MXPA97005737A - Substitute indianilidinacylukinides, procedure for its preparation, its use as medicines or diagnostic agents and medicines containing them - Google Patents

Abstract

Indanylidine acetylguanidines I and their pharmaceutically acceptable salts wherein R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10 and X have the meanings given in the claims, are effective inhibitors of sodium / proton cell antiport (exchanger Na + / H +) which in numerous diseases (essential hypertension, atherosclerosis, diabetes and the like) is also increased in those cells which are easily accessible for measurements, such as, for example, in erythrocytes, platelets or leukocytes. They are also advantageous for the preparation of a medicament for the treatment or prophylaxis of disorders of lipid metabolism

Description

Substituted indanilidinacetilguanidinas, procedure for its preparation, its use as medicines or diagnostic agents and medicines that contain them: The present invention relates to indanylidinacetylguanidines, to the process for their preparation, to their use as medicaments, to their use as diagnostic agents and to medicaments containing them. The indanilidinacetilguani-dinas of the invention have the formula I: wherein, R 1, R 2, R 3, R 4 and R 5 individually or collectively represent H, C 1 -C 1 alkyl, haloalkyl with 1-6 carbon atoms, O-C x C x alkyl, haloalkoxy with 1-6 carbon atoms, halogens such as F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OH; O-lower alkyl, O-aryl, O-lower alkyl-aryl, O-substituted aryl, aryl substituted with lower O-alkyl, 0-C (= 0) -alkyl Cx-C4-aryl, 0-C (= 0 ) - NH-CX-C alkyl? 0-C (= 0) -N (C ^ -C *) alkyl *, N02, CN, CF3 NH2, NH-C (= 0) -C C4 alkyl, NH-C (= 0) -NH2, COOH , C (= 0) -O-Cx-C4 alkyl, C (= 0) -NH2, C (= 0) -NH-Cx-C4 alkyl, C (= 0) -N (C-C-alkyl. -., Cx-C4-COOH, C4-C4 alkyl (= 0) -O-C -C4 alkyl, S03H, S02-alkyl, S03-alkylaryl, S02-N- (alkyl) 2 S02-N (alkyl) (alkylaryl), C (= 0) -Rxx, alkyl C -C oC (= 0) -Rxx, C2-Cxo alkenyl-C (= 0) -R x, C2-Cxo alkynyl-C (= 0) ) -Rx? NH-C (= 0) -alkyl Cx-Cxo-C (= 0) -R xo O-alkyl Cx-C x-C (= 0) -R x; Rll is Cx-C4 alkyl, C ^ -C ^ alkynyl, aryl, substituted aryl, NHa, NH-Cx-C4 alkyl, N- (CX-C4 alkyl) 2, S03H, S02-alkyl, S02-alkylaryl, S02- N- (alkyl) 2, S02-N (alkyl) (alkylaryl); X is O, S or NH; R7, R8, R9 and RIO are individually or collectively H, alkyl, cycloalkyl, aryl or alkylaryl; or R8 and R9 together are part of a heterocyclic ring with 5-6 or 7- mieres; or its salts with an organic or mineral acid, non-toxic. Examples of pharmaceutically acceptable, non-toxic acids A are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid, and oxalic acid. Throughout this description, unless otherwise indicated, it is to be understood that the following terms have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon group which may have straight or branched chain. Preferred alkyl groups do not have more than about 12 carbon atoms and can be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. "Lower alkyl" means an alkyl group as described above, having 1 to about 6 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tere-butyl, n-pentyl, isopentyl and neopentyl.

"Cycloalkyl" means a saturated monocyclic aliphatic carbocyclic group. Preferred groups have from about 3 to about 6 carbon atoms, and examples of these groups include cyclopropyl, cyclopentyl and cyclohexyl. "Alkenyl" means an unsaturated aliphatic hydrocarbon group. Preferred groups do not have more than about 12 carbon atoms. Examples of these groups include all the structural and geometric isomers of ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl and dodecenyl or buta-dienyl, pentadienyl etc. "Lower alkenyl" means alkenyl of about 2 to 6 carbon atoms. Preferred groups include ethenyl, propenyl, butenyl, isobutenyl, and all their structural and geometric isomers. "Alkynyl" means an unsaturated aliphatic hydrocarbon group. Preferred groups have no more than about 12 carbon atoms and contain one or more triple bonds, including all the structural or geometric isomers of ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecylny etc. "Lower alkynyl" means alkynyl of about 2 to 6 carbon atoms. Preferred groups include structural isomers of propynyl, butynyl and pentyls. "Aryl" means phenyl and substituted phenyl. "Substituted phenyl" means a phenyl group in which one or more of the hydrogens have been replaced by the same or different substituents including halogen, lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, nitro, amino, acylamino, hydroxy, carboxyl, lower alkoxy, aryl-lower alkoxy, acyloxy-lower alkanoyl, cyano, amido, lower alkyl-amino, lower alkoxy-amino, aralkylamino or lower alkyl-sulfonyl.

"Aralkyl" means an alkyl group in which one or more hydrogens have been substituted with an aryl group. Preferred groups are phenalkyl and substituted phenalkyl. "Phenalkyl" means an alkyl group substituted with a phenyl group. "Substituted phenalkyl" means a phenalkyl group in which one or more phenyl hydrogens are replaced as indicated above with respect to the substituted phenyl.

"Substituted phenalkenyl" means a phenalkenyl group in which the phenyl group is substituted as indicated above with respect to the substituted phenyl. "Heterocyclic ring" or "heterocycle" means a 3, 5, 6 or 7 membered ring having 1 to 3 heteroatoms which may be nitrogen, oxygen or sulfur, including pyrrole, pyrrolidine, pyridone, heptamethyleneiminyl, pyrazole, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, isoxazolyl, fu-ryl, thienyl, oxazolyl, thiazolyl, piperidyl, orpholinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl, thiamorpholinyl, azepinyl and ethylene-nyl. "Substituted heterocycle" means a heterocycle group in which one or more of the hydrogens on the ring carbons, have been replaced by substituents as indicated above with respect to the substituted phenyl. The term "halo" or "halogen" includes the four halogens; This is fluorine, chlorine bromine and iodine. The haloalkyl, halophenyl and pyridyl substituted with halogen groups, having more than one halo substituent which may be the same or different, such as trifluoromethyl, l-chloro-2-bromo-ethyl, chlorophenyl and 4-sloropyridyl. "Acyl" means an organic carbonyl radical of a lower alkanoic acid. Preferred acyl groups are lower alkanoyl groups such as acetyl and propionyl.

"Aroyl" means an aromatic acid radical such as benzoyl, toluoyl.

"Lower alkanoyl" means the acyl radical of a lower alkanoic acid, such as acetyl, propionyl, butyroyl, valeryl, stearoyl, and the like. "Alkoxy" means an alkyloxy group and includes hydroxyalkyl groups. Preferred lower alkoxy groups are methoxy, ethoxy, n-propoxy and isopropoxy, isobutoxy, n-butoxy and t-butoxy. Preferred compounds of the invention are compounds of formula II wherein, R 1, R 2, R 3, R 4, R 5 and R 6 individually or collectively represent H, C 1 -C 6 alkyl, haloalkyl with 1-6 carbon atoms, O-C -C alkyl, haloalkoxy with 1-6 carbon atoms carbon, halogens such as F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OH, O-lower alkyl, O-aryl, O-lower alkyl-aryl, O-substituted aryl, aryl substituted with O -lower alkyl, 0-C (= 0) -alkyl Cx-C4-aryl, 0-C (= 0) -NH-C-C4 alkyl, 0-C (= 0) -N (CX-C alkyl?) 2, N02, CN, CF3, NH2, NH-C (= 0) -alkyl Cx-C4, NH-C (= 0) -NH2, COOH, C (= 0) -O-alkyl Cx-C4, C ( = 0) -NH2, C (= 0) -NH-Cx-C alkyl? , C (= 0) -N (Cx-Cu alkyl) 2, Cx-C? -COOH, Cx-C? -C alkyl (= 0) -0-Cx-C4 alkyl, S03H, S02-alkyl, S02- alkylaryl, S02-N- (alkyl) 2, S02-N (alkyl) (alkylaryl), C (= 0) -Rxx, alkyl Cx-Cxo-C (= 0) -Rxx, alkenyl C2-Cxo-C (= 0) -Rx, C2-Cxo alkynyl-C (= 0) -Rxx, NH-C (= 0) -alkyl Cx-Cxo-C (= 0) -Rxx, O-alkyl Cx-Cxx-C ( = 0) -Rxx; Rll is Cx-C4 alkyl, Cx-C4 alkynyl, aryl, substituted aryl, NH2, NH-Cx-C4 alkyl, N- (CX-C4 alkyl) a, S03H, S02-alkyl, S02-alkylaryl, S02-N- (alkyl) 2, S02-N (alkyl) (alkylaryl); X is O, S or NH but preferably X is oxygen; and their pharmaceutically acceptable salts. The compounds of the present invention contain geometric isomers and the invention relates to both the E-isomers and the Z-isomers. The compounds of the present invention may contain asymmetric centers and the invention relates to both the S-configuration and the to those of R configuration. The compounds can exist as optical isomers, as racemates or as their mixtures. According to the invention there is also provided a process for the preparation of a compound of the formula I which comprises reacting a compound of the formula V wherein R1, R2, R3, R4, R5 and R6 are as defined above and Y is a leaving group selected from O-alkyl (Cx-C <), halogen or imidazolyl, with a guanidine of the formula VI wherein R7, R8, R9 and RIO are as defined above, and if it is desired to convert the product into pharmaceutically tolerated salts. Representative samples of the compounds of this invention are detailed in Table 1 wherein: R5 and R6 are H; and X is oxygen; A is CH3S03H.

Table 1: The compounds of the formula I are substituted acylguanidines. The most important representative of acylguanidines is the pyrazine derivative, amiloride, which is used in therapy as a potassium-sparing diuretic. Many other compounds of the amiloride type are described in the literature, such as for example dimethylamiloride or ethylisopropylamiloride. Studies have been described that also indicate antiarrhythmic properties of amiloride [Circulation 79, 1257-1263 (1989)]. However, its wide use as an antiarrhythmic is hindered by the fact that this effect is only slight and is accompanied by an antihypertensive and salutary action and these side effects are undesirable in the treatment of cardiac rhythm disorders. Indications of the antiarrhythmic properties of amiloride have also been obtained from experiments on hearts isolated from animals [Eur. Heart J. 9. { supplement 1. #} : 167 (1988) (book of abstracts)]. Thus, for example, it has been found that in rat hearts, it is possible to completely suppress artificially induced ventricular fibrillation with amiloride. The aforementioned amiloride derivative, ethylisopropylamiloride was even more potent than the amiloride in this model. In the European Offenlegungsschrift document 416499, benzoylg-anidines having antiarrhythmic properties are described. U.S. Patent 3780027 also discloses acylguanidines, which differ fundamentally from the compounds of formula I according to the invention described herein, in that they are trisubstituted benzoylguanidines which are derived in their model of substitution of commercially available diuretics, such as bumetanide and furosemide and have an amino group, which is important for the salidiuretic action sought, in position 2 or 3 relative to the carbonyl group of guanidine. A potent salidiuretic action has been described correspondingly for these compounds.

It was therefore surprising that the compounds according to the invention have no undesirable or adverse salidiuretic properties but very good antiarrhythmic properties, so that they can be used in the treatment of health disorders such as deficiency symptoms. oxygen. As a result of their pharmacological properties, the compounds are primarily suitable as antiarrhythmic drugs that have a cardioprotective component for infarction prophylaxis and infarction treatment and for the treatment of angina pectoris, where they also preventively prevent or greatly reduce the pathophysiological processes in the development of ischemically induced damage, in particular the initiation of cardiac arrhythmias induced ischemically. Because of their protective actions against hypoxic and ischemic pathological situations, the compounds of the formula I according to the invention, as a result of the inhibition of the cellular exchange mechanism Na + / H +, can be used as medicaments for the treatment of all acute and chronic damage caused by ischemia or diseases induced in a primary or secondary way by it. This applies to their use as drugs for surgical interventions, for example organ transplants, where the compounds can be used both for protection of the organs in the donor before and during their separation, as well as for protection of the separate organs, by example during treatment with them or storage thereof in physiological bath fluids and also during transfer to the recipient organism. Compounds are also valuable drugs that have a protective action while performing angioplasty surgical procedures., for example on the heart and also on the peripheral blood vessels. In accordance with their protective action against ischemia-induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system (CNS), where they are suitable, for example, for the treatment of stroke or cerebral edema. In addition, the compounds of formula I according to the invention are also suitable for treatment of shock forms, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock. The compounds of the formula I according to the invention are further distinguished by a potent inhibitory action on cell proliferation, for example proliferation of fibroblast cells and proliferation of vascular smooth muscle cells. The compounds of formula I are therefore possible valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as antiatherosclerotic agents and as agents delaying diabetic complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and hypertrophies and hyperplasias of organs, in particular protatic hyperplasia or prostatic hypertrophy. The compounds according to the invention are effective inhibitors of the sodium / proton cell antiport (Na + / H + exchanger) which in many diseases (essential hypertension, atherosclerosis, diabetes and the like) is also increased in those cells which are easily accessible for measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds according to the invention are therefore suitable as primordial and simple scientific instruments, for example for their use as diagnostic agents for the determination and differentiation of certain forms of hypertension, and also of atherosclerosis, diabetes, proliferative diseases and the like. The compounds of the formula I are also suitable for preventive therapy for preventing the origin of high blood pressure, for example essential hypertension.

It has further been found that the compounds of the formula I have a favorable effect on the serum lipoproteins. It is generally recognized that for the formation of arteriosclerotic vascular changes, particularly in coronary heart disease, excessively high values of blood lipids, so-called hyperlipoproteinemias, are a significant risk factor. For the prophylaxis and regression of atherosclerotic changes, the reduction of elevated serum lipoproteins is therefore of extreme importance. In addition to the reduction of total serum cholesterol, the reduction in the proportion of specific atherogenic lipid fractions of this total cholesterol, in particular the reduction of low density lipoproteins (LDL) and very low density lipoproteins (VLDL) is of particular importance, since these lipid fractions are an ate-rogenic risk factor. In contrast, high density lipoproteins are related to a protective function against coronary heart disease. Therefore, hypolipidemic agents should be able not only to lower total cholesterol, but in particular the VLDL and LDL fractions of serum cholesterol. It has now been found that the compounds of formula I have valuable therapeutically usable properties with respect to the effect on serum lipid levels. Thus, said compounds significantly reduce the high concentrations of LDL and VLDL in serum, which are observed, for example as a result of an increased dietary intake with a diet rich in cholesterol and lipids or in the case of pathological metabolic changes, for example hyperlipidemias related to genetic factors. They can therefore be used for the prophylaxis and for the regression of atherosclerotic changes, thereby eliminating a causal risk factor. These changes include not only primary hyperlipidemias, but also certain secondary hyperlipidemias, such as those that occur, for example, in diabetes. In addition, the compounds of the formula I lead to a marked reduction in the infarcts induced by etabolic anomalies and in particular to a significant decrease in the size of the induced infarction and its degree of severity. In addition, the compounds of formula I result in effective protection against damage due to metabolic abnormalities of induced endothelial damage. With this protection of the blood vessels against the syndrome of endothelial dysfunction, the compounds of the formula I are valuable drugs for the prevention and treatment of coronary vascular spasms, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and of thrombotic disorders. The mentioned compounds are therefore advantageously used for the production of a medicament for the treatment of hypercholesterolemia; for the production of a medicament for the prevention of atherogenesis; for the production of a medicament for the prevention and treatment of atherosclerosis; for the production of a medicament for the prevention and treatment of diseases that are induced by high cholesterol levels, for the production of a medicament for the prevention and treatment of diseases that are induced by endothelial dysfunction, for the production of a medicament for the prevention and treatment of hypertension induced by atherosclerosis, for the production of a drug for the prevention and treatment of thrombosis induced by atherosclerosis, for the production of a drug for the prevention and treatment of ischemic damage and post-ischemic reperfusion injury induced by hypercholesterolemia and by endothelial dysfunction, for the production of a drug, for the prevention and treatment of cardiac hypertrophies and cardiomyopathies induced by hypercholesterolemia and by endothelial dysfunction, for the production of a medicament for the prevention and treatment of co-ronal vascular spasms; myocardial infarctions induced by hypercholesterolemia and by endothelial dysfunction, for the production of a drug for the treatment of conditions mentioned, in combination with hypotensive substances, preferably with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, a combination of an NHE inhibitor of formula I with an active compound that reduces the level of blood lipids, preferably with an inhibitor of HMG-CoA-re-ductase (for example lovastatin or pravastatin), the latter contributing to a hypolipidemic action and thereby increasing the hypolipidemic properties of the NHE inhibitor of formula I, which proves to be a combination favorable with improved action and reduced use of the active compound. This invention also relates to the process for the preparation of compounds of the formula I. The preparation of the compounds of the invention is illustrated, but not limited, by the preparation of compounds of the invention, which are used as examples. The synthesis of compounds of the formula I was achieved through an intermediate of the formula III, wherein R1, R2, R3, R4, R5 and R6 are as defined above. The compounds of the formula III are prepared by known methods. One of the methods is by cyclization of 3-phenylpropanoic acid using polyphosphoric acid. The compounds of formula III are converted to acids of formula IV, - - wherein R1, R2, R3, R, R5 and R6 are as defined above, by treatment with Witting reagent (Ph) 3P + = CHCOOEt.Br ~ at temperatures from 200 to 250 ° C, net, for 10- 12 hours and subsequent treatment. The activated acid derivatives of the formula V in which Y is an alkoxy group, preferably a methoxy group, an activated phenoxy group, a phenylthio group, methylthio, 2-pyridylthio or a heterocycle with nitrogen, such as imidazolyl, which can be prepared from the acid chloride (formula V, Y = Cl) which in turn can be prepared from the acid, formula IV by treatment with thio-nyl chloride. Other methods of activating the esters can be used, which are known in the area of peptides to activate the acid by coupling reaction. The imidazolides of formula V, Y = imidazolides, can also be prepared from a compound of formula IV, by treating them are 1,1'-carbonyldiimidazole [C. Staab, Angew. Chem. Int. Eng Edn. 351-367 (1962)]. A compound of the formula V (Y = Cl) by treatment with the compound of the formula VI under the Schotten-Baumann conditions also gives a compound of the formula I. A further mixed anhydride related to the formula V can be prepared, as with CICOOEt, tosyl chloride, triethylphosphoryl chloride in the presence of triethylamine or any other base in an inert solvent. Activation of the COOH group in the compounds of formula IV can also be achieved with DCC. Other methods of preparation of the activated carboxylic acid derivative of the type of the formula V are given with indication of bibliographic sources, in J. March, Advanced Organic Chemistry, 3rd Edition (John Wiley &Son, 1985), page 350. The coupling reaction between compounds of formulas V and VI can be performed in various ways in protic or aprotic polar solvents, but inert organic solvents are preferred. In this regard, methanol, THF, DMF, N-methylpyrrolidone, HMPA etc., between room temperature and the boiling point of these solvents, have proven to be suitable for the reaction of formula V (Y = OMe) with guanidine. The reaction of the compounds of the formula V with guanidine free of salt is advantageously carried out in inert aprotic solvents such as THF, dimethoxyethane, DMF or dioxane. In the case where the compound of the formula IV is treated directly with carbonyldiimidazole to activate the carboxyl group, polar aprotic solvents such as DMF, dimethoxyethane are used, followed by the addition of the compound of the formula VI. The compounds of the formula I can be converted into pharmacologically acceptable acid addition salts with model salts as described at the beginning of this description. The active compounds of the present invention can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the specific clinical need of the disease. In this regard, the compounds of form-mule I can also be used alone or together with pharmaceutical auxiliaries, and both in veterinary and in human medicine. Auxiliary products that are suitable for the desired pharmaceutical formulation are familiar to those skilled in the art based on their practical knowledge. In addition to the solvents, gel-forming agents, suppository bases, tablet auxiliaries and other excipients of the active compound, antioxidants, dispersants, emulsifiers, antifoam agents, flavor correctors, preservatives, solubilizers or colorants can be used. For a form of oral use, the active compounds are mixed with the appropriate additives for this purpose, They are prepared as excipients, stabilizers or inert diluents and are prepared in suitable forms of administration such as tablets, coated tablets, hard gelatin sachets, aqueous solvents, alsoholic or oily, by the usual methods. Inert excipients that can be used are, for example, gum arabic, magnesia, magnesium sarbonate, potassium phosphate, cheese, glucose, or starch, in particular corn starch. In this case, the preparation can take place in the form of both dry and wet granules. Suitable oily solvents or solvents are, for example, animal or vegetable oils, such as sunflower oil or cod liver oil. For subcutaneous or intravenous administration, the desired active compounds are placed in solution, suspension or emulsion with the usual substances for this purpose such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are for example: water, physiological saline, or alcohols, for example ethanol, propanol, glycerol, and additionally, also sugar solutions such as glucose or mannitol solutions, or alternatively, a mixture of the various solvents mentioned. Pharmaceutical formulations adapted for administration in the form of aerosols or sprays are, for example, solusions, suspensions or emulsions of the aspent compound of formula I in aseptable pharmaceutical solvents, such as somo, in particular, ethanol or water or a mixture of such solvents. If required, the formulation may also contain other auxiliary fillers, such as surfactants, emulsifiers and stabilizers and also a propellant gas. Such a preparation normally contains the active compound in a concentration of about 0.1 to 10, in particular about 0.3 to 3,% by weight. The dosifisation of the astute substance of the formula I to be administered and the administration fressensia depends on the potency and hardness of the sedation of the used substance; - 1 - and additionally also of the nature and severity of the disease to be treated and of the sex, age, weight and individual response of the mammal to be treated. On average, the daily dose of a compound of the formula I in a suspension of approximately 75 kg is a minimum of 0.001 mg, preferably 0.01 mg to a maximum of 10 mg, preferably 1.0 mg maximum. In acute outbreaks of the disease, for example immediately after suffering a sardia-like infarction, even higher and, above all, more frequent doses may be necessary, for example up to 4 individual doses per day. In particular, for i.v. For example, in a patient with a heart attack in the intensive care unit, up to 100 mg per day may be necessary.

Experimental section: Synthesis of the representative example, 4-methyl-i-indanylidinasetilguanidin-methanesulfoniso acid (given No. 4 of formula I of Table 1).

A. Synthesis of Compound No. 4 of Table 1: to. Synthesis of compounds is formula III: Methyl 3- (2-methylphenyl) -propan-l-oiso (14 g, 0.085 mol) is a very acid polyphosphoric acid (PPA, 140 g) and the mixture is dissolved at 80-85. ° C are mesanisa agitation. After 1.0 hour the reassessing mixture became reddish solor, the reaction was terminated by pouring the mixture over cold water. The yellow slaro obtained was filtered, washed with water, dried and purified by chromatography on a solumn to isolate the desired product, melting point 91 ° C. IR: (KBr), sm-1: 2910, 1700, 1600, 1450, 1370, 1260, 1040 and 790.

- - NMR (CDC13): d: 2.30 (s, 3H, CH3); 2.80 (m, 2H, CH2); 3.25 (m, 2H, CHa); 7-7.5 (m, 3H, Ar-H). b. Synthesis of blanks are formula IV: 4-Methylindanone (4.5 g, 0.03 mol) are ethyl trife-nylphosphenase acetate (Witting reagent, 10.4 g, 0.04 mol) in a round-bottomed flask and the mixture was heated at 190-200 ° C in a salt bath for 5-6 hours. The reassión was fulfilled and the produsto srudo was purified by chromatography in solumna. The prodrug chromatogram was hydrolyzed when they were ethanolic acid (2 eq.), Which resulted in 4-methyl-1-indanylidinesetiso, melting point 80 ° C. IR: (KBr), cm-3": 3100-2900, 1700, 1450, 1330, 1225 and 950. NMR (CDC13): d: 2.40 (s, 3H, CH ..; 3.65 (m, 2H, CH2), 6.50 (s, 1H, = CH), 7.00-7.40 (m, 3H, Ar-H.) • or. Synthesis of blanks are formula I: The 4-methyl-1-indanylidinasetiso acid (1.0 g, 0.0053 mol) was converted into the corresponding acid sluride (using S0C12). The acid slurry in THF (seεo, 20 ml) was added dropwise to a suspension of free guanidine (0.9 g, 0.015 mol) in THF (seεo, 20 ml) are stirred at room temperature. After the admission, the reaction mixture was stirred for 1/2 hour, after which it was finished (after confirming that the TLC reaction had been completed) adding ice-cold water (50 ml). The produst was extracted are EtOAs (3 x 100 ml). The sap of EtOAs was blended and sonsented to obtain produsto srudo which was purified by chromatography in a solumn. 4-Methyl-l-indanylidinasetilguanidin-methane-sulfoniso acid was obtained by dissolving the free base in dry EtOAs and adding 1.0 equivalent of methanesulfonic acid. The salt was presipred by cooling in an ice bath, melting point 225 ° C.

IR: (KBr), sm 1: 3350, 3150, 1710, 1620, 1490, 1380, 1170, 1050 and 850. NMR (DMSO-d6): d: 2.30 (s, 3H, CH.a); 2.40 (s, 3H, C3S03H); 3.00 (m, 2H, CH.a); 3.30 (m, 2H, CHa); 6.60 (s, 1H, = CH); 7.00-7.40 (m, 3H, Ar-H); 8.30 (bs, 2H, NH2, in-usable are D20); 11.30 (bs, NH, intersambiable are DaO).

Analysis C% H% N% S% Calsulated for CX4HX9N304S: 51.69 5.84 12.92 9.84 Probed 51.36 5.76 12.20 9.45 Pharmacological methods to evaluate the antiarrhythmic and cardioprotester action: Inhibition of the Sodium-Proton exchange in sonoe erythrosites: Albino rabbits from New Zealand were fed a diet containing 2% cholesterol for six weeks before resogering their blood for certain Nation of the intersambiadora astivity of Na + / H + in the erythrosites. It has been pointed out that hypersolerymia insures intersambrous astigmatism in sonex erythrosites (Ssholz et al., 1990).; Arteriosklerose- Neue Aspekte aus Zellbiologie and Molekulargenetik, Epidemiologie und Klinik; Assmann, G. Et al, Eds, Braunsshweig, Wiesbaden, Vieweg, 296-302). Blood samples were collected from the vein of the ear and the hematosite was determined. Approximately 200 μl of blood was added at 37 ° C for 1 hour, and hyperosmolar sasarose buffer solution containing 0.1 mmol of Ouabaine in the presence and absence of the test sample. After the period of insubassion, the reassessment was stopped by admission of 5 ml of cooled MgCl 2 solvation are ice containing 0.1 mmol of Ouabaine. The erythrosites were washed three times are sanctities of 5 ml of the MgCl2 solution. They were hemolyzed by the addition of 4 ml of distilled water and the sodium content of the hemolyzed was determined by flame photometry. The astivity of som- - - test station was determined by its sapasidad to reduce the sodium content of the erythrosites and was expressed somso that is the sonsentrasión nesesaria to redusir the sontenido of sodium of the erythrositos up to 50%.

Table 2:

Claims (15)

1. An indanylidinesetilguanidine of formula I: wherein, R1, R2, R3, R4, R5 and R6 individually or solsively are H, Cx-CxO alkyl; haloalkyl are 1-6 atoms of sarbon, O-alkyl Cx-Cxo, haloalsoxy are 1-6 atoms of sarbon, F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OH, O-lower alkyl, O-aryl, O-lower alkyl-aryl, substituted O-aryl, substituted aryl are O-lower alkyl, 0-C (= 0) -alkyl CX-C4-aryl, 0-C (= 0) -NH-alkyl Cx-C4, 0-C (= 0) -N (CX-C4 alkyl) 2, NO: CN, CP. NH 2 I NH-C (= 0) -alkyl Cx-C4, NH-C (= 0) - NH 2 / COOH, C (= 0) -O-alkyl Cx-C4, C (= 0) -NH2, C (= 0) -NH- c-C4 alkyl, C (= 0) -N (CX-C4 alkyl) Cx-C4-C00H, Cx-Cd-C (= 0) -O-CX-C alkyl? , S03H, S02-alkyl; SOa-alkyl, SOa-N- (alkyl) 2, S02- N (alkyl) (alkylaryl), C (= 0) -Rxx, alkyl Cx-Cxo-C (= 0) -Rxx, alkenyl Ca-C oC (= 0) -Rxx, alkynyl Ca-Cxo-C (= 0) -Rx, NH-C (= 0) -alkyl Cx-Cxo-C (= 0) -Rxx or O-alkyl Cx-Cxx-C (= 0) -Rxx; Rll is C -C4 alkyl, Cx-C4 alkynyl, aryl, substituted aryl, NH2, NH-Cx-C4 alkyl, N- (CX-C4 alkyl) a, S03H; S02-alkyl, S02-alkylaryl, SOa-N- (alkyl) 2 or SOa-N (alkyl) (alkylaryl); is O, S or NH; R7, R8, R9 and RIO are individually or collectively H, alkyl, cisloalkyl, aryl or alkylaryl; or R8, R9 together are part of a heterocyclic ring are 5-6 or 7- members; or its pharmaceutically assumable salts.

2. A compound of formula I according to claim 1, wherein R 1, R 2, R 3, R 4, R 5 and R 6 individually or solesively represent H, C x C x alkyl, haloalkyl are 1-6 atoms of sarbon, O-C x alkyl -Cl-haloalsoxy are 1-6 atoms of sarbon, halogens such as F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OH, O-lower alkyl, O-aryl, O-lower alkyl -aryl, substituted O-aryl, substituted aryl are O-lower alkyl, 0-C (= 0) -alkyl Cx-C4-aryl, 0-C (= 0) -NH-Cx-C4 alkyl, 0-C ( = 0) -N (Cx-C4 alkyl) a, NOa, CN, CF3, NHa, NH-C (= 0) -alkyl Cx-C4, NH-C (= 0) -NH2, COOH, C (= 0) ) -0-alkyl Cx-Cd C (= 0) -NH2, C (= 0) -NH-Cx-C4 alkyl, C (= 0) - N (CX-C4 alkyl) 2, Cx-C4- COOH, C 1 -C 4 alkyl (= 0) -0- C x C 4 alkyl, S 0 3 H, SO a -alkyl, S 0 2 alkylaryl, S 0 2 -N- (alkyl) a, S 0 2 -N (alkyl) (alkylaryl), C (= 0) - Rxx, alkyl Cx-Cxo-Ct = 0) -Rxx, alkenyl Ca-C or C (= 0) - Rxx, alkynyl C2-Cxo-C (= 0) -R, NH-C (= 0 ) -alkyl Cx- Cxo-C (= 0) -Rxx, O-alkyl Cx-Cxx-C (= 0) -Rxx; Rll is Cx-C4 alkyl, Cx-C4 alkynyl, aryl, substituted aryl, NHa, NH-Cx-C4 alkyl, N- (Cx-C4 alkyl) a, S03H; S02-alkyl, SOa-alkylaryl, SOa-N- (alkyl) 2, S02-N (alkyl) (alkylaryl); R7, R8, R9 and RIO are hydrogen; X is O, S or NH. - -

3. A compound of formula I according to claims 1 or 2, wherein R 1, R 2, R 3, R 4, R 5 and R 6 individually or collectively represent H, C x C x alkyl, haloalkyl with 1-6 carbon atoms, O-alkyl Cx-Cxo, haloalsoxy are 1-6 atoms of sarbon, halogens such as F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OH, O-lower alkyl, O-aryl, O-lower alkyl- aryl, substituted O-aryl, substituted aryl are O-lower alkyl, 0-C (= 0) -alkyl C ^ -C ^,, 0-C (= 0) -NH-Cx-C4 alkyl, O-C ( = 0) -N (Cx-C4 alkyl) a, N02, CN, CF3, NH2, NH-C (= 0) - C1-C alkyl? , NH-C (= 0) -NH2, COOH, C (= 0) -0-Cx-C4 alkyl, C (= 0) -NH2, C (= 0) -NH-Cx-C4 alkyl, C (= 0) -N (Cj.-C * alkyl) = Cx-C4-COOH, CX-C4-C alkyl (= 0) -0-Cx-C4 alkyl, S03H, S02-alkyl, S02-alkylaryl, S02-N - (alkyl) 2, SOa-N (alkyl) (alkylaryl), C (= 0) -Rxx, alkyl Cx-Cxo-C (= 0) -Rxx, alkenyl C2-Cxo-C (= 0) -Rxx, alkynyl Ca-Cxo-C (= 0) -Rxx, NH-C (= 0) -alkyl Cx-Cxo-C (= 0) -Rxx, O-alkyl Cx-Cxx-C (= 0) -Rxx; Rll is Cx-C4 alkyl, Cx-C4 alkynyl, aryl, substituted aryl, NH2, NH-Cx-C4 alkyl, N- (CX-C4 alkyl) 2, S03H, SOa-alkyl, SOa-alkylaryl, SOa-N- (alkyl) 2, S02-N- (alkyl) (alkylaryl); R7, R8, R9 and RIO are hydrogen; X is O.

4. A preparation for the preparation of a compound of the formula I according to claim 1, which assumes a solution of the formula V - - wherein R1, R2, R3, R4, R5 and R6 are somo have been defined in claim 1 and Y is a labile group selessioned between -O-alkyl (Cx-C4), halogen or imidazolyl, are a guanidine of the formula VI wherein R7, R8, R9 and RIO are somo have been defined in claim 1, and if desired, convert the produsto into pharmaceutically tolerated salts.

5. The use of a compound of the formula I according to claim 1, for the production of a medisamento for the treatment of sardia arrhythmias.

6. The use of a compound of the formula I according to claim 1, for the preparation of a medisamento for the treatment or prophylaxis of sardiasar infarcts.

7. The use of a compound of the formula I according to claim 1, for the preparation of a raedisamento for the treatment or prophylaxis of angina de pesho.

8. The use of a compound of the formula I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions.

9. The use of a compound of formula I according to claim 1, for the preparation of a medisamento for the treatment or prophylaxis of ischemic states of the central and peripheral nervous system and of apoplexy.

10. The use of a compound of the formula I according to claim 1, for the preparation of a medisamento for the treatment or prophylaxis of ischemic states of peripheral organs and extremities

11. The use of a compound of the formula I according to claim 1 , for the preparation of a medisamento for the treatment of shosk states.

12. The use of a composition of the formula I according to claim 1, for the preparation of a medisamento for use in surgical operasions and organ transplants.

13. The use of a compound of the formula I according to claim 1, for the preparation of a medisamento for the preservation and storage of transplants for surgical measures.

14. The use of a compound of the formula I according to claim 1, for the preparation of a medisamento for the treatment of diseases in which the proliferation of the sellar is the main or secondary cause and therefore its use as an antiatherosclerosis or somo agent agent agent that delays diabetic somplisasions, sanserous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and protatisa hyperplasia.

15. The use of a compound of the formula I according to claim 1, for the preparation of a device for the inhibition of the Na + / H + inter-coupler and for the diagnosis of hypertension and proliferative diseases. 16 The use of a compound of the formula I according to claim 1, for the treatment or prophylaxis of disorders of the metabolism of lipids. 17. A medisamento that suffers an effessive sanctity of a package of the formula I according to the reivindisasión 1.