SI9500362A - Substituted benzoyl guanidines, process for the preparation thereof, use thereof as a medicine or as a diagnostic agent as well as a medicine containing them - Google Patents

Abstract

Hydroxylated benzoyl-guanidines (I) and their salts are new: R<1> = R<6>-CO; or R<7>R<8>N-CO; R<6> = 1-8C alkyl, perfluoro-1-8C alkyl; 3-8C alkenyl; or -CnH2n-R<9>; n = 0-4; R<9> = 3-8C cycloalkyl; or phenyl, biphenylyl or naphthyl opt. mono-, di- or trisubstd. by F, Cl, CF3, Me, OMe or NR<10>R<11>; R<10>,R<11> = H; 1-4C alkyl; or perfluoro-1-4C alkyl; R<7> = H; 1-8C alkyl, perfluoro-1-8C alkyl; 3-8C alkenyl; or -CnH2n-R<9>; and R<8> = H; 1-4C alkyl; or perfluoro-1-4C alkyl; or R<7> + R<8> = tetra- or pentamethylene with 1 CH2 opt. replaced by O,S,NH,NMe or N-benzyl; R<2> = a) R<1>; H; OH; F; Cl; Br; I; CN; NO2; 1-8C alkyl, perfluoro-1-8C alkyl; 3-8C alkenyl or -CnH2n-R<9>; b) N- or C-bonded 1-9C heteroaryl opt. mono-, di- or trisubstd. by F, Cl, CF3, Me, OMe, NHMe or NMe2; c) SR<18>; OR<18>; NR<18>R<19>; or CR<18>R<19>R<20>; d) R<6>-SOm-; or R<7>R<8>N-SO2-; e) R<33>X-; f) SR<40>; OR<40>; NHR<40>; NR<40>R<41>; CHR<40>R<42>; CR<42>R<43>OH; C IDENTICAL CR<45>; CR<46>=CR<45>; or -ÄCR<47>R<48>Üu-CO-ÄCR<49>R<50>Üv-R<44>; g) R<55>-NH-SO2; R<18> = -CaH2a-1-9C heteroaryl opt. mono-, di- or trisubstd. by F, Cl, CF3, Me, OMe, OH, NH2, NHMe or NMe2; a = 0-2; m = 1-2; R<19>,R<20> = H; R<18>; 1-4C alkyl; or perfluoro-1-4C alkyl; X = O; S; NR<34>; (D=O)A-; or NR<34>C=MN*R<35>, with A and N* being bonded to the Ph gp. in (I); M = O or S; A = O or NR<34>; D = C or SO; b = 0 or 1; d = 1-7; R<33>, R<35> = 1-8C alkyl; 3-8C alkenyl; -(CH2)bCdF2d+1; or -CnH2n-R<9>; R<34> = H; 1-4C alkyl; or perfluoro-1-4C alkyl; or R<33> + R<34> = tetra- or pentamethylene with 1 CH2 opt. replaced by O, S, NH, NMe or N-benzyl; R<40>,R<41> = -(CH2)p(CHOH)q-(CH2)r-(CHOH)t-R<51>; or -(CH2)p-O-(CH2-CH2O)q-R<51>; u,t = 1-4; p,q,r,v = 0-4; R<42>,R<43> = H or 1-6 alkyl; or CR<42>R<43> = 3-8C cycloalkyl; R<44> = H; 1-6C alkyl; 3-8C cycloalkyl; or -CeH2e-R<45>; e = 0-4; R<45> = phenyl or 1-9C heteroaryl opt. mono-, di- or trisubstd. by F, Cl, Me, OMe or NR<52>R<53>; or 1-6C alkyl opt. mono-, di- or trisubstd. by OH; R<46>-R<51> = H or Me; R<52>,R<53> = H or 1-4C alkyl; R<55> = R<56>R<57>N-(C=Y)-; Y = O; S; or NR<58>; R<56>,R<57> = H; 1-8C alkyl; 3-6C alkenyl; or -CfH2f-R<59>; f = 0-4; R<59> = 5-7C cycloalkyl or phenyl opt. mono-, di- or trisubstd. by F, Cl, CF3, OMe or 1-4C alkyl; or R<56> + R<57> = tetra- or pentamethylene with 1 CH2 opt. replaced by O,S, NH, NMe or NBz; R<58> = R<56> or amidino; R<3>-R<5> = R<1> or R<2>; provided that at least 1 of R<2>-R<5> is OH.

Description

HOECHST AKTIENGESELLSCHAT

Substituted benzoylguanidines, process for their preparation, use as a medicament or diagnostician as well as medicament containing

The invention relates to benzoylguanidines of formula I

where they mean

R (1) R (6) -C0 or R (7) R (8) N-CO;

R (6) (C-Cgj alkyl, (C ^ Cgj-perfluoroalkyl, (C ₃ -C _g) -alkenyl or

-0, ^ (9), n 0,1,2, 3 or 4;

R (9) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (10) R (11); R (10) and R (ll)

H, (Cj-CJ-alkyl or a (C ₁ -C ₄₎ -perfluoroalkyl;

R (7) is H, (C _f C ₈₎ -alkyl, (C ₁ -C ₈₎ -perfluoroalkyl, (C ₃ -C _g) -alkenyl or <7 ^ (12), n is 0,1,2,3 or 4;

R (12) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (13) R (14); R (13) and R (14)

H, (C ₁ -C ₄ ) -alkyl or (C 1 -CJ-perfluoroalkyl;

R (8) is H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl, or

R (7) and R (8) together or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl;

R (2) defined as R (1) or H, OH, F, Cl, Br, J, CN, NO ₂ , (C _f C ₈ ) -alkyl, (C _f C ₈ ) perfluoroalkyl, (C ₃ -C ₈ ) -alkenyl or -CH _2n -R (15), n 0,1, 2,3 or 4;

R (15) (C ₃ -C ₈ ) -cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (16) R (17;

R (16) and R (17)

H, (C1-C6-alkyl or (C1-C6-perfluoroalkyl; or

R (2) (C ₁ -C _g ) -heteroaryl which is bonded via C or N and is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

or

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

R (18) -C _a H _2a - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

a is 0,1 or 2;

R (19) R (20) independently of one another are defined as R (18) or are hydrogen, (C _x -C ₄₎ alkyl or (C ₁ -C ₄₎ -perfluoroalkyl;

or

R (2) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 1 or 2;

R (21) (C-Cgj-alkyl, (Cl-Cgj-perfluoroalkyl, (C ₃ -C _g) -alkenyl or -C "IVR (24), n is 0,1,2,3 or 4;

R (24) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (27) R (28;

R (27) andR (28)

H, (C _f C ₄ ) -alkyl or (C _f C ₄ ) -perfluoroalkyl;

R (22) H, (C ₁ -C ₈ -alkyl, (C ₁ -C ₈ -perfluoroalkyl, (C ₃ -C ₈ ) -alkenyl or

-cjVRm n 0.1, 2.3 or 4;

R (29) (C ₃ -C ₈ ) -cycloalkyl, phenyl, biphenylyl or naphthyl, the aromatics being unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (30) R (31);

R (30) and R (31)

H, (Cj-CJ-alkyl or a (C ₁ -C ₄₎ -perfluoroalkyl;

R (23) is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or

R (22) and R (23) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl;

or

R (2) R (33) X-;

X 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 C or SO;

R (33) (C ₁ -C _g) alkyl, (C ₃ -C ₈₎ -alkenyl, (CH _{2) b} C _d F _{2d + 1} or - ^C "H ₂ ^{N-R (36),} 'b 0 or 1;

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

n 0,1,2,3 or 4;

R (36) (C ₃ -C ₈ ) -cycloalkyl, phenyl, biphenylyl or naphthyl, wherein the aromatics are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (37) R (38);

R (37) and R (38)

H, (Cj-C ^ alkyl or (C ₁ -C ₄₎ -perfluoroalkyl;

R (34) is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl;

R (35) defined as R (33);

or

R (33) and R (34) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl;

wherein A and N are attached to the phenyl core of the benzoylguanidine base skeleton; or

R (2) 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)] _in -CO- [CR (49) R (50)] _in -R ( 44);

R (40) and R (41) independently of one another are - (CH2-CHOH4-CH2V2CHOHVRCS1) or - (CH2-O ^ CH / MjC4-Rp1);

R (51) is hydrogen or methyl;

in 1,2,3 or 4;

in 0,1,2,3 or 4;

p, q and r independently of each other 0,1,2,3 or 4; t 1,2,3 or 4;

R (42) and R (43) independently of one another are hydrogen or (C1-C4-alkyl) or

R (42) and R (43) together with the carbon atom joining them wears, (C ₃ -C _g) -cycloalkyl;

R (44) is hydrogen, (C _f C ₆₎ -alkyl, (C ₃ -C _g) -cycloalkyl, -C _e H _2e -R (45);

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

R (45) phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53);

R (52) and R (53)

H or (C1-C6-alkyl;

or

R (45) (C 1 -C 16 -heteroaryl, which is unsubstituted or substituted as phenyl;

or

R (45) (C 1 -C 6 alkyl, unsubstituted or substituted with 1 to 3 OH;

R (46), R (47), R (48), R (49) and R (50) independently of one another are hydrogen or methyl; or

R (2) R (55) -NH-SO ₂ -;

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

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

R (56) and R (57) independently of one another hydrogen, (C ^ Cgj -alkyl, (C ₃ -C ₆₎ -alkenyl or -C ^ R ^); f 0,1,2,3 or 4;

R (59) (C ₅ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methoxy and (C 1 -C 6) alkyl ;

or

R (56) and R (57) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted with oxygen, S, NH, N-CH ₃ 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), with at least one of the substituents R (2), R (3), R (4) and R (5) is equal to OH;

as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula I in which they mean:

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

R (6) (C _f C ₈ ) -alkyl, CF ₃ (C ₃ -C ₈ ) -alkenyl, -C _n H _2n - ^R (9), η Ο or 1;

R (9) (C ₃ -C ₈ ) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (10) R ( ll);

R (10) and R (ll)

H or CH ₃ ;

R (7) is hydrogen, (C ₁ -C _g) alkyl, CF _3, (C ₃ -C _g) -alkenyl or -CH ^ RtlZ), n is 0 or 1;

R (12) (C ₃ -C ₈ ) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (13) R ( 14),

R (13) and R (14)

HaliCH ₃ ;

R (8) is hydrogen or CH ₃ ;

R (2) defined as R (1) or H, OH, F, Cl, Br, I, CN, NO ₂ , (C _f C ₈ ) -alkyl, CF ₃ , (C ₃ C ₈ ) -alkenyl or -CH _2n -R (15), n 0,1 or 2;

R (15) (C ₃ -C _g) -cycloalkyl or phenyl;

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

R (16) and R (17) are hydrogen or CH ₃ ;

or

R (2) (C1-Cgj-heteroaryl, which is linked via C or N and is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino , methylamino and dimethylamino;

or

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

R (18) -C _a H _2a - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino, dimethylamino;

a is O or 1;

R (19) and R (20) are independently defined from each other as R (18) or hydrogen or CH ₃ ; or

R (2) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 2;

R (21) (C ₁ -C ₈ alkyl, CF ₃ , (C ₃ -C ₈ ) -alkenyl or -C _n H _2n -R (24), n 0 or 1;

R (24) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (27) R (28); R (27) and R (28) are hydrogen or CH ₃ ;

R (22) is hydrogen, (C ₁ -C ₈ ) -alkyl, CF ₃ , (C ₃ -C ₈ ) -alkenyl or -C 1 -R 4), n 0 or 1,

R (29) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (30) R ( 31);

R (30) and R (31) are hydrogen or CH ₃ ;

R (23) is hydrogen or CH ₃ ;

or

R (22) and R (23) together are 4 or 5 methylene groups, of which one group of CH _{2 may be} replaced by oxygen, S, NH, N-CH ₃ or N-benzyl;

or

R (2) R (33) X-;

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

M oxygen;

A is oxygen or NR (34);

R (33) (C1-C8-alkyl, (C ₃ -C ₈ ) -alkenyl, (CH ₂ ) _b C _d F _{2d + 1} or -CH _2n- R (36), b 0 or 1;

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

n is 0 or 1;

R (36) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (37) R (38);

R (37) and R (38) are hydrogen or CH ₃ ;

R (34) is hydrogen or (C ₁ -C ₄ ) -alkyl;

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

R (33) and R (34) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted with oxygen, S, NH, N-CH ₃ or N-benzyl;

wherein A and NO are attached to the phenyl core of the benzoylguanidine base skeleton;

or

R (2) 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)] _in -CO- [CR (49) R (50)] _in -R ( 44);

R (40) and R (41) independently of one another - (CH ₂ ) _p - (CHOH) _q - (CH ₂ ) _r - (CHOH) _t R (51) or - (CH ₂ ) _p -O- (CH ₂ -CH ₂ O) _q -R (51);

R (51) is hydrogen or methyl; in 1, 2, 3 or 4; in 0,1, 2,3 or 4;

p, q and r independently of each other 0,1,2,3 or 4; t 1,2,3 or 4; 'J

R (42) and R (43) independently of one another are hydrogen or (C ₁ -C ₆₎ -alkyl or together with the carbon atom joining them wears, (C ₃ -C _g) -cycloalkyl;

R (44) (C _f C ₆₎ -alkyl, (C ₃ -C _g) -cycloalkyl or -C _e H _2e -R (45); e is 0,1,2,3 or 4;

R (45) phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53);

R (52) and R (53) are hydrogen, CH ₃ ;

or

R (45) (C ₁ -C ₉ ) -heteroaryl, which is unsubstituted or substituted as phenyl, or

R (45) (C 1-6 alkyl which is unsubstituted or substituted with 1 to 3 OH;

R (46), R (47), R (48), R (49) and R (50) independently of one another are hydrogen or methyl; or

R (2) R (55) -NH-SO ₂ -;

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

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

R (56) and R (57) independently of one another hydrogen, (C ^ Cgj -alkyl, (C ₃ -C ₆₎ -alkenyl or -C _f H _2f -R (59);

f O or 1;

R (59) (C ₅ -C ₇ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methoxy and (C ₁ -C ₄ ) -alkyl;

or

R (56) and R (57) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ 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), with at least one of the substituents R (2), R (3), R (4) and R (5) are OH;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I in which they mean:

R (1) R (6) -C0 or R (7) R (8) N-CO;

R (6) (C ₁ -C ₄ ) -alkyl, CF ₃ or -CH 2 _n -R (9), n 0;

R (9) (C ₃ -C 8) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (10) R (ll);

R (10) and R (11) independently of one another are hydrogen or CH ₃ ; R (7) is hydrogen, (C ₁ -C ₄ ) -alkyl, CF ₃ or n 0;

R (12) (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (13) R (14),

R (13) and R (14) are hydrogen or CH ₃ ;

R (8) is hydrogen or CH ₃ ;

R (2) is defined as R (1) or H, OH, F, Cl, Br, I, (C 1 -C 6 -alkyl, CF ₃ or -CH 2 _n- R (15), n 0,1 or 2;

R (15) (C ₃ -C ₈ ) -cycloalkyl or phenyl;

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

R (16) and R (17) are hydrogen or CH ₃ ;

or

R (2) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy , amino, methylamino and dimethylamino;

or

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

R (18) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

or

R (2) R (33) X-;

X is oxygen, S or NR (34);

R (33) (C-Cgj-alkyl, (CH ^ C ^ s or -CH ₂ "-R (36), b is 0 or 1;

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

η Ο or 1;

R (36) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF _y methyl, methoxy and NR (37) R (38);

R (37) and R (38) are hydrogen or CH ₃ ;

R (34) is hydrogen or (C ₁ -C ₄ ) -alkyl; or

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

R (45) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53); R (52) and R (53) are hydrogen or CH ₃ ;

R (3) defined as R (1) or H, OH, F, Cl, Br, I, (C _f C ₈ ) -alkyl, CF ₃ or -CH _2n- R (15), n 0,1 or 2 ;

R (15) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF _y methyl, methoxy and NR (16) R (17) );

R (16) and R (17)

HaliCH ₃ ;

or

R (3) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino;

or

R (3) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 2;

R (21) (C ₁ -C ₄ ) -alkyl or CF ₃ ;

R (22) is hydrogen, (C? -Alkyl, CF ₃ or CH _2n -R (29);

n is 0 or 1;

R (29) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (30) R (31);

R (30) and R (31) are hydrogen or CH ₃ ;

R (23) is hydrogen or CH ₃ ; or

R (3) -C ^ CR (45);

R (45) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53);

R (52) and R (53) are hydrogen or CH ₃ ;

R (4) and R (5) independently of one another are hydrogen, OH or NHR (60);

R (60) (C ₁ -C ₄ ) -alkyl;

wherein at least one of the substituents R (2), R (3), R (4) and R (5) must be OH, as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I in which they mean:

R (1) R (6) -CO;

R (6) (C ₁ -C ₄ ) -alkyl or CF ₃ ;

R (2) is defined as R (1) or H, OH, F, Cl, Br, I, (C ₁ -C ₈ ) -alkyl or CF ₃ ;

or

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

R (18) pyridyl which is linked via C or N and is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino ;

or

R (2) R (33) X-:

X is oxygen or S;

R (33) (C ₁ -C ₈ ) -alkyl or -CH 2 _n -R (36); n is 0 or 1;

R (36) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and

NR (37) R (38);

R (37) and R (38) are hydrogen or CH ₃ ;

R (3) H, OH, F, Cl, Br, I, (C ₁ -C ₈ ) -alkyl, CF ₃ or -CH 2 -R 4); n is 0.1 or 2;

R (15) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (16) R (17);

R (16) and NR (17) are hydrogen or CH ₃ ; or

R (3) R (21) -SO _m ; m 2;

R (21) (C ₁ -C ₄ ) -alkyl or CF ₃ ;

R (4) and R (5) independently of one another are hydrogen, OH or NHR (60);

R (60) (C ₁ -C ₄ ) -alkyl;

however, at least one of the substituents R (2), R (3), R (4) and R (5) must be the same OH as their pharmaceutically acceptable salts.

By (C ₁ -C ₉ ) -heteroaryl is meant in particular residues derived from phenyl or naphthyl in which one or more CH groups are replaced by N and / or in which at least two adjacent CH groups are formed (to form a five-membered aromatic rings) are replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of the bicyclic residues (as in indolizinyl) may also be N atoms.

Furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolin, indazolyl, quinolyl, indazolyl, quinolyl, indazolyl, quinolyl, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolyl, indazolyl, quinolin, quinolinyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, indazolyl, quinolin, quinolinol

If one of the substituents R (1) to R (60) contains one or more asymmetry centers, both S and R may be configured. The compounds may thus be present as optical isomers, as diastereomers, as racemates, or as mixtures thereof.

The labeled alkyl residues can be both straight and branched.

The invention further relates to a process for the preparation of compound I, wherein the compound of formula II

is reacted with guanidine, where R (1) to R (5) have the indicated meaning, and L stands for a readily nucleophilic substitutable leaving group.

Activated acid derivatives of formula II, wherein L represents alkoxy, preferably methoxy group, phenoxy group, phenylthio, methylthio, 2-pyridylthio group, nitrogen heterocycle, preferably 1-imidazolyl, are obtained in a known manner from basic carboxylic acid chlorides (formula II , L = Cl), which in turn are obtained in a known manner from basic carboxylic acids (formula II, L = OH), e.g. with thionyl chloride.

In addition to the carboxylic acid chlorides of formula II (L = Cl), further activated acid derivatives of formula II can also be prepared in a known manner directly from basic benzoic acid derivatives (formula II, L = OH), such as e.g. methyl esters of formula II with L = OCH ₃ treated with gaseous HC1 in methanol, imidazolides of formula II treated with carbonyldiimidazole (L = 1-imidazolyl, Staab, Angew.Chem. Int. Ed. Eng. 1.351367 (1962) ), mixed anhydrides II with C1-COOC ₂ H ₅ or tosyl chloride in the presence of triethylamine in an inert solvent, as well as the activation of benzoic acids by dicyclohexylcarbodiimide (DCC) or by O - [(cyano (ethoxycarbonyl) -methylene) amino] -1, 1,3,3tetramethyluronium tetrafluoroborate (TOTU) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of formula II are cited when citing literature in J. March,

Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The activated carboxylic acid derivative of formula II is reacted with guanidine in a known or non-protic polar but inert organic solvent. Methanol, isopropanol or THF were treated with guanidine in the reaction of benzoic acid methyl esters (II, L = OMe) between 20 ° C and the boiling point of these solvents. Most of the metabolites of Compounds II with guanidine without salt are advantageously employed in aprotic inert solvents such as THF, dimethoxyethane, dioxane. Water can also be used as a solvent, using a base such as a base. NaOH, in metabolism II with guanidine.

When L is Cl, it is advantageous to add acid binding agents, e.g. in the form of excess guanidine for the binding of hydrochloric acid.

A portion of the basic benzoic acid derivatives of formula II is known and described in the literature. The unknown compounds of formula II can be prepared by methods known in the literature. The benzoic acid obtained according to one of the above described variants of the process is converted to the compounds I according to the invention.

The introduction of some of the substituents into positions 3, 4 and 5 succeeds with the known methods of the palladium-mediated cross-couplings of aryl halides or palladium. aryltriflates with e.g. organostanes, organoboric acids, or organoborans, or organobacilli or. - zinc compounds.

Benzoylguanidines I are generally weak bases and can bind acid when salt is formed. Acid addition salts include salts of all pharmacologically tolerable acids, e.g. halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluenesulfonates.

Compounds I are substituted acylguanidines.

The most prominent representative of acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. Many other amiloride type compounds have been reported in the literature, such as e.g. dimethylamiloride or ethylisopropylamiloride.

About NH II II C.

nh ₂ amiloride: R ', R = H dimethylamiloride: R', R = CH ₃ ethylisopropylamiloride: R '= C ₂ H ₅ , R = CH (CH ₃ ) ₂

In addition, investigations are known to indicate the antiarrhythmic properties of amiloride (Circulation 79,1257-63 (1989). However, widespread use as an antiarrhythmic is hampered by the fact that this effect is only weakly expressed and is accompanied by a decrease in blood pressure and saluretic effect These side effects are undesirable in the treatment of heart rhythm disorders.

Indications of the antiarrhythmic properties of amiloride were also obtained in experiments on isolated animal hearts [Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)]. Thus, for example, found in the hearts of rats that artificially triggered ventricular tremors could be completely prevented by amiloride. Even stronger than amiloride in this model was the abovementioned amiloride derivative ethylisopropylamiloride.

U.S. Patent No. 5,091,394 (HOE 89 / F 288) discloses benzoylguanidines having the hydrogen atom in the corresponding R (1) position. Benzoylguanidines have been proposed in German patent application P 42 04 575.4 (HOE 92 / F 034), in which the substituents do not have the required meanings according to the present invention.

In US Patent 3,780,027, acylguanidines, which are structurally similar to compounds of formula I and derived from commercially available foam diuretics such as bumetanide, have been proposed for protection. Accordingly, these compounds have been reported to have potent salidiuretic efficacy.

It was, therefore, surprising that they do not have the compound of the invention of the undesirable and deleterious salidiuretic properties but have very good antiarrhythmic properties, such as are important in the treatment of diseases occurring e.g. for the occurrence of oxygen deficiency. Due to their pharmacological properties, the compounds are well-suited as antiarrhythmic agents with a cardioprotective component for infarction prophylaxis and for the treatment of infarction as well as for the treatment of angina, preventing or severely reducing pathophysiological processes in the production of ischemically induced injuries, especially in triggering ischemic heart failure. arrhythmia. Due to their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I of the invention can be used as a treatment for inhibiting the cellular Na ⁺ / H ⁺ exchange mechanism as a treatment for all acute or chronic ischemia-induced injuries, or thus primary or secondary induced diseases. This refers to their use as medicines for surgery, e.g. organ transplants, wherein the compounds can be used both to protect the organs in the donor from before and during collection, to protect the organs removed, e.g. when treated with or stored in physiological bath fluids as well as when translated into a recipient organism. The compounds are also valuable, protective effect agents in performing angioplasty surgeries, e.g. on the heart as well as on the peripheral veins. In accordance with their protective effect against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular the central nervous system, for example. to treat stroke or brain edema. In addition, the compounds of formula I of the invention are also suitable for the treatment of shock forms, such as e.g. allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of formula I of the invention are characterized by a potent inhibitory effect on cell proliferation, e.g. fibroblast cell proliferation and vascular smooth muscle cell proliferation. Therefore, the compounds of formula I are considered to be valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause and can therefore be used as anti-atherosclerotic agents, late-onset diabetic agents, cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or renal fibrosis, organic hypertrophies and hyperplasia, especially in prostate hyperplasia or. prostate hypertrophy.

The compounds of the invention are effective inhibitors of the cellular antiporter sodium (a ^{+ +} H ⁺ exchanger), which in many diseases (essential hypertension, atherosclerosis, diabetes, etc.) is also elevated in such cells as are readily available for measurement, such as . in erythrocytes, platelets or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific tools, e.g. in its use as a diagnostic tool for determining and differentiating between various forms of hypertension, as well as atherosclerosis, diabetes, proliferative diseases, etc. In addition, the compounds of formula I are suitable for preventive therapy to prevent the genesis of high blood pressure, e.g. essential hypertension.

Compounds of the invention have significantly improved water solubility compared to known compounds. Therefore, they are significantly more suitable for i.v. applications.

Medicaments containing compound I may be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration depending on the particular appearance of the disease. Compounds I can be used alone or together with galenic auxiliaries, both in veterinary and human medicine.

Which of the excipients is suitable for the desired drug formulation is known to one skilled in the art based on his or her expertise. In addition to solvents, gel makers, suppository bases, excipients for tablets and other carriers for effective substances, e.g. antioxidants, dispersants, emulsifiers, foam removers, flavors, preservatives, solubilizers or colorants.

For oral administration, the active compounds are mixed with suitable additives such as carriers, stabilizers or inert diluents, and by conventional methods put into suitable dosage forms such as tablets, dragees, plug caps, aqueous, alcoholic or oily solutions. For example, inert carriers can be used, e.g. arabic gum, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular maize starch. The preparation can be carried out both as dry and wet granules. As oily carriers or as solvents, e.g. vegetable or animal oils such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, optionally with conventional substances, as solvents, emulsifiers or further excipients, are added to the solution, suspension or emulsion. As solvents, for example, for example: water, saline or alcohols, e.g. ethanol, propanol, glycerin and, in addition, sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned. As a pharmaceutical formulation for formulation

1ί · Aerosols or sprays are suitable e.g. solutions, suspensions or emulsions of the active substance of Formula I in a pharmaceutically acceptable solvent, such as in particular ethanol, or mixtures of such solvents.

The formulation may also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as propellant. Such preparation contains the active substance typically in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight.

The dosage of the active substance of formula I to be administered and the frequency of administration depend on the potency and the duration of effect of the compounds used; in addition, the type and severity of the disease to be treated, as well as the sex, age, weight and individual responsiveness of the mammal to be treated.

The average 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, up to a maximum of 10 mg / kg, preferably 1 mg / kg body weight. In acute disease outbreaks, e.g. immediately after a heart attack, even higher and more frequent doses may be needed, e.g. up to 4 individual doses per day. Particularly at i.v. use, e.g. up to 200 mg daily may be required in a patient with intensive care infarction.

List of abbreviations:

MeOH methanol

DMF N, N-dimethylformamide

El electron impact

Desorption-Chemical Ionisation (DCI)

EE ethyl acetate (EtOAc)

HEP n-heptane

ES electronic spray

FAB Fast Atom Bombardment *

CH ₂ C1 ₂ dichloromethane

THF tetrahydrofuran (dppf) 1,1,1-bis (diphenylphosphino) ferrocene

AIBN azabisisobutyronitrile

The experimental part

General regulation for the preparation of benzoyl guanidines (I)

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

1.0 equivalents of the benzoic acid derivative of formula II are dissolved or resp. was suspended in anhydrous THF and then 1.1 equivalents of carbonyldiimidazole were added. After stirring for more than 2 hours at room temperature, 5.0 equivalents of guanidine are introduced into the reaction solution. After stirring overnight, the THF was distilled off under reduced pressure (in a rotary evaporator), water was added, adjusted with 2N HCl to pH 6 to 7, 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 ether hydrochloric acid or other pharmacologically acceptable acids.

General regulation for the preparation of benzoyl guanidines (I)

Option B: benzoic acid alkyl esters (II, L = O-alkyl)

1.0 equivalents of benzoic acid alkyl ester of Formula II as well as 5.0 equivalents of guanidine (free base) are dissolved in isopropanol or suspended in THF and cooked to complete metabolism (thin layer control) at reflux (typical reaction time 2 to 5 hours). The solvent was distilled off under reduced pressure (rotary evaporator), taken up in 300 ml of EE and washed 3 times with NaHCO ₃ solution. It is dried over Na ₂ SO ₄ , the solvent is distilled off in vacuo and chromatographed on silica gel with a suitable eluant, e.g. EE / MeOH 5: 1. (Salt formation cf. variant A)

Example 1

3-acetyl-4-hydroxy-benzoylguanidine o

o

N la)

4-Acetoxy-benzoic acid was converted by a Fries shift of 3 eq. A1C1 ₃ at

2-f

140 ° C to 3-acetyl-4-hydroxy-benzoic acid.

Ib)

1.0 Eq. 3-Acetyl-4-hydroxy-benzoic acid was digested according to variant A with 1.1 eq. of carbonylimidazole and 5 eq. guanidine.

Colorless crystals, m.p. 218.221 ° C.

Example 2:

3-acetyl-6-hydroxy-benzoylguanidine hydrochloride

N

1.0 Eq. 3-Acetyl-6-hydroxy-benzoic acid was reacted according to variant A with 1.1 eq. of carbonyldiimidazole and 5 eq. guanidine and isolated as hydrochloride.

Colorless crystals, m.p. 170-180 ° C.

Example 3: 3-acetyl-5-bromo-4-hydroxy-benzoylguanidine hydrochloride

a)

The 3-acetyl-4-hydroxybenzoic acid methyl ester was reacted in chlorobenzene with 1.1 eq. Of N-bromosuccinimide followed by AIBN to 3-acetyl-5-bromo-4 hydroxybenzoic acid methyl ester.

Colorless crystals, m.p. 106-108 ° C.

3b)

The ester from 3 a) is converted into variant B into guanidide and isolated as hydrochloride. Crystals, m.p. 230 ° C on decomposition.

Example 4:

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

a) Eq. 4-Acetoxy-3-chloro-benzoic acid was mixed with 3 eq. A1C1 ₃ and heated at 140 ° C for 1 h. Treatment with 2N HCl gave 3-acetyl-5-chloro-4-hydroxy benzoic acid. Yellow crystals, m.p. 226-234 ° C.

4b)

The benzoic acid of 4 a) is converted by variant A into guanidide and isolated as hydrochloride.

Yellowish crystals, m.p. Mp 198-203 ° C.

Pharmacological information

Inhibition of the rabbit erythrocyte Na ⁺ / H ⁺ exchanger

White New Zealand rabbits (Ivanovas) were given a standard diet with 2% cholesterol for six weeks to activate the Na ⁺ / H ⁺ exchange, allowing flame photometric determination of Na ⁺ -influx into erythrocytes via Na ⁺ / H ⁺ exchange. Blood was drawn from the ear arteries and made 25 IU of potassium heparin. A portion of each sample was used for double determination of hematocrit by centrifugation. Aliquots each time

100 μΐ were used to measure the output content of Na ⁺ erythrocytes.

To determine amiloride-sensitive sodium influx, 100 μΐ of each blood sample was incubated in each case with 5 ml of hyperosmole salt-sucrose medium (mmol / 1: 140 NaCI, 3 KC1, 150 sucrose, 0.1 ouabain, 20 tris-hydroxymethylaminomethane) at pH

7.4 and 37 ° C. The erythrocytes were then washed 3 times with ice-cold MgCl ₂ ouabain solution (mmol / 1: 112 MgCl ₂ , 0.1 ouabain) and hemolyzed in 2.0 ml distilled water. The intracellular sodium content was determined by flame photometry.

Na ⁺ -net influx was calculated from the difference between sodium baseline and erythrocyte sodium content after incubation. Amyloride inhibitory sodium influx was obtained from the difference in erythrocyte sodium content after incubation with and without amiloride 3 x 10 ^-4 mol / l. In this way, the compounds of the invention were also treated.

Results

Inhibition of Na ⁺ / H ⁺ -exchangers:

Example IC ₅₀ pmol / l

2.0 χ IO ' ⁶

10 χ 10 ' ⁶ > 10 χ 10' ⁶

2-3 χ 10 ' ⁶

For

Hoechst Aktiengesellschaft:

Claims (18)

PATENT APPLICATIONS Claims 1. Benzoylguanidine of the formula I wherein they are R (1) R (6) -CO or R (7) R (8) N-CO; R (6) (C1-C8-alkyl, (C ₁ -C _g ) -perfluoroalkyl, (C ₃ -C _g ) -alkenyl or -CH ₂ '-R (9j, n 0,1, 2, 3 or 4; R (9) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (10) R (11); R (10) and R (ll) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; R (7) H, (C ₁ -C _g ) -alkyl, (C ₁ -C _g ) -perfluoroalkyl, (C ₃ -C _g ) -alkenyl, or -cjVRP ² ). n 0,1,2,3 or 4; R (12) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (13) R (14); R (13) and R (14) H, (C ₁ -C ₄ ) -alkyl or (C 1 -CJ-perfluoroalkyl; R (8) is H, (C 1 -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl, or R (7) and R (8) together A compound of formula I according to claim 1, characterized in that R (1) is R (6) -CO or R (7) R (8) is N-CO; R (6) (C ₁ -C 8) -alkyl, CF ₃ (C ₃ -C ₈ ) -alkenyl, -C _n H _2n -R (9), n O or 1; R (9) (C ₃ -C 8) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (10) R (11l) ); R (10) and R (ll) H or CH ₃ ; R (7) is hydrogen, (C ^ Cgj-alkyl, CF _3, (C ₃ -C _g) -alkenyl or -C ^ -RCIZ), n is O or 1; R (12) (C ₃ -C 8) -cycloalkyl, phenyl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF _y methyl, methoxy and NR (13) R (14) , R (13) and R (14) H or CH ₃ ; R (8) is hydrogen or CH ₃ ; R (2) defined as R (1) or H, OH, F, Cl, Br, I, CN, NO ₂ , (C _f C _g ) -alkyl, CF ₃ , (C ₃ C _g ) -alkenyl or -CH _2n -R (15), n 0,1 or 2; R (15) (C ₃ -C ₈ ) -cycloalkyl or phenyl; which is unsubstituted or substituted with 1 to 3 substituents from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (16) R (17); R (16) and R (17) are hydrogen or CH ₃ ; or R (2) (C ₁ -C ₉ ) -heteroaryl which is bonded via C or N and is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF _and CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (2) SR (18), -OR (18), -NR (18) R (19) or -CR (18) R (19) R (20); R (18) -C _a H _2a - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino, dimethylamino; a is 0 or 1; R (19) and R (20) are independently defined from each other as R (18) or hydrogen or CH ₃ ; or R (2) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 2; R (21) (C ₁ -C ₈ ) -alkyl, CF ₃ , (C ₃ -C ₈ ) -alkenyl or -C _n H _2n -R (24), n 0 or 1; R (24) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (27) R (28); R (27) and R (28) are hydrogen or CH ₃ ; R (22) is hydrogen, (C ₁ -C ₈ ) -alkyl, CF ₃ , (C ₃ -C ₈ ) -alkenyl or -CH _2n- R (29), n 0 or 1, R (29) (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted or substituted with 1 to 3 substituents from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (30) R ( 31); R (30) and R (31) are hydrogen or CH ₃ ; R (23) is hydrogen or CH ₃ ; or R (22) and R (23) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl; or R (2) R (33) X-; X oxygen, S, NR (34), (C = O) A- or NR (34) C = MN (*) R (35) -; M oxygen; A is oxygen or NR (34); R (33) (C 1 -C ₈ ) -alkyl, (C ₃ -C ₈ ) -alkenyl, (CH 2 Cl 2, or -CH 2 _n -R (36), b 0 or 1; d 1,2,3,4,5,6 or 7; n is 0 or 1; R (36) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (37) R (38); R (37) and R (38) are hydrogen or CH ₃ ; R (34) is hydrogen or (C1-C4-alkyl); R (35) defined as R (33); or R (33) and R (34) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted with oxygen, S, NH, N-CH ₃ or N-benzyl; wherein A and NO are attached to the phenyl core of the benzoylguanidine base skeleton; R (2) SR (40), -OR (40), -NHR (40), -NR (40) R (41), -CHR (40) R (42), -CR (42) R (43) OH, -CsCR (45), -CR (46) = CR (45) or - [CR (47) R (48)] _in -CO- [CR (49) R (50)] _in -R (44) ; R (40) and R (41) independently of one another - (CH ₂ ) _p - (CHOH) _q - (CH ₂ ) _r - (CHOH) _t R (51) or - (CH ₂ ) _p -O- (CH ₂ -CH ₂ O) _q -R (51); R (51) is hydrogen or methyl; in 1, 2,3 or 4; in 0,1,2, 3 or 4; p, q and r independently of each other 0,1,2,3 or 4; t 1,2,3 or 4; R (42) R (43) independently of one another are hydrogen or (C ^ -C ^ alkyl, or together with the carbon atom joining them wears, (C ₃ -C _g) -cycloalkyl; R (44) (C _f C ₆₎ -alkyl, (C ₃ -C _g) -cycloalkyl or -C _e H _2e -R (45); e is 0,1,2,3 or 4; R (45) phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53); R (52) and R (53) are hydrogen, CH _g ; or R (45) (C ₁ -C ₉ ) -heteroaryl, which is unsubstituted or substituted as phenyl, or R (45) (C ₁ -C ₆ ) -alkyl which is unsubstituted or substituted with 1 to 3 OH; R (46), R (47), R (48), R (49) and R (50) independently of one another are hydrogen or methyl; or R (2) R (55) -NH-SO ₂ -; R (55) R (56) R (57) N- (C = Y) -; Y is oxygen, S or N-R (58); R (56) and R (57) independently of one another hydrogen, (C ^ Cgj -alkyl, (C ₃ -C ₆₎ -alkenyl or -C _f H _2f -R (59); f is 0 or 1; R (59) (C ₅ -C ₇ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methoxy and (C 1 -C 6) alkyl ; or R (56) and R (57) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ 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). A compound of formula I according to claim 1, characterized in that R (1) R (6) -CO or R (7) R (8) is N-CO; R (6) (C _f C ₄ ) -alkyl, CF ₃ or N (9), n 0; R (9) (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _y methyl, methoxy and NR (10) R (ll); R (10) and R (11) independently of one another are hydrogen or CH ₃ ; R (7) is hydrogen, (C ₁ -C ₄ ) -alkyl, CF ₃ or -C ^ -RGl), n 0; R (12) (C ₃ -C ₈ ) -cycloalkyl or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (13) R (14), R (13) and R (14) are hydrogen or CH ₃ ; R (8) is hydrogen or CH ₃ ; R (2) defined as R (1) or H, OH, F, Cl, Br, I, (C _f C ₈ ) -alkyl, CF ₃ or -CH 2 _n -R (15), n 0,1 or 2 ; R (15) (C ₃ -C _g) -cycloalkyl or phenyl; which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF _y methyl, methoxy and NR (16) R (17); R (16) and R (17) are hydrogen or CH ₃ ; or R (2) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy , amino, methylamino and dimethylamino; or R (2) SR (18), -OR (18) or -NR (18) R (19); R (18) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (2) R (33) X-; X is oxygen, S or NR (34); R (33) (C-Cgj-alkyl, (CH ^ C ^ or-CH _2n -R (36), b is 0 or 1; d 1,2,3,4,5,6 or 7; n is 0 or 1; R (36) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (37) R (38); R (37) and R (38) are hydrogen or CH ₃ ; R (34) is hydrogen or (C1-CJ-alkyl; or R (2) -C = CR (45); R (45) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53); R (52) and R (53) are hydrogen or CH ₃ ; R (3) defined as R (1) or H, OH, F, Cl, Br, I, (C _f C ₈ ) -alkyl, CF ₃ or -CH 2 _n -R (15), η 0,1 or 2 ; R (15) (C ₃ -C _g) -cycloalkyl or phenyl, which is unsubstituted oris substituted with 1 to 3 substituents from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (16) R (17) ; R (16) and R (17) H or CH ₃ ; or R (3) quinolyl, isoquinolyl, pyrrolyl or pyridyl, which are linked via C or N and are unsubstituted or substituted with 1 to 3 substituents of the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (3) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 2; R (21) (C ₁ -C ₄ ) -alkyl or CF ₃ ; R (22) is hydrogen, (C? -Alkyl, CF ₃ or CH _2n -R (29); n is 0 or 1; R (29) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (30) R (31); R (30) and R (31) are hydrogen or CH ₃ ; R (23) is hydrogen or CH ₃ ; or R (3) -C = CR (45); R (45) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53); R (52) and R (53) are hydrogen or CH ₃ ; R (4) and R (5) independently of one another are hydrogen, OH or NHR (60); R (60) (C _f C ₄ ) -alkyl. A compound of formula I according to claim 1, wherein R (1) is R (6) -CO; R (6) (C ₁ -C ₄ ) -alkyl or CF ₃ ; R (2) is defined as R (1) or H, OH, F, Cl, Br, I, (C ₁ -C ₈ ) -alkyl or CF ₃ ; or R (2) -SR (18) or -OR (18); R (18) pyridyl which is linked via C or N and is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino ; or R (2) R (33) X-: X is oxygen or S; R (33) (C ₁ -C ₈ ) -alkyl or -CH 1 -R 4 R 1); n is 0 or 1; R (36) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF _y methyl, methoxy and NR (37) R (38); R (37) and R (38) are hydrogen or CH ₃ ; R (3) H, OH, F, Cl, Br, I, (C ₁ -C ₈ ) -alkyl, CF ₃ or -CH _2n- R (15); n is 0.1 or 2; R (15) is phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (16) R (17); R (16) and NR (17) are hydrogen or CH ₃ ; or R (3) R (21) -SO _m ; m 2; R (21) (C ₁ -C ₄ ) -alkyl or CF ₃ ; R (4) and R (5) independently of one another are hydrogen, OH or NHR (60); R (60) (C _f C ₄ ) -alkyl. 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl; R (2) defined as R (1) or H, OH, F, Cl, Br, J, CN, NO ₂ , (C _f C ₈ ) -alkyl, (C _f C _g ) perfluoroalkyl, (C ₃ -C _g ) -alkenyl or -CH _2n -R (15), n 0,1,2, 3 or 4; R (15) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (16) R (17; R (16) andR (17) H, (C ₁ -C ₄ -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or R (2) (C 1 -C 8 H-heteroaryl, which is linked via C or N and is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; or R (2) SR (18), -OR (18), -NR (18) R (19) or -CR (18) R (19) R (20); R (18) -C _a H _2a - (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , CH ₃ , methoxy, hydroxy, amino, methylamino and dimethylamino; a is 0,1 or 2; R (19) and R (20) are independently defined as R (18) or hydrogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or R (2) R (21) -SO _m or R (22) R (23) N-SO ₂ -; m 1 or 2; R (21) (C-Cgj alkyl, (C ^ Cgj-perfluoroalkyl, (C ₃ -C _g) -alkenyl or -CJVRC24), n 0,1,2, 3 or 4; R (24) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (27) R (28; R (27) andR (28) Η, (C 1 -C 4 -alkyl or (C 1 -C 4 -perfluoroalkyl; R (22) is H, (C _r C ₈₎ -alkyl, (C ₁ -C ₈₎ -perfluoroalkyl, (C ₃ -C ₈₎ -alkenyl or -CH _2d -R (29), n 0,1,2, 3 or 4; R (29) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are unsubstituted or are substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, methoxy and NR (30) R (31); R (30) and R (31) H, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; R (23) is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -perfluoroalkyl; or R (22) and R (23) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl; or R (2) R (33) X-; X 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 C or SO; R (33) (C ₁ -C ₈ -alkyl, (C ₃ -C ₈ ) -alkenyl, (CH ₂ ) _b C _d F _{2d + 1} or -CH _2n- R (36), b Oallyl; d 1,2,3,4,5,6 or 7; n 0,1, 2, 3 or 4; R (36) (C ₃ -C _g) -cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromatic radicals are not substituted or are substituted by 1 to 3 substituents selected from the group consisting of F, Cl, CF _3, methyl, amethoxy and NR (37) R (38); R (37) andR (38) H, (Cj-CJ-alkyl or a (C ₁ -C ₄₎ -perfluoroalkyl; R (34) is hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₃ -fluoroalkyl; R (35) defined as R (33); or R (33) and R (34) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ or N-benzyl; wherein A and NO are attached to the phenyl core of the benzoylguanidine base skeleton; or R (2) 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)] _in -CO- [CR (49) R (50)] _in -R ( 44); R (40) and R (41) independently of one another ^ CHp / CHOFD ^ CHp / CHOH), ^) or - (CH ^ p-O-CH.-CH 2 O-RCSl); R (51) is hydrogen or methyl; in 1,2,3 or 4; in 0,1,2,3 or 4; p, q and r independently of each other 0,1,2,3 or 4; t 1, 2, 3 or 4; R (42) and R (43) independently of one another are hydrogen or (C1-C4-alkyl) or R (42) R (43) together with the carbon atom which carries them, a (C ₃ -C _g) -cycloalkyl; R (44) is hydrogen, (C _f C ₆₎ -alkyl, (C ₃ -C _g) -cycloalkyl, -CH ^ R ^); e is 0,1,2, 3 or 4; R (45) phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methyl, methoxy and NR (52) R (53); R (52) andR (53) H (C ₁ -C ₄ ) -alkyl; or R (45) (C ₁ -C ₉ ) -heteroaryl which is unsubstituted or substituted as phenyl; or R (45) (C ₁ -C ₆ ) -alkyl which is unsubstituted or substituted with 1 to 3 OH; R (46), R (47), R (48), R (49) and R (50) independently of one another are hydrogen or methyl; or R (2) R (55) -NH-SO ₂ -; R (55) 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, ((/ -Cgj -alkyl, (C ₃ -C ₆₎ -alkenyl or -0 ^ (59); f 0,1,2,3 or 4 ; R (59) (C ₅ -C ₇ ) -cycloalkyl, phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, CF ₃ , methoxy and (C 1 -C 4 - alkyl; or R (56) and R (57) together are 4 or 5 methylene groups, one of which may be CH ₂ substituted by oxygen, S, NH, N-CH ₃ 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), with at least one of the substituents R (2), R (3), R (4) and R (5) is equal to OH; as well as its pharmaceutically acceptable salts. 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. A process for the preparation of compound I according to claim 1, characterized in that the compound of formula II R (2) R (3) R (1) R (5) (H) R (4) O is reacted with guanidine, where R (1) to R (5) have the meaning indicated in claim 1 and is L for a readily nucleophilic substitutable leaving group. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of arrhythmias. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of a heart attack. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of prophylaxis of angina. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. Use of compound I according to claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and extremities. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of shock conditions. Use of compound I according to claim 1 for the preparation of a medicament for use in surgical and organ transplants. Use of compound I according to claim 1 for the preparation of a medicament for the preservation and storage of transplants for surgical measures. Use of compound I according to claim 1 for the preparation of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, and therefore for use as anti-atherosclerotic agents, late-onset diabetic agents, cancers, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, prostate hyperplasia. Use of compound I according to claim 1 for the preparation of a scientific tool for inhibiting the Na ⁺ / H ⁺ exchanger, for the diagnosis of hypertension and proliferative diseases. 18. A medicament comprising an effective amount of compound I according to claim 1. For Hoechst Aktiengesellschaft: 25039-x-95-mn SUMMARY Substituted benzoylguanidines, process for their preparation, use as a medicament or diagnostician as well as the medicament containing them Benzoylguanidines of the formula I are described R (1) R (6) -CO or R (7) R (8) N-CO, z R (2) defined as R (1) or H, OH, Hal, CN, NO ₂ , (perfluoro) alk (en) yl, (O ^ (15), or R (2) (C ^ C ^ -heteroaryl, or R (2) SR (18), -O R (18), -NR (18) R (19), -CR (18) R (19) R (20); or R (2) R (21) -SO _m or R (22) R (23) N-SO ₂ -; or R (2) R (33) X-; whereby X oxygen, S, NR (34), (D = O) A-, NR (34) C = MN <') R (35) -; or R (2) 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)] _in -CO- [CR (49) R (50)] _in -R (44); or R (2) R (55) -NH-SO ₂ -, or R (3), R (4) and R (5) are independently defined as R (1) or R (2), with at least one of the substituents R (2), R (3), R (4) and R (5) OH; as well as their pharmaceutically acceptable salts. The compounds of the formula I are useful for their pharmacological properties because of their excellent pharmacological properties, e.g. antiarrhythmic agents, drugs for heart attack, angina pectoris, for ischemic conditions of the heart, ischemic conditions of the peripheral and central nervous system, ischemic conditions of the peripheral organs and extremities, and more.