HK1076449A1 - Fluorinated cycloalkyl-derivatised benzoylguanidines and their use as a medicament - Google Patents

Abstract

N-((4-Polyfluorocycloalkyl-oxy, -thio or -amino)-benzoyl)-guanidine derivatives (I) are new. Benzoyl-guanidine derivatives of formula (I) and their salts are new. [Image] X : O, S or NR 6; R 6H, 1-4C alkyl or -(CH 2) k-CF 3; k, l, m, n, p, r : 0-3; q = 0-3, provided that m + n + p + q + r = at least 2; R 1H, 1-4C alkyl, F, Cl, OR 7, NR 8R 9 or 1-4C perfluoroalkyl; R 7 - R 9H, 1-4C alkyl or -(CH 2) t-CF 3; t : 0-4; R 2H, F, Cl, 1-4C alkyl or CF 3; R 3H, F, Cl, 1-4C alkyl, CF 3 or SO uR 1 0; u : 0-2; R 1 01-4C alkyl or NR 1 1R 1 2; R 1 1, R 1 2H or 1-4C alkyl; R 4H, F, Cl, 1-4C alkyl, OR 1 3, NR 1 4R 1 5 or 1-4C perfluoroalkyl; R 1 3 - R 1 5H, 1-4C alkyl or -(CH 2) w-CF 3; w : 0-4; and R 5H or F. ACTIVITY : Vasotropic; Antiarrhythmic; Cardiant; Antianginal; Cerebroprotective; Cytostatic; Antiarteriosclerotic; Antilipemic; Hypotensive; Anticonvulsant; Tranquilizer; Antidepressant; Neuroleptic; Antidiabetic; Thrombolytic; Anticoagulant; Hepatotropic; Nephrotropic; Antiinflammatory; Antiprotozoal; Antimalarial; Antithyroid. MECHANISM OF ACTION : Cellular sodium-proton antiporter (NHE) inhibitor. N-(4-(3,3-Difluoro-cyclobutoxy)-5-methanesulfonyl-2-methyl-benzoyl)-guanidine (Ia) had IC 5 0 5.9 nM for inhibition of NHE1.

Description

Fluorinated cycloalkyl-derived benzoylguanidines and their use as a medicament

no marking

Fluorinated cycloalkyl-derived benzoylguanidines, a process for their preparation, their use as a medicament and a medicament containing them.

The present invention relates to compounds of formula I:

the meaning of which is:

x is oxygen, sulfur or NR 6;

r6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or (CH)₂)_k-CF₃；

k is 0, 1, 2 or 3;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

q is 1, 2 or 3;

r is 0, 1, 2 or 3;

wherein the sum of m, n, p, q and r is at least 2;

r1 is hydrogen, alkyl having 1, 2, 3 OR 4 carbon atoms, F, Cl, -OR (7), -NR (8) R (9) OR-C_sF_2s+1；

R (7), R (8) and R (9)

Independently of one another, hydrogen, alkyl having 1, 2 or 3 carbon atoms or

(CH₂)_t-CF₃；

s is 1, 2, 3 or 4;

t is 0, 1, 2, 3 or 4;

r2 is hydrogen, F, Cl, alkyl of 1, 2, 3 or 4 carbon atoms or CF₃；

R3 is hydrogen, F, Cl, alkyl of 1, 2, 3 or 4 carbon atoms, CF₃Or SO_uR₁₀；

u is 0, 1 or 2;

r10 is alkyl containing 1, 2, 3 or 4 carbon atoms or NR11R 12;

r11 and R12 are each independently of the other hydrogen or contain 1, 2, 3 or 4 carbon atoms

Alkyl groups of (a);

r4 is hydrogen, alkyl having 1, 2, 3 OR 4 carbon atoms, F, Cl, -OR (13), -NR (14) R (15)

or-C_vF_2v+1；

R (13), R (14) and R (15)

Independently of one another, hydrogen, alkyl having 1, 2 or 3 carbon atoms or

(CH₂)_w-CF₃；

v is 1, 2, 3 or 4;

w is 0, 1, 2, 3 or 4;

r5 is hydrogen or F; and pharmacologically acceptable salts thereof.

Preference is given to compounds of the formula I in which:

x is oxygen, sulfur or NR 6;

r6 is hydrogen, methyl or CH₂-CF₃；

m is 0, 1 or 2;

n is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

wherein the sum of m, n, p, q and r is at least 2;

r1 is hydrogen, methyl, F, Cl, -OR (7), -NR (8) R (9) OR-CF₃；

R (7), R (8) and R (9)

Independently of one another, hydrogen, methyl, CF₃Or CH₂-CF₃；

R2 is hydrogen, F, Cl, methyl or CF₃；

R3 is hydrogen, F, Cl, alkyl of 1, 2, 3 or 4 carbon atoms, CF₃、SO₂CH₃

Or SO₂NH₂；

R4 is hydrogen, methyl, F, Cl, -OR (13), -NR (14) R (15) OR-CF₃；

R (13), R (14) and R (15)

Independently of one another, hydrogen, methyl, CF₃Or CH₂-CF₃；

R5 is hydrogen or F; and pharmacologically acceptable salts thereof.

Particular preference is given to compounds of the formula I in which

X is oxygen, sulfur or NR 6;

r6 is hydrogen, methyl or CH₂-CF₃；

m is 0 or 1;

n is 0, 1 or 2;

p is 0 or 1;

q is 1 or 2;

r is 0 or 1;

wherein the sum of m, n, p, q and r is at least 2;

r1 is hydrogen, methyl, F, Cl, -OR (7), -NR (8) R (9) OR-CF₃；

R (7) is methyl, CF₃Or CH₂-CF₃；

R (8) and R (9)

Independently of one another, hydrogen, methyl or CH₂-CF₃；

R2 is hydrogen, F or Cl;

r3 is CF₃、SO₂CH₃Or SO₂NH₂；

R4 is hydrogen;

r5 is hydrogen or F;

and pharmacologically acceptable salts thereof.

More preferably a compound of formula I selected from:

n- [4- (3, 3-difluoro-cyclobutoxy) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine,

n- [4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine,

n- {4- [ (3, 3-difluoro-cyclobutyl) -methyl-amino ] -5-methanesulfonyl-2-methyl-benzoyl } -guanidine, and

n- {4- [ (3, 3-difluoro-cyclobutyl) -methyl-amino ] -5-ethanesulfonyl-2-methyl-benzoyl } -guanidine, and pharmacologically acceptable salts thereof.

The compounds of the formula I, for example the substituents R1 to R4, contain one or more asymmetric centers and can therefore, independently of one another, be in the S or R configuration. The compounds may exist as optical isomers, diastereomers, racemates or as mixtures thereof.

The present invention includes all tautomeric forms of the compounds of formula I and II.

The alkyl group may be linear or branched. The same holds true if they have substituents or occur as substituents of other groups, such as fluoroalkyl or alkoxy. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl (═ 1-methylethyl), n-butyl, isobutyl (═ 2-methylpropyl), sec-butyl (═ 1-methylpropyl), and tert-butyl (═ 1, 1-dimethylethyl). Preferred alkyl groups are methyl, ethyl, n-propyl and isopropyl. One or more, for example 1, 2, 3, 4 or 5, hydrogen atoms in the alkyl group may be substituted by fluorine atoms. Examples of such fluoroalkyl groups are trifluoromethyl, 2, 2, 2-trifluoroethyl and pentafluoroethyl. The substituted alkyl group may be substituted at any position.

Preferred compounds of formula I are those wherein the sum of m, n, o, p, q and r is from 2 to 6.

The invention also relates to a process for preparing a compound of formula I, which process comprises reacting a compound of formula II:

wherein R (1) to R (5) and m to R have the stated meanings and L is a leaving group which can be readily subjected to nucleophilic substitution.

The active acid derivatives of formula II, wherein L is alkoxy, preferably methoxy, phenoxy, phenylthio, methylthio, 2-pyridylthio, azacyclo, preferably 1-imidazolyl, are conveniently obtained in a manner known to the skilled worker from the corresponding acid chlorides (formula II, L ═ Cl), which are themselves prepared in a manner known to the skilled worker from the corresponding carboxylic acids (formula II, L ═ OH), for example with thionyl chloride.

In addition to the acid chlorides of the formula II (L ═ Cl), it is also possible to prepare other reactive acid derivatives of the formula II directly from the corresponding benzoic acids (formula II; L ═ OH) according to methods known per se, for example by reaction with gaseous HCl in methanol to prepare L ═ OCH₃Is prepared by reaction with carbonyldiimidazole, the imidazolate (imidazolide) of the formula II [ L ═ 1-imidazolyl, Staab, Angew. chem. int. English edition 1, 351-367(1962)]With Cl-COOC₂H₅Or tosyl chloride in the presence of triethylamine in an inert solvent, with Dicyclohexylcarbodiimide (DCC) or with O- [ (cyano (ethoxycarbonyl) -methylene) amino]-1, 1, 3, 3-tetramethyluronium tetrafluoroborate ("TOTU") activating benzoic acid [ Proceedingsof the 21.European Peptide Symposium, Peptides 1990, editors E.Giralt and D.Andreu, Escom, Leiden, 1991]. In J.March, advanced organic Chemistry, 3 rd edition (John Wiley)&Sons, 1985), page 350 describes a number of suitable processes for preparing the activated carboxylic acid derivatives of formula II and gives the original literature.

The reaction of the reactive carboxylic acid derivatives of the formula II with guanidine can be carried out in protic or aprotic polar, inert organic solvents according to methods known to the skilled worker. Has proven suitable for methyl benzoate (II; L ═ OCH)₃) The solvent for the reaction with guanidine is methanol, isopropanol or THF at a temperature of 20 ℃ to its boiling point. Most reactions of compound II with guanidine without salts can be conveniently carried out in aprotic solvents such as THF, dimethoxyethane, dioxane or DMF. However, in the reaction of compound II with guanidine, water may also be used as solvent in the presence of a base such as NaOH.

If L is Cl, it is advantageous to add an acid scavenger, for example in the form of excess guanidine, for combination with the hydrohalic acid.

The carboxylic acid derivatives of formula II can be prepared from compounds of formula III. Certain corresponding benzoic acid derivatives of formula III are known and described in the literature. Unknown compounds of formula III can be prepared by methods known in the literature.

The fluorocycloalkyl nucleophilic group can be introduced at the 4-position by nucleophilic aromatic substitution. Suitably protected benzoic acid derivatives of formula III, such as for example methyl or ethyl esters, may be used in this case. L' is a leaving group susceptible to substitution by nucleophilic aromatic substitution, e.g. F, Cl, Br, I or O-SO₂CF₃。

The resulting benzoic acid derivative of formula II is then reacted according to one of the process variants described above to give the compounds of formula I according to the invention.

Benzoylguanidines of formula I are generally weak bases and can be combined with an acid to form a salt. Suitable acid addition salts are all salts of pharmacologically acceptable acids, for example halides, in particular hydrochloride, lactate, sulfate, citrate, tartrate, acetate, phosphate, methanesulfonate and p-toluenesulfonate.

The compound of formula I is substituted acylguanidine, and can inhibit sodium-proton antiporter (Na) of cell⁺/H⁺-exchanger, NHE).

The compounds of formula I according to the invention are distinguished by particularly advantageous ADME (absorption, distribution, metabolism, excretion) properties, in comparison with the known benzoylguanidines, and also by Na⁺/H⁺Excellent inhibitory activity of the exchanger; these advantageous properties depend on fluorinated cycloalkyl groups.

Unlike the known acylguanidines, the compounds described herein do not exhibit undesirable and disadvantageous urogenic properties.

Due to their NHE-inhibiting properties, the compounds of formula I and/or II and/or their pharmaceutically acceptable salts are suitable for the prevention and treatment of diseases caused by NHE-activated or active NHE as well as secondary diseases caused by injury associated with NHE.

Since NHE inhibitors act primarily through their effect on the regulation of the pH of the cell, they can often be advantageously combined with other compounds capable of regulating the pH in the cell, suitable combination partners being carbonic anhydrase (carbonate dehydratase) inhibitors, inhibitors of the system for transporting bicarbonate ions, such as sodium bicarbonate cotransporter (NEC) inhibitors or sodium-dependent chloride-bicarbonate exchanger (NCBE) inhibitors, as well as NHE inhibitors having an inhibitory effect on other NHE subtypes, since by virtue of them it is possible to enhance or modulate the pharmacologically relevant pH-regulating effect of the NHE inhibitors described herein.

The use of the compounds of the invention relates to the prevention and treatment of acute and chronic diseases in veterinary and human medicine.

Therefore, the NHE inhibitor of the present invention is suitable for the treatment of diseases caused by ischemia and by reperfusion.

The compounds described herein are suitable for use as antiarrhythmic agents due to their pharmacological properties. Due to their cardioprotective component, the NHE inhibitors of formula I and/or their pharmaceutically acceptable salts are very suitable for the prevention and treatment of infarctions and for the treatment of angina pectoris, in which case they can also preventively inhibit or significantly reduce the pathophysiological processes associated with the development of ischemia-induced damage, in particular the occurrence of ischemia-induced cardiac arrhythmias. Because of their protective effect against pathological hypoxic and ischemic states, the compounds of the formula I and/or their pharmaceutically acceptable salts used according to the invention are also useful in the treatment of cellular Na⁺/H⁺Inhibition of the exchange mechanism is therefore useful as a drug for the treatment of all ischemia-induced acute or chronic injuries or diseases primary or secondary to these.

The invention also relates to the use thereof as a medicament for surgical operations. Thus, the compounds may be used in organ transplantation, it being possible to use the compounds to protect the donor's organ before and during transplantation, to protect the transplanted organ, for example during treatment therewith or storage thereof in a physiological bath, and to protect the transplanted organ during implantation in the recipient.

The compounds of the invention are also valuable drugs with protective effects when undergoing angioplasty surgery, for example, on the heart and peripheral organs and vessels.

It has been shown that: the compounds of the present invention are very effective drugs for life-threatening arrhythmias. The compounds terminate ventricular fibrillation and restore physiologic sinus rhythm.

Since inhibitors of NHE1 in human tissues and organs, especially the heart, are not only effective against damage due to ischemia and reperfusion, but also against the cytotoxic effects of drugs, especially drugs used in the treatment of cancer and autoimmune diseases, administration in combination with a compound of formula I and/or a pharmaceutically acceptable salt thereof is suitable for inhibiting the cytotoxic, especially cardiotoxic, side effects of said compound. The reduction in cytotoxic effects, particularly cardiotoxicity, resulting from treatment with NHE1 inhibitors also makes it possible to increase the dosage of cytotoxic therapeutic agents and/or to extend the duration of treatment with such agents. The therapeutic benefit of the cytotoxic treatment can be greatly enhanced by the use in combination with NHE inhibitors.

In addition, the NHE1 inhibitor of formula I and/or its pharmaceutically acceptable salts of the present invention may be used when excessive thyroid hormone production, thyrotoxicosis, or dependence on external supply of thyroid hormones occurs with damage to the heart. Accordingly, the compounds of formula I and/or their pharmaceutically acceptable salts are suitable for use in the treatment of drugs that ameliorate cardiotoxicity.

The compounds according to the invention are also suitable, in terms of their protective action against ischemia-induced damage, as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, and are suitable, for example, for the treatment of stroke or cerebral edema.

The compounds of the formula I and/or their pharmaceutically acceptable salts are also suitable for the treatment and prophylaxis of diseases and disorders which are induced by an excessive excitation of the central nervous system, in particular for the treatment of epileptic disorders, centrally-induced clonic and tonic spasms, psychogenic depressive states, anxiety disorders and psychoses. In these cases, the NHE inhibitors described herein can be used alone or in combination with other substances having anti-epileptic activity or antipsychotic active ingredients or carbonic anhydrase inhibitors, for example with acetazolamide, as well as in combination with other NHE inhibitors or sodium-dependent chloride-bicarbonate exchanger (NCBE) inhibitors.

The compounds of formula I and/or their pharmaceutically acceptable salts for use in the present invention are also suitable for the treatment of various types of shock, such as for example anaphylactic shock, cardiogenic shock, hypovolemic shock and bacterial shock.

The compounds of formula I and/or their pharmaceutically acceptable salts are also useful in the prevention and treatment of thrombotic disorders, since they inhibit platelet auto-aggregation as NHE inhibitors. They also inhibit or prevent the excessive release of inflammatory and coagulation mediators, in particular von willebrand factor and thromboselectin, that occurs after ischemia and reperfusion. Thus, the pathogenic effects of important thrombotic factors can be reduced and eliminated. Thus, the NHE inhibitors of the invention may be used in combination with other anticoagulants and/or thrombolytic active ingredients, such as, for example, recombinant or natural tissue plasminogen activators, streptokinases, urokinases, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, pharmaceutical substances with fibrinolytic activity, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine, and the like. The present NHE inhibitors are particularly advantageously used in combination with NCBE inhibitors and/or with carbonic anhydrase inhibitors such as for example with acetazolamide.

Another significant feature of the compounds of formula I and/or their pharmaceutically acceptable salts for use in the present invention is a strong inhibitory effect on cell proliferation, such as fibroblast proliferation and vascular smooth muscle cell proliferation. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore suitable for use as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, and are therefore useful as anti-atherosclerotic agents, agents for chronic renal failure, cancer.

It can be demonstrated that: the compounds of the invention inhibit cell migration. The compounds of the formula I and/or their pharmaceutically acceptable salts are therefore suitable for use as valuable therapeutic agents for diseases in which cell migration is a primary or secondary cause, such as, for example, cancers with a pronounced tendency to metastasize.

Another significant feature of the compounds of formula I and/or their pharmaceutically acceptable salts is their ability to arrest or prevent fibrotic conditions. They are therefore suitable as excellent drugs for the treatment of cardiac fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis and other fibrotic disorders. They are therefore useful in the treatment of organ hypertrophy and hyperplasia, such as cardiac and prostate hypertrophy and hyperplasia. They are therefore suitable for the prophylaxis and therapy of heart failure (congestive heart failure ═ CHF) and for the therapy and prophylaxis of prostatic hyperplasia or prostatic hypertrophy.

Due to the marked increase in NHE in essential hypertension, the compounds of formula I and/or their pharmaceutically acceptable salts are suitable for the prevention and treatment of hypertension and cardiovascular disorders. In these cases, they can be used alone or with suitable combination and formulation combination components for the treatment of hypertension and cardiovascular disorders. Thus, for example, the following drugs can be combined: one or more diuretics having a thiazide-like action, loop diuretics, aldosterone and pseudo-aldosterone antagonists, such as hydrochlorothiazide, indapamide, polythiazide, furosemide, piretanide, torasemide, bumetanide, amiloride, triamterene, spironolactone or eplerenone. The NHE inhibitors of the present invention may also be used in combination with calcium channel blockers such as verapamil, diltiazem *, amlodipine or nifedipine, and with ACE inhibitors such as, for example, ramipril, enalapril, lisinopril, fosinopril or captopril. Further advantageous combination partners are also beta-blockers such as metoprolol, salbutamol and the like, angiotensin receptors and receptor subtype antagonists such as losartan, irbesartan, valsartan, omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, potassium channel inhibitors and activators such as glibenclamide, glimepiride, diazoxide, crookaine, minoxidil and derivatives thereof, activators of the mitochondrial ATP-sensitive potassium channel (mitok (ATP) channel), kv1.5 inhibitors and the like.

It has been shown that: the NHE1 inhibitors of formula I and/or pharmaceutically acceptable salts thereof have significant anti-inflammatory effects and are therefore useful as anti-inflammatory agents. Of note in this regard is the inhibition of inflammatory mediator release. The compounds can therefore be used alone or in combination with anti-inflammatory agents for the prevention or treatment of chronic and acute inflammatory conditions. Combination components which can advantageously be used are steroidal and non-steroidal anti-inflammatory drugs. The compounds of the invention are also useful for the treatment of protozoan disorders, malaria and coccidiosis in poultry.

It has additionally been found that: the compounds of formula I and/or their pharmaceutically acceptable salts have a beneficial effect on serum lipoproteins. It is generally accepted that excessive blood lipid levels, so-called hyperlipoproteinemia, are an important risk factor for the development of arteriosclerotic vascular lesions, especially coronary heart diseases. Thus, reducing elevated serum lipoproteins is important for the prevention and regression of atherosclerotic lesions. In addition to lowering total serum cholesterol, it is also particularly important to reduce the proportion of specific atherogenic lipid moieties, in particular Low Density Lipoprotein (LDL) and Very Low Density Lipoprotein (VLDL), in the total cholesterol, since these lipid moieties are risk factors for atherogenesis. In contrast, the protective effect against coronary heart disease is due to high density lipoproteins. Thus, hypolipidemic agents should be able to lower not only total cholesterol, but also in particular the VLDL and LDL serum cholesterol fraction. It has now been found that NHE1 inhibitors exhibit valuable therapeutically utilizable properties in affecting serum lipid levels. Thus, as observed, they significantly reduce elevated serum concentrations of LDL and VLDL, e.g., due to increased dietary intake of cholesterol-and lipid-rich foods or pathological metabolic changes, e.g., genetically-related hyperlipidemia. Thus, they are useful for preventing and resolving atherosclerotic lesions by eliminating pathogenic risk factors. Not only primary hyperlipidemia but also certain secondary hyperlipidemia, such as secondary hyperlipidemia associated with diabetes, are included herein. In addition, the compounds of formula I and/or their pharmaceutically acceptable salts can significantly reduce infarctions induced by metabolic abnormalities, in particular the area of the induced infarctions and their severity.

Thus, the compounds of the present invention can be advantageously used for the preparation of a medicament for the treatment of hypercholesterolemia; for the preparation of a medicament for the prevention of atherogenesis; for the preparation of a medicament for the prevention and treatment of atherosclerosis; for the preparation of a medicament for the prevention and treatment of diseases induced by elevated cholesterol levels; for the preparation of a medicament for the prevention and treatment of diseases induced by endothelial dysfunction; for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced hypertension; for the preparation of a medicament for the prevention and treatment of atherosclerosis-induced thrombosis; for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced ischemic injury and post-ischemic reperfusion injury; for the preparation of a medicament for the prevention and treatment of hypercholesterolaemia-induced and endothelial dysfunction-induced cardiac hypertrophy and cardiomyopathy and for the prevention and treatment of Congestive Heart Failure (CHF); for the preparation of a medicament for the prevention and treatment of hypercholesterolemia-induced and endothelial dysfunction-induced coronary vasospasm and myocardial infarction; for the preparation of a medicament for the treatment of said conditions in combination with a hypotensive substance, preferably with an Angiotensin Converting Enzyme (ACE) inhibitor and an angiotensin receptor antagonist. The combination of the NHE inhibitor of formula I and/or a pharmaceutically acceptable salt thereof with a lipid-lowering active ingredient, preferably with an HMG-CoA reductase inhibitor, such as lovastatin or pravastatin, has proved to be an advantageous combination with an enhanced effect and a reduced amount of active ingredient, the latter of which produces a lipid-lowering effect and thus enhances the lipid-lowering properties of the NHE inhibitor of formula I and/or a pharmaceutically acceptable salt thereof.

Thus, the compounds of formula I and/or their pharmaceutically acceptable salts can produce effective protection against endothelial damage caused by a variety of causes. This vasoprotective effect against endothelial dysfunction syndrome means that the compounds of formula I and/or their pharmaceutically acceptable salts are valuable medicaments for the prevention and treatment of coronary vasospasm, peripheral vascular diseases, in particular intermittent claudication, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy and thrombotic disorders.

It has also been found that: benzoylguanidines of formula I and/or a pharmaceutically acceptable salt thereof are suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM), in which case insulin resistance is inhibited. In this respect, it may be beneficial for the compounds of the invention to enhance the anti-diabetic activity and type of action in combination with a biguanide, such as metformin, with anti-diabetic sulfonylureas, such as glibenclamide, glimepiride, tolbutamide, etc., with a glucosidase inhibitor, with a PPAR agonist, such as rosiglitazone, pioglitazone, etc., with insulin products of different modes of administration, with a DB4 inhibitor, with an insulin sensitizer or with meglitinide.

In addition to the acute antidiabetic effect, the compounds of formula I and/or their pharmaceutically acceptable salts may hinder the development of late complications of diabetes and are therefore useful as agents for the prevention and treatment of late damage caused by diabetes such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and other conditions caused by diabetes. In this respect, they may advantageously be used in combination with an antidiabetic agent as described in the treatment of NIDDM. In this respect, the combination with an advantageous dosage form of insulin is of particular importance.

In addition to a protective effect against acute ischemic events and subsequent reperfusion events corresponding to acute stress, the NHE inhibitor of formula I of the invention and/or a pharmaceutically acceptable salt thereof has a direct therapeutically utilizable effect on conditions and injuries of the whole mammalian body which are associated with a long-standing characterization of the aging process and which occur under normal, non-ischemic conditions independently of acute hypoperfusion conditions. These age-related pathological manifestations such as diseases, disorders and deaths induced in long-term aging include disorders and injuries mainly caused by age-related changes in vital organs and their functions, and become increasingly important in the aging body, which can now be treated with NHE inhibitors. Examples of conditions associated with age-related functional impairment, signs of age-related organ aging are vascular responsiveness and hyporesponsiveness associated with systolic and diastolic responses. This age-related decline in vascular responsiveness to systolic and diastolic stimuli, which are important processes in the cardiovascular system and thus vital processes of life and health, can be significantly reduced or eliminated by NHE inhibitors. An important role and method of maintaining vascular responsiveness is to block or slow the age-related worsening of endothelial dysfunction, which can be very significantly eliminated by NHE inhibitors. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore very suitable for the treatment and prevention of age-related endothelial dysfunction, in particular worsening of intermittent claudication.

Another example of variables that characterize the aging process are the decrease in contractility of the heart and the decrease in the adaptability of the heart to the necessary pumping performance of the heart. In most cases, this reduced cardiac efficacy resulting from the aging process is associated with cardiac dysfunction, particularly that caused by the deposition of connective tissue in cardiac tissue. This connective tissue deposition is characterized by increased heart weight, enlarged heart and limited cardiac function. Surprisingly, it is in fact entirely possible to inhibit the aging of such heart organs. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore very suitable for the treatment and prophylaxis of heart failure, Congestive Heart Failure (CHF).

Although earlier patents and patent applications have claimed the treatment of various types of cancer that have emerged, it is now quite surprising that not only can the cancer that has emerged be treated by inhibiting proliferation, but also the age-related incidence of cancer can be prevented and very significantly delayed by NHE inhibitors. One particularly notable finding is: disorders that occur in an age-related manner in all organs, not just certain types of cancer, can be suppressed or their occurrence very significantly delayed. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore very suitable for the treatment and in particular the prevention of age-related forms of cancer.

It has now been found that: not only is the occurrence of age-related disorders delayed, i.e., altered very significantly in time and beyond statistical normality, in all organs studied, including the heart, vessels, liver, etc., but also age-related cancers. In contrast, it is also surprising that life is extended to the extent that heretofore no other class of drugs or any natural products could achieve. In addition to the possibility of using the active ingredient alone in humans and animals, the unique action of NHE inhibitors also makes possible the use of these NHE inhibitors in combination with other active ingredients, methods, substances and natural products used in geriatrics and based on different mechanisms of action. The active ingredients used in the treatment of senile diseases are especially vitamins and vitaminsSubstances with antioxidant activity. Due to the association between heat load or food intake and the aging process, it may also be used in combination with dieting, e.g. with appetite suppressants. Also contemplated are hypotensive agents such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca⁺²Antagonists and the like or in combination with agents which normalize metabolism, such as cholesterol lowering agents. The compounds of formula I and/or their pharmaceutically acceptable salts are therefore very suitable for preventing age-related tissue changes and for prolonging life and maintaining a high quality of life.

The compounds of the invention are potent inhibitors of cellular sodium/proton antiporters (Na/H exchanger), which are also increased in easily detectable cells such as, for example, in erythrocytes, platelets or leukocytes, in a variety of conditions (essential hypertension, atherosclerosis, diabetes, etc.). The compounds used in the present invention are therefore suitable as excellent and simple scientific tools, for example as diagnostic aids for determining and differentiating specific types of hypertension as well as atherosclerosis, diabetes and late complications of diabetes, proliferative disorders, etc.

The invention claims the use of a compound of formula I and/or a pharmaceutically acceptable salt thereof for the production of a medicament for the treatment or prevention of acute or chronic injuries, disorders or indirect sequelae of organs and tissues caused by ischemic events or by reperfusion events; for the treatment or prophylaxis of cardiac arrhythmias, life threatening ventricular fibrillation of the heart, myocardial infarction, angina pectoris; for the treatment or prevention of ischemic conditions of the heart, of the peripheral and central nervous system, of stroke or of peripheral organs and tissues; for the treatment or prophylaxis of states of shock, diseases in which cell proliferation is of primary or secondary origin, cancer, metastasis, prostatic hypertrophy or hyperplasia, atherosclerosis or lipid metabolism disorders, hypertension, particularly essential hypertension, central nervous system disorders, particularly disorders arising from CNS hyperexcitability, such as epilepsy or centrally-induced convulsions, central nervous system disorders, particularly anxiety, depression or psychosis; for the treatment or prevention of non-insulin dependent diabetes mellitus (MDDM) or diabetes-induced late stage injury, thrombosis, endothelial dysfunction-induced conditions, intermittent claudication; for treating or preventing fibrotic disorders of the viscera, liver fibrosis disorders, kidney fibrosis disorders, vascular fibrotic disorders and cardiac fibrotic disorders; for the treatment or prevention of heart failure or congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoans, malaria and coccidiosis in poultry; for use in surgery and organ transplantation; for storing and storing implants for surgical procedures; for preventing age-related tissue changes; for combating aging or prolonging life; can be used for treating and relieving cardiotoxic effects of thyrotoxicosis.

The invention also claims the use of a compound of formula I and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of acute and chronic injuries, disorders or indirect sequelae of organs and limbs caused by ischemic events or by reperfusion events.

Furthermore, medicaments for human, veterinary or plant protection use are claimed, which comprise an effective amount of one or more compounds of the formula I and/or pharmaceutically acceptable salts thereof, alone or in combination with other pharmacologically active ingredients or medicaments, and pharmaceutically acceptable carriers and additives.

Medicaments comprising compound I can also be administered, for example, orally, parenterally, intravenously, rectally, transdermally or by inhalation, the preferred mode of administration depending on the particular manifestation of the condition. Compound I can also be used in veterinary and human medicine, alone or together with pharmaceutically acceptable excipients. The medicaments usually contain from 0.01mg to 1g of the active ingredient of the formula I and/or a pharmaceutically acceptable salt thereof per dosage unit.

The skilled worker is familiar, on the basis of his expert knowledge, with excipients which are suitable for the desired pharmaceutical preparation. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active ingredient carriers, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, taste masking agents, preservatives, solubilizers or colorants.

For oral use, the active compounds can be mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by customary methods, such as tablets, coated tablets, split capsules, aqueous, alcoholic or oily solutions. Examples of inert carriers which can be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Dry granules and wet granules can also be used for the preparation. Examples of suitable oily carriers or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds can be formulated as solutions, suspensions or emulsions, if desired with the addition of substances customary for this purpose, such as solubilizers, emulsifiers or other excipients. Examples of suitable solvents are water, physiological saline or alcohols, for example ethanol, propanol, glycerol, and sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Pharmaceutical preparations which are suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or mixtures of such solvents.

The formulations may also contain other pharmaceutically acceptable excipients such as surfactants, emulsifiers and stabilisers and propellants, if desired. The active ingredient is generally contained in the formulation in a concentration of about 0.1 to 10%, in particular about 0.3 to 3%, by weight.

The dosage and frequency of administration of the active ingredients of formula I depend on the potency and duration of action of the compounds used; but also on the nature and severity of the condition to be treated, as well as the sex, age, weight and individual response of the mammal to be treated.

In general, the daily dosage of a compound of formula I is at least 0.001mg/kg body weight, preferably 0.01mg/kg body weight up to 10mg/kg body weight, preferably 1mg/kg body weight, for a patient weighing about 75 kg. For acute episodes of the condition, such as immediately after experiencing a myocardial infarction, higher doses may be required. Especially for intravenous use, for example for strengthening infarcted patients in a care unit, doses up to 700mg per day may be required. The daily dose may be divided into several, for example no more than 4, divided doses.

List of abbreviations:

ADME absorption-distribution-metabolism-excretion

CDI di-imidazol-1-yl-methanones

DIP diisopropyl ether

DMF N, N-dimethylformamide

EE acetic acid ethyl ester (EtOAc)

EI electron collision

eq. equivalent

ES electrospray ionization

Et Ethyl group

HEP n-heptane

KOtBu 2-methylpropan-2-ol potassium salt

Me methyl group

MeOH methanol

mp melting point

NMP 1-methylpyrrolidin-2-one

MTB 2-methoxy-2-methyl-propane

RT Room temperature

THF tetrahydrofuran

Example 1: n- [4- (3, 3-difluoro-cyclobutoxy) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine

a) (3, 3-difluoro-cyclobutoxymethyl) -benzene

20.0g of 3-benzyloxy-cyclobutanone (Bull. chem. Soc. Jpn. (1984), 57(6), 1637) are dissolved in 150ml of CH₂Cl₂In (b), 25.0g of [ bis (2-methoxyethyl) amino trifluoride are added dropwise at RT]Sulfur in 30ml CH₂Cl₂The solution of (1). After stirring at RT for 5 hours, 12.0g of diethylaminosulfur trifluoride are added. After stirring for a further 20 hours at RT, the reaction mixture is washed three times with 100ml of water each time. Adding Na to the mixture₂SO₄Dried and the solvent removed under vacuum. Chromatography on silica gel eluting with EE/HEP 3: 1 followed by kugelrohr distillation gave 27.6g of a colorless oil.

b)3, 3-difluoro-cyclobutanol

22.4g of (3, 3-difluorocyclobutoxymethyl) benzene were dissolved in 100ml of diethyl ether, and 1.4g of 10% Pd/C were added. At RT, 20 bar H₂Hydrogenation under conditions for 5 hours. The catalyst was washed with 10ml of diethyl ether and the solution was subjected to distillation. 14.0g of product (bp. 80 ℃) are obtained as a mixture with diethyl ether and toluene. The mixture was reacted without further purification.

c)4- (3, 3-difluoro-cyclobutoxy) -5-methanesulfonyl-2-methyl-benzoic acid methyl ester

370mg of 4-fluoro-5-methanesulfonyl-2-methyl-benzoic acid methyl ester, 297mg of 3, 3-difluorocyclobutane and 1.47g of Cs₂CO₃Dissolved in 10ml of anhydrous NMP and stirred at 60 ℃ for 4 hours. The reaction mixture was then washed with 125ml of 50% concentrated NaHCO₃The aqueous solution was diluted and extracted 3 times with 100ml of EE each. Adding Na to the mixture₂SO₄Dried and the solvent removed under vacuum. Chromatography on silica gel eluting with DIP gave 380mg of a colorless oil.

Rf(DIP)＝0.21 MS(DCI)：335

d) N- [4- (3, 3-difluoro-cyclobutoxy) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine

566mg of guanidine chloride (guanidium chloride) was dissolved in 5ml of anhydrous DMF and added to a solution of 604mg of KOtBu in 5ml of anhydrous DMF. The solution of guanidine prepared in this way in DMF is added to a solution of 360mg of methyl 4- (3, 3-difluorocyclobutoxy) -5-methanesulfonyl-2-methylbenzoate in 5ml of DMF and stirred at RT for 24 h. The reaction mixture was washed with 125ml of 50% concentrated NaHCO₃The aqueous solution was diluted and extracted 3 times with 80ml of EE each time. Adding Na to the mixture₂SO₄Dried and the solvent removed under vacuum. Chromatography on silica gel eluting with EE/MeOH 5: 1 gave 175mg of colorless crystals, mp 273 deg.C (with decomposition).

Rf(EE/MeOH 5∶1)＝0.50 MS(ES⁺)：362

Example 2

N- [4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine

a)3, 3-difluoro-cyclobutylamine, hydrochloride

16.7g of 3, 3-difluoro-cyclobutanecarboxylic acid (J.org.chem.1987, 52, 1872) were dissolved in 180ml of CHCl₃In (1), 36ml of H is added₂SO₄(98%). The mixture was heated to 50 ℃ and 16g of NaN were added in portions over 45 minutes at this temperature₃. After stirring at 50 ℃ for 2 hours, the mixture was cooled to room temperature and finally poured onto 250g of ice. The extraction is carried out 3 times with 100ml of diethyl ether each time in order to recover 0.7g of unreacted 3, 3-difluoro-cyclobutanecarboxylic acid. Adjusting pH of the aqueous phase to 12-13 with NaOH solution, and adding CH₂Cl₂Extracting for 3 times with 100ml each time of CH₂Cl₂. The organic phase is washed with 100ml of water, then 130ml of 2N aqueous HCl are added and the volatile constituents are removed in vacuo. 15.3g of a colorless solid were obtainedMp 315 deg.C (decomposition).

b) N- (3, 3-difluoro-cyclobutyl) -methanesulfonamide

0.60g of 3, 3-difluoro-cyclobutylamine, hydrochloride are suspended in 40ml of CH₂Cl₂2.9ml triethylamine were added at RT. A clear solution was obtained. Then 1.0ml of methanesulfonyl chloride was slowly added dropwise at RT and the reaction mixture was left at this temperature for 16 hours. Then, the volatile constituents are removed under vacuum, and 200ml of EE and 100ml of saturated Na are added to the residue₂CO₃The aqueous solution was dispensed. The organic phase is then treated with saturated NaHSO₄Washing with 20ml of aqueous solution 2 times, then with saturated Na₂CO₃The aqueous solution was washed 2 times with 30mL portions of MgSO₄Dried and the solvent removed under vacuum. 700mg of a colorless resinous material were obtained.

Rf(EE)＝0.28 MS(DCI)：186

c)4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoic acid methyl ester

0.70g N- (3, 3-difluoro-cyclobutyl) -methanesulfonamide, 0.93g 4-fluoro-5-methanesulfonyl-2-methyl-benzoic acid methyl ester and 1.5ml N "-tert-butyl-N, N, N ', N' -tetramethyl-guanidine were dissolved in 10ml NMP (anhydrous) and stirred at 150 ℃ for 6 hours. The reaction mixture is cooled to room temperature, diluted with 200ml EE and initially saturated NaHSO₄Washing with 20ml of aqueous solution 3 times, then with saturated Na₂CO₃The aqueous solution was washed 3 times with 30ml each time. With MgSO₄Dried and the solvent removed under vacuum. Chromatography on silica gel eluting with DIP gave 220mg of a colourless foam.

Rf(DIP)＝0.31 MS(ES⁺)：334

d)4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoic acid

210mg of 4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoic acid methyl ester are dissolved in 10ml of dioxane and 0.47ml of2N NaOH in water. Stir at RT for 18 hours, then remove the solvent under vacuum. To the residue was added 10ml of water, then adjusted to pH 2 with aqueous HCl and extracted 3 times with 20ml each time of EE. With MgSO₄Dried and the solvent removed under vacuum. 196mg of amorphous solid are obtained.

Rf(EE)＝0.40 MS(ES^-)：318

e) N- [4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine

40mg of 4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoic acid was dissolved in 1ml of DMF (anhydrous), 26mg of CDI was added at RT and stirred at RT for 6 hours to give the intermediate imidate. Furthermore, 72mg of guanidine-hydrochloride and 70mg of KOtBu are stirred in 1ml of DMF (anhydrous) at RT for 30 minutes. The guanidine-base solution was then added to the imidazolide solution and left at RT for 18 hours. Then diluted with 50ml of water and the pH adjusted to 8 with dilute aqueous HCl. Extracting with EE for 3 times (10 ml each time) with MgSO₄Dried and the solvent removed under vacuum. 37mg of amorphous solid are obtained.

Rf(EE/MeOH 10∶1)＝0.12 MS(ES⁺)：360

NHE-1 inhibition was determined as follows:

FLIPR assay for determination of NHE-1 inhibitors by determining the recovery of pHi in transfected cell lines expressing human NHE-1

The assay was performed in a FLIPR (fluorescence imaging plate reader) using a black-walled 96-well microtiter plate with a transparent bottom. Transfected cell lines expressing various NHE subtypes were seeded the previous day at a density of-25000 cells/well (the parental cell line LAP-1 had no endogenous NHE activity as a result of mutagenesis and subsequent selection).

[ growth medium for transfected cells (Iscove + 10% fetal bovine serum) also contained G418 as a selection antibiotic to ensure the presence of the transfection sequence. ]

Actual measurement to removeGrowth medium and 100. mu.l loading buffer (5. mu.M in 20mM NH) was added to each well₄Cl, 115mM choline hydrochloride, 1mM MgCl₂、1mM CaCl₂5mM KCl, 20mM HEPES, BCECF-AM [2 ', 7' -bis (carboxyethyl) -5- (and-6) -carboxyfluorescein in 5mM glucose, acetoxymethyl ester](ii) a pH 7.4[ adjusted with KOH]) And starting. The cells were then incubated at 37 ℃ for 20 minutes. This incubation loads the cells with a fluorescent dye whose fluorescence intensity depends on pHi and NH which makes the cells slightly basic₄Cl。

[ ester form of non-fluorescent dye precursor BCECF-AM permeable membrane. The efficient dye BCECF which cannot penetrate the membrane is released by esterase in the cell. ]

After 20 min incubation, the cells were washed by washing in a cell washing machine (Tecan Columbus) with 400. mu.l each time of wash buffer (133.8mM choline hydrochloride, 4.7mM KCl, 1.25mM MgCl)₂、1.25mM CaCl₂、0.97mM K₂HPO₄、0.23mM KH₂PO₄5mM HEPES, 5mM glucose; pH 7.4[ adjusted with KOH]) Washing three times to remove NH₄Cl and free BCECF-AM. The residual volume remaining in the wells was 90. mu.l (possibly 50-125. mu.l). This washing step removes free BCECF-AM and due to the removal of external NH₄ ⁺Ions lead to intracellular acidification (-pHi6.3-6.4).

Due to intracellular NH₄ ⁺And NH₃And H⁺The balance between them being due to the removal of extracellular NH₄ ⁺And then NH₃Instantaneously passing through cell membrane to be destroyed, so that the washing process makes H⁺Remains intracellular, which is responsible for intracellular acidification. If maintained for a sufficient period of time, may eventually lead to cell death.

It is important in this respect that the wash buffer is sodium-free (< 1mM) because extracellular sodium ions can transiently restore pHi by cloned NHE isoform activity. It is also important that all buffers used (loading buffer, washing buffer, recovery buffer) do not contain any HCO₃ ^-Ion, because the presence of bicarbonate activates the intervening bicarbonate-dependent pHi regulatory system present in the parent LAP-1 cell line.

The microtiter plates containing the acidified cells were then transferred (no more than 20 minutes after acidification) to a FLIPR. In the FLIPR, the fluorochromes in the cells are excited with light of 488nm wavelength generated by an argon laser, and the measurement parameters (laser power, irradiation time and aperture of the CCD camera fitted in the FLIPR) are chosen so that the mean fluorescence signal per well is 30000 to 35000 relative fluorescence units.

The actual measurement in FLIPR starts with the CCD camera taking a picture every two seconds under software control. After 10 seconds, 90. mu.l recovery buffer (133.8mM NaCl, 4.7mM KCl, 1.25mM MgCl) was added by using a 96-well pipettor equipped in a FLIPR₂、1.25mM CaCl₂、0.97mM K₂HPO₄、0.23mM KH₂PO₄L0mM HEPES, 5mM glucose; pH 7.4[ adjusted with KOH]) Triggering intracellular pH recovery. Positive control wells (100% NHE activity) were those to which pure recovery buffer was added, while negative control wells (0% NHE activity) were to which wash buffer was added. Recovery buffer containing twice the concentration of the test substance was added to all other wells. The measurement in the FLIPR was stopped after 60 measurements (two minutes).

Raw data is input to the ActivityBase program. The program first calculates the NHE activity for each test substance concentration and therefrom calculates the IC of said substance₅₀The value is obtained. Since the pHi recovery process is not linear throughout the experiment, but decreases at the end because NHE activity decreases at higher pHi values, it is important to select the portion where the fluorescence increase of the positive control is linear for assay evaluation.

Examples	NHE1 inhibitory IC50[nM]
		1	5.9

Claims (18)

1. Fluorinated cycloalkyl-derived benzoylguanidines of formula I:

the meaning of which is:

x is oxygen or NH;

m is 1;

n is 0;

p is 0;

q is 1;

r is 1;

r1 is methyl;

r2 is hydrogen;

r3 is SO₂CH₃；

R4 is hydrogen;

and pharmacologically acceptable salts thereof.

2. A compound of formula I according to claim 1, selected from:

n- [4- (3, 3-difluoro-cyclobutoxy) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine, and

n- [4- (3, 3-difluoro-cyclobutylamino) -5-methanesulfonyl-2-methyl-benzoyl ] -guanidine,

and pharmacologically acceptable salts thereof.

3. The use of a compound of the formula I as claimed in any of claims 1 to 2 and/or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of acute or chronic injuries, disorders or indirect sequelae of organs and tissues which are caused by ischemic events or by reperfusion events; for the treatment or prophylaxis of cardiac arrhythmias, life threatening ventricular fibrillation of the heart, myocardial infarction, angina pectoris; for the treatment or prevention of ischemic conditions of the heart, of the peripheral and central nervous system, of stroke or of peripheral organs and tissues; for the treatment or prophylaxis of states of shock, diseases in which cell proliferation is of primary or secondary origin, diseases in which cell migration is of primary or secondary origin, prostatic hypertrophy or hyperplasia, atherosclerosis or abnormal lipid metabolism, hypertension, central nervous system disorders; for the treatment or prevention of non-insulin dependent diabetes mellitus or diabetes-induced late stage injury, thrombosis, endothelial dysfunction-induced conditions, intermittent claudication; for treating or preventing fibrotic disorders of the internal organs; for the treatment or prevention of heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, malaria and coccidiosis in poultry; for use in surgery; for preventing age-related tissue changes; for combating aging or prolonging life; can be used for treating and relieving cardiotoxic effects of thyrotoxicosis.

4. The use of claim 3, wherein the use in surgery is for storing and stocking grafts for surgical procedures.

5. The use of claim 3, wherein the hypertension is essential hypertension.

6. The use according to claim 3, wherein the central nervous system disorder is selected from the group consisting of disorders caused by central nervous system hyperexcitability, anxiety, depression or psychosis.

7. The use of claim 6, wherein the disorder caused by central nervous system hyperexcitability is epilepsy or centrally induced convulsions.

8. The use of claim 3, wherein the disease in which cell proliferation is of primary or secondary origin is cancer.

9. The use of claim 3, wherein the fibrotic condition of the viscera is selected from the group consisting of a liver fibrosis condition, a kidney fibrosis condition, a vascular fibrosis condition, and a cardiac fibrosis condition.

10. The use of claim 3, wherein the heart failure is congestive heart failure.

11. The use of claim 3, wherein the surgical procedure is an organ transplant.

12. Use of a compound of formula I according to any one of claims 1 to 2 and/or a pharmaceutically acceptable salt thereof in combination with a cardiotoxic and cytotoxic drug for the preparation of a medicament with reduced cardiotoxicity and cytotoxicity.

13. The use as claimed in claim 3, wherein the medicament is for the treatment or prevention of acute and chronic injuries, disorders or indirect sequelae of organs and limbs caused by ischemic events or by reperfusion events.

14. The use of claim 3, wherein the medicament is for treating life-threatening ventricular fibrillation of the heart.

15. The use of claim 3, wherein the medicament is for the treatment or prevention of a disease in which cell migration is of primary or secondary cause.

16. The use as claimed in claim 3, wherein the medicament is for the treatment or prevention of fibrotic heart disease, heart failure.

17. The use of claim 16, wherein the heart failure is congestive heart failure.

18. A medicament for humans and/or animals, comprising an effective amount of at least one compound of the formula I according to any one of claims 1 to 2 and/or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers and additives.