC CRIST AOR MUSC COR Control 14 7 126 126 159 436 11 18 72 (17) (11) (75) ( 82) (55) (73) (12) (13) (37) + SDI 254 289 574 168 2,050 5,410 61 33 73 (124) (78) (161) (82) (697) (1,848) (22) ( 20) (39) Diabetic 915 601 1,409 192 1,863 37,006 60 25 177 s \ (371) (282) (412) (70) (623) (6,064) (19) (16) (86) + SDI 3,426 2,379 5,380 901 9,975 48,020 103 68 270 (1,778) (1,160) (1,702) (591) (4,397) (8,513) (65) (24) (116) Mean ± standard deviation (n = 9-13). The figures in parentheses are the standard deviations. UA = previous uvea RET = retina NC = sciatic nerve AOR = aorta UP = posterior uvea CER = brain CRIST = crystalline MUS = muscle COR = heart ? or t-p or if TABLE 3 Effects of 4- [4- (N-N-dimethylsulfamoiDpiperazino] -2-hydroxymethylpyrimidine (SDI) (at a dose of 200 mg / kg.day) on sorbitol and fructose levels in the retina, sciatic and crystalline nerve (nanomoles / g), in rats with diabetes of 5 weeks duration Retina Sciatic Nerve Crystalline Sorbitol Fructose Sorbitol Fructose Sorbitol Fructose Control 126 76 159 814 436 883 (75) (14) (55) (197) (73) (151) + SDI 574 75 2,050 425 5,410,998 (161) (48) (697) (201) (1,848) (207) Diabetic 1,409 1,289 1,863 5,815 37,006 12,676 (412) (178) (623) (1,711) (6,064) (1,261) + SDI 5,381 534 9,975 1,382 48,028 2,700 (1,702) (224) (4,397) (1,358) (8,513) (1,296) Mean ± standard deviation (n = 8-13). The figures in parentheses are the standard deviations It should be understood that the invention is not limited to the particular embodiments described herein, but that various changes and modifications may be made without departing from the spirit or scope of this new concept defined by the following claims. Having described the invention as above, the contents of the following are claimed as properties:

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a .sorbitol dehydrogenase inhibitor in the prerequisite of compositions to reduce denos and tissues resulting from isolation in a material requiring said tremor.

2. The use of a sorbitol dehydrogenase inhibitor according to claim 1, wherein the tissue is tissue from the heart, brain, liver, kidney, lung, gastrointestinal tract, skeletal muscle, spleen, pancreas, retina or intestine.

3. The use of a sorbitol dehydrogenase inhibitor according to claim 2, wherein said mammal is a human being.

4. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is heart tissue.

5. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is brain tissue.

6. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is liver tissue.

7. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is tissue from the kidneys.

8. The use of an inhibitor of sorbitol dehydrogenase according to claim 3, wherein said tissue is tissue from the lungs.

9. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is tissue from the digestive tract.

10. The use of a dehydrogenase inhibitor according to claim 3, wherein said tissue is tissue of skeletal muscles.

11. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is tissue from the spleen.

12. The use of an inhibitor of sorbitol dehydrogenase according to claim 3, wherein said tissue is tissue of the pancreas.

13. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is retinal tissue.

14. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein the effective amount of sorbitol dehydrogenase inhibitor is about 0.1 mg / kg. day at approximately 100 mg / kg. day.

15. The use of a sorbitol dehydrogenase inhibitor according to claim 14, wherein said composition comprising a sorbitol dehydrogenase inhibitor is administered prophylactically.

16. The use of a sorbitol dehydrogenase inhibitor according to claim 14, wherein the composition comprising an inhibitor of sorbitol dehydrogenase is invented before performing cardiac surgery.

17. The use of a sorbitol dehydrogenase inhibitor according to claim 14, wherein said composition comprising an inhibitor of sorbitol dehydrogenase is administered chronically.

18. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said composition comprising an inhibitor of sorbitol dehydrogenase is a substituted pyrimidine compound.

19. The use of a sorbitol dehydrogenase inhibitor according to claim 18, wherein said compound is 4-C4- (N, N-dimethylsulfamoyl)? Iperezino3-2-hi-roxymethylpyrirnidine.

20. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein said tissue is intestinal tissue.

21. The use of a sorbitol dehydrogenase inhibitor according to claim 3, wherein the human being has diabetes.