MXPA97001323A - Benzoilguanidinas replaced in orthodous position, a procedure for its preparation, its use as a diagnostic medicine or agent, so i composed that conti - Google Patents

Abstract

The present invention relates to ortho-substituted benzoylguanidines of the formula I: wherein R (2) and R (3) independently of one another mean hydrogen, C1, Br, I, (C1-C8) alkyl, cycloalkyl (C3-C8) or-OR (5); R (5) (C1-C8) alkyl or CdH2d-cycloalkyl (C3-C8); d zero, 1 or 2, one of both substituents being R (2) and R (3) ) hydrogen, but not both R (2) and R (3) are simultaneously hydrogen, as well as their pharmaceutically compatible salts.

Description

Benzoylguanidines substituted in the ortho position, a process for their preparation, their use as a medicine or diagnostic agent, as well as medicine containing them The invention concerns ortho-substituted benzoylguanidines of the formula I wherein R (2) and R (3) signify independently of one another hydrogen, Cl, Br, I, (C1-Cg) alkyl, (C3-Cg) cycloalkyl or -OR (5); R (5) alkyl (C ^ Cg) or C H2d-cycloalkyl (C3-Cg) d zero, 1 or 2; wherein both R (2) and R (3) are hydrogen, but R (2) and R (3) are simultaneously both hydrogen and their pharmaceutically compatible salts. Preferred are compounds of formula I, in which they mean: 'R (2) and R (3) independently of one another, hydrogen, Cl, Br, I, alkyl (Cj ^ -Cg), cycloalkyl (C3-Cg) or -OR (5); R (5) alkyl (C ^ -Cg); as well as its pharmaceutically compatible salts. Very particular preference is given to the compounds 2-chloro-4-methoxy-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-methoxy-5-trifluoroethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-hydrochloride. -yodo- 5 -trif luoromethyl-benzoyl-guanidine, 2-chloro-3-methyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-n-propyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-Chloro-3-isopropyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-t-butyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-cyclopentyl-5-hydrochloride trifluoromethyl-benzoylguanidine, 2-chloro-4-methyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-4-n-propyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-4-hydrochloride isopropyl-5-trifluoromethyl-benzoyl-guanidine, 2-chloro-4-t-butyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride and 2-chloro-4-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride. If one of the substituents R (2) and R (3) contains one or more centers of asymmetry, these can be configured as both S and R. The compounds are present in the form of optical isomers, as diastereomers, as racemates or as mixtures of these. The alkyl radicals designated can be straight chain or branched. The invention also relates to a process for the preparation of compound I, characterized in that compounds of the formula II are reacted with guanidine. wherein R (2) and R (3) possess the indicated meanings and L represents a readily substitutable labile group nucleophilically. Activated acid derivatives of the formula II, in which L means an alkoxy group, preferably a methoxy group, a phenoxy, phenylthio, methylthio, 2-pyridylthio group, a heterocycle with nitrogen, preferably 1-imidazolyl, are advantageously obtained , in a manner known per se, from the chlorides of carboxylic acids which are presented as their base (formula II, = Cl), which in turn can be prepared from the carboxylic acids which are presented as their base ( formula II, L = OH), in a manner known per se, for example with thionyl chloride. In addition to the carboxylic acid chlorides of the formula II (L = Cl), other activated acid derivatives of the formula II can also be prepared, in a manner known per se, directly from the benzoic acid derivatives which are presented as base (formula II, L = OH), such as the methyl esters of the formula II in which L = OCH3 by treatment with gaseous HC1 in methanol, the i-idazolides of the formula II by treatment with carbonyl-diimidazole [L = 1-imidazolyl, Staab, Angew. Chem. International Edition in English 1, 351 -367 (1962)], mixed anhydrides II with Cl-COOC2H5 or tosyl chloride (toluenesulfonyl) in the presence of triethylamine in an inert solvent, as well as acid activations benzoic acid with dicyclohexylcarbodiimide (DCC) or with 0- [(cyano (ethoxycarbonyl) methylene) -amino] -1,1, 3,3-tetramethyl-uronium ("TOTU") [Weiss and Krowmer, Chemiker Zei tung 98, 817 (1974)]. A number of methods suitable for the preparation of activated carboxylic acid derivatives of formula II are indicated by reference to source literature in J. March, Advanced Organic Chemistry, third edition (John Wiley & amp;; Sons, 1985), page 350. The reaction of an activated carboxylic acid derivative of formula II with guanidine is carried out in a manner known per se in a polar protic or aprotic organic solvent, but inert. In this case, in the case of the reaction of methyl esters of benzoic acid (II, L = OMe) with guanidine, methanol, isopropanol or THF at 20'C have been proved up to the boiling point of these solvents. In the majority of the reactions of compounds II with guanidine free of salts, advantageous work was carried out in inert aprotic solvents such as THF, dimethoxyethane and dioxane. However, water can also be used by using a base such as for example NaOH as solvent in the reaction of II with guanidine. When L means = Cl, it is advantageously worked with the addition of an acid scavenger, e.g. ex. in the form of excess guanidine, for the fixation of hydrogen allogenide. A part of the benzoic acid derivatives of the formula II, which are presented as a basis, is known and described in the literature. The unknown compounds of the formula II can be prepared according to methods known from the literature. The benzoic acids obtained are reacted according to one of the above-described process variants to give compounds I according to the invention. The introduction of some substituents at positions 3, 4 and 5 is achieved according to methods known from the literature, the palladium-mediated cross coupling of aryl halides or aryl triflates (trifluorosulfonates) with, for example, organ-isannans, acids organo-boronic or organo-borane or organic copper or zinc compounds. The benzoylguanidines I are generally weak bases and can fix an acid by forming salts. Suitable acid addition salts are salts of all pharmacologically compatible acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates. The compounds I are substituted acylguanidines. European Patent Application Publication EP 640,588.Al are known compounds with a similar constitution, which can carry in the 5-position, along with a large number of other substituents R (l), also a CF3 group, as well as in position 2, together with a large number of substituents, they can also carry a Cl atom. However, it was not foreseeable that they could develop an outstanding activity precisely these compounds with a trifluoromethyl group and a chlorine atom. It was surprising that the compounds according to the invention not only have no undesired or disadvantageous salidiuretic property, together with very good antiarrhythmic properties, but simultaneously had a shorter, especially favorable half-life, which is frequently undesirably high in the case of known compounds. In addition, the compounds according to the invention are distinguished by good bioavailability, as can be seen from the in vivo values. The compounds, similarly to those known, because of their pharmacological properties, are outstandingly suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and for the treatment of infarction, as well as for the treatment of angina pectoris, inhibiting or diminishing them also strongly in a preventive way the pathophysiological processes when forming ischemically induced lesions, especially in the case of the provocation of cardiac arrhythmias induced ischemically. Because of their protective effects against hypoxic and pathological ischemic situations, the compounds of the formula I according to the invention, as a consequence of the inhibition of the cellular mechanism of exchange between Na + and H +, can be used as medicaments for the treatment of all lesions acute or chronic symptoms caused by ischemia, or of diseases induced primarily or secondarily in this way. This implies its use as drugs for surgical interventions, p. ex. in cases of organ transplants, the compounds can be used both for the protection of organs in the donor before and during extraction, for the protection of extracted organs, for example in the case of treatment with physiological bath liquids or in the of their storage in them, as well as when making the transfer to the recipient's organism. The compounds are also valuable drugs, which act in a protective manner, in the performance of angioplastic surgical interventions, for example in the heart, as well as in peripheral vessels. Corresponding to their protective effect against ischemically induced lesions, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, especially of the CNS (central nervous system), and they are suitable for this purpose. ex. for the treatment of stroke or cerebral edema. In addition, the compounds according to the invention of formula I are also suitable for treatment of shock forms, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shocks. Furthermore, the compounds according to the invention of formula I are distinguished by a strong inhibitory effect on cell proliferations, for example the cell proliferation of fibroblasts and the proliferation of smooth muscle cells of the vessels. Therefore, the compounds of the formula I come into question as valuable therapeutic agents for diseases, in which cell proliferation is a primary or secondary cause and, therefore, can be used as anti-clerical-clerotic agents, as agents against late diabetic complications, cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, hypertrophies and hyperplasias of organs, especially in the case of prostatic hyperplasia or hypertrophy of the prostate. The compounds according to the invention are effective inhibitors of the sodium and proton cell antiporter (exchanger between Na + and H +), which is increased in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) also in cells that are easily accessible to measurements, such as for example in erythrocytes, thrombocytes or leukocytes. The compounds according to the invention are, therefore, suitable as outstanding and simple scientific tools, for example in their use as diagnostic agents for the determination and differentiation of certain forms of hypertonia, but also of atherosclerosis, of diabetes , proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventive therapy in order to prevent the genesis of blood hypertension, for example, essential hypertonia. The drugs, which contain a compound I, can be applied in such cases orally, parenterally, intravenously, rectally or by inhalation, depending on the preferred application of the respective symptomatic picture of the disease. The compounds I can be applied in this case by themselves or in common with galenic adjuvants, and certainly in veterinary medicine as well as in human medicine. A person skilled in the art knows, by virtue of his specialized knowledge, which coadjuvant substances are suitable for the desired drug formulation. In addition to solvents, gel-forming agents, suppository bases, adjuvants for tablets, and other vehicles of active substances, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor correctors, preservatives, solubilizers or dyes. . For a form of oral application, the active compounds are mixed with the appropriate adjuvant substances for this purpose., such as vehicle materials, stabilizers or inert diluents and by the usual methods are brought into the appropriate forms of administration and administration, such as tablets, dragees, nestable capsules and aqueous, alcoholic or oily solutions. As inert vehicles, p. ex. gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. In this case, the preparation can be carried out in the form of both dry and wet granules. Oily vehicle materials or solvents include, for example, animal or vegetable oils, such as sunflower oil or cod liver oil. For subcutaneous application, the active compounds, if desired together with the usual substances for this, such as solubilizers, emulsifiers or other adjuvants, are brought into solution, suspension or emulsion. Suitable solvents are p. ex. in question: water, a physiological solution of sodium chloride or alcohols, p. ex. ethanol, propanol, glycerol, together with them also solutions of sugars such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned. As a pharmaceutical formulation for administration in the form of aerosols or sprays, p. ex. solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically innocuous solvent, such as especially ethanol or water, or a mixture of such solvents. The formulation can, if necessary, also contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, as well as a driving gas. One such preparation contains the active substance usually in a concentration of about 0.1 to 10, in particular about 0.3 to 3,% by weight. The dosage of the active substance of the formula I to be administered and the frequency of administration depend on the intensity of the effect and the duration of such effect of the compounds used.; in addition, they also depend on the type and severity of the disease to be treated, as well as the sex, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of the formula I in the case of a patient weighing 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, up to a maximum of 10 mg / kg. kg, preferably 1 mg / kg of body weight. In the case of acute outbreaks of the disease, for example immediately after suffering a cardiac infarction, even higher and, above all, more frequent dosing may be necessary, eg. ex. of up to 4 individual doses per day. Especially, in the case of the application via i.v. (intravenous), for example in the case of a heart attack patient in the intensive care phase, up to 200 mg per day may be necessary.

List of abbreviations: MeOH methanol NMP N-methyl-2-pyrrolidinone TA room temperature AE ethyl acetate (EtOAc) P.f. melting point THF tetrahydrofuran Experimental part General requirement for the preparation of benzoylguanidines (I) from alkyl esters of benzoic acid (II, L = O-alkyl) They are dissolved in isopropanol or suspended in THF 1.0 eq. of the benzoic acid alkyl ester of the formula II, as well as 5.0 eq. of guanidine (free base) and are heated to boiling until the reaction is complete (control by thin layer chromatography) (typical reaction time of 2 to 5 h). The solvent is removed by distillation under reduced pressure (in a rotary evaporator), collected in EA and washed 3 times with a solution of NaHCO3. Dry over Na 2 SO 4 ', remove the solvent by vacuum distillation and chromatograph on silica gel with an appropriate eluent, e.g. ex. AE / MeOH 5: 1.

Example 1: 2-Chloro-4-methoxy-5-trifluoromethyl-benzoylguanidine hydrochloride: Colorless crystals, P.f. 232 * C Synthetic pathway: a) 2-Chloro-5-iodo-4-methoxy-benzoic acid methyl ester from 2-chloro-4-methoxy-benzoic acid methyl ester by reaction with 1.1 equivalents of N-chlorosuccinimide in the presence of 2 equivalents of potassium iodide in acetic acid at RT for 1 h, yellowish crystals, Pf 120 * C. b) 2-Chloro-4-methoxy-5-trifluoromethyl-benzoic acid methyl ester from a) by heating to 90 ° C with potassium trifluoroacetate in NMP in the presence of copper iodide (I), colorless crystals, P.f. 112 * C. c) 2-Chloro-4-methoxy-5-trifluoromethyl-benzoyl-guanidine hydrochloride from b) according to the general prescription.

Example 2: 2-Chloro-3-iodo-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 268 'C. Synthesis route: a) 2-Chloro-3-iodo-5-trifluoromethyl-benzoic acid methyl ester from 2-chloro-5-trifluoromethyl-benzoic acid methyl ester by reaction with 1 equivalent of N-iodo-succinimide in 5 equivalents of trifluoromethanesulfonic acid at room temperature for 24 h, colorless oil, (M + H) + = 365. b) 2-Chloro-3-iodo-5-trifluoromethyl-benzoyl-guanidine hydrochloride from a) according to the general prescription.

Example 3: 2-Chloro-3-methyl-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 236'C. Synthesis route: a) 2-Chloro-3-methyl-5-trifluoromethyl-benzoic acid methyl ester from 2a) by cross-coupling with 1.5 equivalents of methyl-zinc chloride (from methylmagnesium chloride by transmetalation with zinc chloride (II) -theory in THF) by stirring at RT in the presence of catalytic [1, 1 '-bis- (diphenylphosphino) -ferrocene] -palladium (II) chloride and copper (I) iodide, aqueous treatment, extraction with ethyl acetate and subsequent chromatography on silica gel with ethyl acetate / n-heptane (3: 7), colorless oil, (M + H) + = 253 b) 2-Chloro-3-methyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride from a) according to the general prescription.

Example 4: 2-Chloro-3-n-propyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride: colorless crystals, P.f. 208 * C. Synthesis route: a) 2-Chloro-3-n-propyl-5-trifluoromethyl-benzoic acid methyl ester from 2 a) by cross-coupling with 1.5 equivalents of n-propyl-zinc chloride as described in 3 a), colorless oil, (M + H) + = 281. b) 2-Chloro-3-n-propyl-5-trifluoromethyl-benzoylguanidine hydrochloride from a) according to the general prescription.

Example 5: 2-Chloro-3-isopropyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride: colorless crystals, P.f. 183 'C. Synthesis route: a) 2-Chloro-3-isopropyl-5-trifluoromethyl-benzoic acid methyl ester from 2 a) by cross-coupling with 1.5 equivalents of isopropyl-zinc chloride as described in 3 a ), colorless oil, (M + H) + = 281. b) 2-Chloro-3-isopropyl-5-trifluoromethyl-benzoylguanidine hydrochloride from a) according to the general prescription.

Example 6: 2-Chloro-3-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 160'C.

Synthesis route: a) 2-Chloro-3-cyclopentyl-5-trifluoromethyl-benzoic acid methyl ester from 2 a) by cross-coupling with 1.5 equivalents of cyclopentyl-zinc chloride as described in 3 a ), colorless oil, (M + H) + = 307. b) 2-Chloro-3-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride from a) according to the general prescription.

Example 7: 2-Chloro-4-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride: colorless crystals, P.f. 245 * C. Synthesis route: a) 2-Chloro-4-cyclopentyl-benzoic acid methyl ester from 2-chloro-4-bromo-benzoic acid methyl ester by cross-coupling with 1.5 equivalents of cyclopentyl-zinc chloride as it has been described in 3 a), colorless oil, (M + H) + = 238. b) 2-Chloro-4-cyclopentyl-5-iodo-benzoic acid methyl ester from 7 a) by reaction with 1 equivalent of N-iodo-succinimide in 5 equivalents of trifluoromethanesulfonic acid at RT for 24 hours, colorless oil, (M + H) + = 364. c) 2-Chloro-4-cyclopentyl-5-trifluoromethyl-benzoic acid methyl ester from 7 b) by heating to 90 ° C with potassium trifluoroacetate in NMP in the presence of copper (I) iodide analogously to 1 b ), colorless oil, (M + H) + = 306. d) 2-Chloro-4-cyclopentyl-5-trifluoromethyl-benzoylguanidine hydrochloride from 7 c) according to the general prescription.

Example 8: 2-Chloro-4-n-propyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride: colorless crystals, P.f. 213'C. Synthesis route: a) 2-Chloro-4-n-propyl-benzoic acid methyl ester from 2-chloro-4-bromo-benzoic acid methyl ester by cross-coupling with 1.5 equivalents of zinc chloride - n-propyl as described in 3 a), colorless oil, (M + H) + = 212. b) 2-Chloro-4-n-propyl-5-iodo-benzoic acid methyl ester from 8 a) by reaction with 1 equivalent of N-iodo-succinimide in 5 equivalents of trifluoromethane sulfonic acid at RT for 24 hours h, colorless oil, (M + H) + = 338. c) 2-Chloro-4-n-propyl-5-trifluoromethyl-benzoic acid methyl ester from 8 b) by heating to 90 ° C with potassium trifluoroacetate in NMP in the presence of copper iodide (I) ) analogously to 1 b), colorless oil, (M + H) + = 280. d) 2-chloro-4-n-propyl-5-trifluoromethyl-benzoylguanidine hydrochloride from 8 c) according to the general prescription.

Pharmacological data: Inhibition of the exchanger between Na + and H + of rabbit erythrocytes White rabbits of New Zealand (Ivanovas) received a standard diet with 2% cholesterol for six weeks, in order to activate the exchange between Na + and H + and thus determine the incoming Na + flow in the erythrocytes through the exchange between Na + and H +, by flame photometry. The blood was extracted from the arteries of one ear and made uncoagulable by 25 IU heparin-potassium.

A part of each sample was used for the double determination of the hematocrit by centrifugation. Aliquots in each case of 100 μl were used for the measurement of the starting Na + content of the erythrocytes. To determine the incoming influx of amiloride sensitive sodium, 100 μl of each blood sample was incubated in each case in 5 ml of a hyperosmolar medium of common salt and sucrose (mmdl / 1: 140 of NaCl, 3 of KC1, 150 of sucrose, 0.1 ouabain, 2 tris-hydroxymethyl aminomethane) at a pH of 7.4 and 37 'C. The erythrocytes were then washed three times with an ice-cold solution of MgCl 2 and ouabain (mmol / 1: 112 MgCl 2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. The intracellular sodium content was determined by flame photometry. The net inflow of Na + was calculated from the difference between the starting values of sodium and the sodium content of the erythrocytes after incubation. The incoming sodium influx inhibitable with amiloride was established based on the difference in the sodium content of the erythrocytes, after incubation with and without amiloride, 3 x 10"4 mmol / 1. This also proceeded with the conforming compounds to the invention.

Results Inhibition of the Na + / H + exchanger: Example or Cl50 (mol / l) 1 0.02 x 1 0"6 2 0.05 x 1 0.6 6 0.07 x 1 0 * 6 5 0.02 x 1 0-6 6 0.06 x 1 0"6 7 0.03 x 1 0-6 8 0.01 x 1 0" 6

Claims (14)

1. Claims O-substituted substituted benzoylguanidines of the formula I wherein R (2) and R (3) signify independently of one another hydrogen, Cl, Br, I, alkyl (C ^ Cg), cycloalkyl (C3-Cg) or -OR (5); R (5) (C1-C8) alkyl or CdH2d-cycloalkyl (C3-C8); d zero, l or 2; wherein both R (2) and R (3) are hydrogen, but R (2) and R (3) are simultaneously both hydrogen and their pharmaceutically compatible salts.
2. 2. Compounds of formula I according to claim 1, in which they mean: R (2) and R (3) independently of each other hydrogen, Cl, Br, I, alkyl (C - ^ - Cg), cycloalkyl (C3) -C8) or -OR (5); R (5) (C1-C8) alkyl; as well as its pharmaceutically compatible salts.
3. 3. Compound of formula I according to claim 1, selected from the group consisting of: 2-chloro-4-methoxy-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-methoxy-5-trifluoromethyl hydrochloride -benzoyl-guanidine, 2-chloro-3-iodo-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-methyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-n-hydrochloride -propyl-5-trifluoromethyl-benzoyl-guanidine, 2-chloro-3-isopropyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-3-t-butyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, hydrochloride of 2-chloro-3-cyclopentyl-5-trifluoromethyl-benzoylguanidine, 2-chloro-4-methyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-4-n-propyl-5-trifluoromethyl-benzoyl hydrochloride -guanidine, 2-chloro-4-isopropyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride, 2-chloro-4-t-butyl-5-trifluoromethyl-benzoyl-guanidine hydrochloride and 2-chloro-4-hydrochloride -cyclopentyl-5-trifluoromethyl l-benzoylguanidine.
4. 4. Process for the preparation of a compound of formula I according to claim 1, characterized in that a compound of the formula II is reacted with guanidine wherein R (2) and R (3) have the indicated meanings and L represents a readily substitutable labile group nucleophilically.
5. 5. Use of a compound I according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of diseases caused by ischemic states.
6. 6. Use of a compound according to claim 1, for the preparation of a medicament for the treatment or prophylaxis of cardiac infarction.
7. 7. Use of a compound I according to claim 1 for the preparation of a medicament, intended for the treatment or prophylaxis of angina pectoris.
8. 8. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions.
9. 9. Use of a compound I according to claim 1 for the preparation of a medicament intended for the treatment or prophylaxis of ischemic states of the peripheral and central nervous systems, and of apoplexy.
10. 10. Use of a compound 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. 11. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of shock states.
12. 12. Use of a compound I according to claim 1 for the preparation of a medicament intended for use in surgical operations and for organ transplants.
13. 13. Use of a compound I according to claim 1 for the preparation of a medicament for the preservation and storage of transplanted organs for surgical measures.
14. 14. Use of a compound I according to claim 1 for the preparation of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, and therefore its use for the preparation of an antiathermal otic agent , an agent against late diabetic complications, cancerous diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and prostate hyperplasia. 16. Medicament, characterized by an active content of a compound of formula I according to claims 1 to 3.