CZ2001180A3 - Imidazole derivatives substituted with biphenylsulfonyl group, process of their preparation and medicament or diagnostic preparation in which they are comprised - Google Patents

Abstract

The present invention relates to compounds of formula I wherein the symbols have meaning. The compounds show dramatic effects antiarrhythmic properties and contain cardioprotective properties compound. They can preventively or strongly inhibit reduce pathophysiological processes in the presence of ischemic damage, especially ischemic cardiac arrhythmias. Compounds they also show a strong cellular inhibitory effect proliferation.

Description

Imidazole derivatives substituted with a biphenylsulfone group, process for their preparation and medicament or diagnostic agent containing them

Technical field

The invention relates to imidazole derivatives substituted with a biphenylsulfone group, to a process for their preparation and to a medicament or a diagnostic device containing them.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I

in which the symbols have the following meaning:

R (l) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C _a H2a ^_ phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, methyl group, methoxy group, hydroxyl group or NR (8) R (9) group;

····· · · · · · · · · · ···

R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

a is zero, 1 or 2;

or

R (l) is a group -C _b H _2b -heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3 identical or various substituents from the series fluorine, chlorine, orom, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (10) R (11);

R (10) and R (11) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

b is zero, 1 or 2;

or

R (l) is -C _d H _2d -cycloalkyl having 3, 4, 5, O, or C;

d is zero, 1 or 2;

R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , -CN, -NO ₂ , CH ₂ OR (17), CO-R (6), O-R (7), O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17), or NR (50) R (51);

R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (6) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR (30), or phenyl which is unsubstituted or substituted with 1, 2, or 3 with the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, methyl i

A group, a methoxy group, a hydroxyl group or a NR (31) group R (32);

R (31) and R (32) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52);

R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (7) is hydrogen or alkyl having 1, 2,

3, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (12) R (13);

R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6,

7, δ or 9 carbon atoms which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (14) R (15);

R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (2) and R (3) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl,

having 3, 4, 5, 6 or 7 carbon atoms or -C _g H g _2-phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 identical or different substituents from the series fluorine, chlorine atom, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (18) R (19);

R (18) and R (19) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

g is zero, 1 or 2;

or

R (2) and R (3) independently of one another are -C 1 H ₂ -heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the heteroaryl moiety being unsubstituted or substituted by 1 2 or 3 with the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, methyl group, methoxy group, hydroxyl group or NR (20) R (21) group;

R (20) and R (21) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

is zero, 1 or 2;

or.

R (2) and R (3) independently of one another are SO _n -R (22); n is zero, 1 or 2;

R (22) is alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C _a H ? _s- phenyl which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR ( 34) R (35);

· · · · · · · · · · · * · * · * · * · * * * * * * * * * ·

R (34) and R (35) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

s is zero, 1 or 2;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ , -CN, -NO ₃ , SO _p -R (16), CO-R (23), OR (24), or O- (alkylene, containing 2, 3 or 4 atoms) carbon to) -CR (33);

p is zero, 1 or 2;

R (16) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from a series of atoms fluoro, chloro, bromo, iodo, CF ₃ , methyl, methoxy, hydroxyl or NR (26) R (27);

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

R (23) is hydrogen, alkyl having 1, 2, 3,

4, 5, 6, 7 or 8 carbon atoms, or OR (25);

R (25) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (2.4) is hydrogen, an alkyl group containing 1, 2, 3,

4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 of the same or different sucrose of the series fluorine, chlorine, bromine, iodine, CHN, methyl , methoxy, hydroxyl or NR (28) R (29);

R (28) and R (29) independently of one another are hydrogen or -alkyl having 1, 2, 3 or 4 carbon atoms;

R (3) 4 - Z ** z is a hydrogen atom or an alkyl group containing 1, 2,

5, 6, 7 or 8 carbon atoms;

and their physiologically acceptable salts;

with the proviso that at least one of R (2) or R (3) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51) .

Preferred are compounds of formula I wherein

R (1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or -C _and H _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 same or different substituents from a series of atoms fluoro, chloro, bromo, CF ₂ , methyl, methoxy, hydroxy or NR (8) R (9);

R (8) and R (9) independently of one another are hydrogen or methyl;

a is zero or 1;

or

R (1) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl, methoxy, hydroxy or NR (10) R (11);

R (10) and R (11) independently of one another are hydrogen or a methyl group;

or

R (l) is -C _d H _2d -cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms;

d is zero or 1;

100 ·· * 9 ··

9999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99

R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CH ₂ OR (17), CO-R (6) O-R (7), O- (alkylene containing 2 or 3 carbon atoms) -O-R (17), or NR (50) R (51);

R (17) is hydrogen or alkyl having 1, 2, or 4 carbon atoms;

R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (30), or phenyl which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, Cl, Br, _CF3, methyl, methoxy, hydroxyl or NR (31) R (32);

R (31) and R (32) independently of one another are hydrogen or methyl;

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

R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, CF ₃ , methyl, methoxy, hydroxyl or NR (12) R (13);

R (12) and R (13) independently of one another are hydrogen or methyl;

or

R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, Br, CF ₃ • 4 • ·· «· methyl, methcxylová, hydroxyl or NR (14) R (15);

R (14) and R (15) independently of one another are hydrogen or methyl;

R (50) and R (51) independently of one another are - (alkylene group containing 2 or 3 carbon atoms) -O-R (52);

R (52) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

or

R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C _g H _{2 g} -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (18) R ( 19);

R (18) and R (19) independently of one another are hydrogen or methyl;

g is zero or 1;

or

R (2) and R (3) independently of each other are a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, atom chlorine, bromine, CFO, methyl, methoxy, hydroxyl or NR (20) R (21);

R (20) and R (21) independently of one another are hydrogen or methyl;

or

R (2) and R (3) independently of one another are SO _n -R (22);

n is zero, 1 or 2;

R (22) is an alkyl group containing 1, 2, 3 or 4 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6 or 7 carbon atoms, or a -C ₃ H 2 _S -phenyl group wherein the phenyl moiety is unsubstituted or is substituted by 1 or 2 same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (34) R (35);

R (34) and R (35) independently of one another are hydrogen or methyl;

s is zero or 1;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, CF ₃ group, -CN group, -NO 2 group SOp-R (16), CO-R (23), OR (24), or O- (alkylene containing 2 or 3 carbon atoms) -O-R (33);

p is zero, 1 or 2;

R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, CF group ₃ , methyl, methoxy, hydroxyl or NR (26) R (27);

R (26) and R (27) independently of one another are hydrogen or methyl;

R (23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or OR (25);

R (25) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

• · · ·

R (24) is hydrogen, alkyl having 1, 2, or 4 carbon atoms, or phenyl which is unsubstituted or substituted by 1 or the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl, or atom

NR (28); R (29);

R (28) and R (29) independently of one another are hydrogen or methyl;

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

and their physiologically acceptable salts;

with the proviso that at least one of the substituents O- (alkylene containing 2 or 3 atoms) or NR (50) R (51).

R (2) or R (3) is carbon) -O-R (17)

Particularly preferred are compounds of formula I wherein

R (1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl , methoxy, hydroxyl or NR (8) R (9);

R (8) and R (9) independently of one another are hydrogen or methyl;

(1) is a heteroaryl group containing 1, 2, 3, 4, or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl group, methoxy group, hydroxyl group NR (10) R (11) or NR (10); , ± 1

R (10) and R (11) independently of one another are hydrogen or methyl;

or

R (1) is a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms;

R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CO-R (6), OR (7) ), O-CH2-CH2-OR (17), or NR (50) R (51);

R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (30), or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (31) R (32);

R (31) and R (32) independently of one another are hydrogen or methyl;

R (30) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl group , methoxy, hydroxyl or NR (12) R (13);

R (12) and R (13) independently of one another are hydrogen or methyl;

or

R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6,

7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (14); R (15);

R (14) and R (15) independently of one another are hydrogen or methyl;

R (17) is methyl or ethyl;

R (50) and R (51) independently of one another are -CH ₂ -CH ₂ -OR (52);

R (52) is methyl or ethyl;

or

R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (18) R 19);

R (18) and R (19) independently of one another are hydrogen or methyl;

or

R (2) and R (3), independently of one another, are a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series of fluoro, atom chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (20) R (21);

R (20) and R (21) independently of one another are hydrogen or methyl;

or

R (2) and R (3). independently of one another, SO _{2 is} -R (22); n is zero or 2;

····· * · · · · · · · · · · · · · · · · · · · · · · · ·

R (22) is an alkyl group having 1, 2, 3 or 4 carbon atoms, a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1 or 2 of the same or various substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (34) R (35);

R (34) and R (35) independently of one another are hydrogen or methyl;

R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, CF ₃ , -CN, -NO ₂ , SO _P -R (16), CO-R (23), OR (24), or O-CH ₂ -CH ₂ -OR (33);

p is zero; or

R (23) is hydrogen or 4 carbon atoms,

R (25) is a hydrogen atom or an alkyl group containing 1,

2, 3 or 4 carbon atoms;

R (24) is hydrogen, alkyl having 1, 2, or 3 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (28) R (29);

R (23) and R (29) independently of one another are hydrogen or methyl;

R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom,

2;

alkyl having 1, 2, 3 or OR (25);

CF ₃ , methyl, methoxy, hydroxyl or NR (26) R (27);

R (26) and R (27) independently of one another are hydrogen or methyl;

R (33) is methyl or ethyl; and their physiologically acceptable salts;

with the proviso that at least one of R (2) or R (3) is Q-CH 2 -CH 2 -R (17) or NR (50) R (51).

Particularly preferred are compounds of formula I wherein

R (1) is an alkyl group having 1, 2, 3 or 4 'carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy;

or

R (1) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or a methoxy group; or

R (1) is a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms;

R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, CF ₃ , -CN, CO-R (6), O-R (7), O-CH ₂ -CH ₂ -O-CH ₃ , or NR (50) R (51);

R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR'30), or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy;

• · · · · · · · · · · · · · · · · ·

R (30) is hydrogen, methyl or ethyl;

R (7) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy ;

or

R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6,

7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl or methoxy;

R (50) and R (5 ±) are -CH ₂ -CH ₂ -O-CH ₃ ;

or R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl, which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, CF ₃ group, methyl group and methoxy group;

or

R (2) and R (3) independently of each other are a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, atom chlorine, CF ₃ , methyl or methoxy;

or

R (2) and R (3) independently of one another are SO _n -R (22);

n is zero or 2;

R (22) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, CF ₃ , methyl or a methoxy group;

R (4) and R (5) independently of one another are hydrogen, methyl, fluoro, chloro, CF ₃ , -CN, SO ₂ -R (16), CO-R (23), OR (24) or O-CH ₂ -CH ₂ -O-CH ₃ ;

R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, CF ₃ group, methyl group or methoxy group;

R (23) is hydrogen, methyl or OR (25);

R (25) is hydrogen, methyl or ethyl;

R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy ;

and their physiologically acceptable salts;

with the proviso that at least one of R (2) or R (3) is O-CH ₂ -CH ₂ -O-CH ₃ or NR (50) R (51).

Further preferred are compounds wherein

R (1) is an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, a -CdH _2d -cyclcalkyl group having 3, 4, 5, 6 or 7 carbon atoms, wherein d is is zero, 1 or 2, or -C _and H _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (8) R (9);

R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;

a is zero, 1 or 2;

R (2) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51);

R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52);

R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (3) is hydrogen, -CN, or CO-R (6);

R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or OR (30);

R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;

R (4) is hydrogen, chlorine, fluorine, bromine, iodine, SO- _P- R (16) or O-CH 2 -CH 2 -OR (33);

p is zero, 1 or 2;

R (16) is an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from the series fluorine , chlorine, bromine, iodine, CF6, methyl, methoxy, hydroxyl or NR (26) R (27);

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

R (33) is methyl or ethyl;

R (5) is hydrogen;

and their physiologically acceptable salts.

Also preferred are compounds wherein

R (1) is _-Ca 14 _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (8) R (9);

R (8) and R (9) independently of one another are hydrogen or methyl;

a is zero or 1;

R (2) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51);

R (17) is alkyl having 1, 2, 3 or 4 carbon atoms, especially methyl;

R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52);

R (52) is alkyl having 1, 2, 3 or 4 carbon atoms; R (3) is CO-R (6);

R (6) is hydrogen;

R (4) is an SO ₂ -R (16) group in which R (16) is an alkyl group containing 1, 2, 3 or 4 carbon atoms, in particular a methyl group, or an O-CH ₂ -CK ₂ -O group -C4 ₃ ;

R (5) is hydrogen;

and their physiologically acceptable salts.

Particularly preferred are compounds of formula I wherein

R (2) is a group O-CH ₂ -CH ₂ -OR (17) or NR (50) R (51) R (17) is alkyl having 1, 2, 3 or 4 carbon atoms, especially methyl;

R (50) and R (51) are -CH ₂ -CH ₂ -OR (52) wherein

R (52) is alkyl having 1, 2, 3 or 4 carbon atoms, especially methyl; and

R (1), R (3), R (4) and R (5) are as defined above;

and their physiologically acceptable salts.

Further preferred are compounds of formula I wherein R (1), R (2), R (3), R (4) and R (5) are as defined above and the biphenyl substituent is attached as depicted in formula Ia, 1b , Ic, Id, Ie, If, Ig, Ih, or li, especially in the formula li,

(la) (db)

(Ic)

R ⁵ Sat ₂ nhcn · ··· · · ··· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

Sat ₂ nhcn (Id) (Ie)

(Ih) (li) and their physiologically acceptable salts.

Further preferred are compounds of formula I wherein R (1), R (2), R (3), R (4) as defined above and R (4) to the biphenyl substituent as is and R (5) are as is and R (5) are attached shown in formula Ij,

and their physiologically acceptable salts.

Both alkyl and alkylene groups can be straight or branched. This also applies to the alkylene radicals of formulas CaHja C _b H ~ _b CdHjdz CgHjo and CiHdi · Alkyl radicals and alkylene radicals may also be straight-chain or branched if they are substituted or when they are contained in other groups such as in the alkoxy group in an alkyl mercaptan group or in a fluorinated alkyl group.

Cycloalkyl groups are also meant to include rings substituted with alkyl groups.

Examples of alkyl groups containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are: methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert-butyl, or tert-pentyl. Examples of divalent alkenyl groups derived from the above groups are methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene,

2.2-propylene, 1,3-propylene,

1,4-butylene, 1,5-pentylene,

2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc.

Cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms are, in particular, cyclopropyl, cyclobutvium, cyclopentyl, cyclohexyl, or cycloheptyl; however, these rings may also be substituted, for example, by an alkyl group containing 1, 2, 3 or 4 carbon atoms. An example of substituted cycloalkyl groups is 4-methylcycionexyl a

2,3-dimethyicyclopentyl group.

A heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms means in particular groups derived from a phenyl or naphthyl group in which one or more CH groups are replaced by a nitrogen atom and / or or in which at least two adjacent CH groups (to form a five membered aromatic ring) are replaced by a sulfur atom, an NH group or an oxygen atom. Further, one or both of the atoms at the condensation point of the bicyclic system may be nitrogen atoms (as in the indolicinyl group).

························

Heteroaryl groups are, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, indazinyl, pyrimidinyl, pyrimidinyl an indazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a cinoxalinyl group, a quinazolinyl group, or a cinnolinyl group. Nitrogen heterocycles containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are especially aromatic systems such as 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl group,

1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-yl,

1,2.3-triazol-4-yl or 1,2,3-triazol-5-yl

1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or

1,2.4-triazol-5-yl, 1- or 5-tetrazolyl,

2-, 4- or 5-oxazolyl, 2-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl, 1,2 , 4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl or 1,3,4-oxadiazol-5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2-yl or

1,3,4-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl or

1,2,4-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazol-5-yl, 2-group, 2-, 4

C_ or 4-pyrid 1-, 2-, 3-, 4-, 1-, 2-, 4- or 1-, 3 ~ r 4-, 5-, 2-, 3-, 4-, 5-, 1-, 3-, 4-, 5-, 2-, 4-, 5-, 6-, 3-, 4-, 5-, 6-,

3- or 4-pyridyl 5- or 6-pyrimidinyl, zinyl, pyrazinyl,

A 5-, 6- or 7-indolyl group,

4- or 5-benzimidazolyl,

A 4-, 5-, 6- or 7-indazolyl group,

A 4-, 5-, 6-, 7- or 8-quinolyl group,

A 4-, 5-, 6-, 7- or 8-isoquinolyl group,

4

2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, or 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.

Particularly preferred are nitrogen heterocycles: pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Thienyl means 2-thienyl i

3-thienyl group. Furyl means both 2-furyl and 3-furyl.

Monosubstituted phenyl groups may be substituted at the 2-, 3- or 4- positions, disubstituted at the 2,3- positions,

2,4-, 2,5-, 2,6-, 3,4- or 3,5-, trisubstituted in positions

2.3.4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-.

The situation is similar for nitrogen heterocycles or for the thiophene system.

When substituting a group with two or three substituents, the substituents may be the same or different.

When the compounds of formula I contain one or more acidic or basic groups, or one or more basic heterocycles, the invention also relates to the corresponding physiologically or toxicologically acceptable salts, in particular salts which can be used pharmaceutically. Compounds of formula I which contain acidic groups, for example one or more COOH groups, can be used as salts, for example alkali metal salts, in particular sodium or potassium salts, or alkaline earth metal salts such as calcium salts or magnesium salts or ammonium salts. salts such as salts with ammonia or organic amines or amino acids. Compounds of formula I which contain one or more basic, i.e., protonatable, groups or contain one or more basic heterocyclic rings may also be used in the form of their physiologically acceptable addition salts with inorganic or organic acids, for example as Hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, maleates, gluconates, etc.

If the compounds of the formula I contain both acidic and basic groups in the molecule, the invention also includes, in addition to said salts, the internal salts, i.e. betaines. Salts can be prepared from the compounds of formula I by conventional methods, for example by reaction with an acid or base in a solvent or dispersant, or also from other salts by anion or cation exchange.

Physiologically acceptable salts of the compounds of formula I are also to be understood, for example, as organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, p. 1418 (1985)). Because of their physical and chemical stability and solubility, sodium salts, potassium salts, calcium salts and ammonium salts are among others preferred for acidic groups; for basic groups, hydrochloric acid, sulfuric acid, phosphoric acid, or salts of carboxylic acids or sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid are among others preferred.

The compounds of formula (I) may exist in stereoisomeric forms with appropriate substitution. If the compounds of formula I contain one or more asymmetric centers, these centers may independently have an S-configuration or an R-configuration. The invention relates to all possible stereoisomers, for example enantiomers or diastereoisomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereoisomers, in all ratios. Thus, for example, in the enantiomers, the present invention provides enantiomerically pure compounds, i.e., levorotatory or dextrorotatory antipodes, mixtures of both enantiomers in all ratios, or racemates. In the presence of cis / trans isomerism, the present invention provides both the cis-form and the trans-form, as well as mixtures of these forms in all proportions. Pure stereoisomers may be prepared as desired by resolution of the mixtures by conventional methods or, for example, by stereoselective synthesis. When mobile hydrogen atoms are present, the present invention also includes all tautomeric forms of the compounds of formula I.

The invention also relates to a process for the preparation of the compounds of formula I and their physiologically acceptable salts, characterized in that the compounds of formula II

wherein the substituents are as defined above and which can be prepared by a known method (as described in J. Med. Chem. 1995, 38) are reacted with cyanogen bromide. The reaction is preferably carried out in a dipolar aprotic solvent that does not react with cyanogen bromide, for example acetonitrile, DMA, TMU or NMP, in the presence of a strong low nucleophilic auxiliary base such as K ₂ CO ₃ or Cs ₂ CO ₃ . The reaction temperature is from 0 ° C to the boiling point of the solvent used, preferably from 60 ° C to 120 ° C.

Introduction of the substituents R (2) or R (3), which are alkoxyalkoxy groups, is accomplished by nucleophilic aromatic substitution in compounds of formula II in which R (2) is a nucleofugile leaving group, in particular fluorine atom, chlorine azine or bromine atom, and R (3; is a form group, or in compounds of formula II, wherein R (3) is a nucleofugial leaving group, especially a fluorine atom, a chlorine atom or a bromine atom, and R (2) is a formyl group. a corresponding alcohol, particularly a sodium salt, potassium salt or cesium salt, using the corresponding alcohol

2 'as solvents. The reaction temperature is between 0 ° C and the boiling point of the alcohol, preferably between 40 ° C and the boiling point of the alcohol.

Introduction of the substituent R (2) or R (3), which is a bis (alkoxyalyl) amino group, is accomplished by nucleophilic aromatic substitution in compounds of formula II in which R (2) is a nucleofuge leaving group, in particular fluorine atom, chlorine atom or atom bromine, and R (3) is a formyl group, or in compounds of formula II in which R (3) is a nucleofuge leaving group, especially a fluorine atom, a chlorine atom or a bromine atom, and R (2) is a formyl group. The nucleophile used is either the free corresponding bis (alkoxyalyl) amine or its alkali salt, preferably lithium salt, sodium salt, potassium salt or cesium salt, in a dipolar aprotic solvent. Suitable solvents are THF, DMF, tetramethylurea, N-methylpyrrolidone and hexamethylphosphoric triamide. The reaction temperature is between 0 ° C and the boiling point of the solvent used, preferably between 40 ° C and the boiling point of the solvent.

The introduction of the substituent R (4) is preferably carried out in the stage of the toluene derivative III

wherein Hal is a leaving group useful in the Suzuka reaction, preferably bromine or iodine. Introduction of the SO 0 -alkyl group by chlorosulfonation is described, for example, in J. Med. Chem. 1997, 40, 2017, or in J. Org. Chem. (1991) 56 (16), 4974-4976.

All reactions in the synthesis of compounds of formula I are well known to the person skilled in the art and can be carried out under standard conditions according to (or analogously to) procedures described in the literature, such as in Houben-Weyl, Methoden der Organischen Chemie, Thieme-Verlag, Stuttgart, or in Organic Reactions, John · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Wiley & Sons, New York. In order to avoid side reactions, depending on the circumstances, in the synthesis of the compounds of formula I, it is possible or necessary, in certain cases, for certain functional groups to be temporarily blocked by introducing protecting groups which are then removed or functionalized first in the precursor which is then converted to the desired functional groups in a later reaction step. Such synthetic strategies and protecting groups or precursors that are suitable for the particular case are known to the person skilled in the art. Alternatively, the compounds of the formula I obtained can be purified by conventional methods, for example crystallization or chromatography. The starting compounds for the preparation of the compounds of formula I are commercially available or can be prepared analogously as described in the literature.

The present invention further relates to:

the use of a compound of Formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of a heart attack;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of angina pectoris;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of ischemic heart conditions;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke;

The use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment or prophylaxis of peripheral organs and limb ischemic conditions;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment of shock conditions;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for use in surgical operations and organ transplants;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the preservation and preservation of transplants for surgical procedures;

the use of a compound of formula (I) and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment of diseases in which the primary or secondary cause of cell proliferation; and thus their use in the preparation of anti-atherosclerotics, anti-late diabetic complications, cancer diseases, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis, or prostate hyperplasia;

the use of a compound of formula I and / or a physiologically acceptable salt thereof in the preparation of a medicament for the treatment of respiratory problems;

as well as a medicament comprising an effective amount of a compound of formula I and / or a physiologically acceptable salt.

The compounds of the formula I according to the invention are suitable as inhibitors of sodium-dependent bicarbonate / changer chloride (NCBE) and sodium / bicarbonate-symporter, respectively.

• · · ·

Compounds similar to the compounds of formula I of the invention are known from U.S. Pat. Nos. 5,482,957 and 5,604,251. However, these compounds do not contain the sulfonyl cyanamide side chain present in all compounds of the invention. Imidazole derivatives have also been described as angiotensin II antagonists in WO 9523792, WO 9523791, US 5391732 and EP-A 648763. These known compounds are angiotensin II receptor antagonists of the ATI subtype which do not show the activity found for the compounds of formula I according to invention, or exhibit it only to a small extent.

In the earlier European patent application EP-A 855392, imidazole derivatives with biphenylsulfonylcyanamide side chain have been proposed as NCBE inhibitors.

The novel imidazole derivatives with the biphenylsulfonylcyanamide side chain described in the present invention have a special substituent R (2) and / or R (3) on the imidazole ring and are highly effective in inhibiting cellular Na ⁺ -dependent bicarbonate / chloride transducer as well as improved bioavailability.

The compounds of the formula I according to the invention show very good antiarrhythmic properties, which are important, for example, for the treatment of diseases associated with manifestations of oxygen deficiency.

The compounds of formula (I) are excellent for their pharmacological properties as antiarrhythmic drugs with cardioprotective properties for the prophylaxis and treatment of infarction, as well as for the treatment of angina pectoris, and can also prevent or severely reduce pathophysiological events in ischemically induced damage, especially ischemically induced cardiac arrhythmias.

Because of their protective effects against pathological hypoxic and ischemic situations, due to inhibition of the cellular Na ⁺ -dependent CI- / HCO3 'exchange mechanism (NCBE) or sodium / bicarbonate-symporter respectively, the compounds of formula I according to the invention can be used as therapeutic agents for the treatment all acute or chronic damage caused by ischemia leading to primary or secondary induced diseases. Protects organs with acute or chronic oxygen deprivation by reducing or preventing ischemically induced damage and are therefore useful as medicines in, for example, thromboses, vascular spasms, atherosclerosis or in surgical procedures (for example, organ transplants such as kidney or liver where compounds according to the invention, they can be used to protect organs in the donor body before and during removal, to protect the organs taken, for example, during handling or storage in physiological solutions, and for transfer to the recipient organism) or chronic or acute renal failure.

The compounds of formula (I) are also valuable protective drugs in performing angioplastic surgical procedures, for example, on the heart and peripheral vessels. Because of their protective activity against ischemia-induced injury, these compounds are also suitable for the treatment of nervous system syndrome, especially the central nervous system, and can be used, for example, to treat stroke or brain edema. In addition, the compounds of the formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardicogenic, hypovolemic and bacterial shock.

In addition, the compounds of the formula I according to the invention show a strongly inhibitory activity on cell proliferation, for example fibroblast proliferation and proliferation of vascular smooth muscle cells and mesangium cells. Therefore, the compounds of the formula I according to the invention are considered to be valuable drugs in diseases in which cell proliferation is the primary or secondary cause and can therefore be used as anti-atherosclerotics, drugs for late diabetic complications, cancer, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis, or organ hypertrophy and / or hyperpiaemia, particularly against prostate hyperplasia or hypertrophy.

• 9 · 99 ·· ··· *

The compounds of the formula I according to the invention, and their physiologically acceptable salts, are suitable for use in the therapy and / or prophylaxis of cardiac infarction, angina pectoris, diseases caused by ischemic conditions, respiratory motor disorders, ischemic heart conditions, peripheral and central nervous system ischemic conditions, stroke , ischemic conditions of peripheral organs and limbs, diseases caused primarily or secondary to cell proliferation, or shock conditions, or in surgical operations and organ transplants, or in the preservation and preservation of transplants for surgical procedures.

It has been found that inhibitors of the Na ⁺ -dependent C1 '/ HCO3' transducer (NCBE-inhibitors) and sodium / bicarbonate-symporter respectively can stimulate respiration by increasing the chemosensitivity of respiratory chemoreceptors. These chemoreceptors are largely responsible for maintaining proper breathing. They are activated by hypoxia, lowering of pH and increased concentration of CO 2 (nypercapnia) in the body and lead to adjustment of the minus respiratory volume. While sleeping, breathing is particularly susceptible to disorders and is largely dependent on chemoreceptor activity. Improving respiratory motor by stimulating chemoreceptors with Na ⁺ -dependent C1 / HCO3- inhibiting compounds leads to better breathing in the following clinical conditions and diseases: central respiratory motor disorders (such as central sleep breathing, sudden death in children, postoperative hypoxia), muscular-related respiratory disorders, respiratory disorders following long-term artificial respiration, respiratory disturbances in adaptation to high altitude, obstructive and mixed forms of sleep breathing, acute and chronic lung diseases associated with hypoxia and hypercapnia.

The compounds of the formula I according to the invention and their physiologically acceptable salts can be administered as medicaments to animals, in particular mammals, in particular to humans, alone, in mixtures or in the form of pharmaceutical preparations. It is also an object of the present invention to use the compounds of formula I and their physiologically acceptable salts as medicaments, to use them in the therapy and prophylaxis of said disease states, and to prepare medicaments containing them. The present invention further provides pharmaceutical compositions comprising, as an active ingredient, an effective dose of at least one compound of Formula I and / or a physiologically acceptable salt thereof, in addition to conventional pharmaceutically acceptable carriers and excipients. The pharmaceutical preparations usually contain 0.1 to 99% by weight, preferably 0.5 to 95% by weight, of the compound of the formula I and / or its physiologically acceptable salts. The pharmaceutical preparations can be prepared by methods known per se. For this purpose, a suitable pharmaceutical or dosage form is prepared from the compounds of the formula I and / or their physiologically acceptable salts, together with one or more solid or liquid galenic carriers and / or auxiliaries, optionally in combination with other active substances, which then it can be used as a medicine in human or veterinary medicine.

Dosage forms containing the compound of formula I and / or its physiologically acceptable salts can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred administration being dependent on the particular picture of the disease. The compounds of the formula I can be used alone or in admixture with galenic excipients, both in veterinary and in human medicine.

The choice of suitable excipients for the desired application formulation depends on the skill of the art. In addition to solvents, gelling agents, suppository bases, tabletting aids and other carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers or colorants can be used.

For oral administration, the active compounds are mixed with suitable excipients such as carriers, stabilizers or inert diluents and formulated in suitable dosage forms such as tablets, dragees, push-fit capsules, or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch. Dry or wet granules can be prepared. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds are used in the form of a solution, suspension or emulsion, if desired in admixture with conventional substances such as solubilizers, emulsifiers or other excipients. Suitable solvents are, for example: water, physiological saline solutions or alcohols such as ethanol, propanol, glycerin, or else sugar solutions such as glucose or mannitol, or else a mixture of the various solvents mentioned above.

For use in the form of aerosols or sprays, for example, solutions, suspensions or emulsions of the active compound of the formula I in pharmaceutically acceptable solvents, in particular ethanol or water, or in a mixture of such solvents are suitable.

The dosage form may, if desired, contain other pharmaceutical excipients such as surfactants, emulsifiers or stabilizers as well as a propellant. Such a dosage form usually contains about 0.1 to 10% by weight, preferably about 0.3 to 3% by weight, of the active ingredient.

The doses of active compound to be administered and the frequency of administration depend on the potency and duration of action of the compound used, as well as the type and severity of the disease to be treated. It also depends on the sex, age, weight and individual response of the mammal being treated.

At an approximate patient weight of 75 kg, the average daily dose of the compound of Formula I is at least 0.001 mg / kg, preferably 0.01 mg / kg, to at most 10 mg / kg, preferably 1 mg / kg body weight. In acute outbreaks of disease, for example

4

4

Immediately after a heart attack, higher and more frequent doses may be necessary, for example up to 4 individual doses per day. Especially when administered intravenously, for example in a heart attack patient in an intensive care unit, up to 200 mg per day may be required.

In order to obtain an advantageous therapeutic effect, the compounds of the formula I and / or their physiologically acceptable salts can be used together with other pharmacologically active compounds for the treatment or prophylaxis of the aforementioned diseases, in particular for the treatment of heart and circulatory diseases. Combination with sodium / hydrogen exchanger (NHE) inhibitors and / or cardiovascular active agents is preferred.

The present invention further relates to the combination of a) NCBE inhibitors of formula I, and / or their physiologically acceptable salts, with NHE inhibitors and / or their physiologically acceptable salts; b) NCBE inhibitors of the formula I, and / or their physiologically acceptable salts, with active substances from other classes of cardiovascular active substances and / or their physiologically acceptable salts; c) NCBE inhibitors of the formula I, and / or their physiologically acceptable salts, with NHE inhibitors, and / or their physiologically acceptable salts, and with active substances from other classes of cardiovascular active substances and / or their physiologically acceptable salts.

Known NHE inhibitors of the identified active substances are guanidine derivatives, in particular acylguanidines, as described, inter alia, in Edward J. Cragoe, Jr., "Diuretics, Chemistry, Pharmacology and Medicine, J. Wiley & Sons 1533 , 303-341, or the NHE inhibitors disclosed in DE 19737224.4.

Suitable NHE-inhibitors are, for example, also benzoylguanidines as described in US 5292755, US 5373024, US 5364868,

US 5591754, US 5516805, US 5559153, US 5571842, US 5641792,

US-5631293, EP-A 577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723, EP-A 627413, EP-A 628543, • »

- 36 - • · · · · · • ····· · · · · · · · · · · ··· · · ········ EP-A 640593 EP-A 640588 EP-A 702001 EP-A 713864 EP-A 723956, EP-A 754680, EP-A 765868 EP-A-774459 EP-A 794171, EP-A-814077, EP-A-869116; ortho-substituted benzoylguanidines as described in U.S. Pat EP-A 556673, EP-A 791577; EP-A 794172; ortho-amino- substituted

benzoylguanidines as described in EP-A 690048; isoquinolines as described in EP-A 590455; benzofused five-membered heterocycles as described in EP-A 639573; diacyl-substituted guanidines as described in EP-A 640587; acylguanidines as described in US 5547953; phenyl-substituted alkyl- or alkenyl-carboxyguanidines bearing perfluoroalkyl groups as described in US 5567734 and EP-A 688766; heteroaroylguanidines as described in EP-A 676395; bicyclic heteroaroylguanidines as described in EP-A 682017; indenoylguanidines as described in EP-A 738712; benzoyloxycarbonylguanidines as described in EP-A 748795; phenyl-substituted alkenylcarboxyguanidines bearing fluorophenyl groups as described in EP-A 744397; substituted cinnartoylguanidines as described in EP-A 755919; sulfonimidamides as described in EP-A 771788; benzenedicarboxydiguanidines as described in EP-A 774458 and EP-A 774457; diarylcarboxydiguanidines as described in EP-A 787717; substituted thiophenylalkenylcarbxyguanidines as described in EP-A 790245; bis-ortho-substituted benzoylguanidines as described in ΈΡ-Α 810207; substituted 1- or 2-naphthylguanidines as described in EP-A 810205 and EP-A 810206; indanylideneacetylguanidines as described in EP-A 837055; phenylsubstituted alkenylcarboxyguanidines as described in EP-A 825178;

aminopiperidylbenzoylguanidines as described in EP-A 667341; heterocycloxybenzylguanidines as described in EP-A 694537; ortho-substituted benzoylguanidines as described in EP-A 704431; ortho-substituted • · • ·

Alkyl-benzylguanidines as described in EP-A 699660; ortho-substituted heterocyclyl-benzoylguanidines as described in EP-A 699666; ortho-substituted

5-methylsulfonylbenzoylguanidines as described in EP-A 703088; ortho-substituted 5-alkylsulfonylbenzoylguanidines with 4-amino substituents as described in EP-A 723963; ortho-substituted 5-alkylsulfonylbenzoylguanidines with 4-mercapto-substituents as described in EP-A 743301; 4-sulfonyl- or 4-sulfinyl-benzylguanidines as described in EP-A 758644; alkenylbenzoylguanidines as described in EP-A 760365; benzoylguanidines with fused cyclic sulfones as described in DE 19548708; benzoyl-, polycyclic aroyl- and heteroaroyl-guanidines as described in WO 9426709; 3-aryl / heteroaryl-benzoylguanidines as described in WO 9604241; 3-phenyl-benzoylguanidines with a basic amide at the 5-position as described in WO 9725310; 3-dihaiothienyl- or 3-dihalophenyl-benzoylguanidines having a basic substituent at the 5-position as described in WO 9727183; 3-methylsulfonylbenzoylguanidines with certain amino substituents at the 4-position as described in WO 9512584; amiloride derivatives as described in WO 9512592;

3-methylsulfonylbenzoyiguanidines with certain amino substituents at the 4-position as described in WO 9726253; indoloylguanidines as described in EP-A 622356 and EP-A 708091; indoloylguanidines with an annealed added cyclic system as described in EP 787728; methylguanidine derivatives as described in WO 9504052;

1,4-benzoxazinoylguanidines as described in EP-A 719766; 5-bromo-2-naphthoylguanidines as described in JP 8225513; quinoline-4-carbonylguanidines having a phenyl residue at the 2-position as described in EP-A 726254; cinnamoylguanidines as described in JP 09059245; naphthalene-substituted propenoylguanidines as described in JP 9067332; propenoylguanidines with indole

Substituents as described in JP 9067340; or heteroaryl-substituted acryloylguanidines as described in WO 9711055; and their physiologically acceptable salts.

Preferred NHE-inhibitors are compounds that are mentioned as preferred in the publications mentioned. Particularly preferred are the compounds Cariporide (HOE 642), HOE 694,

EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032 and their physiologically acceptable salts. Most preferred is Cariporide or another physiologically acceptable salt of N- (4-isopropyl-3-methanesulfonylbenzoyl) guanidine.

Examples of classes of cardiovascular active compounds which may advantageously be combined therapeutically with NCBE inhibitors, or additionally with mixtures of NCBE inhibitors and NHE inhibitors, include beta-blockers, calcium antagonists, angiotensin converting enzyme blockers, angiotensin receptor blockers , loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists such as those used to lower blood pressure, cardiac glycosides or other cardiac contraction enhancers used to treat heart failure and congestive heart failure, or class I-IV antiarrhythmics, nitrates, K _AT p-opener a

K _ATP blockers, veratridine activatable sodium channel inhibitors, etc. For example, the following compounds are suitable: beta-blockers propranolol, atenolol, metoproiol; kaicia antagonists diltiazem hydrochloride, verapamil hydrochloride, or nifedipine; ACE-inhibitors captopril, enaiapril, ramipril; trandolapril, qianapril, spirapril, preferably ramipril or trandolapril; angiotensin II receptor antagonists losartan, valsartan, telmisartan, eprosarcan, tasosartan, candesartan, irbesartan; loop diuretics furosemide, piretanide, torasemide; thiazide diuretics hydrochlorothiazide, metolazone, indapamide; potassium sparing diuretics amiloride, triamterene, spironolactone; cardiac glycosides digoxin, digitoxin, strofanthin; antiarrhythmics

amiodarone, sotalol, bretylium, flecainide; nitrate glycerin trinitrate; K ⁺ ATP opens cromakalim, lemakalim, nocorandil, pinacidil, minoxidil; or veratridine-activatable Na ⁺ -channel inhibitors.

Examples of such a particularly preferred combination partner with NCBE inhibitors are non-inactivating sodium channel blockers (veratridine-activated sodium channel). The combination of an NCBE-inhibitor with a non-inactivating sodium channel blocker (veratridine-activated sodium channel) is useful for the prophylaxis of infarction and reinfarction and for the treatment of infarction, as well as for the treatment of angina pectoris and inhibition of ischemically induced cardiac arrhythmias; wherein the combination of an NCBE-inhibitor with a non-inactivating sodium channel blocker also preventively or strongly alleviates pathophysiological processes in the development of ischemically induced damage. Combinations of the invention, comprising an NCBE-inhibitor of Formula I and a non-inactivating sodium channel blocker, for their enhanced protective activity against pathological hypoxic and ischemic situations resulting from an enhanced inhibition of Na ⁺ ion penetration into the cell, can be used to treat any acute or chronic damage caused by ischemia or ischemia of a primary or secondary induced disease. This relates to the use of these combinations as medicaments in surgical procedures, for example in organ transplantation, whereby combinations of an NCBE-inhibitor with a non-inactivating sodium channel blocker can be used to protect organs in the donor body before and during withdrawal or their storage in physiological solutions as well as during transfer to the recipient organism. Combinations of an NCBE-inhibitor with a non-inactivating sodium channel blocker are also valuable protective drugs in performing angioplastic surgical procedures, for example on the heart and peripheral vessels. Because of their protective activity against ischemia-induced injury, combinations of an NCBE-inhibitor with a non-inactivating sodium channel blocker are also suitable for the treatment of ischemia of the nervous system, particularly the central nervous system, and can be used, for example, to treat stroke or brain edema. In addition, the combinations of the invention containing an NCBE inhibitor and a non-inactivating sodium channel blocker are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition to the use in fixed combinations, the present invention also relates to the simultaneous, separate or staggered administration of NCBE inhibitors of formula I and / or their physiologically acceptable salts with NHE inhibitors and / or other active substances from another class of cardiovascular active compounds for the treatment of the above .

The invention further relates to a pharmaceutical therapeutic composition comprising a) an NCBE inhibitor of formula I and / or a physiologically acceptable salt thereof, and an NHE inhibitor and / or a physiologically acceptable salt thereof; or b) an NCBE-inhibitor of the formula I and / or a physiologically acceptable salt thereof, and an active substance from another group of cardiovascular active compounds and / or a physiologically acceptable salt thereof; or c) an NCBE-inhibitor of the formula I and / or a physiologically acceptable salt thereof, an NHE-inhibitor, and an active substance from another group of cardiovascular compounds, and / or a physiologically acceptable salt thereof.

When combined, the effects of the components can potentiate each other, i.e. the efficacy and / or duration of action of the combination of the invention or the composition of the invention is stronger or longer than the effect and / or duration of action of the individual components (synergistic effect). When combined, this leads to a reduction in the doses of each of the components of the combination compared to the use of the components alone. Thus, the combinations and compositions of the invention have the advantage that the applied amounts of the active compounds can be significantly reduced and thus undesirable side effects can be eliminated or greatly reduced.

«· Ra · a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a ·· ·

The present invention further relates to a commercial dosage form comprising, as a pharmaceutically active agent, a) an NCBE-inhibitor of the formula I and an NHE-inhibitor and / or their physiologically acceptable salts; or b) an NCBE-inhibitor of the formula I to that of an active substance from another group of cardiovascular active compounds, and / or physiologically acceptable salts thereof; or (c) an NCBE-inhibitor of the formula I, an NHE-inhibitor and an active substance from another group of cardiovascular active compounds, and / or their physiologically acceptable salts, in each case with instructions for using these combinations for simultaneous, separate or timed use in the treatment or prophylaxis of the aforementioned diseases, in particular in the treatment of cardiovascular diseases.

For example, the pharmaceutical compositions of the invention may be prepared by either intimately mixing the individual components in powder form, or dissolving the components in a suitable solvent, such as a lower alcohol, and subsequently removing the solvent.

A suitable weight ratio of NCBE inhibitor to NHE inhibitor or cardiovascular active agent in the combinations and compositions of the invention is 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10.

The combinations and compositions according to the invention preferably contain in total 0.5 to 99.5% by weight, in particular 4 to 99% by weight, of these active substances.

When administered according to the invention to mammals, especially humans, the doses of the various active ingredients are, for example, in the range of 0.001 to 100 mg / kg / day.

* · · * * * * * «« «« «« «

DETAILED DESCRIPTION OF THE INVENTION

Shortcuts overview:

BCECF 2 ', 7'-bis (2-carboxyethyl) -5,6-carboxyfluorescein

CH 2 Cl 2 dichloromethane

DCI desorption-chemical ionization

DMF N, N-dimethylformamide

EE ethyl acetate (EtOAc)

El electron impact

ES electrospray-ionization

HEP n-heptane

MeOH methanol

NCBE sodium-dependent chloride / bicarbonate transducer

NHE sodium / hydrogen channel

t.m. room temperature

m.p. melting point

CNS central nervous system

General procedure for preparing sulfonyl cyanamides from sulfonamides

The starting sulfonamide material was dissolved in anhydrous acetonitrile (10 mL / mmol), 3 mol equivalents of potassium carbonate were added, one moi-equivalent of a 5 N solution of BrCN in acetonitrile was added, and the reaction mixture was refluxed until reaction was complete. 10 minutes to 6 hours). The reaction mixture is then subjected to silica gel chromatography without further processing.

• 4 4 · · · * · * * * *

Example 1

4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3'-methanesulfonyl-biphenyl-2-sulfonyl-cyanamide

(a) 2-Bromo-5-methyl-benzenesulfonyl chloride

4-Bromotoluene (40 g) was slowly added with stirring at -10 ° C to 250 ml of chlorosulfonic acid. The reaction mixture was stirred at this temperature for 30 minutes, then allowed to warm to 0 ° C and poured into excess. ice. The product is filtered off with suction, washed with a little water and dried over P4O10. 63 g of a colorless solid are obtained, which is used directly further.

b) 2-Bromo-5-methyl-benzenesulfinic acid

Sodium sulfite (37.6 g) was dissolved in 500 mL of water and heated to 70 ° C. 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added portionwise at this temperature. At the same time, a 10 N aqueous sodium hydroxide solution is added dropwise so that the solution still has a pK value of between 9 and 10. The mixture is stirred for 1.5 hours at 70 ° C, then filtered and finally acidified with a saturated aqueous solution in an ice bath. The mixture was stirred for 30 minutes, the product was filtered off with suction, washed with a small amount of water and dried. 49.6 g of white crystals are obtained, m.p. Mp 120-122 ° C.

MS (ES): 236 (M + H) ⁺ .

· · * * * * * · · * · · · · · · · * * · · · · · · · ·· ···· ··

c) Sodium 2-bromo-5-methylbenzenesulfinate

2-Bromo-5-methylbenzenesulfinic acid (49.6 g) was dissolved in 400 mL of methanol and an equimolar amount of NaOH in 50 mL of water was added. The mixture was stirred for 3 hours at room temperature, filtered and the solvents were evaporated in vacuo. Finally, water residues are removed by azeotropic distillation with 50 ml of toluene. The solid residue was dried over P ₄ O 10 in vacuo to give 54.0 g of the product, mp 288-290 ° C (dec.).

d) 1-bromo-2-methanesulfonyl-4-methylbenzene

Sodium 2-bromo-5-methyl-benzenesulfinate (54.0 g) was suspended in

300 ml of anhydrous DMF and 45.7 ml of methyl iodide are added to the suspension. The temperature of the solution rises to 50 ° C. The mixture was stirred for 3 hours at 50 ° C and then the DMF was removed in vacuo. The residue is stirred with 500 ml of water and then stirred at 0 ° C for one hour. After filtration, the product is washed with water, dried and recrystallized from the mixture

400 ml HEP / 250 ml EE using activated carbon. 27.0 g of colorless crystals are obtained, m.p. Mp 110-114 ° C.

R _f (EA / HEP 1: 4) = 0.09. MS (DCI): 250 (M + H) < + & gt ^; .

e) 1-Bromo-4-bromomethyl-2-methanesulfonyl-benzene 1-Bromo-2-methanesulfonyl-4-methyl-benzene (9.9 g) was dissolved in 100 ml of chlorobenzene and 77 mg of benzoyl peroxide and 7.1 mg were added. g of N-bromosuccinimide. The mixture was refluxed for one hour. The solvent was evaporated in vacuo and the residue was taken up in 100 ml of CH2Cl2 and washed twice with 50 ml of saturated aqueous sodium carbonate solution and once with 50 ml of water. After drying over sodium sulfate, the solvent was evaporated in vacuo and the residue was recrystallized from 80 ml KEP / 30 ml EE. 6.5 g of a yellowish solid are obtained, m.p. Mp 120-124 ° C.

R _f (EA / HEP 1: 2) - 0.38. MS (DCI): 329 (M + H) < + & gt ^; .

· · · · · · · · · · · · · · · · · · · ·

f) 3- (4-Bromo-3-methanesulfonyl-benzyl) -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

A mixture of 1.0 g of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde (Chem. Pharm. Bull. 1976, 24 (5), 960), 1.6 g of 1-bromo-4-bromomethyl-2. -methanesulfonyl-benzene, 691 mg of potassium carbonate and 25 ml of anhydrous DMF were stirred at room temperature for 18 hours. The reaction mixture was poured into 300 ml of half-saturated aqueous sodium bicarbonate solution and extracted three times with 150 ml of EE. The extract was dried over sodium sulfate and the solvent was evaporated in vacuo. Chromatography on silica gel in EE / HEP (1: 2) gave 1.2 g of a colorless oil.

R _f (EA / HEP 1: 2) = 0.16. MS (FAB): 454 (M + H) < + & gt ^; .

g) 4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3'-methanesulfonyl-1-biphenyl-2-sulfonic acid tert-butylamide

To a mixture of 970 mg of 3- (4-bromo-3-methanesulfonyl-benzyl) -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 660 mg of N-tert-butyl-2-dihydroxyboran-2-yl- benzenesulfonamide (J. Med. Chem. 1997, 40, 547), 24 mg of Pd (II) acetate and 56 mg of triphenylphosphine in 13 ml of toluene and 3.5 ml of ethanol are added 2.1 ml of a 2 M aqueous solution of Na ₂ CO ₃ . The reaction mixture was refluxed for 105 minutes, then allowed to cool to room temperature and treated with 200 mL of a half-saturated aqueous NaHCO ₃ solution. It is extracted three times with 150 ml of EA each time, the extract is dried over sodium sulphate and the solvent is evaporated off under vacuum.

Chromatography on silica gel in EE / HEP (1: 2) yielded 660 mg of a colorless oil.

R _R - (EA / HEP 1: 2) = 0.12. MS (ES): 587 (M + H) + h 4 '- (4-Chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -3'-methanesulfonyl-biphenyl-2-suifonamide tert-butyl amide 4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3'-methanesulfonyl-biphenyl-2-sulfonic acid (650 mg) was dissolved in 5.6 ml of trifluoroacetic acid and Inject 133 μΐ of anisole into the mixture. The mixture was stirred at room temperature for 8 hours and then the volatiles were removed in vacuo. The residue is taken up in 20 ml of water three times and the water is then evaporated in vacuo. The residue was finally suspended twice in 30 ml of toluene and the volatiles were removed again in vacuo. 570 mg of a yellowish solid product are obtained, which is used in the next step because of its lack of solubility without purification.

R _f (EA / HEP 2: 1) = 0.24.

i) 4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenylimidazol-1-ylmethyl] -3'-methanesulfonyl-biphenyl-2-sulfonamide

A mixture of 330 mg of 4 '- (4-chloro-5-formyi-2-phenyl-imidazol-1-ylmethyl) -3'-methanesulfonyl-biphenyl-2-sulfonamide, 250 mg of sodium hydroxide and 12.5 ml of methoxyethanol is stirred for 2 hours at 90 ° C. The reaction mixture was then cooled to room temperature and poured into 100 mL of half-saturated aqueous NaHCO ₃ solution. The mixture was extracted three times with 100 ml of EA each time, dried over sodium sulfate and the solvent was evaporated in vacuo. 350 mg of a colorless oil are obtained, which, because of its surprisingly high volatility, must be used immediately in the next step without purification.

R _f (EA / HEP 2: 1) = 0.18.

j) 4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3'-methanesulfonyl-biphenyl-2-sulfonyl-cyanamide

4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3'-methanesulfonyl-biphenyl-2-sulfonamide (340 mg) was converted to the title compound as follows: as described in the general procedure for preparing sulfonyl cyanamides from sulfonamides (reaction time 15 minutes). Chromatography on silica gel in EE / MeOH (1: 5) gave 90 mg of white crystals, m.p. Mp> 270 ° C.

R _f (EA / MeOH 1: 5) = 0.27; IR (C = N): 2178.1 cm ^-1 ,

MS (FAB): 595 (M + H) ⁺ .

Example 2

3'-Chloro-4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-yl-methyl] -biphenyl-2-sulfonyl-cyanamide

(a) 4-Bromo-1-bromomethyl-2-chloro-benzene

4-Bromo-2-chlorotoluene (7.1 ml) was dissolved in 20 ml of chlorobenzene and a mixture of 9.4 g of N-bromosuccinimide and 200 mg of dibenzoyl peroxide was added portionwise at 130 ° C. The reaction mixture was refluxed for 30 minutes, then cooled and diluted with 100 mL CH 2 Cl 2 and washed successively once with 50 mL saturated aqueous Na ₂ SO ₃ and once with 100 mL saturated aqueous NaHCO ₃ , dried over sodium sulfate. and the solvent was evaporated in vacuo. 11.0 g of a yellowish oil are obtained.

R _f (EA / HEP 1: 8) = 0.49. MS (DCI): 283 (M + H) < + & gt ^; .

b) 3- (4-3romo-2-chloro-benzyl) -5-chloro-2-phenyl-3K-imidazole-4-carbaldehyde

A mixture of 1.5 g of 4-chloro-5-formyl-2-phenyl-imidazole (Chem. Pharm. Bull. 1976, 24 (5), 960), 5.8 g of K ₂ CO ₃ , 8.0 g of 4- bromo-1-bromomethyl-2-chloro-benzene and 50 mL of DMF were stirred at room temperature for 24 hours. The reaction mixture was diluted with 250 mL EE and washed twice with 100 mL water and once with 100 mL saturated aqueous NaCl. After drying over sodium sulfate, the solvents are evaporated in vacuo and the residue is chromatographed on silica gel in EE / HEP (1: 4). 2.2 g of a colorless oil are obtained.

R _f (EA / HEP 1: 4) = 0.47. MS (ES): 411 (M + H) < + & gt ^; .

c) 3'-Chloro-4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -biphenyl-2-sulfonic acid tert-butylamide

2.2 g of 3- (4-Bromo-2-chloro-benzyl) -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 2.0 g of N-tert-butyl-2-dihydroxyborane-2- yl-benzenesulfonamide (J. Med. Chem. 1997, 40, 547),

140 mg of triphenylphosphine, 64 mg of Pd (II) acetate and 1.2 g of Na ₂ CO ₃ are dissolved in a mixture of 30 ml of toluene, 10 ml of ethanol and 10 ml of water. The reaction mixture was refluxed for 3 hours. After cooling, 200 ml of saturated aqueous NaHCO ₃ and extranuje tnkrat with 200 mi of EA. After drying over magnesium sulfate, the solvent is removed in vacuo and the residue is chromatographed on silica gel. 1.5 g of a colorless foam are obtained.

Rf (DIP) = 0.25. MS (ES): 542 (M + H) < + & gt ^; .

d) 3'-Chloro-4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide

Dissolve 1.5 g of 3'-chloro-4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -biphenyl-2-sulfonic acid tert-butylamide and 340 μl of anisole in 10 ml of trifluoroacetic acid and the solution was stirred at room temperature for 24 hours. The volatiles were removed in vacuo, the residue was extracted twice with 50 ml of toluene and the volatiles were removed in vacuo again. 1.5 g of a colorless foam are obtained.

Rf (DIP) = 0.15. MS (ES): 486 (M + H) < + & gt ^; .

e) 3'-Chloro-4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -biphenyl-2-sulfonamide

A mixture of 280 mg of 3'-chloro-4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -biphenyl-2-sulfonamide, 230 mg of sodium hydroxide and 11.5 ml of methoxyethanol is stirred for 3 hours. hours at 90 ° C. The reaction mixture was cooled and poured into 150 ml of half-saturated aqueous NaHCO ₃ solution. The mixture was extracted three times with 100 ml of EA, dried over sodium sulfate and the solvent was evaporated in vacuo. 310 mg of a colorless oil are obtained, which product is used without further purification. R _f (EA / HEP 2: 1) = 0.37.

f) 3'-Chloro-4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -biphenyl-2-sulfonyl-cyanamide

3'-Chloro-4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -biphenyl-2-sulfonamide (69 mg) was converted to the title compound according to the general procedure for the preparation of sulfonyl cyanamides from sulfonamides (reaction time 1 hour). Chromatography on silica gel in EE / MeOH (1: 5) gave 63 mg of white crystals, mp 195 ° C (dec.). R _f (EA / MeOH 1: 5) = 0.33; IR (CI 4 N): 2178.6 cm ^-1 .

MS (ES): 552 (M + H) ⁺ .

Example 3

4 '- [5-Formyl-2- (4-isopropyl-phenyl) -4- (2-methoxy-ethoxy) -imidazol-1-ylmethyl] -biphenyl-2-sulfonyl-cyanamide

• 9 · · · · · · · · · · · · ·

a) 4 '- [4-Chloro-5-formyl-2- (4-isopropyl-phenyl) -imidazol-1-ylmethyl] -biphenyl-2-sulfonic acid dimethylaminomethylenamide

A suspension of 1.2 g of 5-chloro-2- (4-isopropyl-phenyl) -3H-imidazole-4-carbaldehyde (synthesized analogously to the procedure in Chem. Pharm. Bull. 1976, 24 (5), 960), 9 g of 4'-bromomethyl-biphenyl-2-sulfonic acid dimethylaminomethylenamide and 0.69 g of K ₂ CO ₃ in 25 ml of anhydrous DMF are stirred at room temperature for 8 hours. An additional 0.38 g of 4'-bromomethyl-biphenyl-2-sulfonic acid dimethylaminomethylenamide was added and the reaction mixture was stirred at room temperature for an additional 5 hours. The reaction mixture was diluted with 300 mL of a 10% aqueous NaHCO ₃ solution and extracted three times with 150 mL of EE each. After drying over sodium sulfate, the solvent is removed in vacuo and the residue is chromatographed on silica gel in EE / HEP (2: 1). 1.9 g of a colorless crystalline product melting at 177 DEG C. are obtained.

R _f (EA / HEP 2: 1) = 0.28. MS (ES): 550 (M + H) < + & gt ^; .

b) 4 '- [4-chloro-5-formyl-2- (4-isopropyl-phenyl) -imidazol-1-ylmethyl] -biphenyl-2-sulfonamide

1.9 g of dimethylaminomethylenamide of 4 '- [4-chloro-5-formyl-2- (4-isopropyl-phenyl) -imidazol-1-ylmethyl] -biphenyl-2-sulfonic acid is dissolved in 35 ml of methanol and the solution is added 18 ml of a saturated solution of hydrogen chloride in water. The mixture was refluxed for 90 minutes. After cooling, the reaction mixture was adjusted to pH 5-6 by addition of 6 N aqueous NaOH solution and the precipitated product was filtered off with suction. The product is washed three times with 20 ml of water and dried under high vacuum at 60 ° C. 1.4 g of an amorphous solid are obtained.

R _f (EA / HEP 1: 1) = 0.25. MS (ES): 495 (M + H) < + & gt ^; .

c) 4 '- [4-Chloro-5-formyl-2- (4-isopropyl-phenyl) -imidazol-1-ylmethyl] -biphenyl-2-sulfonyl-cyanamide

4 '- [4-Chloro-5-formyl-2- (4-isopropyl-phenyl) -imidazol-1-ylmethyl] -biphenyl-2-sulfonamide (198 mg) and K ₂ CO ₃ (166 mg) are suspended in Inject 2 ml of anhydrous acetonitrile and inject 80 μΐ of a 5 N solution of BrCN in acetonitrile. The mixture was refluxed for 1 hour. After cooling, the entire reaction mixture was chromatographed on silica gel in EE / MeOH (5: 1).

170 mg of crystalline substance are obtained, mp 217-218 ° C (decomposition). R _f (EA / MeOH 5: 1) = 0.38. MS (ES): 520. (M + H) < + >.

d) 4 '- [5-Formyl-2- (4-isopropyl-phenyl) -4- (2-methoxy-ethoxy) -imidazol-1-ylmethyl] -biphenyl-2-sulfonyl-cyanamide

A solution of 140 mg of 4 '- [4-chloro-5-formyl-2- (4-isopropyl-phenyl) imidazol-1-ylmethyl] -biphenyl-2-sulfonyl-cyanamide and 108 mg of NaOH in 5 ml of methoxyethanol was stirred for 105 minutes at 90 ° C. The mixture is cooled, mixed with 150 ml of 10% aqueous NaHCO ₃ solution and extracted three times with 100 ml of EE each. After drying over Na ₂ SO ₄ , the solvent was evaporated in vacuo and the residue was chromatographed on silica gel in EE / MeOH (10: 1). 90 mg of an amorphous solid are obtained. R _f (EA / MeOH 10: 1) = 0.29. MS (ES): 559 (M + H) < + & gt ^; .

Example 4

4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3' - (2-methoxy-ethoxy) -biphenyl-2-sulfonyl-cyanamide

····· · · · · · · · · · ····················

a) 4-Methyl-3- (2-methoxy) ethoxy-aniline

A solution of 22.0 g of 3-hydroxy-4-methyl-aniline, 24.9 g

Of 2-bromoethyl methyl ether and 233 g of Cs ₂ CO ₃ in 570 mL of DMF was stirred at 40 ° C for 8 hours. Three liters of a 10% aqueous sodium bicarbonate solution are added, the mixture is extracted six times with 750 ml of EA and the extract is washed twice with 1 liter of a 10% aqueous sodium bicarbonate solution each. After drying over sodium sulfate, the solvent was evaporated in vacuo. It is obtained

32.9 g of a yellow oil, which is used in the next step without purification.

R _f (EA / HEP 1: 1) = 0.33.

b) 4-Methyl-3- (2-methoxy) ethoxy-bromobenzene

4-Methyl-3- (2-methoxy) ethoxy-aniline (32.8 g) was suspended in 660 ml of a half-saturated aqueous solution of HBr and a solution of 12.5 g of NaNO ₂ in 25 ml of water was slowly added dropwise at 0 ° C. . The solution was stirred at 0 ° C for 30 minutes and then slowly added to the solution

51.9 g of CuBr in 490 ml of saturated aqueous HBr solution, heated to 50 ° C. Then, the temperature of the reaction mixture slowly increased from 50 ° C to 70 ° C over six hours. After cooling, the mixture was extracted with four 500 ml portions of diethyl ether and the extract was washed with 500 ml of saturated aqueous NaCl solution. After drying over sodium sulphate and chromatography on silica gel (1: 8 EE / HEP), 15.4 g of a colorless oil are obtained.

R _f (EA / HEP 1: 1) = 0.41. MS (DCI): 245 (M + H) < + & gt ^; .

c) 4-Bromomethyl-3- (2-methoxy) ethoxy-bromobenzene

To a solution of 15.3 g of 4-methyl-3- (2-methoxy) ethoxybromobenzene in 300 ml of chlorobenzene was added portionwise under reflux a mixture of 11.1 g of N-bromosuccinimide and 125 mg of benzyl peroxide. The reaction mixture was refluxed for 24 hours, the solvent was evaporated in vacuo and the residue is taken up in 500 ml CH ₂ C1 _2nd The dichloromethane solution was washed first with 200 ml of saturated aqueous sodium sulfate solution and then with 100 ml of saturated aqueous sodium carbonate solution. After drying over sodium sulfate, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel in EE / HEP (1:15). 12.8 g of a yellowish oil are obtained.

R _f (EA / HEP 1: 4) = 0.42. MS (DCI): 323 (M + H) < + & gt ^; .

d) 3- [4-Bromo-2- (2-methoxy-ethoxy) -benzyl] -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

620 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 970 mg of 4-bromo-1-bromomethyl-2- (2-methoxy-ethoxy) -benzene and 415 mg of K are suspended in 15 ml of anhydrous DME. ₂ CO ₃ and the suspension is stirred at room temperature for 15 hours. 75 ml of saturated aqueous Na ₂ CO ₃ solution and 75 ml of water are added and the mixture is extracted three times with 100 ml of EE each. After drying over sodium sulfate, the solvent is removed in vacuo and the residue is chromatographed on silica gel in EE / HEP (1: 4). 640 mg of a colorless oil are obtained.

Rf (EE / HEP 1: 2) = 0.26. MS (ES): 450 (M + H) h

e) 4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3'- (2-methoxy-ethoxy) -biphenyl-2-sulfonic acid tert-butylamide

To a mixture of 620 mg of 3- [4-bromo-2- (2-methoxy-ethoxy) -benzyl] -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 420 mg of 2-dihydroxyboryl- tert -butyl amide. benzenesulfone, mg of Pa (II) acetate and 36 mg of triphenylphosphine in 8 ml of toluene and 2 ml of ethanol are added 1.4 ml of a 2 N aqueous Na ₂ CO ₃ solution. The reaction mixture is refluxed for 4 hours, then allowed to cool and diluted with 75 ml of saturated aqueous solution:

Na ₂ CO ₃

m.

water. It is extracted three times with 100 ml each, the extract is dried over sodium sulphate and the solvent is evaporated off under vacuum. Chromatography on silica gel in EE / HEP (1: 2) gave 600 mg of a colorless oil.

R _f (EA / HEP 1: 2) = 0.20. MS (ES): 583 (M + H) < + & gt ^; .

• ························································

f) 4 '- (4-Chior-5-formyl-2-phenyl-imidazol-1-ylmethyl) -3' - (2-methoxy-ethoxy) -biphenyl-2-sulfonamide

To a solution of 570 mg of 4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -3'- (2-methoxy-ethoxy) -biphenyl-2-sulfonic acid tert-butylamide in 5 ml of trifluoroacetic acid, add 117 μΐ of anisole. The mixture was stirred at room temperature for 8 hours and then the solvent was removed in vacuo. The residue was chromatographed on silica gel with EE / HEP (1: 1). 350 mg of an amorphous solid are obtained.

R _f (EA / HEP 1: 1) = 0.27. MS (ES): 527 (M + H) < + & gt ^; .

g) 4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3' - (2-methoxy-ethoxy) -biphenyl-2-sulfonamide

340 mg of 4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) -3'- (2-methoxy-ethoxy) -biphenyl-2-sulfonamide and 260 ml are dissolved in 13 ml of 2-methoxyethanol. mg NaOH. The solution was stirred at 90 ° C for 7 hours. After cooling, the reaction mixture was diluted with 100 ml of 10% aqueous NaHCO ₃ solution and extracted three times with 100 ml of EE each. After drying over sodium sulfate, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel with EE / HEP (2: 1) to give 230 mg of an amorphous solid.

R _f (EA / HEP 2: 1) = 0.33. MS (ES): 566 (M + H) < + & gt ^; .

h) 4 '- [5-Formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3' - (2-methoxy-ethoxy) -biphenyl-2-sulfonyl-cyanamide

210 mg are suspended in 4 ml of anhydrous acetonitrile

4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-imidazol-1-ylmethyl] -3' - (2-methoxy-ethoxy) -biphenyl-2-suifonamide and 154 mg K ₂ CO ₃ .

Inject 74 μΐ of a 5 N solution of BrCN in acetonitrile to this suspension. The mixture was refluxed for 3 hours and after cooling, the entire reaction mixture was subjected to a reaction time. Chromatography on silica gel in EE / MeOH (10: 1) system. 170 mg of white crystals are obtained, m.p. Mp 162 ° C.

R _f (EA / MeOH 10: 1) = 0.11. MS (ES): 591 (M + H) < + & gt ^; .

Pharmacological data

Inhibition of Na ⁺ -dependent C1 '/ HCO ₃ ' transducer (NCBE) in human endothelial cells

Human endothelial cells (ECV-304) are released from the culture flasks using trypsin / EDTA buffer (0.05 / 0.02% in phosphate buffer) and after centrifugation (100 g, 5 minutes) suspended in buffered saline (mmol / ml). 1: 115 NaCl, 20 NH ₄ Cl, 5 KCl,

CaCl ₂ , 1 MgSO ₄ , 20 N- (2-hydroxyethyl) piperazine-N-2-ethanesulfonic acid (HEPES), 5 glucose and 1 g / l bovine serum albumin; pH 7.4). This cell suspension is incubated for 20 minutes at 37 ° C with 5 μΜ of BCECF-acetoxymethyl ester. The cells are then washed and resuspended in a buffer solution containing no sodium or bicarbonate (mmol / 1: 5 HEPES,

133.8 cnoline chloride, 4.7 KCl, 1.25 MgCl ₂ , 0.97 K ₂ HPO ₄ ,

0.23 KH ₂ PO ₄ , 5 glucose; pH 7.4).

For subsequent fluorescence measurements in FLIPR (Fluorescent Imaging Plate Reader), 100 μΐ of this suspension containing 20,009 cells per well is pipetted into each well of a 96-well microplate and centrifuged (100 g, 5 minutes).

In the FLIPR, 100 μΐ of buffer solution is removed from the next prepared microtiter plate and pipetted into each of the 96 wells of the plate for measurement. In this case, a buffer solution containing bicarbonate and sodium ions (mmol / 1: 5 HEPES) is used for 100% control, i.e. restoration of intracellular pH (pHJ over NCBE).

93.8 NaCl, 40 NaHCO ₃ , 4.7 KCl, 1.25 CaCl ₂ , 1.25 MgCl ₂ , 0.97 Na ₂ HPO ₄ , 0.23 NaH ₂ PO ₄ , 5 glucose; pH 7.4), which contains μE HOE 642. For 0% control, ie no regeneration of pH ₁ , a buffer solution not containing bicarbonate ions but containing sodium ions (mmol / 1: 5 HEPES) is used. , 133.8 NaCl,

glucose; pH 7.4) to which 50 μΜ HOE 642 has also been added. The compounds of the invention are added at various concentrations to a solution containing sodium and bicarbonate ions.

After addition of the buffer solutions and dyed acidified cells situated on a microtiter plate, with each well of the plate measured increase of the fluorescence intensity, which corresponds to the increase _ρΗ Σ. Kinetics are measured at 35 ° C over a time period of 2 minutes.

The increase in fluorescence intensity for various concentrations of the compounds of the invention is then related to both controls and the inhibitory effect of these compounds is calculated.

Results

Residual NCBE activity at inhibitor concentration 10 μΜ (%)

The compound of Example no.

18, 9 29, 6 13.5 • 444 4 44 44 44 44 4444 · 44 44 '

Claims (15)

PATENT CLAIMS 1 is zero, 1 or 2; sky R (2) and R (3) independently of one another are SO _n -R (22); n is zero, 1 or 2; R (22) is alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C _a H _2s- phenyl which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (34) R (35); R (34) and R (35) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; s is zero, 1 or 2; R (4) and R (5), independently of the salt, are hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, fluorine, chlorine, bromine, iodine, CF ₃ , -CN, -NO ₂ , SO _p -R (16), CO-R (23), OR (24), or O- (alkylene, containing 2, 3 or 4 carbon atoms) -O-R (33); p is zero, 1 or 2; R (16) is an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from the series fluorine , atoi chlorine, bromine, iodine, CF _3, methyl, methoxy, hydroxyl or NR (26) R (27); R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (23) is hydrogen, alkyl having 1, 2, 3, Compounds of formula I wherein the symbols have the following meanings: R (i) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C _and H _2a -phenyl wherein the phenyl moiety is unsubstituted or substituted with 1, 2 or 3 with the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, iodine atom, CE ₃ group, methyl group, methoxy group, hydroxy group or NR (8) R (9) group; R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a is zero, 1 or 2; or R (l) is a group -C _b H _2b -heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 sky 9 carbon atoms, where the heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3 identical or with various substituents from the series fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ , methyl, methoxy, hydroxyl or NR (10) R (11); R (10) and R (11) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; b is zero, 1 or 2; or R (l) is -C _d H _2d-alkyl cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms; d is zero, 1 or 2; R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , -CN, -NO ₂ , CH ₂ OR (17), CO-R (S), O-R (7), O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17), or NR (50) R (51); R (17) is hydrogen or alkyl having 1, 2, Compounds of formula I according to claim 1, wherein R (1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or -C _and H _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 same or different substituents from a series of atoms fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (8) R (9); R (8) and R (9) independently of one another are hydrogen or methyl; a is zero or 1; or R (1) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 3, 4, 5, 6, 7 or 8 carbon atoms; R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52); R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (3) is hydrogen, -CM or CO-R (6); R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or OR (30); R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (4) is hydrogen, chlorine, fluorine, bromine, iodine, SO _P R (I6) or a group O-CH ₂ -CH ₂ -OR (3 3); ρ is zero, 1 or 2; R (16) is an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 same or different substituents from the series fluorine , chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (26) R (27); R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (33) is methyl or ethyl; R (5) is hydrogen; and their physiologically acceptable salts. Compounds of formula I according to claim 1 and / or claim 2, wherein R (1) is a hydrogen atom, an alkyl group containing 1, 2, 3 or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from a series a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, a methyl group, a methoxy group, a hydroxyl group or an NR (8) R (9) group; R (8) and R (9) independently of one another are hydrogen or methyl; or R (1) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group , methyl, methoxy, hydroxyl or NR (10) R (11); R (10) and R (11) independently of one another are hydrogen or methyl; or R (1) is a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms; R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, 3 or 4 carbon atoms, and their physiologically acceptable salts; with the proviso that at least one of R (2) or R (3) is O- (alkylene containing 2 or 3 carbon atoms) -O-R (± 7) or NR (50) R (51) . 3 or 4 carbon atoms; · · * • · · · · · · · · R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (30), or phenyl which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, Cl, Br, _CF3, methyl, methoxy, hydroxyl or NR (31) R (32); R (31) and R (32) independently of one another are hydrogen or methyl; R (30) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, CF ₃ , methyl, methoxy, hydroxyl or NR (12) R (13); R (12) and R (13) independently of one another are hydrogen or methyl; or R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 3, 4, 5, 6, 7 or 8 carbon atoms; and their physiologically acceptable salts; with the proviso that at least one of R (2) or R (3) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51) ). · * * * * * * * * * * * * * 3, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (12) R (13); R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 3, 4, 5, 6, 7 or 8 carbon atoms, an OR (30) group, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (31) R (32); R (31) and R (32) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (3Q) is a hydrogen atom or an alkyl group containing 1; 2, 3, 4, 5, 6, 1 or 8 carbon atoms; R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52); R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; • · · R (7) is hydrogen or alkyl having 1, 2, 3 Λ σ £ 2 7 ry, V- \ QO Ετη ι ' ¹ ] i - ί-ι 1 b- 1 i · Ό f ‘ci f 2 f C f-Ό O. _ Ό li li li 1 la la li li li Ό Ό li li li C C J. C C F R (6) is hydrogen or alkyl having 1, 2, Compounds of formula I according to one or more of claims 1 to 3, wherein R (1) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by a substituent. from the series fluorine atom, chlorine atom, CF ₃ group, methyl group or methoxy group; or R (1) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 4, 5, 6, 7 or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl a group, a methoxy group, a hydroxyl group or a NR (28) R (29) group; R (28) and R (29) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (33) is hydrogen or alkyl having 1, 2, 4, 5, 6, 7 or 8 carbon atoms, or OR (25); R (25) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (24) is hydrogen, alkyl having 1, 2, 3, Compounds of formula I according to one or more of claims 1 to 4, wherein R (l) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -C _d H _2d -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, wherein d is zero, 1 or 2, or -C _and H _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 of the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 10 (RS); R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a is zero, 1 or 2; ····· · · · · · · · · · · · · · · · · · · · · · · · · R (2) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51); R (17) is hydrogen or alkyl having 1, 2, Compounds of formula I according to one or more of claims 1 to 5, wherein R (1) is -C _and H _2a -phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (8) R (9); R (8) and R (9) independently of one another are hydrogen or methyl; a is zero or 1; R (2) is O- (alkylene containing 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (5i); R (17) is an alkyl group having 1, 2, 3 or 4 carbon atoms; R (50) and R (51) independently of one another are - (alkylene having 2, 3 or 4 carbon atoms) -O-R (52); R (52) is alkyl having 1, 2, 3 or 4 carbon atoms; R (3) is CO-R (6); R (6) is hydrogen; R (4) is SO ₂ R (16), where R (16) is alkyl having 1, 2, 3 or 4 carbon atoms or a group O-CH ₂ -CH ₂ -O-CH _3; R (5) is hydrogen; and their physiologically acceptable salts. - 6 / -NO ₂ , CO-R (6), CR (7), O-CH ₂ -CH ₂ -OR (17), or NR (50) R 15 '); R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (3C), or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine CF ₃ , methyl, methoxy, hydroxyl or NR (31) R (32); R (31) and R (32) independently of one another are hydrogen or methyl; R (30) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (7) is hydrogen or alkyl having 1, 2, or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl group, methoxy, hydroxyl or NR (12) R (13); R (12) and R (13) independently of one another are hydrogen or methyl; or R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, Compounds of formula I according to one or more of claims 1 to 6, wherein R (2) is a group O-CH ₂ -CH ₂ -OR (17) or NR (50) R (51) R (17) is an alkyl group having 1, 2, 3 or 4 carbon atoms; • · · · · · · · · R (50) and R (51) are -Cn ₂ -CH ₂ -OR (52) wherein R (52) is an alkyl group containing 1, 2, 3 or 4 carbon atoms; and their physiologically acceptable salts. Compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically acceptable salts, characterized in that they are used as medicaments. 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, MeOH group or methoxy group; R (50) and R (5i) are -CH ₂ -CH ₂ -O-CH ₃ ; or R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl which is unsubstituted or is substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl and methoxy; or R (2) and R (3) independently of each other are a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, atom chlorine, CF ₃ , methyl or methoxy; or R (2) and R (3) independently of one another are SO _n -R (22); n is zero or 2; R (22) - is an alkyl group containing 1, 2, 3 or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, CF ₃ , methyl group or methoxyl with a group / R (4) and R (5) independently of one another are hydrogen, methyl, fluoro, chloro, CF ₃ , -CN, SO ₂ -R (16), CO-R (23), oR (24) or the group 'O-CH ₂ ^- CH ₂ -O-CH _3; R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ methyl or methoxy; R (23) is hydrogen, methyl or QR (25); R (25) is hydrogen, methyl or ethyl; R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ methyl or methoxy; and their physiologically acceptable salts; with the proviso that at least one of R (2) or R (3) is O-CH ₂ -CH ₂ -O-CH ₃ or NR (50) R (51). 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (14) R (15); R (14) and R (15) independently of the methyl group; R (17) is methyl R (50) and R (51) independently of one another are hydrogen or ethyl; they are a group -CH ₂ -CH ₂ -OR (52); R (52) is methyl or ethyl; or R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (18) R (19); R (13) and R (19) independently of one another are hydrogen or methyl; or R (2) and R (3) independently of each other are a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, atom chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (20) R (21); R (20) and R (21) independently of one another are hydrogen or methyl; or R (2) and R (3) independently of one another are SO-R (22); n is zero or 2; R (22) is an alkyl group having 1, 2, 3 or 4 carbon atoms, a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms or a phenyl group which is unsubstituted or is substituted by 1 or 2 of the same or various substituents from the series - fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (34) R (35); R (34) and R (35) independently of one another are hydrogen or methyl; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, CF ₃ , -CN, -NO ₂ , SO _P -R (16), CO-R (23), OR (24), or O-CH ₂ -CH ₂ -OR (33); p is zero or 2; R (23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or OR (25); R (25) is hydrogen or alkyl having 1, 2 or 3 carbon atoms; R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl group , methoxy, hydroxyl or NR (28) R (29); R (28) and R (29) independently of one another are hydrogen or methyl; R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by a substituent from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group, methyl group, methoxy group , hydroxyl or NR (26) R (27); R (26) and R (27) independently of one another are hydrogen or methyl; R (33) is methyl or ethyl; and their physiologically acceptable salts; with the proviso that at least one of R (2) or R (3) is O-CH ₂ -CH ₂ -OR (17) or NR (50) R (5y). 7, 8 or 9 carbon atoms which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (14) R (15); R (14) and R (15) independently of one another are hydrogen or methyl; R (50) and R (51) independently of one another are - (alkylene group containing 2 or 3 carbon atoms) -O-R (52); R (52) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (2) and R (3) independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl containing 3, 4, 5, 6 or 7 carbon atoms or -C _g H _2g- phenyl, wherein the phenyl moiety is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxy or NR (18) R ( 19); R (18) and R (19) independently of one another are hydrogen or methyl; g is zero or 1; or R (2) and R (3i), independently of one another, are a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, Cl, Br, _CF3, methyl, methoxy, hydroxy group, or NR (20) R (21); R (20 'and R (21) independently of one another are hydrogen or methyl; or R (2) and R (3) independently of one another are SO _n -R (22; n is zero, 1 or 2). R (22) is a carbon alkyl group, a cycloalkyl group of carbon atoms, or a group wherein the phenyl moiety contains 1, 2, 3 or 4 m atoms and contains 3, 4, 3, 6 or -C _s H _2s -phenyl, unsubstituted or. substituted with 1 or 2 same or different substituents from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (34) R (35); R (34) and R (35) independently of one another are hydrogen or methyl; s is zero or 1; R (4) and R (5) independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, CF ₃ group, -CN group, -NO group ?, SO _P R (16), CO-R (23), oR (24) or a group 0- (alkylene group having 2 or 3 carbon atoms), -0-R (33); p is zero, 1 or 2; R (16) is an alkyl group having 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1 or 2 same or different substituents from the series fluorine atom, chlorine atom, bromine atom, CF ₃ group , a methyl group, a methoxy group, a hydroxyl group or a group NR (26) R (27); R (26) and R (27) independently of one another are hydrogen or methyl; R (23) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or OR (25); R (25) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl which is unsubstituted or substituted by 1 or 2 of the same or different substituents from the series fluorine atom, chlorine atom, bromine atom, CF ₃ , methyl, methoxy, hydroxyl or NR (28); R (29); 7, 8 or 9 carbon atoms which is unsubstituted or substituted by 1, 2 or 3 with the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (14) R (15); R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (2) and R (3) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or a group -CgH ₂ g sulfones, wherein the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 identical or different substituents from the series fluorine, chlorine, bromine, iodine, CF _3, methyl, methoxy , hydroxyl or NR (18) R (19); R (18) and R (19) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; g is zero, 1 or 2; About Heaven R (2) and R (3) independently of one another are -C ₁ H ₂ i-heteroaryl · containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the heteroaryl moiety being unsubstituted or is substituted with 1, 2 or 3 of the same or different substituents from the series fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR (20) R (21); R (2Q) and R (21) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy; or R (1) is a cycloalkyl group containing 3, 4, 5, 6 or 7 carbon atoms; R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, CF ₃ , -CN, CO-R (6), O-R (7), O-CH ₂ -CH ₂ -O-CH ₃ , or NR (50) R (51); R (6) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (30), or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy; R (30) is hydrogen, methyl or ethyl; R (7) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, CF ₃ , methyl or methoxy ; or 9 9 9 9 9 9 9 9 9 99 99 99 9999 99 R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 8 or 9 carbon atoms which is unsubstituted or substituted by a substituent from the series fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR (10) R (11); R (10) and R (11) independently of one another are hydrogen or methyl; or R (l) is -C _d H2d-cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms; d is zero or 1; R (2) and R (3) independently of one another are hydrogen, fluorine, chlorine, bromine, CF 6, -CN, -NCR, CH ₂ OR (17), CO-R (. S), OR (7), O- (alkylene containing 2 or 3 carbon atoms) -O-R (17), or NR (50) R (51); R (17) is hydrogen or alkyl having 1, 2, A pharmaceutical composition comprising an effective amount of a compound of formula I according to one or more of claims 1 to 7, and / or a physiologically acceptable salt thereof. · · 9 9 «9« · · « R (28) and R (29) independently of one another are hydrogen or methyl; R (33) is hydrogen or alkyl having 1, 2, 9 · · · · · · · · · Pharmaceutical composition according to claim 9, characterized in that it additionally contains an effective amount of an NHE-inhibitor and / or an active substance from another group of cardiovascular active substances, and / or their physiologically acceptable salts. Use of compounds of formula I according to one or more of claims 1 to 7, and / or their physiologically acceptable salts, as inhibitors of sodium-dependent bicarbonate / chloride exchanger. Use of the compounds of the formula I according to one or more of claims 1 to 7, and / or their physiologically acceptable salts, in the therapy and / or prophylaxis of cardiac infarction, angina pectoris, diseases caused by ischemic conditions, respiratory motor disorders, ischemic heart conditions, ischemic conditions peripheral and central nervous systems and strokes, ischemic conditions of peripheral organs and limbs, diseases caused primarily or secondary by cell proliferation, or in shock conditions, or in surgical operations and organ transplants, or in the preservation and preservation of transplants for surgical procedures. Use of compounds of formula I according to one or more of claims 1 to 7, and / or physiologically acceptable salts thereof, as an anti-atherosclerotic, as a medicament against diabetic late, complications, cancer, fibrotic disease or hypertrophy and / or organ hyperplasia. Pharmaceutical composition according to claim 9 and / or 10, characterized in that it is used in the treatment and / or prophylaxis of heart attack, angina pectoris, diseases caused by ischemic conditions, respiratory motor disorders, ischemic heart conditions, peripheral and central ischemic conditions nervous system and stroke, ischemic conditions of peripheral organs and limbs, diseases caused primarily or secondary by cell proliferation, in shock conditions, or in surgical operations and organ transplants, or in the preservation and preservation of transplants for surgical procedures. Pharmaceutical composition according to claim 9 and / or 10, characterized in that it is used as * an anti-atherosclerotic, as a medicament against diabetic late complications, cancer, fibrotic disease, or against organ hypertrophy and / or hyperplasia.