MXPA96001424A - Indenoilguanidines replaced antiarrhythmic and cardioprotect - Google Patents

Abstract

The present invention relates to indenoylguanidines of formula I, the process for their preparation, their use as medicaments, medicaments containing them, their use as diagnostic agents and medicaments containing them. The compounds I are useful for treating cardiac arrhythmias. In addition, these compounds are useful as cardioprotective agents in mammals, which comprises administering to said mammal the compound of formula I with the above properties, in combination with a pharmaceutically acceptable excipient.

Description

Substituted antiarrhythmic indenoylguanidines and cardioprotec-toras.

The invention relates to indenoylguanidines, to a process for their preparation, to their use as caments, to their use as diagnostic agents and to drugs containing them. More particularly, the present invention relates to indenoylguanidines having the formula I wherein they are: R (l) and R (2) individually or collectively, hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; cycloalkyl having 3, 4, 5, or 6 carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms, 0-C (= O) -alkyl having 1, 2, 3 or 4 atoms carbon, CmH2m-NR (12) R (13), R (12) and R (13) independently of each other, hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms; m is zero, 2, 3 or 4; NH-C (= 0) -NH2, C (= 0) -0-alkyl having 1, 2, 3 or 4 carbon atoms, C (= 0) -NH2, C (= 0) -NH-alkyl which has 1, 2, 3 or 4 carbon atoms, C (= 0) -N (alkyl) 2 qe has 1, 2, 3 6 4 carbon atoms in each alkyl group, alkenyl having 2, 3, 4, 5 , 6, 7, 8, 9 or 10 carbon atoms, alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl having 1, 2, 3 or 4 carbon atoms carbon in the alkyl, alkenyl-aryl group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl, alkynyl-aryl group having 2, 3, 4, 5 , 6, 7, 8, 9 or 10 carbon atoms in the alkynyl group, aryl substituted with C-C4 alkyl, heteroaryl-C1-C4 alkyl, heteroaryl-C1-C4 alkenyl, aminoalkyl-aryl having 1, 2, 3 or 4 carbon atoms in the alkyl, substituted aryl, heteroaryl and substituted heteroaryl group; R (3), R (4), R (5) and R (6) individually or collectively, hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms , O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, halogens (such as F, Cl, Br, I), OH, aryl, substituted aryl, heteroaryl , substituted heteroaryl, O-lower alkyl, 0-aryl, O-lower alkyl aryl, 0-substituted aryl, O-aryl substituted lower alkyl, 0-C (= 0) -alkyl C1-C4-aryl, O- C (= 0) -NH-C ^ Cj alkyl, 0-C (= 0) -N (C? -C ^ alkyl) 2, N02, CN, CF3, NH2, NH-C (= 0) - alkyl of C ^ C ^ NH-C (= 0) -NH2, COOH, C (= 0) -0-alkyl of C (= 0) -NH2, C (= 0) -NH-alkyl of ^ -04, C (= 0) -N (-4-4 alkyl) 2, Cl-C4 ~ COOH, C1-C4-C4 alkyl (= 0) -0-alkyl of -04, SO3H, S02-alkyl, S02- alkylaryl, S02-N- (alkyl) 2, S02 ~ N (alkyl) - (alkylaryl), C (= 0) -R (11), alkyl of C? -C1Q-C (= 0) -R (11) , alkenyl of C2-C1Q-C (= 0) -R (11), alkynyl of C2-C10-C (= O) -R (ll), NH-C (= 0) -alkyl of C1-C10-C (= O) - R (ll), O-C1-C11 alkyl-C (= 0) -R (11), R (H) C2-C4 alkyl, C ^ -C ^ alkynyl, aryl substituted with aryl, NH2, NH-C ^ - C4 alkyl, N- (2-alkyl, SO3H, S02-alkyl, S02-alkylaryl , S02-N- (alkyl) 2, S02-N (alkyl) (alkylaryl); - X O, S O NH; R (7), R (8), R (9) and R (10) individually or collectively, hydrogen, alkyl, cycloalkyl, aryl or alkylaryl; or R (8) and R (9) together can be part of a 5, 6 or 7 membered heterocyclic ring; and A absent or a non-toxic organic or mineral acid. Exemplary acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, toluene sulphonic acid, acetic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid. , oleic acid and oxalic acid. Throughout this description, it is to be understood that, unless otherwise indicated, the terms and expressions that follow have the following meanings: "Alkyl" means a saturated aliphatic hydrocarbon which may be straight chain or branched chain. Preferred alkyl groups have not 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 having 1 to 6 carbon atoms, approximately. 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 about 3 to about 6 carbon atoms, and exemplary groups include cyclopropyl, cyclopentyl and cyclohexyl. "Alkenyl" means an unsaturated aliphatic hydrocarbon. Preferred groups have no more than about 12 carbon atoms. Exemplary groups include any structural and geometric isomers of ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl and dodecenyl or butadiene, pentadienyl, etc. "Lower alkenyl" means alkenyl of about 2 to 6 carbon atoms. Preferred groups include ethenyl, propenyl, butenyl, isobutenyl and all its structural and geometric isomers. "Alkynyl" means an unsaturated aliphatic hydrocarbon. Preferred groups have no more than about 12 carbon atoms and contain one or more triple bonds, including any structural isomers or isomers of ethinyl, propinyl, butinyl, pentynyl, hexynyl, heptinyl, octinyl, noninyl, decinyl, undecinyl, dodecinyl, etc. . "Lower alkynyl" means alkynyl of about 2 to 6 carbon atoms. Preferred groups include structural isomers of propynyl, butynyl and pentynyl. "Aryl" means phenyl and substituted phenyl. "Substituted phenyl" means a phenyl group in which one or more of the hydrogens has been replaced with 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 replaced by 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 hydrogens of the phenyl 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, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, morpholiniol, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolium-dyl, piperazinyl, thiamorpholinyl, azepinyl and ethylene-nyl. "Substituted heterocycle" means a heterocycle wherein 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" and "halogen" include the four halogens; that is, fluorine, chlorine, bromine and iodine. The haloalkyls, halophenyl, and halo substituted pyridyl groups having more than one halo substituent, which may be the same or different, are such as trifluoromethyl, l-chloro-2-bromoethyl, chlorophenyl, and 4-chloropyridyl. "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 a radical of an aromatic acid such as benzoyl or toluoyl. "Lower alkanoyl" means the acyl radical of a lower alkanoic acid such as acetyl, propionyl, butyryl, valeryl, stearoyl, and the like. "Alkoxy" means an alkyloxy group and includes hydroxy alkyl groups. Preferred lower alkoxy groups are methoxy, ethoxy, n-propoxy and isopropoxy, isobutoxy, n-butoxy and t-bu oxy.

The non-toxic organic or mineral acids, A, which form the addition salts are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, lactic acid, salicylic acid, benzoic acid, nicotinic acid, phthalic acid, stearic acid, oleic acid and oxalic acid. Preferred compounds of the invention are compounds of formula II II wherein are:, R (1) hydrogen, C 1 -C alkyl, NR (12) R (13) R (12) and R (13) independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, alkyl of CL-C4-NH2, aryl-alkyl-NH2, O-alkyl, C (= 0) -NH (lower alkyl), C (= 0) -N (lower alkyl) 2, C (= 0) -0-lower alkyl, substituted alkyl, aryl, substituted aryl; R (2) hydrogen, alkyl alkyl of C-C4-NH2, aryl-alkyl-NH2, substituted alkyl, aryl, substituted aryl; R (3), R (4), R (5) and R (6) individually or collectively, F, Cl, Br, I, OH, O-lower alkyl, O-aryl, O-lower alkyl-aryl, OR -substituted aryl, O-lower alkyl-substituted aryl, COOH, C (= 0) -0-lower alkyl, CN, CF3, NH2, NH-lower alkyl, N (lower alkyl) 2, O-lower alkyl-NH2, O-lower alkyl-NH (lower alkyl), O-alkyl lower-N (lower alkyl) 2, S02-lower alkyl, SO3H, S02-NH2, S02-NH-lower alkyl, S02-N (lower alkyl) 2, heteroaryl and substituted heteroaryl; the preferred groups being for heteroaryl, pyridyl, thienyl, furyl, quinyl and isoquinyl; the preferred substituents being for substituted heteroaryl F, Cl, Br, I, OH, NH2, O-lower alkyl, O-lower alkyl-aryl, COOH, C (= 0) -0-lower alkyl, CN, NH-lower alkyl , N (lower alkyl) 2 SO ^ H, S02-NH2, S02-NH-lower alkyl and S02-N (lower alkyl) 2; X 0, S or NH, but preferably X is 0. The compounds of the present invention may contain asymmetric centers; The invention relates to both compounds, of the S configuration and the R configuration. The compounds can exist as optical isomers, as racemates or as mixtures thereof. Representative examples of the compounds of this invention are listed in Table 1 and Table 2. p where they are: R (l) and R (3) H, R (2) CH3; X O in formula II Table 1: Table 2 where they are: R (l), R (2) and R (3) H; X O in formula II Table 3 where X = 0 and A = CH3S03H The compounds of formula I are substituted acylguanidines. The most salient representative of acylguanidines is the pyrazine derivative, amiloride, which is used in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloride type are described in the scientific literature, such as, for example, dimethylamiloride or ethylisopropylamiloride. In addition, studies indicating antiarrhythmic properties of amiloride have been described [Circulation, 79, 1257-1263 (1989)]. However, extensive use as an antiarrhythmic is prevented by the fact that this effect is only slight and takes place accompanied by an antihypertensive and saluretic action, and these side effects are undesirable for the treatment of heart rhythm disorders. Indications of antiarrhythmic properties of amiloride have also been obtained from experiments on isolated hearts of animals [Eur. Heart J. 9. { supplement 1.}. : 167 (1988) (book of abstracts)]. Thus, for example, it has been found in rat hearts that it was possible to completely suppress artificially induced ventricular fibrillation by amiloride. The amiloride derivative ethylisopropylamiloride, cited above, was even more potent than amiloride in this model. Benzoylguanidines having antiarrhythmic properties are described in the specification of European Patent No. 416,499 left open to public inspection. U.S. Pat. No. 3,780,027 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 substitution scheme, from diuretics available commercially. , such as bumetanide and furosemide, and possess an amino group, which is important for the salidiuretic action sought, in position 2 or 3 with respect to the carbonylguanidine group. Correspondingly, a potent salidiuretic activity has been indicated for these compounds.

Circulation, 79, 1257-1263, describes antiarrhythmic properties of amiloride - a molecule containing an acylguanidine unit. The specification of U.S. Pat. 3,780, 2,734,904 and 4,544,670, also describe acylguanidines. These patents refer to acylguanidines in which the heterocyclic moiety (Circulation) or phenyl (specification of the US patents) is attached to the acylguanidine unit. In the present invention, the heterocyclic or aromatic moiety is separated from the acylguanidine unit by an ethylene bond in trans geometry, in the form of a five-membered carbocyclic ring. It has been found that these compounds possess very good antiarrhythmic properties. These compounds have a considerable advantage over the currently available antiarrhythmic pharmaceuticals, and are useful as cardioprotective compounds for the treatment of infarcts as well as for the treatment of angina pectoris. It was surprising that the compounds according to the invention did not have undesirable and adverse salidiuretic properties, but very good antiarrhythmic properties, so they can be used for the treatment of cardiac disorders, such as symptoms of oxygen deficiency. As a result of their pharmacological properties, the compounds are, outstandingly, suitable as antiarrhythmic drugs having a cardio-protective component, for the prophylaxis and treatment of infarcts, as well as for the treatment of angina pectoris, where they , also preventively, inhibit or greatly reduce the pathophysiological processes in the development of ischemically induced damage, in particular the initiation of cardiac arrhythmias induced ischemically. Due to their protective actions against the hypoxic and ischemic pathological situation, the compounds of the formula I according to the invention, as a result of the inhibition of the cellular Na + / H + exchange mechanism, can be used as medicaments for the treatment of all acute or chronic damage caused by ischemia or diseases induced by it, principally or secondarily. This applies to their use as medicaments for surgical interventions, for example organ transplantation, wherein the compounds can be used for the protection of the organs of the donor before and during separation, for the protection of the separate organs, for example during treatment with them or their storage in physiological bath fluids, as well as during transfer to the recipient organism. The compounds are also valuable drugs which have a protective action at the time when angioplastic surgical procedures are being carried out, for example on the heart as well as on the peripheral vessels. According to their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, in particular the CNS, where they are suitable, for example, for the treatment of stroke or cerebral edema. 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 formula I according to the invention are furthermore distinguished by a potent action of inhibition on cell proliferations, for example fibroblastic cell proliferation and proliferation of smooth vascular muscle cells. The compounds of formula I are, therefore, valuable therapeutic agents possible for diseases in which cell proliferation is a primary or secondary cause and, therefore, can also be used as anti-atherosclerotic compounds and as agents of delayed diabetic complications. , cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and hypertrophies and hyperplasias of organs, in particular hyperplasia of the prostate or hypertrophy of the prostate. 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 accessed with ease to perform measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds according to the invention are, therefore, suitable as outstanding and simple scientific instruments, for example in their use as diagnostic reagents for the determination and differentiation of certain forms of hypertension, as well as of atherosclerosis, diabetes, proliferative diseases. and similar. The compounds of the formula I are also suitable in preventive therapy for the prevention of the origin of high blood pressure, for example essential hypertension. The invention also relates to the process for the preparation of compounds of formula I. The preparation of the compounds of the invention is illustrated, although not limited, by the preparation of exemplary compounds of the invention. The synthesis of compounds of formula I, when R (2) = other than H, was achieved through the intermediate of formula III, which in turn are prepared by methods known to those skilled in the organic synthesis. One of the methods is by generation of the anion on methylene activated by NaH / THF followed by alkylation using substituted benzyl bromides. The compounds of formula III are converted to 3-substituted indene-2-carboxylic acids of formula IV, by treatment with concentrated sulfuric acid, at room temperature, in 10-12 hours, and subsequent aqueous treatment. The synthesis of compounds of formula I, when R (2) = H was achieved through the intermediate of formula V.

R (6) which in turn is prepared by methods known to those skilled in the organic synthesis. One of the methods is by generating the anion on the activated methylene adjacent to the carbonyl group, using butyllithium, followed by acylation using ethyl chloroformate. Alternatively, the same product can be obtained using the acylation method Enamine of carbonyl compounds. The compounds of formula V are converted to indene-2-carboxylic acids of formula IV by reduction of the carbonyl group by sodium borohydride followed by acid catalyzed dehydration (p-toluenesulfonic acid) in anhydrous benzene. The values of R (l), R (2), R (3), R (4), R (5) and R (6) for formulas III and IV and formula VI they have the same meanings that have been defined for formula I. For formula V, R (l), R (3), R (4), R (5) and R (6) have the same values that have been defined for the formula I. The invention also relates to a process for preparing compounds of formula I, which comprises reacting compounds of formula VI with a free guanidine or with a compound of formula VII -36- wherein R (7), R (8), R (9) and R (10) have the values defined above in formula I, and Y is a removable group that can be easily displaced by a nucleophile. The activated acid derivatives of the formula VI in which Y is an alkoxy group, preferably a methoxy group, an activated phenoxy group, a phenylthio group, methylthio or 2-pyridylthio or a nitrogen heterocycle, such as imidazolyl, can be prepared starting from acid chloride (formula VI, Y = Cl) which in turn can be prepared from the acid, formula IV, by treatment with thionyl chloride. Other methods of activation by esters can be used, which are known in the field of peptides to activate the acid for coupling reactions. The imidazolides of formula VI, Y = imidazolides, can also be prepared from a compound of formula IV, by treatment thereof with 1,1-carbonyldiimidazole [C.Staab, Ange. Chem. Int. Eng Edn. 351-367 (1962)]. The compound of formula VI (Y = Cl) by treatment with the compound of formula VII under the Schotten-Baumann condition, also provides the compound of formula I. Other mixed anhydrides related to formula VI, such as with CICOOEt, can be prepared, tosyl chloride, triethylphosphoryl chloride in the presence of triethylamine or any other base, in an inert solvent. The activation of the COOH group in the compounds of the formula IV can also be achieved with DCC. Other methods of preparing activated carboxylic acid derivatives of the type of those of formula VI are provided with indication of the original literature, in Advanced Organic Chemistry, J.March, 32 Edition (John Wiley and Son, 1985), page 350. The coupling reaction between compounds of formula VI and VII can be carried out in a variety of 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 been shown to be suitable for the reaction of the compound of formula VI (Y = OMe) with guanidine. The reaction of the compounds of formula VI 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 formula IV is treated directly with carbonyldiimidazole to activate the carboxy group, polar aprotic solvents such as DMF or dimethoxyethane are used, followed by the addition of the compound of formula VII. The compounds of the formula I can be converted into pharmacologically acceptable acid addition salts with exemplary salts, as described above in this description. The active compounds of the present invention can be administered orally, parenterally, intravenously or rectally, or by inhalation, the preferred administration depending on the specific clinical need of the condition to be treated. In this regard, the compounds of formula I can also be used in isolation or together with pharmaceutical auxiliaries, and both in human medicine and in veterinary medicine. Which auxiliaries are suitable for the desired pharmaceutical formulation is familiar to those skilled in the art based on their experience. In addition to solvents, gel forming agents, suppository bases, tablet auxiliaries and other excipients for the active compound, antioxidants, dispersants, emulsifying agents, defoaming agents, flavor correctors, preserving agents, solubilizing agents or dyes can be employed. For a pharmaceutical form for oral use, the active compounds are mixed with suitable additives for this purpose, such as excipients, stabilizers or inert diluents, and are brought to the appropriate forms of administration, such as tablets, coated tablets, hard capsules of gelatin and aqueous solutions, alcoholic or oily, by the usual methods. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can take place both as dry granules and as wet granules. Oily excipients or suitable solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. For subcutaneous or intravenous administration, the active compounds, if desired with the usual substances for this purpose such as solubilizing agents, emulsifying agents or other auxiliary products, are put into solution, suspension or emulsion. Suitable solvents are, for example: water, physiological saline or alcohols, for example ethanol, propanol, glycerin and, in addition, also sugar solutions such as glucose or mannitol solutions, or alternatively, a mixture of the various solvents mentioned. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of formula I in pharmaceutically acceptable solvents, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the formulation may also contain other pharmaceutical auxiliary compounds such as surfactants, emulsifying agents and stabilizers, as well as a propellant gas. Such preparations usually contain the active compound in a concentration of about 0.1 to 10, in particular about 0.3 to 3,% by weight. The dose of the active compound of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used, and additionally also on the nature and severity of the condition 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 formula I in a patient of approximately 75 kg of weight is at least 0.001 mg, preferably 0.01 mg, up to at most 10 mg, preferably at most 1.0 mg, per kg of weight. In acute outbreaks of the diseaseFor example, immediately after suffering a cardiac infarction, still higher and, above all, more frequent doses may be required, for example up to 4 individual doses per day. Particularly in i.v. use, for example in a heart attack patient in the intensive care unit, up to 100 mg per day may be needed.

EXPERIMENTAL SECTION: The synthesis of representative examples, the 3-methylinden-2-oilguanidine monohydrochloride (compound No. 1 of formula I of Table 1) and the inden-2-hydroquinidine-methanesulfonic acid (compound No. 13 of formula I of Table 2). Other compounds were also synthesized using such sequences or other sequences.

A. Synthesis of Compound No. 1 of Table 1 to. Synthesis of compounds of formula III: NaH (13.8 g, 0.6 mol) was washed twice with hexane (2 x 50 mL) and suspended in 250 mL of freshly distilled THF. Then, ethyl acetoacetate (75 ml, excess) was carefully added dropwise while the receiving flask was cooled to -10 ° C. After the addition was complete, it was stirred at -10 ° C for 2 hours and at room temperature for 30 minutes. To the above solution, benzyl bromide (51.0 g, 0.3 mol) in THF was added dropwise at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction was terminated the next day by pouring into ice-cooled water, brought to neutral pH and extracted with ether / ethyl acetate. The combined ether / ethyl acetate extracts were washed over brine and dried over Na2SO4. Removal of the solvent followed by careful distillation in vacuo gave ethyl benzylacetoacetate, e.g. 2762C.

IR: (pure), cm "1: 2900-3050, 1690-1760 (wide), 1665.

NMR (CDC13): 6: 1.25 (t, 3H, CH2CH3); 2.25 (s, 3H, COCH3); 3.20 (d, 2H, benzylic CH2); 3.8 (t, 1H, COCHCO); 4.20 (q, 2H, OCH2CH3); 7.15-7.35 (m, 5H, Ar-H). b. Synthesis of compounds of formula IV: Ethyl benzylacetoacetate (37 g) was added to a mixture of sulfuric acid (98%, 360 g) and water (15 g) cooled to -22 C for 45 minutes, with vigorous stirring. The solution, now dark reddish brown, was stirred at 4 C for 2 hours and then, overnight, at 15-202 C, and then poured into ice water (2.0 1). This mixture was heated to 50-60 ° C to coagulate the mud and then filtered and treated. 3-Methylidene-2-carboxylic acid was purified by column chromatography followed by recrystallization; p.f. 2002C.

IR: (KBr), cm "1: 2900-3100 (wide), 1640-1680, 1600 NMR: (CDC13): d: 2.45 (s, 3H, CH3); 3.55 (s, 2H, CH2); 7.20-7.40 (m, 4H, Ar-H).

Analysis: c% H% Calculated for C ^ H ^^: 76, 99 5, 79 Found: 76, 43 5, 86 c. Synthesis of compounds of formula I: 1. 0 g of 3-methylidene-2-carboxylic acid and 5 ml of Thionyl chloride was heated at reflux for 4 hours. By careful separation of the solvent, by distillation under reduced pressure, 3-methylidene-2-oyl chloride was obtained.

The acid chloride dissolved in THF was added dropwise to a mixture of guanidine and sodium hydroxide at room temperature over a period of 10 minutes, and stirred for one hour. The reaction was terminated by treatment and the product was purified by column chromatography. The 3-methylidene-2-oilguanidine monohydrochloride was obtained by dissolving the free base in methanol, followed by addition of ethereal HCl, to pH 2.0 and stirring. The salt precipitated by cooling in an ice bath. White crystalline powder, m.p. 250-2512C.

IR: (KBr), cm "1: 3100-3350 (wide); 1690, 1655.

NMR: (CDC13): 6: 2.45 (s, 3H, CH3); 4.0 (s, 2H, CH2); 7.4-7.7 (m, 4H, Ar-H); 8.4 (bs, 2H, NH2, exchangeable with D20).

Analysis: C% H% N% Cl% Calculated for C12H1602N3C1: 53.42 5.90 15.57 13.16 Found: 53.12 5.42 15.94 13.68 B. Synthesis of compound No. 13 of Table 2 d. Synthesis of compounds of formula V: 1-Indanone (1.5 g, 11.36 mmol) was dissolved in anhydrous THF in a three-necked flask equipped with nitrogen inlet, septum and a safety tube. The flask was cooled to -20 ° C for 10 minutes. Then butyllithium (11.37 ml, 12.48 mmol) was added dropwise through the septum using the syringe. The reaction mixture was allowed to stand at -20 ° C. for 45 minutes and then ethyl chloroformate (1.08 ml, 10 mmol) was added dropwise using a syringe. The reaction mixture was stirred at -20 ° C for 30 minutes and slowly brought to room temperature in about one hour. The reaction mixture was treated by evaporating the THF and the product was chromatographed to obtain 2-carbethoxy-1-indanone.

NMR: (CDC13) 6: 1.25 (t, 3H, 0CH2CH3); 3.45 (d, 2H, benzylic CH2); 3.65 (t, 1H, COCHCO); 4.2 (q, 2H, OCH2CH3); 7.4-7.5 (m, 4H, Ar-H). and. Synthesis of compounds of formula IV: 2-Carbetoxy-l-indanone was dissolved in anhydrous methanol at room temperature, to which solution sodium borohydride was added in three runs while the reaction mixture was kept stirring. The reaction mixture was subsequently stirred for 30 minutes, after which the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in anhydrous benzene, to which a catalytic amount of p-toluenesulfonic acid had been added, and the reaction mixture was stirred for one hour. The p-toluenesulfonic acid was filtered and the filtrate was concentrated to obtain ethyl indene-2-carboxylate. The ethyl indene-2-carboxylate was dissolved in methanol and 1.0 equivalent of aqueous sodium hydroxide solution was added, and the reaction mixture was kept stirring overnight. The next day, the reaction was terminated by evaporating the methanol, followed by dilution of the residue with water, bringing the pH to neutral, and the indene-2-carboxylic acid which precipitated was filtered.

NMR; (CDCl 3): 6: 3.75 (s, 2H, benzylic CH 2); 7.4-7.7 (m, 4H, Ar-H); 7.95 (s, 1H, olefinic H).

F. Synthesis of compounds of formula 1: The same procedure described above was followed in experimental section A-c to prepare compound No. 1, for the synthesis of compound 13 of table 2 from indene-2-carboxylic acid.

The inden-2-oilguanidine-methanesulfonic acid was obtained by dissolving the free base in ethyl acetate at room temperature, followed by the addition of methanesulfonic acid (1 eq.). The salt was precipitated by cooling in an ice bath. Yellow crystalline powder, m.p. 164-1652C NMR: (CDC13): d: 3.75 (s, 2H, benzylic CH2); 7.4-7.7 (m, 4H, Ar-h); 8.05 (s, 1H, olefinic H); 8.35 and 11.09 (bs, NH and NH2, changeable with D20).

Pharmacological methods to evaluate the antiarrhythmic and cardioprotective action: Inhibition of sodium-proton exchange in rabbit erythrocytes: Albino rabbits of the New Zealand breed were fed a 2% cholesterol diet for six weeks before collecting blood for the determination of the Na + / H + exchange activity in the erythrocytes. It has been reported that hypercholesterolemia increases the exchange activity in rabbit erythrocytes (Scholz et al., 1990, Arterios-klerose - Neue Aspekte aus Zellbiologie und Molekulargenetik, Epidemiologie und Klinik, Assmann, G, et al., Eds. Braun- schweig, iesbaden, Vieweg, 296-302). Blood samples were collected from the vein of the ear and the hematocrit was determined. Approximately 200 μl of blood was incubated at 372C for 1 hour with hyperosmolar sucrose buffer containing 0.1 mM ouabain, in the presence and absence of the test sample. After the incubation period, the reaction was stopped by the addition of 5 ml of ice cold MgCl 2 solution, containing 0.1 mM ouabain. The erythrocytes were washed three times with 5 ml portions of gC ^ solution. They were then hemolysed by the addition of 4 ml of distilled water and the sodium content of the hemolysate was determined by flame photometry. The activity of the compound under test was determined by its ability to reduce the sodium content of the erythrocytes and was expressed as IC5Q, which is the concentration necessary to reduce the sodium content of erythrocytes to 50%.

Table 4 I Compound No. IC50 (uM) 0.09 10 0.018 Arrhythmias induced by reperfusion in the isolated heart of the rat: Male Charles Foster rats of either sex (250-300 g) were sacrificed by beating and exsanguination. The hearts were rapidly separated and subjected to perfusion according to the Langendorff method. Different concentrations of the compound under test were added to the perfusion medium. After After 20 minutes of the equilibration period, the left anterior descending coronary artery (LAD) was ligated. 15 minutes later the ligature was removed and left in reperfusion for the next 30 minutes. During the reperfusion period the ECG was checked. The duration of ventricular fibrillation (VFD) was the main test parameter. The antiarrhythmic activity was examined as the concentration of the test compound necessary to cause a 50% reduction of the VFD.

Table 5 Ischemic induced arrhythmias in anesthetized rats: Male Charles Foster rats (220-260 g) were anesthetized with sodium pentobarbital. The animals were artificially ventilated. Blood pressure was recorded through the carotid artery. A thoracotomy was performed to expose the heart. The left anterior descending coronary artery (LAD) was identified. The compound under test was administered either orally 10 minutes before anesthesia (40 minutes before ligation of the LAD artery) or intravenously (5 minutes before ligating the LAD artery). The resulting arrhythmias during the 15-minute ligation period were recorded and analyzed according to the Lambeth Convention (Walker M.J.A. et al, 1988, Cardiovascular Research, 22, 447-455). The antiarrhythmic effect of the compound under test was expressed as a dose-dependent inhibition of the duration of ventricular tachycardia (VT) and ventricular fibrillation (VF).

Table 6: Oral administration: NP - There is no protection.

Intravenous administration Generation of myocardial infarctions in the anesthetized rat: Rats were prepared as in the previous experiments. The compounds were administered intravenously 5 minutes before ligation. The experiment consisted of one hour of ligation followed by one hour of reperfusion. The generation of myocardial infarction was determined using the double dye technique using Evans blue and 2,3,5-triphenyltetrazolium to identify the risk zone and the infarct zone, respectively. The extent of the infarction was expressed as a percentage of the risk area. (Simpson et al., Circulation Research, 60, 666-673, 1987).

Table 7

Claims (16)

1. - An indenoylguanidine of formula I r wherein R (D and R (2) individually or collectively, hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; cycloalkyl having 3, 4 , 5, or 6 carbon atoms, O-alkyl having 1, 2, 3 or 4 carbon atoms, 0-C (= 0) -alkyl having 1, 2, 3 or 4 carbon atoms, CmH2m-NR (12) R (13), R (12) and R (13) independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; m zero, 2, 3 or 4; NH-C (= 0) -NH2, C (= 0) -O-alkyl- having 1, 2, 3 or 4 carbon atoms, C (= 0) -NH2, C (= 0) -NH-alkyl having 1 , 2, 3 or 4 carbon atoms, C (= 0) -N (alkyl) 2 having 1, 2, 3 or 4 carbon atoms in each alkyl group, alkenyl having 2, 3, 4, 5, 6 , 7, 8, 9 or 10 carbon atoms, alkynyl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl having 1, 2, 3 or 4 carbon atoms in the alkyl, alkenyl-aryl group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkenyl group, alkynyl-aryl having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the alkynyl group, aryl substituted with C-, C4-alkyl, heteroaryl-alkyl of -0.0, heteroaryl -C1-C4 alkenyl / aminoalkyl-aryl having 1, 2, 3 or 4 carbon atoms in the alkyl, substituted aryl, heteroaryl and substituted heteroaryl group; R (3), R (4), R (5) and R (6) individually or collectively, hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms , O-alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, halogens (such as F, Cl, Br, I), OH, aryl, substituted aryl, heteroaryl , substituted heteroaryl, O-lower alkyl, O-aryl, O-lower alkyl aryl, O-substituted aryl, O-aryl substituted lower alkyl, 0-C (= 0) -alkyl C1-C4-aryl, 0- C (= 0) -NH-C1-C4 alkyl, 0-C (= 0) -N (C? -C) alkyl 2, N02, CN, CF3, NH2, NH-C (= 0) -alkyl NH-C (= 0) -NH2, COOH, C (= 0) -O-C1-C4 alkyl, C (= 0) -NH2, C (= 0) -NH-C1-C4 alkyl, C (= 0) -N (C 1 -C 4 alkyl "C00H" C 1 -C C alkyloxy (= 0) -O-C 1 -C 4 alkyl, SO 3 H, S 0 2 -alkyl, S 0-2 alkylaryl, S 0 2- N- (alkyl) 2, S0 -N (alkyl) (alkylaryl), C (= 0) -R (11), alkyl of Cj-C10-C (= O) -R (ll), C2-C10 alkenyl -C (= O) -R (ll), C2-C10-C alkynyl (= O) -R (ll), NH-C (= 0) -alkyl of C1-C1Q-C (= 0) -R (11), O-C1-C11 alkyl-C (= 0) -R (11), R (ll) C 1 -C 4 alkyl, C 1 -C 4 alkynyl, aryl substituted aryl, NH 2, C 1 -C 4 alkyl NH, N- (C 1 -C 4 alkyl) 2 , SO3H, S02-alkyl, S02-alkylaryl, S02-N- (alkyl) 2, S02-N (alkyl) (alkylaryl); X O, S or NH; R (7), R (8), R (9) and R (10) individually or collectively, hydrogen, alkyl, cycloalkyl, aryl or alkylaryl; R (8) and R (9) together can be part of a 5, 6 or 7 membered heterocyclic ring; A absent, or a non-toxic organic or mineral acid.

2. A compound according to claim 1, of formula II II wherein they are: R (l) hydrogen, C 1 C alkyl, NR (12) R (13) R (12) and R (13) independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, C 1 -C 4 alkyl-NH 2, aryl-alkyl-NH 2, O-alkyl, C (= 0) -NH (lower alkyl), C (= 0) -N (lower alkyl) 2, C ( = 0) -O-lower alkyl, substituted alkyl, aryl, substituted aryl; R (2) hydrogen, C1-C4 alkyl alkyl-NH2, aryl-alkyl-NH2, substituted alkyl, aryl, substituted aryl; R (3), R (4), R (5) and R (6) individually or collectively, F, Cl, Br, I, OH, O-lower alkyl, O-aryl, O-lower alkyl-aryl, OR -substituted aryl, O-lower alkyl-substituted aryl, COOH, C (= 0) -O-lower alkyl, CN, CF3, NH2, NH-lower alkyl, N (lower alkyl) 2, O-lower alkyl-NH2, O-lower alkyl-NH (lower alkyl), O-lower alkyl-N (lower alkyl) 2, S02-lower alkyl, S03H, S02-NH2, S02-NH-lower alkyl, S02-N (lower alkyl) 2, heteroaryl, (selected from the group consisting of pyridyl, thienyl, furyl, quinyl and isoquinyl) or heteroaryl, substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, NH 2, O -lower alkyl, O-lower alkyl-aryl, COOH, C (= 0) -O-lower alkyl, CN, NH-lower alkyl, N (lower alkyl) 2 S03H, S02-NH2, S02-NH-lower alkyl, S02-N (lower alkyl) 2; X 0, S or NH.

3. A compound of formula I or II, according to one or more of claims 1-2, wherein they are: R (l) hydrogen, C ^ C ^ alkyl, NR (12) R (13) R ( 12) and R (13) independently of one another, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, C 1 -C 4 alkyl-NH 2, aryl-alkyl-NH 2, O-alkyl, C (= 0) -NH (lower alkyl), C (= 0) -N (lower alkyl) 2, C (= 0) -0-lower alkyl, substituted alkyl, aryl, substituted aryl; R (2) hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-NH 2, arylalkyl-NH 2, substituted alkyl, aryl, substituted aryl; R (3), R (4), R (5) and R (6) individually or collectively, F, Cl, Br, I, OH, O-lower alkyl, O-aryl, O-lower alkyl-aryl, OR -substituted aryl, O-lower alkyl-substituted aryl, COOH, C (= 0) -0-lower alkyl, CN, CF3, NH2, NH-lower alkyl, N (lower alkyl) 2, O-lower alkyl-NH2, O-lower alkyl-NH (lower alkyl), O-lower alkyl-N (lower alkyl) 2, S02-lower alkyl, SO3H, S02-NH2, S02-NH-lower alkyl, S02-N (lower alkyl) 2, heteroaryl, (selected from the group consisting of pyridyl, thienyl, furyl, quinyl and isoquinyl) or heteroaryl, substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, OH, NH 2, O -lower alkyl, O-lower alkyl-aryl, COOH, C (= 0) -0-lower alkyl, CN, NH-lower alkyl, N (lower alkyl) 2 S03H, S02-NH2, S02-NH-lower alkyl, S02-N (lower alkyl) 2; X O. 4.- A process for the preparation of a compound of formula I according to claim 1, comprising a) reacting a compound of formula VI wherein R (l), R (2), R (3), R (4), R (5) and R (6) are according to claim 1, and wherein Y is a removable group selected from among - O-C- ^ - C ^ alkyl, halogen or imidazo-lyl, with a guanidine of formula VII wherein R (7), R (8), R (9) and R (10) are according to claim 1, and, if appropriate, converting the product into a pharmaceutically tolerated salt. 5. The use of a compound of formula I according to claim 1 for the production of a medicament for the treatment of cardiac arrhythmias. 6. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of cardiac infarction. 7. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of angina pectoris. 8. The use of a compound of 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 medicament for the treatment or prophylaxis of ischemic states of the nervous, peripheral and central nervous system, and of apoplexy. 10. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of ischemic states of peripheral organs and extremities. 11. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the treatment of shock states. 12. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for use in surgical operations and organ transplants. 13. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the preservation and storage of transplants for surgical measures. 1

4. The use of a compound of formula I, according to claim 1, for the preparation of a medicament for the treatment of ailments in which cell proliferation is the primary or secondary cause and, consequently, its use as antiatherosclerotic agent or agent against delayed diabetic complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and hyperplasia of the prostate. 1

5. The use of a compound of formula I, according to claim 1, for the preparation of a scientific tool for the inhibition of the Na + / H + exchanger and for the diagnosis of hypertension and proliferative diseases. 1

6. A medicine comprising an effective amount of a compound of formula I according to one or more of claims 1 to 3.