SK66497A3 - Bis-ortho-substituted benzoylguanidines, manufacturing process thereof, their us as a drug or diagnostic agent, as well as drug containing the same - Google Patents

Abstract

Bis-ortho-substituted benzoyl-guanidines (I) and their salts are new: R1-R3 = R10-SOa-; R14R15N-SO2-; SR21; OR22; NR23R24; CR25R26R27; H; F; Cl; Br; I; CN; -(Xa)dg-CdaH2da+1; -(Xb)dh-(CH2)db-CdeF2de+1; 3-8C alkenyl; -CdfH2dfR30; NR40R41; -(Xe)-(CH2)ebR45; -CHR52R53; or -C(OH)R55R56; R4, R5 = 1-4C alkyl; 1-4C alkoxy; OH; F; Cl; Br; I; CN; or -On-(CH2)o-(CF2)p-CF3; a = 0-2; da = 0-8; db, df = 0-4; de = 0-7; dg, dh = 0 or 1; eb = 0-4; n = 0 or 1; o, p = 0-2; R10, R14, R15 = 1-8C alkyl; 1-8C perfluoroalkyl; 3-6C alkenyl; or -CabH2ab-R16; or R14 and R15 are both H; or R14+R15 = tetra- or pentamethylene with 1 CH2 optionally replaced by O, S or NQ; Q = H; Me or benzyl; ab = 0-4; R16 = 3-7C cycloalkyl or Ph optionally mono-, di- or trisubstituted by F, Cl, CF3, Me, OMe or NR17R18; R17, R18 = H; CF3; or 1-4C alkyl; R21-R23 and R25 = -CbH2b-(1-9C)-heteroaryl optionally mono-, di- or trisubstituted by F, Cl, CF3, Me, OMe, OH, NH2, NHMe or NMe2; b = 0-2; R24, R26, R27 = H; 1-4C alkyl; or 1-4C perfluoroalkyl; Xa = O; S; or R33; Xb = O; S; or NR34; R33, R34 = H; 1-4C alkyl; or 1-4C perfluoroalkyl; R30 = 3-8C cycloalkyl; or Ph, biphenylyl or naphthyl optionally mono-, di- or trisubstituted by F, Cl, CF3, Me, OMe or NR31R32; R31, R32 = H; 1-4C alkyl; or 1-4C perfluoroalkyl; R40, R41 = H; 1-8C alkyl; 1-8C perfluoroalkyl; or (CH2)e-R42; or R40+R41 = tetra- or pentamethylene with 1 CH2 optionally replaced by O, S or NQ; e = 0-4; R42 = 3-7C cycloalkyl or Ph optionally mono-, di- or trisubstituted by F, Cl, CF3, Me, OMe or NR43R44; R43, R44 = H; CF3; or 1-4C alkyl; Xe = O; S; or NR47; R47 = H; 1-4C alkyl; or 1-4C perfluoroalkyl; R45 = 3-7C cycloalkyl or Ph optionally mono-, di- or trisubstituted by F, Cl, CF3, Me, OMe, NR50R51 or -(Xfa)-(CH2)ed-(Xfb)R46; Xfa = CH2; O; S; or NR48; Xfb = O; S; or NR49; R46 and R48-R51 = H; 1-4C alkyl; or 1-4C perfluoroalkyl; ed = 1-4; R52 = -(CH2)g-(CHOH)h-(CH)i-(CHOH)k-R54 or -(CH2)g-O-(CH2-CH2O)h-R54; R53 = H or 1-4C alkyl; R54 = H or Me; g, h, i = 0-4; k = 1-4; R55 = H; 1-4C alkyl; or CH2OH; R56 = H or 1-4C alkyl; or R55+R56 = 3-6C cycloalkyl.

Description

Bis-ortho-substituted benzoylguanidines, processes for their preparation, their use as medicaments or diagnostics, and medicaments containing them

Technical field

The present invention relates to bis-ortho-substituted benzoylguanidines, a process for their preparation, their use as a medicament or a diagnosis, as well as a medicament containing them. Said bis-ortho-substituted benzoylguanidines, characterized by the general formula I below, are novel compounds from the group of substituted acylguanidines, characterized by their extremely high potency in inhibiting Na * / H * exchange, very good antiarrhythmic properties, accompanied by a cardioprotective component and moreover, a favorable effect on serum lipoproteins and also sufficient water solubility.

BACKGROUND OF THE INVENTION

Compounds which are similar to the compounds of the formula I according to the invention are known, for example, from EP-OS 628 543 (HOE 93 / F 154; New Zealand Patent No. 260 681). Although they are also substituted in both ortho-positions, they always have acyl or acylamino groups in the 3-position, which do not occur in the compounds according to the invention.

EP-OS 690 048 (HOE 94 / F 182; New Zealand Patent No. 272 449) also discloses compounds substituted in both ortho positions, but each substituent is ortho-amino.

EP-OS 704 431 (South African Patent No. 95 07)

161) discloses compounds with one ortho-substitution, but not with a substitution at both ortho-positions.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides bis-ortho-substituted benzoylguanidines of formula I

(I) in which:

R ^1, R ² and R ^3, independently of one another are R ^xo _and -SO - or R-ris n -SO -;

and zero, 1 or 2;

R ^xo , R ¹⁴ and R ^xs , independently, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, an alkenyl group having 3, 4, 5 or 6 carbon atoms or -CH-R ^X6 ;

^r ato 2 a to b is zero, 1, 2, 3 or 4;

R ^{xe is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group or NR ^{x in} R ^xe ;

R R ^{X X 7} and independently of one another, hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ⁴ and R ¹⁵ together are 4 or 5 methylene groups, of which one _CH2 group ~ can be replaced by oxygen, S, NH, metyliminoskupinou or N-benzyl;

or

R ( ¹⁴⁾ and R ( ^{15) are} hydrogen;

or

R ^1, R ² and R ^3, independently of one another, SR ^2X, -OR ^22, -NR ²³ R ²⁴ or -CR ^{2 S} R ²⁶ R ^27;

R ²¹ , R ²² , R ²³ and R ^2S , independently of one another, -C 1 H 4 -heteroaryl radical having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group;

b is zero, 1 or 2;

R ( ²⁴⁾ , R ( ²⁶⁾ and R ( ²⁷ ) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

or

R ^1, R ² and R ^3, independently of one another are H, F, Cl, Br, I, nitrile, grouping

- (Xa) -CH, - (Xb) - (CH) -CF. alkenyl having 3, 4, 5, 6, 7 or 8 carbon atoms or -CHR ³ °;

^c df 2 3 31 (Xa) an oxygen atom, a sulfur atom or an NR ³³ group;

R ( ³³⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2 or 4 carbon atoms;

dg is zero or 1;

(Xb) an oxygen atom, a sulfur atom, or an NR ³⁴ group;

R ( ³⁴⁾ is hydrogen, alkyl having 1, 2, 3, or carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

dh is zero or 1;

will give zero, 1, 2 3, 4, 5, 6, 7 or 8; db zero 1 2 3 or 4; de zero 1 2 3, 4, 5, 6 or 7; df zero I 2 3 or 4;

R ^{3 is} cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, a phenyl radical, a diphenylyl radical or a naphthyl radical, wherein the aromatic radicals phenyl, diphenylyl or naphthyl are unsubstituted or substituted by 1 to 3 substituents selected a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ³¹ R ^{32 group} ;

R ( ³¹⁾ and R ( ^{32) are} hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

or

R ^1, R ² and R ^3, independently of one another, NR ^{4 O} or R ^4X are - (Xe) - (CH) R ^{4 S;}

R ⁴ ° and R ^{4 ' L} , independently of one another, a hydrogen atom, an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a perfluoroalkyl group with 1, 2, 3, 4, 5, 6, 7 or C 8 or (CH ₂ ) _e -R ⁴² ;

e is zero, 1, 2, 3 or 4;

R ^{42 is} cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ ;

R ( ⁴³⁾ and R ( ⁴⁴⁾ , independently of one another, are hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ⁴ ° and R ^4X together, 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an imino group, an N-methyl group or an N-benzyl group;

(Xe) oxygen, sulfur or NR ⁴⁷ ;

R ( ⁴⁷⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2,3 or 4 carbon atoms;

or p ⁴⁵ or

R ^1, R ²

R ^is zero, 1, 2, 3 or 4;

cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group, group NR ^SO R ⁵¹ and - (Xfa) - (CH) - (Xfb) R ^4e ;

Od.

Xfa methylene, O, S or NR ^{4 S;}

Xfb is oxygen, sulfur or NR ⁴³ ;

R ( ⁴⁾ , R ( ⁴³⁾ , R ( ⁵ ) and R ( ⁵¹ ) independently of one another are hydrogen, alkyl having 1, 2 or 4 carbon atoms or per-fluoroalkyl having 1, 2, 3 or carbon atoms;

ed 1,2,3 or 4;

R ( ⁴⁶⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

and R ³ , independently of one another, is -CHR ^{S 2} R ^{S 3} ;

are - _(CH2) ^ - (CHOH) _II - (CH) _i - (CHOH) _{1 c} R ^54, or are - (CH 2) g ^-0- (CH 2 CH ₂ O) _h R ~ ^{S 4;}

R ( ⁵⁴⁾ is hydrogen or methyl;

g, h, i, equal or different, zero, 1, 2, 3 or

4;

k 1,2,3 or 4;

R ( ³⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ¹ , R ² and R ³ , independently of each other, -C (OH) R ⁵⁵ R ⁵⁶ ;

R ^pp and R ^S6, identical or different, are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ^pp and R ^S6 together are cycloalkyl having 3, 4, 5 or 6 carbon atoms;

or

R ^{55 is} -CH 2 OH;

and

R ^d and R ^s , independently of one another, an alkyl group having 1, 2, 3 or carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, nitrile, -O- (CH) - (CF) -CF;

n is zero or 1;

zero, 1 or 2;

p is zero, 1 or 2;

as well as pharmaceutically acceptable salts thereof.

Preferred are compounds of formula I wherein:

R ¹ , R ² and R ³ , independently of each other, R ¹⁰ -SO _and -;

R ¹⁰ is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl, 2, 3, 4, 5, 6, or 8 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon atoms or a -C H -R ^16;

a.) 2ab and b, zero, 1, 2, 3 or 4;

R ^{X6 is} cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group or NR 17 R 15;

R ¹ 'and R @ ^{7 x s,} each independently of one another, hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ^x, R ² and R ^3, independently of one another -OR ^22, or -CR ²⁶ R R ^{2 S 2 V;}

R ²² and R ²⁵ , independently of one another, -CH 1 -heteroaryl radical having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy, hydroxyl, amino, methylamino and dimethylamino;

b is zero, 1 or 2;

R ( ^2e) and R ( ² ) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

or

R ¹ , R ² and R ³ , independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitrile group, an -O-CH group, an -O (CH) -C group, alkenydd da 2da + X ' ^c ' 2 '<a. Of 2-t-1 ^'J fishing having 3, 4, 5 or 6 carbon atoms or

dg zero or 1; dh zero or 1; will give zero, 1, 2, 3 or 4; db zero, 1, 2, 3 or 4; de zero, 1, 2, 3, 4, 5, 6 df zero, 1, 2, 3 or 4;

or 7;

R ^{3 is} cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, a phenyl radical, a diphenylyl radical or a naphthyl radical, wherein the aromatic radicals phenyl, diphenylyl or naphthyl are unsubstituted or substituted by 1 to 3 substituents selected a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group and a methoxy group;

or

R ^1, R ² and R ^3, independently of one another are -O- (CH ₂₎ ^{4 S} R _ethoxy;

eb is zero, 1 or 2;

R ^{4 S is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and are - (X _{£ a)} - (CH _{2) OTII} - _(± X. _t>) R ⁱ⁶ J

_{X6 and} methylene, oxygen, sulfur or ^NR4e ;

X is O, S or NR ⁴⁹ ;

ed 1 or 2;

R ( ^4e) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

R ( ⁴⁾ and R ( ⁴⁹ ) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms;

or

R ¹ , R ² and R ³ , independently of each other, -CHR ^{S 2} R ^{S 3} ;

R ^{S2 is} - (CH 2) 4 - (CHOH) h - (CH 2) ± - (CHOH) i -R ⁵⁴ or - (CH 2) 4 - O- (CH 2 -CH 2 O) h - R ^{S 4} ?

R ^S3 and R ^S4 , independently of one another, are hydrogen or methyl;

g, h, i, equal or different, zero, 1 or 2;

k is 1 or 2;

or

R ¹ , R ² and R ³ , independently of each other, -C (OH) R ⁵⁵ R ^5e ;

R ^pp and R ^56, identical or different, are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R ^{5 S,} and ^R, together are cycloalkyl having 3, 4,5 or 6 carbon atoms;

or

R ^{55 is} -CH ₂ OH;

R ⁴ and R ^s independently of one another, alkyl having 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy, fluorine, chlorine, nitrile, a group -0 - (CF) ^-CF3 ;

n 2 p n zero or 1;

p is zero, 1 or 2;

as well as pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I wherein:

R ¹ , R ² and R ³ , independently of each other, R ¹⁰ -SO ₂ -;

R ¹⁰ is alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 3, 4,5 or 6 carbon atoms or a radical CH-R ^s;

R ^{16 is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group and methoxy group ;

or

R ¹ , R ² and R ³ , independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, a nitrile group, a trifluoromethyl group, an alkyl group having 1, 2, 3 or 4 carbon atoms, a 5 or 6 cycloalkyl group carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms;

or

R ^x, R ^z and R ^3, independently of one another are -O- (CH ₂₎ ^{4 S} R _ethoxy;

eb is zero or 1;

R ( ^{45) is} cycloalkyl having 1, 2, 3 or 4 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group and methoxy group;

or

R ^1, R ² and R ^3, independently of one another are -CH _{(CH3) -CH2} OH, -C (OH) (CH _{3) 2} or -C (OH) (CH ₃ S-CH OH;

or

R ⁴ and R ^s independently of one another, alkyl having 1, 2, 3 or carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, hydroxy, fluoro, chloro, CN or trifluoromethyl;

as well as pharmaceutically acceptable salts thereof.

The heteroaryl radical having 1 to 9 carbon atoms means in particular radicals which are derived from phenyl or naphthyl and in which one or more -CH groups are replaced by a nitrogen atom and / or in which at least two adjacent -CH groups (to form a five-membered aromatic group) ring) are replaced by an oxygen atom, a sulfur atom or an imino group. Furthermore, one or both of the atoms at the condensation site of bicyclic residues (such as indolizinyl) may also be nitrogen atoms.

As heteroaryl radicals, in particular furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolinyl, phthalazinyl, phthalazinyl, phthalazinyl, phthalazinyl.

If one of R ^x and ^R comprises one or more centers of asymmetry, they can have either the S or the R compounds can be present as optical isomers, as diastereomers, as racemates or as mixtures thereof.

The labeled alkyl and perfluoroalkyl groups may have straight or branched chains.

The invention further relates to a process for the preparation of a compound of the formula I, characterized in that the compound of the formula II is used

wherein the substituents R ¹ to R ^s are as defined above and L is an easily nucleophilically substitutable leaving group, and easily, is reacted with guanidine.

Activated acid derivatives of the general formula II in which L represents an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio group, a methylthio group,

2-pyridylthio or nitrogen heterocycle, preferably

The 1-imidazolyl are preferably obtained in a known manner from the corresponding carboxylic acid chlorides (formula II, L = chlorine), which can be prepared again in a known manner from the corresponding carboxylic acids (formula II, L = hydroxyl group), for example with thionyl chloride.

In addition to the carboxylic acid chlorides of the formula II (L = chlorine), other activated acid derivatives of the formula II can be prepared in known manner directly from the corresponding benzoic acid derivatives (formula II, L = hydroxyl group), such as methyl esters of formula (II) in which L = methoxy by reaction with hydrogen chloride gas in methanol, imidazolides of formula (II) by reaction with carbonyldiimidazole (L = 1-imidazolyl; Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367), 1962), mixed anhydrides of formula II by reaction with ethyl chloroformate or tosyl chloride in the presence of triethylamine in a non-compatible solvent, also by activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or O - [(cyano (ethoxycarbonyl) methylene, 1, 3) amino] -1] 3-tetramethyluronium tetrafluoroborate (TOTU) (see Weiss and Krommer, Chemiker Zeitung 98, 817, 1974). A number of suitable methods for the preparation of activated carboxylic acid derivatives of formula II are described, including references, by J. Mark, Advanced Organic Chemistry, Third Edition (John Wiley &amp; Sons, 1985), p. 350th

The reaction of the activated carboxylic acid derivative of the formula II with guanidine takes place in a known manner in a protic or aprotic polar but non-compatible solvent. The reaction of methyl esters of benzoic acids (formula II, L = methoxy) with guanidine has proven to be methanol, isopropyl alcohol or tetrahydrofuran at temperatures from 20 ° C to the boiling point of these solvents. Most of the reactions of the compounds of formula II with guanidine in the form of a base are preferably carried out in aprotic, non-covalent solvents such as tetrahydrofuran, dimethoxyethane or dioxane. Water is also useful as a solvent when added to a base, such as sodium hydroxide, in the reaction of compounds of formula II with guanidine.

When L = chlorine, the addition of an acid binding agent, for example in the form of excess guanidine, which binds the hydrohalic acid, is preferably carried out.

The starting benzoic acid derivatives of the formula (II) are partly known and described in the literature. The unknown compounds of formula II can be prepared by methods known in the literature. The benzoic acids obtained are then introduced by one of the above-mentioned preparative variants into the compounds of the formula I according to the invention.

The introduction of some substituents on the benzene nucleus is accomplished by methods known in the literature by cross-linking (with the aid of palladium) aryl halides or aryl triflates, for example with organostananes, organoboric acids or organoboranes, or with organic copper or zinc compounds.

The benzoylguanidines of formula I are generally weak bases and can bind acids to form salts. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.

The compounds of the formula I according to the invention, like the known compounds, do not initially mention the undesirable and disadvantageous salidiuretic effects. On the contrary, they exhibit very good antiarrhythmic properties compared to known compounds, which are, for example, important in the treatment of diseases which occur in manifestations of oxygen deficiency.

The compounds of the formula I are particularly advantageous, because of their pharmacological properties, as antiarrhythmic drugs with a cardioprotective component, both for the prophylaxis and for the treatment of infarction, as well as for the treatment of angina pectoris, while preventing or substantially reducing pathophysiological events in development of ischemic-induced damage, particularly in the development of ischemic-induced cardiac arrhythmias. Due to their protective action against pathological hypoxic and ischemic situations and due to inhibition of the cellular Na 2 / H * exchange mechanism, the compounds of the formula I can be used as medicaments for the treatment of all acute or chronic lesions caused by ischemia, possibly as a result or secondary emerging diseases. This relates to their use as medicaments in surgical interventions, for example in organ transplants, in which the compounds according to the invention can be used both to protect organs in the donor before and after the donation, to protect the organs taken, for example during handling or storage in physiological liquids, but also when transferred to the recipient. The compounds of the invention are also valuable, protective-acting drugs in carrying out angioplastic surgical procedures, for example on the heart or also on peripheral vessels. In accordance with their protective action against ischemically induced damage, the compounds of the invention are also useful as medicaments for the treatment of ischemia of the nervous system, in particular of the central nervous system, and are equally useful for the treatment of stroke or brain edema. In addition, the compounds of the formula I according to the invention are also useful in the treatment of various forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of formula (I) according to the invention exhibit an even strong inhibitory effect on cell proliferation, for example fibroblast cell proliferation and vascular smooth muscle cell proliferation. Therefore, compounds of formula I are useful as valuable therapeutics in diseases in which cell proliferation is a primary or secondary cause and can therefore be applied as anti-atherosclerotic agents, as agents against late diabetic complications, cancer diseases, fibrotic diseases such as pulmonary fibrosis. , hepatic fibrosis or kidney fibrosis, hypertrophy or hyperplasia of the organs, and in particular in the hyperplasia of the forefoot or in the hypertrophy of the forefoot.

The compounds of the invention are potent inhibitors of the sodium-proton cell exchange (Na * / H * exchanger), which is elevated in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) even in cells readily accessible for measurement, such as erythrocytes, thrombocytes or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific aids, for example in their use as diagnosis to determine and distinguish certain forms of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula (I) of the invention are useful in preventive therapies to prevent the development of high blood pressure, such as essential hypertension.

Generally, in blood vessels, too much reduction in high reduction in total content is also important and a decrease in fraction of this total

It has been found that the compounds of formula (I) have a beneficial effect on serum lipoproteins. that for the formation of arteriosclerotic, especially coronary heart disease, high blood lipid levels, hyperlipoproteinemia, a significant risk factor. Therefore, it has extraordinary serum lipoprotein levels for the prophylaxis and regression of atherosclerotic changes. In addition to serum cholesterol, it has an extremely specific atherogenic lipid content of cholesterol, particularly low density lipoproteins (LDLs) and very low density lipoproteins (VLDLs), since these lipid fractions represent an atherogenic risk factor. In contrast, high density lipoproteins are attributed a protective function to cardiac ducts. Accordingly, they should not only reduce total cholesterol, and fractions of LDL in total cholesterol.

anti-coronary ochohypolipidemic agents, but especially VLDL

It has now been found that the compounds of formula I exhibit valuable properties which can be therapeutically evaluated in terms of their effect on serum lipid levels. Thus, for example, they significantly reduce elevated serum LDL and VLDL concentrations that can be observed, for example, in increased dietary intake of a cholesterol-rich and lipid-rich diet, or in pathological changes in metabolism, such as genetic hyperlipidemia. They can therefore be used in the prophylaxis and regression of atherosclerotic changes, as they override the causal risk factor. This includes not only primary hyperlipidemia, but also certain secondary hyperlipidemia, such as occur in, for example, diabetes. In addition, the compounds of formula (I) act to significantly reduce the incidence of infarcts caused by anomalies in the metabolism, and in particular to significantly reduce the induced infarct size and reduce its severity. Further, the compounds of formula I provide effective protection against endothelial damage induced by metabolic anomalies. With this vascular protection against endothelial dysfunction syndrome, the compounds of formula I become valuable drugs for the prevention and therapy of coronary vascular spasms, atherogenesis and atherosclerosis, left ventricular hypertrophy and dilated cardiopathy, as well as thrombotic diseases.

Thus, the above compounds can be advantageously used for the manufacture of a medicament for the treatment of hypercholesterolemia; for the manufacture of a medicament for the prevention of atherogenesis; for the manufacture of a medicament for the prevention and treatment of atherosclerosis; for the manufacture of a medicament for the prevention and treatment of diseases caused by elevated cholesterol levels; for the manufacture of a medicament for the prevention and treatment of diseases caused by endothelial dysfunction; for the manufacture of a medicament for the prevention and treatment of atherosclerosis-induced hypertension; for the manufacture of a medicament for the prevention and treatment of atherosclerosis-induced thromboses; for the manufacture of a medicament for the prevention and treatment of hypercholesterolaemia and endothelial dysfunction caused by ischemic lesions and postischemic reperfusion lesions; for the manufacture of a medicament for the prevention and treatment of hypercholesterolaemia and endothelial dysfunction induced by cardiac hypertrophy and cardiomyopathy; for the manufacture of a medicament for the prevention and treatment of hypercholesterolaemia and endothelial dysfunction induced by coronary vascular spasm and myocardial infarction; for the manufacture of a medicament for the treatment of said diseases in combination with blood pressure lowering agents, in particular ACE inhibitors (Angiotensin Converting Enzymes) and angiotensin receptor antagonists; combining an NHE inhibitor of formula I with an active agent that lowers blood lipid levels, preferably an HMG-CoA reductase inhibitor (e.g. Lovastine or Pravastin), the latter having a hypolipidemic effect and thereby enhancing the hypolipidemic properties of the NHE inhibitor of formula I , has proven to be a beneficial combination with enhanced potency and reduced drug consumption.

The administration of sodium-proton exchange inhibitors of the formula I as modern medicaments for reducing elevated blood lipid levels as well as combinations of sodium-proton exchange inhibitors with drugs which lower blood pressure and / or act hypolipidemically are claimed.

Medicaments containing a compound of formula I may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred route of administration being dependent on the present manifestations of the disease. The compounds of the formula I can be applied either alone or in combination with galenic excipients, both in veterinary and in human medicine.

Which excipients are suitable for the desired dosage form will be apparent to those skilled in the art on the basis of their expert knowledge. In addition to solvents, gelling agents, suppository bases, tabletting aids and other active ingredient carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers or colorants can be used.

For an oral dosage form, the active ingredients are mixed with suitable excipients such as carriers, stabilizers or non-diluent diluents, and are formulated into suitable dosage forms such as tablets, dragees, capsules or aqueous, alcoholic or oily solutions by conventional methods. As incompatible carriers, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch. The preparation can take the form of dry or wet granulation. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired, are brought into solution, suspension or emulsion form with the aid of customary substances such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, water, physiological saline or alcohols, for example ethanol, propyl alcohol or glycerol, in addition also sugar solutions, for example glucose or mannitol solutions, or else mixtures of the various solvents mentioned.

Suitable pharmaceutical preparations for application in the form of aerosols or sprays are, for example, solutions, suspensions, or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of these solvents.

If desired, the formulation may contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation usually contains the active compound in a concentration of from about 0.1 to about 10% by weight, in particular from about 0.3 to about 3% by weight.

How much the dosage of the active compound of the formula I is to be administered and how often the application is to be administered depends on the potency and duration of action of the compounds used; furthermore, the nature and severity of the disease to be treated and, of course, the sex, age, weight and individual reactivity of the mammal to be treated.

On average, a daily dose of a compound of Formula I in a patient weighing about 75 kg is at least 0.001 mg / kg, preferably 0.01 mg / kg, to at most 10 mg / kg, preferably 1 mg / kg body weight. In an acute outbreak of the disease, approximately immediately after a heart attack, higher and especially more frequent doses may be required, for example up to 4 individual doses per day. Especially when administered intravenously, for example in a heart attack patient in an intenal care unit, the required dose may be up to 200 mg per day.

DETAILED DESCRIPTION OF THE INVENTION

Experimental part

General formula for the preparation of benzoylguanidines of the general formula I

Variant A: from benzoic acids (general formula II, L = hydroxyl group)

1.0 equivalent of the benzoic acid derivative of the formula II is dissolved or suspended in anhydrous tetrahydrofuran (5 ml / mmol) and 1.1 equivalents of carbonyldiimidazole are immediately added. After stirring for 2 hours at room temperature, 5.0 equivalents of guanidine are added to the reaction solution. After stirring overnight, tetrahydrofuran was distilled off under reduced pressure (rotary evaporator), the residue was quenched with water, adjusted to pH 6-7 with 2 N hydrochloric acid, and the corresponding benzoylguanidine (Formula I) was filtered off. The benzoylguanidines thus obtained can be converted to the corresponding salts by treatment with aqueous, methanolic or ethereal hydrogen chloride or other pharmacologically acceptable acids.

General formula for the preparation of benzoylguanidines of the general formula I

Variant B: from alkyl esters of benzoic acids (formula II, L = O-alkyl)

A mixture of 1.0 equivalent of the benzoic acid alkyl ester of formula II and 5.0 equivalent of guanidine (free base) is dissolved in isopropyl alcohol or suspended in tetrahydrofuran and refluxed until the reaction is complete (thin layer control). A typical reaction time is 2 to 4 hours. The solvent was distilled off under reduced pressure (rotary evaporator), the residue was taken up in ethyl acetate and washed three times with sodium hydrogen carbonate solution. After drying over sodium sulfate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel using a suitable eluent, for example ethyl acetate-methanol (5: 1).

(For salt preparation see variant A)

Example 1

2,6-dichlorobenzoylguanidine hydrochloride colorless crystals, m.p. &gt; 300 ° C, M + + H = 269, from 2,6-dichlorobenzoic acid according to variant A.

Example 2

Colorless crystals of 3-chloro-2,6-dimethoxybenzoylguanidine, m.p. 148 DEG C., from 3-chloro-2,6-dimethoxybenzoic acid according to variant A.

Example 3

4-Hydroxy-2,3,5,6-tetrafluorobenzoylguanidine hydrochloride colorless solid, m.p. 184 DEG C., from 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid according to variant A.

Example 4

2,6-Difluorobenzoylguanidine hydrochloride colorless crystals, m.p. 208-210 ° C, from 2,6-difluorobenzoic acid according to variant A.

Example 5

2-Fluoro-6-trifluoromethylbenzoylguanidine hydrochloride colorless solid, m.p. 178-180 ° C, from 2-fluoro-6-trifluoromethylbenzoic acid according to variant A.

Example 6

3-Trifluoromethyl-2,6-dimethoxybenzoylguanidine hydrochloride colorless crystals, m.p. 189 DEG C., from 3-bromo-2,6-dimethoxybenzoic acid by reaction with potassium trifluoroacetate in the presence of copper (I) iodide in dimethylformamide and subsequent treatment according to variant A.

Pharmacological data

Inhibition of Na * / H * exchange in rabbit erythrocytes

White New Zealand rabbits (Ivanovas) received a standard 2% cholesterol diet for six weeks to activate Na * / H * exchange and be determined by flame infrared Na * photometry by erythrocytes by Na * / H * exchange. Blood was collected from the ear arteries and by cleavage of 25 IU potassium heparin was removed. A portion of each sample was used for duplicate determination of hematocrit by centrifugation. Aliquots of 100 μΐ were used to measure the initial Na * content in erythrocytes.

To determine the amiloride-sensitive sodium influx, 100 μ 100 of each sample was incubated in 5 ml of hyperosmolar medium containing sodium chloride and sucrose (mmol / liter: 140 sodium chloride, 3 potassium chloride, 150 sucrose, 0.1 ouabaine, 20 tris-hydroxymethylaminomethane) at pH 7.4 and 37 ° C. Then, the erythrocytes were washed three times with an ice-cold solution of magnesium chloride with ouabaine (mmol / liter: 112 magnesium chloride, 0.1 ouabaine) and hemolyzed in 2.0 ml of distilled water. Intracellular sodium content was determined by flame photometry.

Net influx Na * was calculated from the difference between baseline sodium and sodium content in erythrocytes after incubation. The sodium influx that was inhibited by amiloride resulted from the difference in sodium content in erythrocytes after incubation with and without amiloride 3 x 10 ^-4 mol / liter. The compounds according to the invention were also treated in this way.

The results

Inhibition of Na * / H * exchange:

Example

_The IC (pmol / L)

8.5

0.3> 10> 10

Industrial usability

The novel compounds, the bis-ortho-substituted benzoylguanidines which form the subject of the present invention, due to their favorable pharmacodynamic and physical properties (sufficient water solubility), are suitable starting materials for the manufacture of medicaments which are indicative of circulatory and nervous system diseases and diseases. which causes elevated cholesterol levels in the body. In combination with conventional pharmaceutical excipients, they can be formulated into various dosage forms for use in conventional methods of administration.

Claims (16)

Bis-ortho-substituted formula I (I) wherein: R ^1, R ² and R ^3, independently of one another are R ~ ^lo -S0a or a group R ¹⁴ R ^LS-N-SO2-; and zero, 1 or 2; R ^xo, R ¹ and R ^{x s,} independently of one another, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl having 1,2,3,4,5,6, 7 or 8 carbon atoms, an alkenyl group having 3, 4,5 or 6 carbon atoms or a group -CH-R ^xe ; ^x and b and b and b are zero, 1, 2, 3 or 4; R ^{xe is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group or NR ^{x in} R ^xe ; R ^xv and R ^xa , independently of one another, are hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms; or R ¹⁴ and R ¹⁵ together, 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an imino group, a methylimino group or an N-benzyl group; or R ( ¹⁴⁾ and R ( ^{15) are} hydrogen; or R ^1, R ² and R ^3, independently of one another, SR ^21, -OR ^22, -NR ²³ R ²⁴ or -CR ^{2 S} R ²⁶ R ^27; R ^21, R ^22, R ^23, and R ^{2 S,} independently, -C _f H _2to -heteroaryl radical having 1 to 9 carbon atoms, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group; b is zero, 1 or 2; R ^24, R ²⁶ and R ^{2 V,} independently, is H, alkyl having 1, 2,3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; or R ^x, R ² and R ^3, independently of one another are H, F, Cl, Br, I, nitrile, are - (X a) CH, are - (X b) - (CH) -CF , alkenyl having 3, 4, 5, 6, 7 or 8 carbon atoms or -CHR ³ °; ^c ? SL? 2df (Xa) is oxygen, sulfur or NR ³³ ; R ( ³³⁾ is hydrogen, alkyl having 1, 2, 3 or 4 atoms. carbon or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; dg is zero or 1; (Xb) an oxygen atom, a sulfur atom, or an NR ³⁴ group; R ( ³⁴⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; dh zero or 1; will give zero, 1, 2, 3, 4, 5, 6, 7 or db zero, 1, 2, 3 or 4; de zero, 1, 2, 3, 4, 5, 6 or 7; df zero, 1, 2, 3 or 4; R ^{3 is} cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, a phenyl radical, a diphenylyl radical or a naphthyl radical, wherein the aromatic radicals phenyl, diphenylyl or naphthyl are unsubstituted or substituted by 1 to 3 substituents selected a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group and a NR ^{3 X} R ^{32 group} ; R ( ³⁾ and R ( ^{32) are} hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; or R ^1, R ² and R ^3, independently of one another, NR ^{4 O} or R ^4X are - (Xe) - (CH) R ^{4 S;} ' ⁹ ' 2 ⁹ eb R ⁴ ° and R ⁴¹ , independently of one another, a hydrogen atom, an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a perfluoroalkyl group s 1, 2, 3, 4, 5, 6, Ί or 8 carbon atoms or _{(CH2) e} ~ R ^42; e is zero, 1, 2, 3 or 4; R ^{42 is} cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and NR ⁴³ R ⁴⁴ ; R ( ⁴³⁾ and R ( ⁴⁴⁾ , independently of one another, are hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms; or R ⁴ ° and R ⁴¹ , taken together, 4 or 5 methylene groups, of which one CH ₂ group may be replaced by an oxygen atom, a sulfur atom, an imino group, an N-methyl group or an N-benzyl group; (Xe) oxygen, sulfur or NR ^4-7 ; R ( ⁴⁷⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; eb is zero, 1, 2, 3 or 4; R ^{43 is} cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group , NR ^{BO S1} and R are - (Xfa) - _{(CH2) e <i} - (XFB) R ^46; Xfa is a methylene, oxygen, sulfur or NR ⁴ ® group; Xfb is O, S or NR ⁴⁹ ; R ^{4 S,} R ^49, R ^a and R @ ⁵¹ independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or a perfluoroalkyl group having 1, 2, 3 or 4 carbon atoms; ed 1,2,3 or 4; R ( ⁴⁶⁾ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; or R ^x, R ² and R ^3, independently of one another are -CHR ^S2 R ^S3; R ^{S2 is} - (CH 2) g - (CHOH) h - (CH) - - (CHOH) -R ⁵⁴ or - (CH 2) 4 - O- (CH ₂ -CH ₂ O) _{ii -} R ⁵⁴ ; R ^S4 is H or methyl; g, h, i, equal or different, zero, 1, 2, 3 or 4; k is 1, 2, 3 or 4; R ( ⁵³⁾ is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R ^1, R ² and R ³ independently of one another are -C (OH) R R ^{SS S6;} R ^pp and R ^56, identical or different, are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R ^{@ 5 S} and R ^{@ 6} , taken together, represent a cycloalkyl group having 3,4,5 or 6 carbon atoms; or R ^ss -CH ₂ OH; and R ⁴ and R ^s independently of one another, alkyl having 1, 2.3, or 4 carbon atoms, alkoxy of 1, 2, 3 or 4 carbon atoms, hydroxyl, fluorine, chlorine, bromine, iodine, nitrile, n zero or 1; zero, 1 or 2; p is zero, 1 or 2; as well as pharmaceutically acceptable salts thereof. A compound of formula I according to claim 1, wherein: R ^1, R ² and R ^3, independently of one another are R _& ^xo -SO -; R ^{10 is} alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, perfluoroalkyl group s 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon atoms or -CH-R ^X6 ; ^c is> 2ab and b is zero, 1, 2, 3 or 4; R ^{x is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted 1 to 3 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, a methoxy group or an NR @ ¹³ R @ ^{13 group} ; R ^1-7 and R ¹³ independently of one another hydrogen, trifluoromethyl or alkyl having 1, 2, 3 or 4 carbon atoms; or R ^1, R ² and R ^3, independently of one another -OR ^22, or -CR ²⁶ R ^{2 S} R ^{2 '7;} R ²² and R ^2S , independently of one another, -C 1 _to H ₂ -heteroaryl radical having 1 to 9 carbon atoms which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group a methyl group, a methoxy group, a hydroxyl group, an amino group, a methylamino group and a dimethylamino group; b is zero, 1 or 2; R ²⁶ and R ^2-7 , independently of one another, a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms or a perfluoroalkyl group having 1, 2, 3 or 4 carbon atoms; or R ^x , R ² and R ³ , independently of one another, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a non-3,4-iodo group, a nitrile group, an -O- (CH) -C group, alkenyl dh '2'<a.ID 2de + l ' ^J 5 or 6 carbon atoms or a group 2 <£ SL ág zero or 1; dh zero or 1; will give zero 1 2 3 or 4; db zero 1 2 3 or 4; de zero 1 2 3, 4, 5, 6 or 7 df is zero, 1, 2, 3 or 4; R @ ^{3 is} cycloalkyl having 3,4; 5, 6, 7 or 8 carbon atoms, phenyl, diphenylyl or naphthyl, wherein the phenyl, diphenylyl or naphthyl aromatic radicals are unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl a methyl group and a methoxy group; or R ^1, R ² and R ^3, independently of one another are -O- _{(CH2) eb} R ^{4 S;} eb is zero, 1 or 2; R ^{4 S is a} cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group, methoxy group and - (X _{f &} ) - (CH ₂ ) _oca '( ^x _ft> ) ^{R 6 group} X _{6 and a} methylene, oxygen, sulfur or NR ⁴ ® group; _£ X _is O, S or NR ^49; ed 1 or 2; R ( ^4S) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; R ^A and R ^49, independently of one another, H or alkyl having 1, 2, 3 or 4 carbon atoms or perfluoroalkyl having 1, 2, 3 or 4 carbon atoms; or R ¹ , R ² and R ³ , independently of each other, -CHR ^{S 2} R ⁵³ ; R ³² are - (CH2) ^ - (CHOH) h- (CH2) ± - (CHOH) ^ - R ^S4 or the moiety - (CH 2) _g -O- (CH ₂ CH ₂ O) _h R ^54; R ( ³⁾ and R ( ⁵⁴ ) independently of one another are hydrogen or methyl; g, h, i, equal or different, zero, 1 or 2; k is 1 or 2; or R ^1, R ² and R ³ independently of one another are -C (OH) R R ^{SS S6;} R ^pp and R ^56, identical or different, are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R ( ^5S) and R ( ^S6) together are cycloalkyl having 3, 4, 5 or 6 carbon atoms; or R ^ss -CH ₂ 0H; R ⁴ and R ^s independently of one another, alkyl having 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxy, fluorine, chlorine, nitrile, -O _n - (CF _{2) p} -CF ³ ; n is zero or 1; p zero, 1 or 2. A compound of formula I according to claim 1 or 2, wherein: R ^x, R ² and R ^3, independently of one another, a group of -S0 ₂ R ^xo ~; R ^xo alkyl having 1, 2, 3 or 4 carbon atoms, perfluoroalkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 3, 4, 5 or 6 carbon atoms or a -CH R ^{16; x} alo 2ab R ^{x <a} cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, trifluoromethyl, methyl, and methoxy; or R ^x, R ² and R ^3, independently of one another are H, F, Cl, hydroxy, nitrile, trifluoromethyl, alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 5 or 6 carbon atoms or alkoxy having 1, 2, 3 or 4 carbon atoms; or R ^x, R ² and R ^3, independently of one another are -O- (CH ₂₎ ^{4 S} _et R; eb is zero or 1; R ( ^{45) is} cycloalkyl having 1, 2, 3 or 4 carbon atoms or a phenyl radical which is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of fluorine atom, chlorine atom, trifluoromethyl group, methyl group and methoxy group; or R ^1, R ² and R ^3, independently of one another are -CH _(CH3) -CH__OH, -C (OH) (CH _{3) 2} or -C (OH) (CH ₃₎ CH ₂ OH; or R ⁴ and R ^s independently of one another, alkyl having 1, 2, 3 or C 4 -C 4 alkoxy, 1, 2, 3 or 4 carbon atoms, hydroxyl, fluorine, chlorine, nitrile or trifluoromethyl. wherein R ¹ -R ⁵ are as defined above and L represents a readily nucleophilically substituted and readily removable group, reacts with guanidine. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of a heart attack. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of shock conditions. Use of a compound of formula I according to claim 1 for the manufacture of a medicament useful in surgical operations and organ transplants. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the preservation and storage of transplants for surgical purposes. The use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, and thus its use in the manufacture of anti-atherosclerotics, agents for late diabetic complications, cancer diseases, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis or hyperplasia of the uterine. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment or prophylaxis of lipid metabolism disorders. A medicament comprising an effective amount of a compound of formula I according to one or more of claims 1 to 4.