RS52202B - PROCEDURE FOR OBTAINING SUBSTITUTED Aryloxy-2,3-EPOXIPROPANE - Google Patents

Abstract

A process for the preparation of substituted aryloxy-2,3-epoxypropane of the general formula (1) wherein Ar is naphthyl, substituted nautyl. phenylalkyl, wherein the compound of general formula (1) is obtained by reacting the corresponding nucleophilic anion obtained from an arylhydroxy compound in the presence of an aqueous solution of sodium or potassium hydroxide at elevated temperature, with epichlorohydrin under conditions of semi-continuous or continuous reaction in a semi-continuous or continuous reaction. 8 patent claims.

Description

SUPSHTUISANIBENZOYL-GWAMDINI, PROCEDURE

FOR THEIR PRODUCTION, THEIR APPLICATION

AS A MEDICINE AND AS A DIAGNOSTIC REAGENT I

MEDICINE CONTAINING THESE COMPOUNDS

Substituted benzofl-guanclines, procedure for their production,

their reception as medicines and as diagnostic reagents and medicines containing compounds

The invention relates to benzoyl-guanidines of Formula I

in which they indicate:

Rl hydrogen, F, CI, Br, J, NO* CN, -X.-(CHi)^-(CT2), -CF3, R5-SOm-, R6-CO-,

R6R7N-CO- or R6R7N-SO2-;

X is oxygen, -S- or NR14;

m zero, 1 or 2;

o zero or 1;

p zero, 1 or 2;

q zero, 1, 2, 3, 4, 5 or 6;

R5iR6

independently of each other (C 1 -C 4 -alpharyl, (C 1 -C 4 -alkenyl, -C 1 -H 2 n -R 8 orCF 3 );

n zero, 1, 2, 3 or 4;

R8 (C3-C7>cycloalkyl or phenyl,

which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR9R10;

R9iR10

H and H are (C1-C4)-alkyl;

if

R6 is hydrogen;

R7 is hydrogen or (C1-C4-aM;

or

R6iR7

together 4 or 5 methylene groups, of which one CH2 group can be

substituted with oxygen, S, NH, N-CH3 or N-benzyl; R 2 -Y-p-(C 6 H 4 )-R 1 , -V-m-CC 6 H 4 -R 1 or -Y-o-CC 6 H 4 >R 1 ;

Rl 1 (C^-C^-heteroaryl, which is connected through C and H N and which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, CH3) methoxy, hydroxy, amino, methymino, dimethylamino and benzyl,

Y is oxygen, -S- or NR12;

R12 H iH (CrC4>afldU

R3 is defined the same as R1;

or

R3 (C1-C1aD1-X-R13;

X is oxygen, -S- or NR14;

R14

HiliCd-C,)^;

R13

H, (C-CO-alkyl, (QrC8>cycloalkyl and H -CfcHft-R15; b zero, 1,2, 3 or 4;

R15

feral, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR9R10;

R9iR10

Hffi(Q-GO-alkfl;

iH

R13 and R14

together 4 or 5 methylene groups, of which one CH2- group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl;

R4 F, Cl, Br, J or (Ci-GO-aM;

as well as their pharmaceutically acceptable salts.

Priority is given to compounds of Formula I, in which they denote:

Rl hydrogen, F, Ci CN, CF3, R5-SOm-, R6-CO-, R6R7N-CO- or R6R7N-SCV,

m zero, 1 or 2;

R5iR6

independent of each other (C1-C2-aDjl, (Oj-C2-alkenyl,

-CnHn-RS or CF3,

n zero or 1;

R8 (C3-Qs>cyclo]alkyl and H phenyl,

which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR9R10;

R9iR10

H and H methyl;

iH

R6 is hydrogen;

R7 is hydrogen or methyl;

R2 -Y-p-(C*H4)-Rl 1, -V-m-CCcFiO-Rl 1 or -Y-o<QH4>Rl 1;

R1 1 (C1-C4-heteroaryl, which is connected through C and HN and which is unsubstituted and H is substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, methamino, dimethicamino and benzyl;

Y is oxygen, -S- or NR12;

R12 HCI-C2-A1;

R3 is hydrogen, methyl, CN, CF3, F or Cl;

R4 is F, Cl or C1-C4alkyl;

as well as their pharmaceutically acceptable salts.

Compounds of Formula I, in which they mean:

R1 is hydrogen, F, Cl, CN, CF3 or R5-SOm-;

m zero, 1 or 2;

R5

methyl iH CF3;

R2 -Y-p-(C6H4)-R1 1, -Y-m<C6H4)-R1 1 or -Y-o<C6H4>R1 1;

R 1 1 (C 1 -C 9 )-heteroaryl, which is linked through C and H N and is unsubstituted and H is substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, dimethylamino and benzyl;

Y oxygen;

R3 hydrogen, methyl, CN, CF3, F and H Cl;

R4 d-Cralldl;

likewise their pharmaceutically acceptable juice

Compounds of Formula I, in which they mean:

Rl hydrogen, F, Cl, CN, CF3 fli R5-SO2-;

R5 is methyl and HCF;

R2 ^-p-CCsfLO-Rl 1, ^-m-CCsaO-Rl 1 or -Y-o<C(SH4>Rl 1;

R 1 1 (C 1 -C 5 )-heteroary], which is linked through C and N and is unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CF 3 , CH 3 , methoxy, dimethylamino and benzyl;

Y oxygen;

R3 hydrogen;

R4 Ct-Craflol;

as well as their pharmaceutically acceptable salts

Compounds of Formula I, in which they mean:

R1 is CF3;

R2 -Y-p-(CfiHO-Rn, -Y-m-(C6H4>R11 or -Y-o-(C6H4>R11);

R1 1 imidazolyl, or triazolyl, which is sometimes unsubstituted or substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, dimethylamino and benzyl;

Y oxygen;

R3 hydrogen;

R4 methyl,

as well as their pharmaceutically acceptable salts

The indicated allelic residues can be linear as well as branched.

By (Ci-Q))-heteroaryl is meant especially residues, which are derived from phenyl or naphthyl, in which one or more CH-groups are replaced by N and/or in which at least two adjacent CH-groups (with the formation of a five-membered aromatic ring) are replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of the bicyclic residue (as in indolizinyl) can also be N-atoms.

As heteroaryl, especially furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indoEl, indazoles, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl; especially furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyridyl, indoCl, quinolyl and isoquinolyl

The invention further relates to a process for the production of compound I, which is characterized in that the compound of Formula II wherein R1 to R4 have the above meanings and L stands for a volatile group that can be easily nucleophilically substituted,

treated with guanidine.

The activated acid derivative of Formula n, where L denotes an alkoxy group, primarily a methoxy group, a phenoxy group, a phenylthio-, methylthio-, 2-pyridylthio group, a nitrogen heterocycle, primarily 1-imidazolyl, is obtained primarily in its own way on the basis of carboxylic acid chloride (Formula II, L = Cl), which in turn can also be produced on the basis of carboxylic acids (Formula n, L = OH ) for example works with thionyl chloride.

In addition to carboxylic acid chloride of Formula II (L = Cl), other activated acid derivatives of Formula II can also be produced in a specific known way directly from basic derivatives of benzoic acid (Formula II, L = OH), such as methyl ester of Formula Et with L = OCH3 by treatment with gaseous HC1 in methanol, imidazoles of Formula II through treatment with carboryl-diimidazole [L = 1-imidazoles, Staab, Angew. Chem. bit. Ed. Engl 1. 351 - 367 (1962)], mixed anhydrides of H with Cl-COOCiHyli tosyl chloride in the presence of triethylamine in some inert solvent, as well as activation of benzoic acids with dexmohexylcarbodiiride (DDC) and U with O-[(cyano(ethoxyfluoroboryl)ra ethylene)amino]-1, 1,3,3-tetramethyluronium -terafluoroborate

("TOTU") [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of methods contemplated for the production of activated carboxylic acid derivatives of Formula II are set forth in the reference data in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), page 350.

The conversion of an activated carboxylic acid derivative of Formula II with guanidine takes place in a known manner in a protic or aprotic polar aH inert organic solvent. Methanol, isopropanol or THF at a temperature of 20°C up to the boiling point of these solvents performed well in the conversion of benzoic acid methyl ester (n, L = OMe) with guanidine. With the greatest number of conversions of compound II with guanidine, which does not contain salts, it is advantageous to do it in aprotic inert solvents such as TMF, dimethoxyethane, dioxane.

But water can also be used as a solvent when a base such as NaOH is used in the reaction of compound II with guanidine.

When L = Cl, it is convenient to work with the addition of some substance that binds the acid, for example in the form of excess guanidine in order to bind hydrochloric acid.

Some of the benzoic acid derivatives that are based on Formula II are known and described in the literature. Unknown compounds of Formula II can be produced by methods known in the literature.

The introduction of some substituents in the 2-, 3-, 4- and 5-positions is achieved by the application of methods known in the literature that use a palladium mediator for cross-coupling arUhalides, i.e., anltrifluoromethanesulfonates with, for example, organostanns, organoboronic acid, or organoboranes, or with organocopper, i.e., zinc compounds.

Benzoyl-guankyins I are generally weak bases and can bind acids with the formation of salts. Acid addition salts include salts of all pharmacologically acceptable acids, for example, halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates metflsulfonates, p-toluenesulfonates.

Compounds I are substituted acyl-guanidines

Compounds similar to compounds I are known from European patent application 640 593 (HOE 93/F 220). However, these compounds always contain different substituents in the R4 position (ortho-position); the substituents defined in this invention are neither mentioned nor represented therein

Compared to the known compounds, the compounds defined in this invention are characterized by an exceptionally high activity in inhibiting Na<+>/H<+->exchange, as well as improved solubility in water.

These compounds, just like the known ones, do not have unwanted and harmful salidiuretic properties, however, they show very good antiarrhythmic properties, which, for example, are important for the treatment of diseases that occur when there is a lack of oxygen. Due to their pharmacological properties as an antiarrhythmic drug with a cardio-protective component, these compounds are extremely suitable for the prevention of heart attacks and the treatment of heart attacks, as well as for the treatment of angina pectoris, while they also preventively inhibit or greatly reduce the pathophysiological processes in the occurrence of diseases that are induced by ischemia, especially in the occurrence of ischemia-induced cardiac arrhythmia. Due to their protective action in relation to pathological hypoxic and ischemic conditions, the compounds of Formula I, which are defined by this invention, by inhibiting the cellular Na<+>/H<+-> exchange, can be used as a medicine for the treatment of all acute or chronic diseases caused by ischemia or primary or secondary diseases caused by it. of the donor before and during the intake, for the protection of the taken organ, for example, when processing it with or storing it in a physiological solution, as well as when transferring it to the recipient's organism. The compounds are also valuable drugs that have a protective effect when performing angioplasty procedures, for example, on the heart as well as on peripheral blood vessels. Corresponding to their protective action against ischemic-induced diseases, these compounds are suitable as a drug for the treatment of ischemia of the nervous system, especially of the central nervous system, while they are suitable, for example, for the treatment of stroke or brain edema. Furthermore, the compounds of Formula I, which are defined by this invention, are also suitable for the treatment of various shocks, for example due to allergic, cardiogenic, hypovolemic and bacterial shock.

Furthermore, the compounds of Formula I, which are defined by this invention, are characterized by a strong inhibitory effect on cell proliferation, for example on cell proliferation of fibroblasts and proliferation of smooth muscle cells of blood vessels. As a result, it comes into consideration that the compounds of Formula I are used as valuable therapeutic agents for diseases in which cell proliferation is the primary or secondary cause and can therefore be used as antiatherosclerotics, agents against diabetic complications, cancerous diseases, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis, hypertrophy and hyperplasia of organs, especially in prostate hyperplasia or prostate hypertrophy.

The compounds, which are defined by this invention, are effective inhibitors of the cellular rathrium protein antiport (NaVH* exchanger), which in many diseases

( essential hypertension, atherosclerosis, diabetes, etc. ) is increased in such cells that are easily accessible for measurements, for example in erythrocytes, platelets and H leukocytes. The compounds defined by this invention are therefore suitable to be used as an extraordinary and simple scientific tool, for example in their application as a diagnostic reagent for determining and distinguishing certain types of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. Furthermore, the compounds of Formula I are suitable for preventive therapy in order to prevent the genesis of high blood pressure, for example to prevent essential hypertension.

In addition, it was found that the compounds of Formula I show a beneficial effect on lipoproteins in the blood. It is generally known that for the occurrence of arteriosclerotic changes in blood vessels, especially coronary heart disease, an important risk factor is excessively high levels of fat in the blood, the so-called hyperlipoproteinemia. For the prevention and regression of atherosclerotic changes, the lowering of increased levels of Hpoprotein in the blood is therefore of extraordinary importance. In addition to the reduction of total cholesterol in the blood, there is also a significant reduction in the share of specific atherogenic fractions of Hpid of this total cholesterol, especially low density Hpoprotein (LDL) and very low density Hpoprotein (VLDL), since these fractions of Hpid represent an atherogenic risk factor. In contrast, high density lipoproteins are attributed to have a protective function against coronary heart disease. Accordingly, blood lipid-lowering agents should be able not only to reduce total cholesterol, but especially VLDL and LDL cholesterol fractions in the blood. It has now been found that the compounds of Formula I exhibit valuable therapeutically useful properties in terms of their effect on blood lipid levels. Thus, they lower significantly increased concentrations of LDL and VLDL in the blood, such as are observed, for example, with increased dietary intake of some food rich in cholesterol and lipids or with pathological changes in the metabolism of substances, for example, due to genetically determined hyperlipidemia. They can therefore be used for the purpose of prophylaxis and regression of atherosclerotic changes, whereby they remove one causal risk factor. This includes not only primary hyperlipidemias, but also certain secondary hyperlipidemias, such as, for example, occur in diabetes. Furthermore, the compounds of Formula I lead to a clear reduction of infarcts induced by abnormalities in metabolism and in particular to a significant reduction of the induced infarct size and degree of severity. Furthermore, Formula I compounds lead to effective protection against endothelial damage caused by metabolic anomalies. Because they protect blood vessels from endothelial dysfunction syndrome, Formula I compounds are valuable medications for the prevention and treatment of coronary spasms, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiomyopathy, and thrombotic diseases.

The mentioned compounds are therefore primarily used for the production of a medication for the treatment of hypercholesterolemia; for the production of a medication for the prevention and treatment of atherogenesis; for the production of a drug for the prevention and treatment of diseases that occur as a result of increased cholesterol levels, for the production of a drug for the prevention and treatment of diseases that occur as a result of endothelial dysfunction, for the production of a drug for the prevention and treatment of hypertension induced by atherosclerosis, for the production of a drug for the prevention and treatment of thrombosis that occur as a result of atherosclerosis, for the production of a drug for the prevention and treatment of ischemic damage resulting from hyperhocsterinemia and endothelial dysfunction, and post-ischemic reperfusion diseases, for the production of a medicine for the prevention and treatment of cardiac hypertrophies and cardiomyopathies that occurred as a result of hypercholesterolemia and endothelial dysfunction, for the production of a medicine for the prevention and treatment of spasms of coronary blood vessels and myocardial infarction that occur as a result of hypercholesterolemia and endothelial dysfunction, for the production of a medicine for the treatment of the aforementioned blood diseases in combination with substances for lowering blood pressure, primarily with Angiotensin Converting Enzvme (ACE)- inhibitors and angiotensin-receptor antagonists. The combination of an NHE-inhibitor of Formula I with a substance for lowering blood fat levels, primarily with an HMG-CoA-reductase inhibitor (for example, tovastatin or prevastatin), whereby the latter contributes to the hypolipidemic effect and thus increases the hypolipidemic properties of the NHE-inhibitor of Formula L, proves to be a favorable combination with an enhanced effect and reduced intake of the active substance.

Administration of a sodium proton exchange inhibitor of Formula I as a new therapeutic agent for lowering elevated blood lipids is protected, as is the combination of a sodium proton exchange inhibitor with blood pressure lowering agents and/or with agents having a hypoHpidemic effect.

Medicines, which contain compound J, can be administered orally, parenterally, intravenously, rectabio or by inhalation, whereby the optimal method of administration always depends on the phenotype of the disease. Compounds I can be used alone or together with galenic auxiliary substances, both in veterinary medicine and in human medicine.

Which auxiliaries are considered to be used for the desired drug formulation should be decided by the expert on the basis of his previously acquired professional knowledge. In addition to solvents, gelling agents, bases for suppositories, auxiliaries for tablets and other active substance carriers, antioxidants, dispersing agents, emulsifiers, anti-foaming agents, flavor correctors, preservatives, solubilizing agents or colors can be used, for example.

For the purpose of oral use, active compounds together with suitable additives, such as active substance carriers, stabilizers or inert diluents, are mixed and prepared by usual methods into forms suitable for administration, such as tablets, dragees, capsules, aqueous, alcoholic or oily solutions. Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch, can be used as an inert carrier. starch. In doing so, the preparation can be granulated dry or wet. Suitable oil carriers or solvents are vegetable or animal oils, for example sunflower oil or fish oil.

For subcutaneous or intravenous administration, a solution, suspension or emulsion of the active compounds with substances, which are usual for this, such as solvent agents, emulsifiers or other auxiliary agents, is prepared as desired. As solvents they come into consideration, for example. water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerin, in addition to sugar solutions such as glucose solution or mannitol solution, but also mixtures of various mentioned solvents.

As pharmaceutical formulations for administration in the form of aerosols or sprays, for example, solutions, suspensions or emulsions of the active substance of Formula I in a solvent, whose use in pharmacy does not cause any doubt, such as especially ethanol or water, or a mixture of such solvents, are suitable.

If necessary, the formulation may also contain other pharmaceutical aids such as surfactants, emulsifiers, stabilizers and some propellant gas. Such a preparation contains the active substance usually in a concentration of about 0.1 to 10, especially from about 0.3 to 3 wt. %.

The dosage of the active substance of Formula I, which is administered as a medicine, and the frequency of administration depend on the strength of action and the duration of action of the applied compound; in addition, they also depend on the type and severity of the disease that needs to be treated, as well as on the gender, age, weight and individual reactivity of the patient that needs to be treated.

On average, the daily dose of Formula I compounds in a patient weighing about 75 kg is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg, especially at least 0.1 mg/kg to a maximum of 10 mg/kg, preferably at most up to 1 mg/kg of body weight. In acute sudden outbreaks of the disease, such as immediately after a heart attack, even higher and above all more frequent dosages may be required, for example up to 4 single doses per day. Especially with intravenous administration, as in a patient with a heart attack in intensive care, doses of up to 200 mg per day may be required.

List of abbreviations

CDI carbonyldiimidazole

MeOh m ethanol

DMF N,N-dimethylformamide

RT room temperature

EE ethyl acetate (EtOAc)

eq equivalent

ES electrospray ionization

Experimental part:

Example 1

4-[(Imidazol-1-yl)-phenoxy]-2-m is a colorless solid, M<*>+ H (ES) = 404.

Synthesis method:

a) 4-[(toidazoM-ity-phenoxy]-2-methyl-5^ benzoic acid via the reaction of 4-fluoro-2-methyl-3-trifluoromethyl-methyl ester of benzoic acid with 1 eq of 4-(imidazol-1-yl)-phenol in the presence of 4 cq of potassium carbonate in DMF at a temperature of 120°C for 16 h. After evaporation of the solvent, the treatment is carried out with plenty of water and with EE shaking. after drying the solvent was evaporated, colorless oil, M<*>(ES) = 376. b) 4-[(imidazol-1-yl)-phenoxy]-2-methU-5-trifluoromethyl-benzoic acid by base hydrolysis with an excess of 2N NaOHaq in MeOH at room temperature for 2 h. After acidification with 2N HCl followed by extraction with EE, after drying the solvent and evaporation, a colorless oil is isolated, M<*>(ES) = 362. c) 4-[(7midazoM-iI)-phenoxy]-2-methylL5-r^ via activation with 2 eq CDI in DMF followed by reaction with 6 eq guanidine hydrochloride in the presence of 7 eq diisopropylethylamine at room temperature for 3 h. After the removal of the solvent, preparative HPLC (CH3CN/H20) follows, and finally the formation of salts with ethereal hydrogen chloride.

Example 2: 4-(Triazol-1-i])-phenoxy-2-methyl-3-trifluoromethu-beryse colorless solid, M<*>+ H (ES) = 405.

Synthesis method:

a) 4-[(Triazol-1-yl)-phenoxy]-2-ethyl-5-trifluoromethyl^ acids analogous to 1 a) by reaction with 1 eq of 4-(triazol-1-yl)-phenol,

colorless oil, M<*>(ES) = 377.

b) 4-[(TriazoM-yl)-phenoxy]-2-methyl-5-tri^ acid analogous to 1 b),

colorless oil, M<*>(ES) = 363.

c) 4-[(Triazol-1-fl)-phenoxy]-2-methyl-5-trifluoroacetate analogous to 1 c), but salt formation using trifluoroacetic acid.

Claims (19)

1. Benzoyl-guanidines of Formula I indicated by the fact that they denote: Rl hydrogen, F, Cl, Br, J, NOj, CN, - X0-( CHi%-( CF1\- CF3, R5-SOm-, R6-CO-, R6R7N-CO- or R6R7N-SO2-; X oxygen, -S-fli NR14; m zero, 1 or 2; o zero or 1; p zero, 1 or 2; q zero, 1, 2, 3, 4, 5 or 6; R5 and R6 independently of each other (C1-Q)-alkf1, (C1-Q)-alkenyl, -C1-R5 or CF3; n zero, 1, 2, 3 fli 4; R8 (CrC^cfldoalkfl fli fenfl, which is not substituted or is substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR9R10; R9 and R10 H or (d-O-alkyl; iH R6 is hydrogen; R7 is hydrogen and H (C1-C4)-alkyl; iH R6 and R7 together 4 and H 5 methylene groups, of which one CH 2 group may be replaced by oxygen, S, NH, N-CH 3 and H N-benzyl; R2 -Y-p-(C6H4)-R1 1, -Y-m-(C6H4).R1 1 and H -Y-o<C6H4>R1 1; R 1 is (C 1 -C 4 )-heteroaryl, which is linked through C or N and which is not substituted iH is substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy hydroxy amino, metflamamino, dimethylamino and benzyl; Y oxygen, -S- fliNR12; R 12 H w (C 1-6 B 1 ; R 3 defined in the same way as R 1 ; and H R 3 (C 1 -C 5 -alkyl fli -X-R 13 ; X oxygen, -S-fli NR14; R14 C 1 -C 1 -C 1 -alkyl; R13 H, (C 1 -C 4 alkfl, (CrC 8 J -cycloalkfl iH -ChHa-RlS; b zero, 1,2, 3 fli 4; R15 phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR9R10; R9 and R10 HiH(Ci-C4>alkfl; iH R13 and R14 together 4 or 5 methylene groups, of which one CH2- group can be replaced by ldsionic, S, NH, N-CH3 or N-benzyl; R 4 F, Cl, Br, J and H C 1 -Gralkyl, as well as their pharmaceutically acceptable soh. 2. Compounds of Formula L defined according to Claim 1, characterized by the fact that in the formula Rl denotes hydrogen, F, Cl, CN, CF3, R5-SOm-, R6-CO-, R6R7N-CO- and H R6R7N-SO2-; m zero, 1 or 2; R5 and R6 independently of each other (C 1 -C 4 -alkyl, (C 3 -C 4 )-alkenyl, -C 1 -C 4 -RS and HCF 3 ; n nulliHl, R8 (C3-C6>cycloalkyl and H phenyl, unsubstituted is substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF 3 , methyl, methoxy and NR 9 R 10 ; R9 and R10 H and H methyl; iH R6 is hydrogen; R7 is hydrogen fl m ethyl; R2 -V-p-CCTO-Rl 1, -Y-m<C6H4)-Rl 1 fli -V-o-CCsUJ-Rl 1; Rl 1 (Ci-Cs^-heteroaryl, which is connected via C and H N and which is not substituted fli is substituted with 1 to 3 substituents selected from groups consisting of F, Cl, CF3, CH3, methoxy, hydroxy, amino, metflamamino, dimethylamino and benzyl, Y oxygen, -S-fli NR12; R12 H and H (CrC4>alkyl; R3 hydrogen, methyl, CN, CF3) F fli Cl; R4 F, ClfliCi-Cralkfl; as well as their pharmaceutically acceptable salts. 3. Compounds of Formula I, defined according to Claim 1 or 2, marked by the following meaning in them: R1 is hydrogen, F, Cl CN, CF3 or R5-SOB-; m zero, 1 or 2; R5 methyl or CF3; R2 -Y-p-(C6H4)-R11, -V-nKC3J-R11 or -Y-o-(C14)-R11; R1 is 1 (C1-C9)-heteroaryl which is C or N linked and which is not substituted or is substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, dimethylamino and benzyl, Y oxygen; R3 is hydrogen, methyl, CN, CF3, F or Cl; R4 (C1-C4>alkyl; as well as their pharmaceutically acceptable salts. 4. Compounds of Formula I defined according to Claims 1 or 2, indicated by the fact that in the formula R1 means hydrogen, F, Cl, CN, CF3 or R5-SO2-; R5 methyl and H CF; R2 -Y-p-(C<H4)-Rl 1, -Y-m<C6H4)-Rl 1 and H -Y-o-(C6H4>Rl 1; Rl 1 (Ci-Ci)-heteroary], which is connected through C and H N and which substituted iH is substituted with 1 to 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, dimethylamino and benzyl, Y oxygen; R3 is hydrogen; R 4 (C 1 -C 4 >alkyl; as well as their pharmaceutically acceptable soH. 5. Compounds of Formula L defined according to one or more Claims 1 to 3, indicated by the following meaning in the formula: R1 CF3; R2 -Y-p-(C6H4)-Rl 1, -Y-m-(C^rLO-Rl 1 or -Y-o-(C6H4>Rl 1); R1 1 is imidazolyl or triazolyl, which is sometimes unsubstituted or is substituted with 1 to 2 substituents selected from the group consisting of F, Cl CF 3 , CH 3 , methoxy, dimethylamino and benzyl; Y oxygen; R3 is hydrogen; R 4 is methyl, as well as pharmaceutically acceptable salts thereof. 6. A method for the production of a compound of Formula L characterized by the fact that the compound of Formula II wherein R 1 and R 4 have the meanings indicated and L stands for a volatile group which can be readily nucleophilically substituted, converts with guanadine. 7. Application of a compound L which is defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment or prophylaxis of diseases caused by ischemic conditions. 8. Methods for the treatment and prophylaxis of diseases caused by ischemic conditions, indicated by the fact that an effective amount of a compound L defined according to Claim 1 is mixed with common additives and prepared in forms suitable for drug administration. 9. Application of a compound L defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment or prophylaxis of heart attacks and arrhythmias. 10. Application of a compound I, defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment or prophylaxis of angina pectoris. 11. Application of a compound I, which is defined according to Claim 1, for the production of a medication, indicated by the fact that it serves for the treatment or prophylaxis of ischemic conditions of the heart, 12. Application of a compound I, defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 13. Application of a compound I, defined according to Claim 1, for production </> medication, indicated by the fact that it serves for the treatment and prophylaxis of ischemic conditions of peripheral organs and extremities. 14. Application of a compound I, defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment of shock conditions. 15. Application of a compound I, defined according to Claim 1, for the production of a medication, indicated by the fact that it is intended for use in surgical operations and organ transplantation. 16. Application of some compound I, defined according to Claim 1, for the production of medication, indicated by the fact that it serves for preservation and storage of transplants for surgical measures. 17. Application of a compound I, defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment of diseases in which cell proliferation is the primary or secondary cause 18. Application of a compound I, defined according to Claim 1, for the production of a medicament, indicated by the fact that it serves for the treatment and prophylaxis of metabolic disorders. 19. Medicines, indicated by the fact that they contain an effective amount of a compound I, which is defined according to one or more of Claims 1 to 4.