HRP950570A2 - Substituted benzoylguanidine, process for its preparation, its use as medicament or diagnostic agent as well as medicaments containing it - Google Patents

Description

This invention relates to benzoylguanidine of formula I

[image]

whereby:

R(1) is R(6)-CO or R(7)R(8)N-CO;

R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or CnH2n-R(9),

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

R(9) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl,

wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(10)R(11), where R(10) and R(11) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R[7] is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(12);

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

R(12) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl,

wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(13)R(14), where R(13) and R(14) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(8) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or

R(7) and R(8) are together

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

R(2) is as defined in R(1), or is H, OH, F, Cl, Br, I, CN, NO2, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3 -C8)-alkenyl or -CnH2nR(15);

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

R(15) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR( 16)R(17);

R(16) and R(17) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

or

R(2) is (C1-C9)-heteroalkyl,

which is bonded through C or N, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine;

or

R(2) is SR(18), -OR(18), -NR(18)R(19) or -CR(18)R(19)R(20);

R(18) is -CaH2a-(C1-C9)-heteroalkyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine, dimethylamine;

a is zero, 1 or 2;

R(19) and R(20)

independently of one another are as defined R(18) or hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

or

R(2) is R(21)-SOm or R(22)R(23)N-SO2-;

m is 1 or 2;

R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(24);

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

R(24) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl,

wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(27)R(28); where R(27) and R(28) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(22) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(29);

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

R(29) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl,

wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(30)R(31); where R(30) and R(31) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(23) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or

R(22) and R(23)

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

or

R(2) is R(33)X-;

X is oxygen, S, NR(34), (D=O)A- or NR(34)C=MN(*)R(35)-;

M is oxygen or S;

A is oxygen or NR(34);

D is C or SO;

R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or -CnH2n-R(36);

b is zero or 1;

d is 1, 2, 3, 4, 5, 6 or 7;

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

R(36) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR( 37)R(38); where R(37) and R(38) are

H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(34) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(35) is defined as R(33);

or

R(33) and R(34)

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

where A and N(*) are attached to the phenyl nucleus of the benzoylguanidine base body;

or

R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42), -CR(42)R( 43)OH, -C=CR(45), -CR(46)=CR(45) or -[CR(47)R(48)]u-CO-[CR49)R(50)]v-R(44) ;

where R(40) and R(41)

independently of each other are -(CH2)p-(CHOH)q-(CH2)r-(CHOH)t-R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51);

u is 1, 2, 3 or 4;

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

p, q and r

independently of each other are zero, 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

R(42) and R(43)

are independently hydrogen or (C1-C6)-alkyl;

or

R(42) and R(43)

together with the carbon atom bearing them are (C3-C8)-cycloalkyl;

R(44) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, -CeH2e-R(45);

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

R(45) is phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3: methyl, methoxy or NR(52)R(53); where R(52) and R(53) are

H or (C1-C4)-alkyl;

or

R(45) is (C1-C9)-heteroalkyl,

unsubstituted or substituted as phenyl;

or

R(45) is (C1-C6)-alkyl,

unsubstituted or substituted with 1-3 OH;

or

R(46), R(47), R(48), R(49) and R(50)

are independently hydrogen or methyl;

or

R(2) is R(55)-NH-SO2-;

R(55) is R(56)R(57)N-(C=Y)-;

Y is oxygen, S or N-R(58);

R(56) and R(57)

independently of one another are hydrogen, (C1-C8)-alkyl, (C3-C6)-alkenyl or -CfH2f-R(59);

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

R(59) is (C5-C7)-cycloalkyl, phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methoxyl and (C1-C4)-alkyl;

or

R(56) and R(57)

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

R(58)

is defined as R(56) or is amidine;

R(3), R(4) and R(5) are independently defined as R(1) or R(2), however at least one of the substituents R(2), R(3), R (4) and R(5) must be equal to OH;

as well as their pharmaceutically harmless salts.

Compounds according to formula I are recommended, in which:

R(1) is R(6)-CO or R(7)R(8)N-CO;

R(6) is (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl, CnH2n-R(9),

n is zero, or 1;

R(9) is (C3-C8)-cycloalkyl, phenyl,

which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(10)R(11), where R(10) and R(11) are H or CH3;

R[7] is hydrogen, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(12);

n is zero or 1;

R(12) is (C3-C8)-cycloalkyl, phenyl,

which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, CL CF3, methyl, methoxyl and NR(13)R(14), wherein R(13) and R(14) are H or CH3;

R(8) is hydrogen or CH3;

R(2) is as defined in R(1), or is H, OH, F, Cl, Br, I, CN, NO2, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2nR(15);

n is zero, 1 or 2;

R(15) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl,

which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17), where R(16) and R(17) are hydrogen or CH3;

or

R(2) is (C1-C9)-heteroalkyl,

which is bonded through C or N, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine;

or

R(2) is -SR(18), -OR(18), -NR(18)R(19) or -CR(18)R(19)R(20);

R(18) is -CaH2a-(C1-C9)-heteroalkyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine, dimethylamine;

a is zero or 1;

R(19) and R(20)

are independently defined as R(18) or are hydrogen or CH3;

or

R(2) is R(21)-SOm or R(22)R(23)N-SO2-;

m is 2;

R(21) is (C1-8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(24);

n is zero or 1;

R(24) is (C3-C8)-cycloalkyl or phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(27)R(28); where R(27) and R(28) are

hydrogen or CH3;

R(22) is hydrogen, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(29);

n is zero or 1;

R(29) is (C3-C8)-cycloalkyl or phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(30)R(31); where R(30) and R(31) are

hydrogen or CH3;

R(23) is hydrogen or CH3; or

R(22) and R(23)

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

or

R(2) is R(33)X-;

X is oxygen, S, NR(34), (C=O)A- or NR(34)C=MN(*)R(35)-;

M is oxygen;

A is oxygen or NR(34);

R(33) is (C1C8)alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or -CnH2n-R(36);

b is zero or 1;

d is 1, 2, 3, 4, 5, 6 or 7;

n is zero or 1;

R(36) is (C3-C8)-cycloalkyl or phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl methoxyl and NR(37)R(38); where R(37) and R(38) are hydrogen or CH3;

R(34) is hydrogen or (C1-C4)-alkyl;

R(35) is defined as R(33);

or

R(33) and R(34)

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

wherein A and N(*) are attached to the phenyl nucleus of the bezoylguanidine backbone;

or

R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42), -CR(42)R( 43)OH, -C=CR(45), -CR(46) = CR(45) or -[CR(47)R(48)]u-CO-[C(R49)R(50)]v-R( 44);

where R(40) and R(41)

independently of each other are -(CH2)p-(CHOH)q-(CH2)r-(CHOH)t-R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51);

R(51) is hydrogen or methyl;

u is 1, 2, 3 or 4;

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

p, q and r

independently of each other are zero, 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

R(42) and R(43)

independently of each other are hydrogen or (C1-C6)-alkyl or together with the carbon atom bearing them are (C3-C8)-cycloalkyl;

R(44) is (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -CeH2e-R(45);

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

R(45) is phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(52)R(53); where R(52) and R(53)

are hydrogen, CH3;

or

R(45) is (C1-C9)-heteroalkyl,

unsubstituted or substituted as phenyl;

or

R(45) is (C1-C6)-alkyl,

unsubstituted or substituted with 1-3 OH;

or

R(46), R(47), R(48), R(49) and R(50)

are independently hydrogen or methyl;

or

R(2) is R(55)-NH-SO2-;

R(55) is R(56)R(57)N-(C=Y)-;

Y is oxygen, S or N-R(58);

R(56) and R(57)

are independently oxygen, (C1-C8)-alkyl; (C3-C6)-alkenyl or -CfH2f-R(59);

f is zero or 1;

R(59) is (C5-C7)-cycloalkyl, phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methoxyl and (C1-C4)-alkyl;

or

R(56) and R(57)

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

R(58) is defined as R(56);

R(3), R(4) and R(5) are independently defined as R(1) or R(2),

whereby at least one of the substituents R(2), R(3), R(4) and R(5) must be equal to OH;

as well as their pharmaceutically harmless salts.

Particularly recommended are compounds according to formula I, in which:

R(1) is R(6)-CO or R(7)R(8)N-CO;

R(6) is (C1-C4)-alkyl, CF3 or -CnH2n-R(9),

n is zero;

R(9) is (C3-C8)-cycloalkyl or phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(10)R(11); R(10) and R(11)

are independently hydrogen or CH3;

R[7] is hydrogen, (C1-C4)-alkyl, CF3 or -CnH2n-R(12);

n is zero;

R(12) is (C3-C8)-cycloalkyl or phenyl,

which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(13)R(14), where R(13) and R(14) are hydrogen or CH3;

R(8) is hydrogen or CH3;

R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3, or -CnH2nR(15);

n is zero, 1 or 2;

R(15) is (C3-C8)-cycloalkyl or phenyl,

which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17),

where R(16) and R(17)

are hydrogen or CH3;

or

R(2) is quinolyl, isoquinolyl, pyrrolyl or pyridyl,

which are bound via C or N, and which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine;

or

R(2) is R(33)X-;

X is oxygen, S or NR(34);

R(33) is (C1-C8)-alkyl, (CH2)bCdF2d+1 or -CnH2n-R(36);

b is zero or 1;

d is 1, 2, 3, 4, 5, 6 or 7;

n is zero or 1;

R(36) is phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl methoxyl and NR(37)R(38); R(37) and R(38) are hydrogen or CH3;

R(34) is hydrogen or (C1-C4)-alkyl;

or

R(2) is -C=CR(45);

R(45) is phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(52)R(53); where R(52) and R(53) are hydrogen or CH3;

R(3) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3 or -CnH2nR(15);

n is zero, 1, or 2;

R(15) is (C3-C8)-cycloalkyl or phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3: methyl, methoxy and NR(16)R(17);

R(16) and R(17) are

H or CH3;

or

R(3) is quinolyl, isoquinolyl, pyrrolyl or pyridyl,

which are bound via C or N, and which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine;

or

R(3) is R(21)-SOm or R(22)R(23)N-SO2-;

m is 2;

R(21) is (C1-C4)-alkyl or CF3;

R(22) is hydrogen, (C1-C4)-alkyl, CF3 or CnH2n-R(29);

n is zero or 1;

R(29) is phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(30)R(31); where R(30) and R(31) are

H or CH3;

R(23) is hydrogen or CH3;

or

R(3) is -C=CR(45);

R(45) is phenyl,

unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(52)R(53);

where R(52) and R(53) are

hydrogen or CH3;

R(4) and R(5)

are independently hydrogen, OH or NHR(60); R(60) is (C1-C4)-alkyl;

where at least one of the substituents R(2), R(3), R(4) and R(5) must be equal to OH,

as well as their pharmaceutically harmless salts.

Above all, compounds according to formula I are recommended, in which

R(1) is R(6)-CO;

R(6) is (C1-C4)-alkyl or CF3;

R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl or CF3;

or

R(2) is -SR(18) or -OR(18);

R(18) is pyridyl,

which is bonded through C or N, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine;

or

R(2) is R(33)X-;

X is oxygen or S;

R(33) is (C1-C8)-alkyl or -CnH2n-R(36);

n is zero or 1;

R(36) is phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(37)R(38); where R(37) and R(38) are hydrogen or CH3;

R(3) is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3 or -CnH2nR(15);

n is zero, 1, or 2;

R(15) is phenyl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17); R(16) and R(17) are H or CH3;

or

R(3) is R(21)-SOm;

m is 2;

R(21) is (C1-C4)-alkyl or CF3;

R(4) and R(5)

are independently hydrogen, OH or NHR(60);

R(60) is (C1-C4)-alkyl;

where at least one of the substituents R(2), R(3), R(4) and R(5) must be equal to OH,

as well as their pharmaceutically harmless salts.

By (C1-C9)-heteroaryl is meant especially residues that are separated from phenyl or naphthyl, and in which one or more CH-groups are replaced by N and/or in which at least two adjacent CH-groups (when forming one five-membered aromatic ring) replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of the bicyclic residue (as in indolizinyl) may also be N-atoms.

Examples of heteroaryl include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinolinyl.

If one of the substituents R(1) to R(60) has one or more sites of asymmetry, then they can have both S and R configurations. The compounds may occur as optical isomers, diastereomers, racemates or as mixtures thereof.

The described alkyl residues can be straight-chain or branched.

Furthermore, the present invention relates to a process for the production of compound L characterized by the fact that one compound of formula II

[image]

reacts with guanidine, where R(1) to R(5) have the indicated meanings, and L denotes a leaving group easily replaced by a nucleophile.

Activated acid derivatives of the formula II, where L denotes an alkoxyl-, preferably methoxyl group, phenoxylyl group, phenylthio-, methylthio-, 2-pyridylthio group, nitrogen heterocyclic compound, preferably 1-imidazolyl, are obtained in a known manner from basic chlorides carboxylic acids of formula II (L=CI), which can again be produced in a known manner from basic carboxylic acids (formula II, L=OH), for example with thionyl chloride.

In addition to carboxylic acid chloride of formula II (L=CI), other activated acid derivatives of formula II can be produced directly from basic benzoic acid derivatives (formula II, L=OH) in a known manner, such as, for example, methyl ester of formula II with L=OCH3 by treatment with gaseous HCl in methanol, imidazolide of formula II by treatment with carbonyldi-imidazole [L=1-imidazolyl: Staab, Agnew. Chem. Int. Ed. English 1, 351-367 (1962)], mixed anhydrides II with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as well as activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano-(ethoxylcarbonyl)methylene) amino]-1,1,3,3-tetramethyluronium-tetrafluoroborate ("TOTU") [Proceedings of the 21st European Peptide Symposium, Peptides 1990, published by E. Giralt and D. Andreu, Escom, Leiden, 1991]. In J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), a series of suitable procedures for the production of activated carboxylic acid derivatives of formula II is given, with bibliography indicated.

The reaction of an activated carboxylic acid derivative of formula II with guanidine yields a protic or aprotic polar but inert organic solvent in a known manner. During the conversion of methylester of benzoic acid (II, L=OMe) with guanidine, methanol, isopropanol or THF were preserved from 20°C to the boiling temperature of these solvents. In most reactions of compounds II with salt-free guanidine, it is preferably carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane. Water can also be used as a solvent in the conversion of II with guanidine, with the use of a base such as NaOH.

When L=CI, it is preferably done with the addition of an acid scavenger, e.g. in the form of excess guanidine to bind hydrohalic acid.

A part of the subject benzoic acid derivatives of formula II is known and described in the literature. Unknown compounds of formula II can be produced by methods known from the literature. The obtained benzoic acids are converted into compounds I in accordance with the present invention according to one of the variants of the procedure described above.

The introduction of some substituents in the 3-, 4- and 5-positions is achieved using cross-linking procedures known from the literature, with the help of palladium, aryl halides or aryltriflates with, for example, organostannates, organoboronic acids or organoboranes or organic copper compounds or zinc.

Benzoylguanidine I are generally weak bases and can bind acids to form salts. Additive acid salts include salts of all pharmacologically harmless acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Compounds I are substituted acylguanidine.

The most important representative of acylguanidine is the pyrazine derivative amiloride, which finds therapeutic use as a potassium-sparing diuretic. A whole series of further compounds of the amiloride type are described in the literature, such as dimethylamiloride or ethylisopropylamiloride.

[image]

Amiloride: R', R" = H

Dimethylamiloride: R', R" = CH3

Ethylisopropylamiloride: R' = C2H5, R" = CH(CH3)2

Furthermore, studies are known that indicate the antiarrhythmic properties of amiloride (Circulation 79, 1257-63 (1989). Wider use as an antiarrhythmic is opposed by the fact that this effect is only weakly expressed and is accompanied by a lowering of blood pressure and a saluretic effect, and these side effects are undesirable in the treatment of rhythmic disturbances of the heart.

Experiments on isolated animal hearts also indicated the antiarrhythmic properties of amiloride [Eur. Heart J. 9(suppl.1):167 (1988) (book of abstracts)]. For example, it was established in the rat heart that artificially induced ventricular fibrillation can be completely suppressed by amiloride. Even stronger than amiloride in that model was the above-mentioned amiloride derivative ethylisopropylamiloride.

US patent 5 091 394 (HOE 89/F 288) describes benzoylguanidines which carry one hydrogen atom in the position corresponding to the residue R(1). In the German Patent Application P 42 04 575.4 (HOE 92/F 034), benzoylguanidines are proposed, but in which the substituents have no meaning according to the patent claims of the subject invention.

US Patent 3,780,027 claims acylguanidines that are structurally similar to compounds of formula I and are derived from marketed diuretics such as bumetanide. Accordingly, strong salidiuretic activity is reported for these compounds.

It has been established that the compounds according to this invention do not have unwanted and harmful salidiuretic properties, but rather very good antiarrhythmic properties, which are important for the treatment of diseases that occur with a lack of oxygen. Due to their pharmacological properties, these compounds are extremely suitable as an antiarrhythmic drug with a cardioprotective component for the prophylaxis and treatment of heart attacks, as well as for the treatment of angina pectoris, whereby they also preventively stop or greatly weaken the pathophysiological processes in the occurrence of ischemic-induced damage, especially in the outbreak of ischemic-induced cardiac arrhythmias. Due to their protective action against pathological hypoxic and ischemic situations, the compounds of formula I according to this invention, and due to the suspension of the cellular mechanism of Na+/H+ exchange, can be used as a medicine for the treatment of all acute or chronic damage caused by ischemia or diseases induced by it primarily or secondarily. This refers to their use as medicine for surgical procedures, e.g. in organ transplants, where the compounds can be used both for the protection of organs in the donor before and during extraction, for the protection of extracted organs, for example when manipulating organs or their storage in physiological fluids, as well as when transferring organs to the recipient's body. The compounds in question are also a valuable drug with a protective effect when performing angioplasty operations, for example on the heart as well as on peripheral blood vessels. Thanks to their protective action against ischemic induced damage, these compounds are also suitable as a medicine for the treatment of ischemia of the nervous system, especially the central nervous system, whereby they are, for example, suitable for the treatment of stroke or cerebral edema. Furthermore, the compounds of formula I according to the present invention are also suitable for the treatment of various forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shocks.

Furthermore, the compounds of formula I according to the present invention stand out for their strong inhibitory effect on cell proliferation, for example the proliferation of fibroblast cells and the proliferation of blood vessel smooth muscle cells. For this reason, the compounds of formula I come into consideration as valuable therapeutics in diseases, in which cell proliferation is the primary or secondary cause, and for this reason they can be used as an antiathero-sclerotic agent, a means against late diabetic complications, cancer diseases, inflammatory diseases such as inflammation lungs, inflammation of the liver or kidneys, organic hypertrophy and hyperplasia, especially hyperplasia or hypertrophy of the prostate.

The compounds according to the present invention are effective inhibitors of cellular sodium-proton-antiporters (Na+/H+-exchanger), which are elevated in numerous diseases (essential hypertension, atherosclerosis, diabetes, etc.) and in such cells that are easily accessible for measurements, such as what is it in erythrocytes, platelets or leukocytes. The compounds according to this invention are therefore suitable as an extraordinary and simple scientific tool, for example in their use as diagnostics for determining and differentiating certain forms of hypertension, but also atherosclerosis, diabetes, proliferative diseases, etc. Furthermore, the compounds of formula I are suitable for preventive therapy to reduce the genesis of high blood pressure, for example essential hypertension.

In contrast to known compounds, the compounds according to the present invention have significantly increased solubility in water. Therefore, they are much more suitable for intravenous administration.

Medicines containing one compound I can be administered orally, parenterally, intravenously, rectally or by inhalation, and the recommended method of administration depends on each individual picture of the disease. Compounds I can be used alone or together with galenic excipients, both in veterinary medicine and in human medicine.

The decision on which excipients are suitable for the desired drug formulation is left to the expert based on his professional knowledge. In addition to solvents, gel-forming agents, suppository bases, tablet excipients and other active substance carriers, antioxidants, dispersing agents, emulsifiers, defoamers, taste-correcting agents, preservatives, solubilizing agents or colors can be used.

For a form suitable for oral administration, the active compounds are mixed with appropriate additives, such as carriers, stabilizers or inert diluents, and are prepared by conventional methods in suitable forms for administration such as tablets, dragees, suppositories, aqueous, alcoholic or oily solutions. As an inert carrier substance, it can be used, for example. gum arabic, bitters, magnesium carbonate, potassium phosphate, soft sugar, glucose or starch, especially corn starch. At the same time, preparation can be both in the form of dry and in the form of wet granules. Suitable oil 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 are placed in a solution, suspension or emulsion, optionally with the usual substances such as solvents, emulsifiers or further additives. Possible solvents include: water, physiological solutions of table salt or alcohols, e.g. ethanol, propanol, glycerin, and in addition sugar solutions such as glucose or mannitol solution, or also a mixture of different known solvents.

As a pharmaceutical formulation for administration in the form of an aerosol or spray, they are suitable, e.g. solutions, suspensions or emulsions of the active substance of formula I in one pharmaceutically safe solvent, such as in particular ethanol or water, or one mixture of such solvents.

If necessary, the formulation can also contain other pharmaceutical auxiliary substances such as surfactants, emulsifiers and stabilizers, as well as propellant gas. Such a preparation contains the active substance usually in a concentration of approximately 0.1 to 10, preferably 0.3 to 3% by weight.

The dosage of the active substance of formula I for administration to the patient, and the frequency of administration depends on the strength and duration of action of the applied compound; in addition, it depends on the type and severity of the disease being treated, as well as on the sex, age, weight and responsiveness (sensitivity) of the treated patient.

The average daily dose of the compound of formula one is, in a patient weighing approximately 75 kg, at least 0.001 mg/kg, preferably 0.01 mg/kg, up to a maximum of 10 mg/kg, preferably 1 mg/kg of body weight. In acute disease outbreaks, approximately immediately after experiencing a heart attack, stronger and above all more frequent doses may be needed, e.g. up to 4 individual doses per day. Especially with intravenous administration, for example in a patient who has had a heart attack and is in intensive care, up to 200 mg per day may be required.

List of abbreviations:

[image] Experimental part

General regulation for the production of benzoyl-guanidine (II)

Variant A: from benzoic acid (II, L=OH)

1.0 eq. benzoic acid derivative of formula II dissolves or suspended in anhydrous THF (5 ml/mmol) and then mixed with 1.1 eq. carbonyldiimidazoles. After stirring for 2 hours at RT, 5.0 eq. of guanidine into the reaction solution. After stirring overnight, the THF is distilled off under reduced pressure (rotary evaporator), mixed with water, brought to pH 6 to 7 using 2N Hcl, and the corresponding benzoylguanidine (formula I) separated by filtration. Benzoylguanidine obtained in this way can be converted into appropriate salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically harmless acids.

General regulation for the production of benzoyl-guanidine (I)

Variant B: from the alkyl ester of benzoic acid (II, L=0-alkyl)

1.0 eq. of benzoic acid alkylester of formula II as well as 5.0 equiv. guanidine (free base) is dissolved in isopropanol or suspended in THF, and refluxed until complete conversion (thin layer control) (typical reaction time 2 to 5 h). The solvent is separated by distillation under reduced pressure (rotary evaporator), placed in EE and washed 3 times with NaHCO3 solution. It is dried over Na2SO4, the solvent is separated in vacuum by distillation, and it is chromatographed on silica gel with a suitable eluent, e.g. EE/MeOH 5:1. (Salt formation same as variant A)

Examples

Example 1:

3-acetyl-4-hydroxyl-benzoylguanidine

[image]

1a)

4-acetoxyl-benzoic acid is prepared by Fries displacement with 3 equiv. AICI3 converts to 3-acetyl-4-hydroxyl-benzoic acid at 140°C.

1 b)

1.0 eq. 3-Acetyl-4-hydroxyl-benzoic acid is converted according to variant A with 1.1 eq. carbonyldiimidazole and 5 equiv. guanidine.

Colorless crystals, melting point 218-221 °C.

Example 2:

3-acetyl-6-hydroxyl-benzoylguanidine hydrochloride

[image]

1.0 eq. 3-acetyl-6-hydroxyl-benzoic acid is converted according to variant A with 1.1 eq. carbonyldiimidazole and 5 equiv. of guanidine and isolated as the hydrochloride.

Colorless crystals, melting point 170-180°C.

Example 3:

3-acetyl-5-bromo-4-hydroxyl-benzoylguanidine hydrochloride

[image]

3a)

methyl ester of 3-acetyl-4-hydroxylbenzoic acid in chlorobenzene with 1.1 equiv. It converts N-bromosuccinimide and traces of AIBN into 3-acetyl-5-bromo-4-hydroxylbenzoic acid methyl ester.

Colorless crystals, melting point 106-108°C.

3 b)

The ester from 3a) is converted according to Variant B to guanidine and isolated as the hydrochloride.

Crystals, melting point 230°C with decomposition.

Example 4:

3-acetyl-5-chloro-4-hydroxyl-benzoylguanidine hydrochloride

[image]

4a)

1 eq. 4-acetoxyl-3-chloro-benzoic acid is mixed with 3 eq. AICI3 and heated at 140°C for 1 h. Treatment with 2N HCl gave 3-acetyl-5-chloro-4-hydroxyl-benzoic acid.

Yellow crystals, melting point 226-234°C.

4 b)

Benzoic acid from 4a) is converted into guanidine according to variant A and isolated as hydrochloride.

Yellowish crystals, melting point 198-203°C.

Pharmacological data:

Inhibition of rabbit erythrocyte Na+/H+ exchanger

White New Zealand rabbits (Ivanovas) were kept on a standard diet with 2% cholesterol for six weeks, in order to activate Na+/H+-exchange, and flame-photometrically determined Na+-influx in erythrocytes via Na+/H+-exchange. Blood was taken from oral artery and using 25 IU of potassium-heparin prepared so that it cannot clot. One portion of each sample was used for double determination of hematocrit by centrifugation. Aliquots of approximately 100 µl were used to measure the Na+-initial amount of erythrocytes.

To determine amiloride-sensitive sodium influx, 100 µl of each blood sample was incubated in approximately 5 ml of hyperosmolar saline-sucrose medium (mmol/l: 140 NaCl, 3 Kcl, 150 sucrose, 0.1 ouabain, 20 tris -hydroxylmethyl-aminomethane) at pH 7.4 and at 37° C. The erythrocytes were then washed three times with ice-cold MgCl2-ouabain solution (mmol/l: 112 MgCl2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled Intracellular sodium content was determined by flame photometry.

Na+-net influx was calculated from the difference between the initial sodium values and the sodium content in erythrocytes after incubation. The sodium influx that is prevented (stopped) by amiloride was obtained from the difference in sodium content in erythrocytes after incubation with and without amiloride 3 x 10--4 mol/l. Compounds according to this invention were also treated in this way.

The results:

Inhibition of Na+/H+-exchanger:

[image]

Claims (19)

1. Benzoylguanidine according to formula I [image] indicated by the fact that: R(1) is R(6)-CO or R(7)R(8)N-CO; R(6) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or CnH2n-R(9): n is zero, 1, 2, 3 or 4; R(9) is (C3-C8)-cycloalkyl, phenyl, biphenyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(10)R(11), where R(10) and R(11) mean H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R[7] is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(12); n is zero, 1, 2, 3 or 4; R(12) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(13)R(14), where R(13) and R(14) are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R(8) is H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or R(7) and R(8) are together 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, CN, NO2, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8 )-alkenyl or -CnH2nR(15); n is zero, 1, 2, 3 or 4; R(15) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17); R(16) and R(17) are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or R(2) is (C1-C9)-heteroalkyl, which is linked via C or N, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine; or R(2) is SR(18), -OR(18), -NR(18)R(19) or -CR(18)R(19)R(20); R(18) is -CaH2a-(CrC9)-heteroalkyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine, dimethylamine; a is zero, 1 or 2; R(19) and R(20) are independently defined as R(18) or are hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or R(2) is R(21)-SOm or R(22)R(23)N-SO2-; m is 1 or 2; R(21) is (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(24); n is zero, 1, 2, 3 or 4; R(24) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(27)R(28); where R(27) and R(28) are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R(22) is H, (C1-C8)-alkyl, (C1-C8)-perfluoroalkyl, (C3-C8)-alkenyl or -CnH2n-R(29); n is zero, 1, 2, 3 or 4; R(29) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(30)R(31); where R(30) and R(31) are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R(23) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; or R(22) and R(23) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; or R(2) is R(33)X-; X is oxygen, S, NR(34), (D=O)A- or NR(34)C=MN(*)R(35)-; M is oxygen or S; A is oxygen or NR(34); D is C or SO; R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or -CnH2n-R(36); b is zero or 1; d is 1, 2, 3, 4, 5, 6 or 7; n is zero, 1, 2, 3 or 4; R(36) is (C3-C8)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR( 37)R(38); where R(37) and R(38) are H, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R(34) is hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl; R(35) is defined as R(33); or R(33) and R(34) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; wherein A and NM are attached to the phenyl nucleus of the benzoylguanidine backbone; or R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42), -CR(42)R( 43)OH, -C=CR(45), -CR(46)=CR(45) or -[CR(47)R(48)]u-CO-[C(R49)R(50)]v-R( 44); where R(40) and R(41) independently of each other are -(CH2)p-(CHOH)q-(CH2)r-(CHOH)r R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51); u is 1, 2, 3 or 4; v is zero, 1, 2, 3 or 4; p, q and r independently of each other are zero, 1, 2, 3 or 4; t is 1, 2, 3 or 4; R(42) and R(43) are independently hydrogen or (C1-C6)-alkyl; or R(42) and R(43) together with the carbon atom bearing them are (C3-C8)-cycloalkyl; R(44) is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, -CeH2e-R(45); e is zero, 1, 2, 3 or 4; R(45) is phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy or NR(52)R(53); where R(52) and R(53) are H or (C1-C4)-alkyl; or R(45) is (C1-C9)-heteroalkyl, unsubstituted or substituted as phenyl; or R(45) is (C1-C6)-alkyl, unsubstituted or substituted with 1-3 OH; or R(46), R(47), R(48), R(49) and R(50) are independently hydrogen or methyl; or R(2) is R(55)-NH-SO2-; R(55) is R(56)R(57)N-(C=Y)-; Y is oxygen, S or N-R(58); R(56) and R(57) are independently hydrogen, (C1-C8)-alkyl, (C3-C6)-alkenyl or -CfH2f-R(59); f is zero, 1, 2, 3 or 4; R(59) is (C5-C7)-cycloalkyl, phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methoxyl and (C1-C4)-alkyl; or R(56) and R(57) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; R(58) is defined as R(56) or is amidine; R(3), R(4) and R(5) are independently defined as R(1) or R(2), whereby at least one of the substituents R(2), R(3), R(4) and R(5) must be equal to OH; as well as their pharmaceutically acceptable salts. 2. The compound of formula I according to claim 1, characterized in that: R(1) is R(6)-CO or R(7)R(8)N-CO; R(6) is (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl, CnH2n-R(9), n is zero, or 1; R(9) is (C3-C8)-cycloalkyl, phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(10)R(11), where R(10) and R(11) are H or CH3; R[7] is hydrogen, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(12); n is zero or 1; R(12) is (C3-C8)-cycloalkyl, phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxy and NR(13)R(14), where R(13) and R(14) are H or CH3; R(8) is hydrogen or CH3; R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, CN, NO2, (C1-C8)-alkyl, CF3) (C3-C8)-alkenyl or -CnH2nR (15); n is zero, 1 or 2; R(15) is (C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17), where R(16) and R(17) are hydrogen or CH3; or R(2) is (C1-C9)-heteroalkyl, which is attached via C or N and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine; or R(2) is -SR(18), -OR(18), -NR(18)R(19) or -CR(18)R(19)R(20); where R(18) is -CaH2a-(C1-C9)-heteroalkyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine, dimethylamine; a is zero or 1; R(19) and R(20) are independently defined as R(18) or are hydrogen or CH3; or R(2) is R(21)-SOm or R(22)R(23)N-SO2-; m is 2; R(21) is (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(24); n is zero or 1; R(24) is (C3-C8)-cycloalkyl or phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(27)R(28); where R(27) and R(28) are hydrogen or CH3; R(22) is hydrogen, (C1-C8)-alkyl, CF3, (C3-C8)-alkenyl or -CnH2n-R(29); n is zero or 1; R(29) is (C3-C8)-cycloalkyl or phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(30)R(31); where R(30) and R(31) are hydrogen or CH3; R(23) is hydrogen or CH3; or R(22) and R(23) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; or R(2) is R(33)X-; X is oxygen, S, NR(34), (C=O)A- or NR(34)C=MN(*)R(35)-; M is oxygen; A is oxygen or NR(34); R(33) is (C1-C8)-alkyl, (C3-C8)-alkenyl, (CH2)bCdF2d+1 or -CnH2n-R(36); b is zero or 1; d is 1, 2, 3, 4, 5, 6 or 7; n is zero or 1; R(36) is (C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl methoxyl and NR(37)R(38); where R(37) and R(38) are hydrogen or CH3; R(34) is hydrogen or (C1-C4)-alkyl; R(35) is defined as R(33); or R(33) and R(34) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; where A and N(*) are attached to the phenyl nucleus of the base body of bezoylguanidine; or R(2) is -SR(40), -OR(40), -NHR(40), -NR(40)R(41), -CHR(40)R(42), -CR(42)R( 43)0H, -C=CR(45), -CR(46)=CR(45) or -[CR(47)R(48)]u-CO-[C(R49)R(50)]v-R( 44); where R(40) and R(41) independently of each other are -(CH2)p-(CHOH)q-(CH2)r-(CHOH)t- R(51) or -(CH2)p-O-(CH2-CH2O)q-R(51); R(51) is hydrogen or methyl; u is 1, 2, 3 or 4; v is zero, 1, 2, 3 or 4; p, q and r independently of each other are zero, 1, 2, 3 or 4; t is 1, 2, 3 or 4; R(42) and R(43) are independently hydrogen or (C1-C6)-alkyl or together with by the carbon atom carrying them are (C3-C8)-cycloalkyl; R(44) is (C1-C6)-alkyl, (C3-C8)-cycloalkyl or -CeH2e-R(45); e is zero, 1, 2, 3 or 4; R(45) is phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(52)R(53); where R(52) and R(53) are hydrogen, CH3; or R(45) is (C1-C9)-heteroalkyl, unsubstituted or substituted as phenyl; or R(45) is (C1-C6)-alkyl, unsubstituted or substituted with 1-3 OH; or R(46), R(47), R(48), R(49) and R(50) are independently hydrogen or methyl; or R(2) is R(55)-NH-SO2-; R(55) is R(56)R(57)N-(C=Y)-; Y is oxygen, S or N-R(58); R(56) and R(57) are independently hydrogen, (C1-C8)-alkyl. (C3-C6)-alkenyl or -CfH2{-R(59); f is zero or 1; R(59) is (C5-C7)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methoxyl and (C1-C4)-alkyl; or R(56) and R(57) together there are 4 or 5 methyl groups, one of which CH2-group can be replaced by oxygen, S, NH, N-CH3 or N-benzyl; R(58) is defined as R(56); R(3), R(4) and R(5) are independently defined as either R(1) or R(2). 3. Compounds of formula I according to claim 1, characterized in that: R(1) is R(6)-CO or R(7)R(8)N-CO; R(6) is (C1-C4)-alkyl, CF3 or -CnH2n-R(9), n is zero; R(9) is (C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(10)R(11); R(10) and R(11) independently of each other are hydrogen or CH3; R[7] is hydrogen, (C1-C4)-alkyl, CF3 or -CnH2n-R(12); n is zero; R(12) is (C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(13)R(14), where R(13) and R(14) are hydrogen or CH3; R(8) is hydrogen or CH3; R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3, or -CnH2nR(15); n is zero, 1 or 2; R(15) is (C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted with 1-3 substituents from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17), where R(16) and R(17) are hydrogen or CH3; or R(2) is quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are bonded through C or N, and which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine; or R(2) -SR(18), -OR(18) or NR(18)R(19); R(18) is quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are bonded through C or N, and which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine; or R(2) is R(33)X-; X is oxygen, S or NR(34); R(33) is (C1-C8)-alkyl, (CH2)bCdF2d+1 or -CnH2n-R(36); b is zero or 1; d is 1, 2, 3, 4, 5, 6 or 7; n is zero or 1; R(36) is phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl methoxyl and NR(37)R(38); R(37) and R(38) are hydrogen or CH3; R(34) is hydrogen or (C1-C4)-alkyl; or R(2) is -OCR(45); R(45) is phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(52)R(53); where R(52) and R(53) are hydrogen or CH3; R(3) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3 or -CnH2nR(15); n is zero, 1, or 2; R(15) is (C3-C8)-cycloalkyl or phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(16)R(17); R(16) and R(17) are H or CH3; or R(3) is quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are bonded through C or N, and which are unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine and dimethylamine; or R(3) is R(21)-SOm or R(22)R(23)N-SO2-; m is 2; R(21) is (C1-C4)-alkyl or CF3; R(22) is hydrogen, (C1-C4)-alkyl, CF3 or CnH2n-R(29); n is zero or 1; R(29) is phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(30)R(31); where R(30) and R(31) are H or CH3; R(23) is hydrogen or CH3; or R(3) is -C=CR(45); where R(45) is phenyl, unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(52)R(53); where R(52) and R(53) are hydrogen or CH3; R(4) and R(5) are independently hydrogen, OH or NHR(60); R(60) is (C1-C4)-alkyl. 4. Compounds of formula I according to claim 1, characterized in that: R(1) is R(6)-CO; R(6) is (C1-C4)-alkyl or CF3; R(2) is defined as R(1), or is H, OH, F, Cl, Br, I, (C1-C8)-alkyl or CF3; or R(2) is -SR(18) or -OR(18); R(18) is pyridyl, which is linked through C or N, and which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxyl, hydroxyl, amine, methylamine, dimethylamine; or R(2) is R(33)X-; X is oxygen or S; R(33) is (C1-C8)-alkyl or -CnH2n-R(36); n is zero or 1; R(36) is phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(37)R(38); where R(37) and R(38) are hydrogen or CH3; R(3) is H, OH, F, Cl, Br, I, (C1-C8)-alkyl, CF3 or -CnH2nR(15); n is zero, 1, or 2; R(15) is phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxyl and NR(16)R(17); R(16) and R(17) are H or CH3; or R(3) is R(21)-SOm; m is 2; R(21) is (C1-C4)-alkyl or CF3; R(4) and R(5) are independently hydrogen, OH or NHR(60); R(60) is (C1-C4)-alkyl; 5. Compounds of formula I according to claim 1, characterized in that at most two of the substituents R(2), R(3), R(4) and R(5) are OH-groups. 6. Process for the production of compound I according to claim 1, characterized in that one compound of formula II [image] reacts with guanidine, where R(1) to R(5) have the meaning given in Patent Claim 1, and L denotes a nucleophile easily replaceable leaving group. 7. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment of arrhythmia. 8. A method for the treatment of arrhythmia, characterized in that an effective amount of one compound I according to Patent Claim 1 is combined (mixed) with common additives and given to the patient in a suitable form. 9. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of heart attack. 10. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment or prophylaxis of angina pectoris. 11. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic elderly hearts. 12. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and apoplexy. 13. Use of compound I according to claim 1, characterized in that it is used for the production of a drug for the treatment or prophylaxis of ischemic conditions of peripheral organs and extremities. 14. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for the treatment of shock conditions. 15. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for use in surgical operations and organ transplants. 16. Use of compound I according to claim 1, characterized in that it is used for the production of a medicine for preservation and storage of grafts for surgical procedures. 17. Use of compound I according to claim 1, characterized by the fact that it is used for the production of a drug for the treatment of diseases in which cell proliferation is the primary or secondary cause, and thus its use as an antiatherosclerotic agent, agents against diabetic late complications, cancer diseases, fibrotic diseases such as pneumonia, inflammation of the liver or inflammation of the kidneys, hyperplasia of the prostate. 18. Application of compound I according to claim 1, characterized in that it is used for the production of scientific tools (aids) for inhibition of Na+/H+ for the diagnosis of hypertension and proliferative diseases. 19. Medicine, characterized in that it contains an effective amount of compound I according to Patent Claim 1.