DE19741636A1 - New 1-benzyl-imidazole and known tetrazole derivatives - Google Patents

Abstract

1-Benzylimidazole derivatives of formula (I) and their salts are new. R1 = H, 1-8C alkyl, -CaH2a-Ar or -CaH2a-(3-7C)cycloalkyl; a = 0-2; Ar = phenyl or 1-9C heteroaryl (both optionally substituted by 1-3 F, Cl, Br, I, CF3, Me, OMe, OH or NR8R9); R8, R9 = H or 1-4C alkyl; R2, R3 = H, F, Cl, Br, I, CF3, CN, NO2, CH2OR17, COR6 or OR7, 1-8C alkyl, 3-7C cycloalkyl, -CaH2a-Ar or -SOa-R22; R17= H or 1-8C alkyl; R6 = H, 1-8C alkyl, OR30 or phenyl (optionally substituted as in Ar); R7 = H, 1-8C alkyl or Ar; R22 = 1-8C alkyl, 3-7C cycloalkyl or -CaH2a-Ph; R4, R5 = H, 1-8C alkyl, F, Cl, Br, I, CF3, CN, NO2, SOa-R16, COR23 or OR24; R16 = 1-8C alkyl or phenyl (optionally substituted as in Ar); R23 = H, 1-8C alkyl or OR25; R24 = H, 1-8C alkyl or phenyl (optionally substituted as in Ar); and R25 = H or 1-8C alkyl. Also claimed is the treatment or prophylaxis of ischaemia-mediated conditions or the treatment of respiratory disorders using a tetrazole derivative.

Description

The invention relates to compounds of the formula I.

in which the symbols have the following meaning:
R1 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C _a H _2a phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or (C ₁ -C ₄ ) alkyl;
a zero, 1 or 2;
or
R1 -C _b H _2b - (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or (C ₁ -C ₄ ) alkyl;
b zero, 1 or 2;
or
R1 -C _d H _2d - (C ₃ -C ₇ ) cycloalkyl;
d zero, 1 or 2;
R2 and R3
independently of one another hydrogen, F, Cl, Br, I, CF ₃ , -C∼N, -NO ₂ , CH ₂ OR17, CO-R6 or O-R7;
R17 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
R6 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or (C ₁ -C ₄ ) alkyl;
R30 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or (C ₁ -C ₄ ) alkyl;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or (C ₁ -C ₄ ) alkyl;
or
R2 and R3
independently of one another alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
Cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _g H _2g -phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or (C ₁ -C ₄ ) alkyl;
g zero, 1 or 2;
or
R2 and R3
-C _l H _2l - (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or (C ₁ -C ₄ ) alkyl;
l zero, 1 or 2;
or
R2 and R3
SO _n -R22;
n zero, 1 or 2;
R22 alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _S H _2s -phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of group F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
independently of one another H or (C ₁ -C ₄ ) alkyl;
s zero, 1 or 2;
R4 and R5
independently of one another hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO-R23 or O-R24;
p zero, 1 or 2;
R16 alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or (C ₁ -C ₄ ) alkyl;
R23 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR25;
R25 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or (C ₁ -C ₄ ) alkyl;
as well as their physiologically acceptable salts.

Compounds of the formula I are preferred in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -C _a H _2a phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or methyl;
a zero or 1;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or methyl;
or
R1 -C _d H _2d - (C ₃ -C ₇ ) cycloalkyl;
d zero or 1;
R2 and R3
independently of one another hydrogen, F, Cl, Br, CF ₃ , -C = N, -NO ₂ , CH ₂ OR17, CO-R6 or O-R7;
R17 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or methyl;
R30 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or methyl;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or methyl;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _g H _2g -phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or methyl;
g zero or 1;
or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or methyl;
or
R2 and R3
SO _n -R22,
n zero, 1 or 2;
R22 alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _S H _2s -phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
selected from the group consisting of H or methyl;
s zero or 1;
R4 and R5
independently of one another hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO- R23 or O-R24;
p zero, 1 or 2;
R ¹⁶ alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
that is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or methyl;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or methyl;
as well as their physiologically acceptable salts.

Compounds of the formula I are particularly preferred in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or methyl;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or methyl;
or
R1 (C ₃ -C ₇ ) cycloalkyl;
R2 and R3
independently of one another hydrogen, F, Cl, Br, CF ₃ , -C∼N, -NO ₂ , CO-R6 or O-R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or methyl;
R30 is hydrogen or alkyl with 1, 2 or 3 carbon atoms
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or methyl;
or
R7
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or methyl;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or methyl;
or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or methyl;
or
R2 and R3
SO _n -R22;
n zero or 2;
R22 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 with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
independently of one another H or methyl;
R ⁴ and R ^{5 are} independent of one another
Hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO-R23 or O- R24;
p zero or 2;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or methyl;
R16 alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or methyl;
as well as their physiologically acceptable salts.

Compounds of the formula I, in which:
R1 alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , CH ₃ and methoxy;
or
R1 (C ₃ -C ₇ ) cycloalkyl;
R2 and R3
independently of one another hydrogen, F, Cl, CF ₃ , -C∼N, CO-R6 or O-R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R30 is hydrogen, methyl or ethyl;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ and methoxy;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , CH ₃ and methoxy;
or
R2 and R3
SO _n -R22;
n zero or 2;
R22 alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R4 and R5
independently of one another hydrogen, methyl, F, Cl, CF ₃ , -C∼N, SO ₂ -R16, CO-R23 or O-R24;
R ¹⁶ alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R23 is hydrogen, methyl or OR25;
R25 is hydrogen, methyl or ethyl;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
as well as their physiologically acceptable salts.

Alkyl can be straight-chain or branched.  

Cycloalkyl is also understood to mean alkyl-substituted rings. (C ₁ -C ₉ ) heteroaryl means in particular residues which are derived from phenyl or naphthyl, in which one or more CH groups have been replaced by N and / or in which at least two adjacent CH groups (to form a five-membered aromatic ring) are replaced by S, NH or O. Furthermore, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.

Heteroaryl is especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, Triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, Pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, Quinoxalinyl, quinazolinyl, cinnolinyl.

Any stereo centers that occur can be both (R) and (S) -configured.

Physiologically acceptable salts of compounds of the formula I are understood both their organic and inorganic salts, such as those in Remington's Pharmaceutical Sciences [17th Edition, page 1418 (1985)]. Due to the physical and chemical stability and the solubility are for acidic groups including sodium, potassium, calcium and ammonium salts prefers; for basic groups include salts of hydrochloric acid, Sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as e.g. B. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, Tartaric acid and p-toluenesulfonic acid are preferred.

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

wherein the radicals are as defined above and which are either known from J. Med. Chem. 1995, 36, 2357 or were prepared analogously, with cyanogen bromide. The reaction takes place in a dipolar aprotic solvent that is stable against cyanogen bromide, for example acetonitrile, DMA, TMU or NMP with a strong auxiliary base that is not very nucleophilic, such as K ₂ CO ₃ or Cs ₂ CO ₃ . A temperature of 0 ° C. and the boiling point of the solvent used are suitable as the reaction temperature; a temperature of 60 ° C. and 120 ° C. is preferred.

The invention further relates to the use of a compound of the formula

in which mean:

• a) X, Y and Z
  same or different, N or CR (102)
• b) R (1)
• 1. (C ₁ -C ₁₀ ) alkyl, 2. (C ₃ -C ₁₀ ) alkenyl, 3. (C ₃ -C ₁₀ ) alkynyl, 4. -OR (103), 5. (C ₃ - C ₈ ) -cycloalkyl, 6. (C ₄ -C ₁₀ ) -cycloalkylalkyl, 7. (C ₅ -C ₁₀ ) -cycloalkylalkenyl, 8. (C ₅ -C ₁₀ ) -cycloalkylalkynyl, 9.- (CH ₂ ) _m -B- (CH ₂ ) _n -R (104), 10. -Benzyl, 11. a radical as defined under b) 1., 2., 3. or 9. which is monosubstituted with CO ₂ R (103) , 12. a radical as defined under b) 1., 2., 3. or 9., in which 1 to all H atoms are substituted by fluorine, or 13. the radical defined under b) 10., which is at the phenyl 1 or 2 identical or different radicals from the series halogen, (C ₁ -C ₄ ) alkoxy and nitro is substituted,
• c) R (102)
• 1. hydrogen, 2. halogen, 3. nitro, 4. C _v F _{2v + 1} , 5. pentafluorophenyl, 6. cyano, 7. -OR (106), 8. phenyl, 9. phenyl- (C ₁ -C ₃ ) alkyl, 10. (C ₁ -C ₁₀ ) alkyl, 11. (C ₃ -C ₁₀ ) alkenyl, 12. phenyl- (C ₂ -C ₆ ) alkenyl, 13. 1-imidazolyl- ( CH ₂ ) _m -, 14. 1,2,3-triazolyl- (CH ₂ ) _n -, 15. tetrazolyl- (CH ₂ ) _m -, 16. - (CH ₂ ) _o-1 -CHR (107) - OR (105), 17th - (CH ₂ ) _o -O-CO-R (103), 18th - (CH ₂ ) _o -SR (106), 19th S (O) _r -R (119), 20.CH = CH- (CH ₂ ) _m -CHR (103) -OR (106), 21.CH = CH- (CH ₂ ) _m -CO-R (108), 22. -CO-R (108) , 23. -CH = CH- (CH ₂ ) _m -O-CO-R (107), 24. (CH ₂ ) _m -CH (CH ₃ ) -CO-R (108), 25. - (CH ₂ ) _o -CO-R (108), 26. - (CH ₂ ) _o -O- [C = W] -NH-R (109), 27. - (CH ₂ ) _o -NR (107) - [C = W] -OR (109), 28.- (CH ₂ ) _o -NR (107) -CO-NHR (109), 29.- (CH ₂ ) _o -NR (107) -SO ₂ R (109) , 30. - (CH ₂ ) _o -NR (107) - [C = W] -R (109), 31. - (CH ₂ ) _n F, 32. - (CH ₂ ) _n -O-NO ₂ , 33. -CH ₂ -N ₃ , 34. - (CH ₂ ) _n -NO ₂ , 35. -CH = N-NR (105) R (107), 36. phthalimido (CH ₂ ) _n -,
  
• 41. phenyl-SO ₂ -NH-N = CH-,
  
• 43. (CH ₂ ) _n -SO ₂ -NR (107) -CS-NR (106) R (109), 44. - (CH ₂ ) _n SO ₂ -NR (107) -CO-NR (106) R (109), 45. - (CH ₂ ) _o -SO ₂ R (109), 46. a radical as defined under c) 8. or 9., the phenyl with 1 or 2 identical or different radicals from the halogen series , Hydroxy, methoxy, trifluoromethyl, CO ₂ R (103) and phenyl, 47. a radical as defined under c) 10, 11 or 19, in which one to all H atoms are substituted by fluorine, 48. the radical defined under c) 14, which is substituted by 1 or 2 identical or different radicals from the series methoxycarbonyl and (C ₁ -C ₄ ) -alkyl, 49. -CH ₂ ) _n SO ₂ -NR (107) - CO-R (106), 50 .-- (CH ₂ ) _n -SO ₂ -NR (107) CS-R (106),
• d) R (3)
• 1. hydrogen, 2. (C ₁ -C ₈ ) -alkyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 4. phenyl, 5. benzyl, 6. the radical defined under d) 2., wherein 1 to all H atoms are substituted by fluorine;
• e) R (104)
• 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₂ -C ₄ ) alkenyl or 5. (C ₂ -C ₄ ) - Alkynyl;
• f) R (105)
• 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. phenyl or 5. benzyl;
• g) R (106) and R (109)
  identical or different 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of (C ₁ -C ₆ ) alkoxy, which in turn is substituted with 1- 3 radicals from the series hydroxy, (C ₁ -C ₆ ) -alkoxy, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino can be substituted, (C ₂ - C ₁₀ ) -alkenyl, hydroxy, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino, (C ₆ - C ₁₂ ) aryl- (C ₁ -C ₄ alkoxycarbonylamino, (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₃ ) alkyl, (C ₁ -C ₉ ) heteroaryl, carboxy and (C ₁ -C ₄ ) alkoxycarbonyl; 3. (C ₃ -C ₈ ) cycloalkyl,
  wherein the cycloalkyl part is unsubstituted or substituted with 1-3 substituents selected from the group consisting of
  (C ₁ -C ₄ ) alkyl and (C ₂ -C ₄ ) alkenyl; 4. (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, 5. (C ₆ -C ₁₂ ) aryl, preferably phenyl, 6. (C ₆ -C ₁₀ ) aryl- ( C ₁ -C ₄ ) alkyl, 7. (C ₁ -C ₉ ) heteroaryl,
  which can be partially or completely hydrogenated, 8. a radical as defined under g) 5th, 6th, 7th, 9th, 15th, 16th, 17th, 19th, 20th or 21st substituted with 1 or 2 identical or different radicals from the series halogen, hydroxy, (C ₁ -C ₄ ) alkyl, methoxy, nitro, cyano, CO ₂ R (103), trifluoromethyl, NR (111) R (112) and
  
• 9. (C ₁ -C ₉ ) heteroaryl- (C ₁ -C ₃ ) alkyl,
  the heteroaryl part can be partially or completely hydrogenated,
• 10. (C ₁ -C ₆ ) alkyl, in which 1 to all H atoms are substituted by fluorine, 11. (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkenoyl or (C ₂ - C ₁₀ ) alkadienyl, 12. (C ₃ -C ₈ ) cycloalkenyl, 13. (C ₃ -C ₈ ) cycloalkenyl (C ₁ -C ₃ ) alkyl, 14. bi- or tricyclic (C ₄ -C ₁₀ ) - cycloalkenyl- (C ₁ -C ₄ ) alkyl,
  which can still be substituted with 1-3 (C ₁ -C ₄ ) alkyl radicals;
• 15. (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₄ ) alkyl, 16. (C ₆ -C ₁₀ ) aryl- (C ₃ -C ₆ ) -alkenyl, 17. (C ₁ -C ₉ ) heteroaryl- (C ₃ -C ₆ ) alkenyl, 18. (C ₃ -C ₆ ) alkynyl, 19. (C ₆ -C ₁₀ ) aryl- (C ₃ -C ₆ ) - Alkynyl, 20. (C ₁ -C ₉ ) -he teroaryl- (C ₃ -C ₆ ) alkynyl, 21. R (106) and R (109) together with the N atom carrying them are a heteroaryl,
  that can also be partially or fully hydrogenated;
• h) R (107)
• 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₆ -C ₁₂ ) aryl (C ₁ -C ₆ ) alkyl , preferably benzyl, 5. phenyl or 6. (C ₁ -C ₉ ) -he teroaryl;
• i) R (108)
• 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. phenyl- (CH ₂ ) _q -, 5. OR (106), 6. NR ( 111) R (112) or 7.
  
• j) R (110)
  Cyano, nitro or CO ₂ R (107);
• k) R (111) and R (112)
  identical or different, 1. hydrogen, 2. (C ₁ -C ₄ ) -alkyl, 3. phenyl, 4. benzyl, or 5. α-methylbenzyl;
• l) D NR (113), O or CH ₂ ;
• m) R (113)
  Hydrogen, (C ₁ -C ₄ ) alkyl or phenyl;
• n) A biphenylyl,
  that is unsubstituted or substituted with 1-4, preferably 1 to 2 identical or different substituents R (114) or R (115);
• o) R (114)
• 1. halogen, 2. nitroso, 3. nitro, 4. amino, 5. cyano, 6. hydroxy, 7. (C ₁ -C ₆ ) alkyl, 8. (C ₁ -C ₄ ) alkanoyl, 9. (C ₁ -C ₄ ) alkanoyloxy, 10.CO ₂ R (103), 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. -CO-NH-OR (109), 14. -SO ₂ -NR (106) R (107), 15. -CH ₂ -OR (107), 16. (C ₁ -C ₉ ) heteroaryl- (CH ₂ ) _q -, preferably 1-tetrazolyl, 17. (C ₇ -C ₁₃ ) aroyl , 18th
  or
• 20. (C ₆ -C ₁₂ ) aryl;
• p) R (115)
• 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₆ -C ₁₂ ) aryl, 5. (C ₇ -C ₁₃ ) - Aroyl, 6. (C ₁ -C ₄ ) alkoxy, 7. (C ₁ -C ₄ ) alkanoyloxy, 8. (C ₁ -C ₉ ) heteroaryl, 9. CO ₂ R (103), 10. halogen , 11th cyano, 12th nitro, 13th NR (106) R (107), 14th hydroxy, 15th -CO-NH-CHR (105) -CO ₂ R (103), 16th sulfo, 17th - SO ₃ R (103), 18. -SO ₂ -NR (107) -CO-NR (106) R (109) or -SO ₂ -NR (107) -CS-NR (106) R (109), 19th -NR (107) -CO-NR (106) -SO ₂ -CH ₂ -R (105), 20. -C (CF ₃ ) ₂ OH, 21. Phosphonooxy, 22. -PO ₃ H ₂ , 23. -NH-PO (OH) ₂ , 24. S (O) _r R (106), 25. -CO-R (108), 26. -CO-NR (106) R (109), 27. -CR ( 120) (OH) -PO (OH) ₂ , 28. the remainder defined under o) 20.,
  
• 32. 5-tetrazolyl-NH-CO-, 33. -CO-NH-NH-SO ₂ -CF ₃ ,
  
• 40. -CO-NH-SO ₂ -R (119), 41. -SO ₂ -NH-CO-R (106) or 42. the radical defined under p) 4., substituted with 1 or 2 identical or different radicals from the series halogen, cyano, nitro, NR (106) R (107) and hydroxy; 43. R (115) together with R (114) means -CO-NH-SO ₂ -, 44. -SO ₂ -NH-CO-OR (106), 45. -SO ₂ -NH-SO ₂ -NR ( 106) R (109), 46. -SO ₂ -NH-SO ₂ -R (106);
• q) B O, NR (107) or S;
• r) W O or S;
• s) L (C ₁ -C ₃ ) alkanediyl;
• t) R (116)
  CO ₂ R (103) or CH ₂ CO ₂ R (103);
• u) R (117)
  Hydrogen, halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy;
• v) R (118)
  Hydrogen, (C ₁ -C ₄ ) alkyl or phenyl;
• w) R (119)
• 1. (C ₁ -C ₆ ) alkyl, 2. (C ₃ -C ₈ ) cycloalkyl, 3. phenyl, 4. benzyl or 5. the radical defined under w) 1., wherein one to all H atoms are substituted by fluorine,
• x) T 1. a single bond, 2. -CO-, 3. -CH ₂ -, 4. -O-, 5. -S-, 6. -NR (121) -, 7. -CO-NR (121 ), 8. -NR (121) -CO-, 9. -O-CH ₂ -, 10. -CH ₂ -O-, 11. -S-CH ₂ -, 12. -CH ₂ -S, 13. -NH-CR (120) R (122), 14. -NR (121) -SO ₂ , 15. SO ₂ -NR (121) -, 16. -CR (120) R (122) -NH, 17. -CH = CH-, 18. -CF = CF-, 19. -CH = CF-, 20. -CF = CH-, 21. -CH ₂ -CH ₂ -, 22. -CF ₂ -CF ₂ -, 23. -CH [OR (103)] -, 24. -CH (OCOR (105)) -, 25. -C [N = R (123)] - or 26.- [R (124) O] -C - [OR (125)] -;
• y) R (120) and R (122)
  identical or different, hydrogen, (C ₁ -C ₅ ) alkyl, phenyl, allyl or benzyl;
• z) R (121)
  Hydrogen, (C ₁ -C ₆ ) alkyl, benzyl or allyl;
  a ') R (123)
• 1. NR (120) R (121), 2. ureido, 3. thioureido, 4. toluene-4-sulphonyl or 5. benzenesulfonylamino;
  b ') R (124) and R (125)
  identical or different, (C ₁ -C ₄ ) -alkyl or together - (CH ₂ ) _q -;
  c ') Q CH ₂ , NH, O or S;
  d ') m 1, 2, 3, 4 or 5;
  e ') n 1, 2, 3, 4 or 5;
  f ') o 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  g ') q zero or 1;
  h ') r zero, 1 or 2;
  i ') v 1, 2, 3, 4, 5 or to 6;
  as well as their physiologically tolerable salts for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions, and for the manufacture of a medicament for the treatment of disturbed respiratory drive.

The invention further relates to the use of a compound of the formula I for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions;
and the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of heart attack;
and the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris;
and the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the heart;
and the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke;
and the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs;
and the use of a compound of formula I for the manufacture of a medicament for the treatment of shock conditions;
and the use of a compound of formula I for the manufacture of a medicament for use in surgical operations and organ transplants;
and the use of a compound of formula I for the manufacture of a medicament for the preservation and storage of grafts for surgical measures;
and the use of a compound of formula I for the manufacture of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause; and thus their use for the preparation of an antiatherosclerotic, an agent for late diabetic complications, cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or kidney fibrosis, prostatic hyperplasia;
and the use of a compound of formula I for the manufacture of a medicament for the treatment of impaired respiratory drive;
and a medicament characterized by an effective content of a compound of formula I.

Compounds of the formula I according to the invention are similar compounds from U.S. Patents 5,482,957 (HOE91 / F001K) and 5,604,251 (HOE92 / F058) known. However, they do not always have the according to the invention existing sulfonylcyanamide side chain. Imidazole derivatives as angiotensin II-antagonists are also described in WO 9523792, WO 9523791, US 5 391 732, EP-A 648763. Furthermore, in US 5 281 614, triazole derivatives, in WO 9220662 and J. Med. Chem. (1994), 37 (17), 2808-2824 triazolinone derivatives as Angiotensin II receptor antagonists are described. The known connections are angiotensin II receptor antagonists of the AT1 subtype, which have an effect on the compounds I according to the invention not or only to a small extent is available.

The compounds of the formula I according to the invention have very good antiarrhythmic properties, such as are important, for example, for the treatment of diseases which occur in the presence of oxygen deficiency symptoms. Because of their pharmacological properties, the compounds I are outstandingly suitable as antiarrhythmic medicaments with a cardioprotective component for preventing and treating infarction and for treating angina pectoris, while also preventively inhibiting the pathophysiological processes in the occurrence of ischemically induced damage, in particular when triggering ischemically induced cardiac arrhythmias or decrease significantly. Because of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can inhibit the cellular Na⁺-dependent Cl⁻ / HCO ₃ ⁻ exchange mechanism or the sodium / bicarbonate symporter as a medicament for the treatment of all acute or chronic damage caused by ischemia or diseases primarily or secondarily induced. This affects their use as medicines for surgery, e.g. B. in organ transplants, the compounds can be used both for protecting the organs in the donor before and during removal, for protecting removed organs, for example during treatment with or their storage in physiological bath fluids, as well as for the transfer into the recipient organism . The compounds of formula I are also valuable, protective pharmaceuticals when performing angioplasty surgery, for example on the heart as well as on peripheral vessels. According to their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemia of the nervous system, in particular the central nervous system. B. are suitable for the treatment of stroke or brain edema. In addition, the compounds of the formula I according to the invention are also suitable for treating forms of shock, such as, for example, allergic, cardiogenic, hypovolemic and bacterial shock.

In addition, the compounds of formula I according to the invention are distinguished by a strong inhibitory effect on the proliferation of cells, for example fibroblast cell proliferation and smooth proliferation Vascular muscle cells, from. Therefore, the compounds of formula I come as valuable therapeutic agents for diseases in question, in which cell proliferation is a represents primary or secondary cause, and can therefore be considered Antiatherosclerotics, remedies for late diabetic complications, Cancer, fibrotic diseases such as pulmonary fibrosis, liver fibrosis or Kidney fibrosis, organ hypertrophy and hyperplasia, especially in Prostate hyperplasia or prostate hypertrophy can be used.

It was found that inhibitors of the Na⁺-dependent Cl⁻ / HCO ₃ ⁻ exchanger or the sodium / bicarbonate symporter can stimulate respiration by increasing the chemosensitivity of the respiratory chemoreceptors. These chemoreceptors are largely responsible for maintaining orderly breathing. They are activated by hypoxia, a drop in pH and an increase in CO ₂ (hypercapnia) in the body and lead to an adjustment of the minute ventilation. Breathing is particularly susceptible to disruption during sleep and is highly dependent on the activity of the chemoreceptors.

An improvement in respiratory drive through stimulation of the chemoreceptors with substances that inhibit the Na⁺-dependent Cl⁻ / HCO ₃ exchange leads to an improvement in respiration in the following clinical conditions and diseases: Impaired central respiratory drive (e.g. central sleep apneas, sudden child death, postoperative hypoxia), muscular-related breathing disorders, breathing disorders after long-term ventilation, breathing disorders when adapting to high mountains, obstructive and mixed form of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.

Drugs containing a compound of formula I can be taken orally, parenterally, intravenously, rectally or by inhalation, the preferred application of the respective appearance of the disease is dependent. The compounds of formula I can be used alone or together with galenic auxiliaries, both in the Veterinary as well as human medicine.

Which excipients are suitable for the desired pharmaceutical formulation is familiar to the specialist on the basis of his specialist knowledge. In addition to solvents, Gelling agents, suppository basics, tablet excipients, and others Active substance carriers can, for example, antioxidants, dispersants, Emulsifiers, defoamers, flavoring agents, preservatives, Solubilizers or dyes are used.

For an oral form of use, the active compounds with the for it suitable additives, such as carriers, stabilizers or inert Diluent mixed and by the usual methods in the appropriate Dosage forms brought, such as tablets, coated tablets, capsules, aqueous, alcoholic or oily solutions. As inert carriers such. B. gum arabic, Magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or Starch, especially corn starch, can be used. The preparation can  done both as dry and as wet granules. As an oily carrier or vegetable or animal oils come in as solvents Consider how sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds, if desired with the usual substances such as solubilizers, Emulsifiers or other auxiliaries in solution, suspension or emulsion brought. As solvents such. B. in question: water, physiological Saline or alcohols, e.g. As ethanol, propanol, glycerin, in addition Sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

As a pharmaceutical formulation for administration in the form of aerosols or sprays are suitable e.g. B. solutions, suspensions or emulsions of Active ingredient of formula I in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such Solvent.

If required, the formulation can also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers and contain a propellant. A such preparation usually contains the active ingredient in a concentration of about 0.1 to 10, in particular about 0.3 to 3 wt .-%.

The dosage of the active ingredient of formula I to be administered and the frequency the administration depend on the strength and duration of action of the used Connections from; also on the type and strength of the treatment Illness as well as gender, age, weight and individual responsiveness of the mammal to be treated. On average, the daily dose of a compound of formula I is one patients weighing approximately 75 kg at least 0.001 mg / kg, preferably 0.01 mg / kg, up to at most 10 mg / kg, preferably 1 mg / kg body weight. In acute Outbreaks of the disease, such as immediately after suffering a heart attack, even higher and above all more frequent doses may be necessary, e.g.  B. up to 4 single doses per day. Especially with i.v. Application, for example Infarct patients in the intensive care unit may need up to 200 mg a day become.

The compounds of the formula I can be used as the only active ingredients or in combination be used with other pharmacologically active compounds.

The compounds of formula I and / or their physiologically tolerable salts can also be used to achieve a beneficial therapeutic effect with other pharmacologically active compounds for treatment or Prophylaxis of the above-mentioned clinical pictures, in particular for the treatment of Cardiovascular diseases can be used. The combination with is preferred Inhibitors of the sodium / hydrogen exchanger (NHE) and / or with active ones Substances from other cardiovascular drug classes.

The invention further relates generally to the combination of a) NCBE inhibitors and / or their physiologically tolerable salts with NHE inhibitors and / or their physiologically tolerable salts; b) NCBE inhibitors and / or their physiologically compatible salts with active substances from other cardiac circles running active ingredient classes and / or their physiologically tolerable salts and c) of NCBE inhibitors and / or their physiologically tolerable salts NHE inhibitors and / or their physiologically tolerable salts and with active Substances from other cardiovascular drug classes and / or their physiologically acceptable salts. Combinations are preferred in which NCBE inhibitors of the general formula I and / or their physiological compatible salts can be used.

The known active substances identified as NHE inhibitors are are guanidine derivatives, preferably acylguanidines, including how they in Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine," J. WILEY & Sons (1983), 303-341 are described or around in DE 197 37 224.4 NHE inhibitors listed.

Suitable NHE inhibitors are, for example, benzoylguanidines, as described in  US 5 292 755, US 5 373 924, US 5 364 868, US 5 591 754, US 5 516 805, US 5 559 153, US 5 571 842, US 5 641 792, US 5 631 293, EP-A 577 024, EP-A 602 522, EP-A 602 523, EP-A 603 650, EP-A 604 852, EP-A 612 723, EP-A 627 413, EP-A 628 543, EP-A 640 593, EP-A 640 588, EP-A 702 001, EP-A 713 864, EP-A 723 956, EP-A 754 680, EP-A 765 867, EP-A 77 4459, EP-A 794 171, DE 196 24 178.2, DE 197 13 427 .0 are described; ortho-substituted benzoylguanidines, as described in EP-A 556 673, EP-A 701 577, EP-A 794 172, DE 196 24 178.2; ortho-amino-substituted benzoyl guanidines, as described in EP-A 690 048; Isoquinolines as described in EP-A 590 455; Benzocondensed 5-ring He terocycles as described in EP-A 639 573; Diacyl substituted Guanidines as described in EP-A 640 587; Acylguanidines as described in US 5,547,953 are described; Phenyl-substituted alkyl or perfluoroalkyl groups Alkenyl carboxylic acid guanidines, as described in US Pat. No. 5,567,734, EP-A 688 766 are described; Heteroaroyl guanidines as described in EP-A 676 395; Bicyclic heteroaroyl guanidines as described in EP-A 682 017; Indenoylguanidines as described in EP-A 738 712; Benzyloxycarbonyl guanidines as described in EP-A 748 795; Carrying fluorophenyl groups Phenyl-substituted alkenylcarboxylic acid guanidines, as described in EP-A 744 397 are described; substituted cinnamic acid guanidines, as described in EP-A 755 919 are described; Sulfonimidamides as described in EP-A 771 788; Benzene dicarboxylic acid diguanidines, as described in EP-A 774 458, EP-A 774 457 are described; Diarylcarboxylic acid diguanidines, as described in EP-A 787 717 are described; substituted thiophenylalkenylcarboxylic acid guanidines, as described in EP-A 790 245 are described; Bis-ortho-substituted benzoylguanidines, as described in DE 196 21 319.3 are described; Substituted 1- or 2-naphthylguanidines, such as they are described in DE 196 21 482.3 and DE 196 21 483.1; Indanylidine acetylguanidines as described in EP 96 112 275.1; Phenyl substituted Alkenylcarboxylic acid guanidines, as described in DE 196 33 966.9 Aminopiperidyl-benzoylguanidines as described in EP 667 341; Heterocycloxy-benzylguanidines as described in EP-A 694 537; ortho-substituted benzoylguanidines as described in EP 704 431; ortho-substituted alkyl-benzylguanidines as described in EP-A 699 660; ortho-substituted heterocyxcyl-benzoylguanidines, as described in EP-A 699 666  are described; ortho-substituted 5-methylsulfonyl-benzoylguanidines, as they EP-A 708 088 are described; ortho-substituted 5-alkylsulfonyl-benzoylguanidines with 4-amino substituents as described in EP-A 723 963; ortho-substituted 5-alkylsulfonyl-benzoylguanidines with 4-mercapto substituents as they are described in EP-A 743 301; 4-sulfonyl- or 4-sulphinyl-benzylguanidines, as described in EP-A 758 644; Alkenylbenzoylguanidine, as described in EP-A 760,365; Benzoylguanidines with fused, cyclic sulfones, as described in DE 195 48 708; Benzoyl, polycyclic aroyl and Heteroaroyl guanidines as described in WO 9426709; 3-aryl / heteroaryl ben zoylguanidines as described in WO 9604241; 3-phenyl-ben zoylguanidine with a basic amide in the 5-position, as described in WO 9725310 are described; 3-dihalothienyl or 3-dihalophenyl benzoyl guanidines with a basic substituent in the 5-position, as described in WO 9727183 are described; 3-Methylsulfonylbenzoylguanidinen with certain Amino substituents in the 4-position as described in DE WO 9512584; Amiloride derivatives as described in WO 9512592; 3-methylsulfonyl benzoylguanidines with certain amino substituents in the 4-position as described in WO 9726253 are described; Indoloylguanidines, as described in EP-A 622 356 and EP-A 708 091; Indoloylguanidine with a fused additional Ring system as described in EP 787 728; Methyl guanidine derivatives, such as they are described in WO 9504052; 1,4-Benzoxazinoylguanidine, as described in EP-A 719,766; 5-bromo-2-naphthoylguanidines, as described in JP 8225513 are described; Quinolin-4-carbonylguanidines with a phenyl radical in the 2-position, as described in EP-A 726 254; Cinnamoylguanidines as described in JP 09059245 are described; Propenoylguanidine with a naphthalene sub substituents as described in JP 9067332; Propenoylguanidine with Indole substituents as described in JP 9067340; or heteroaryl sub substituted acroylguanidines, as described in WO 9711055, and their physiologically acceptable salts.

Preferred NHE inhibitors are preferred in the publications mentioned highlighted connections. The compounds are very particularly preferred Cariporid (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550,  KBR-9032, as well as their physiologically acceptable salts. Most preferred Cariporid or its physiologically acceptable salt.

Examples of cardiovascular active substance classes which can be combined therapeutically advantageously with NCBE inhibitors or which can additionally be combined with combinations of NCBE inhibitors and NHE inhibitors are beta-receptor blockers, calcium antagonists, angiotensin conversion enzyme inhibitors , Angiotensin receptor blockers, loop diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists, such as those used, for example, in lowering blood pressure, and cardiac glycosides or other contraction-enhancing agents in the treatment of heart failure and congestive heart failure, as well as antiarrhythmics of classes I-IV, class I-IV _ATP openers, K _ATP blockers, inhibitors of the veratridine-activatable sodium channel etc. For example, the following are suitable: the beta blockers propanolol, atenolol, metoproiol; the calcium antagonists diltiazem hydrochloride, verapamil hydrochloride, nifedipine; the ACE inhibitors captopril, enalapril, ramipril; Trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; the angiotensin II receptor antagonists losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; the loop directives furosemide, piretanide, torasemide; the thiazide diuretics hydrochlorothiazide, metolazone, indapamide; the potassium-saving diuretics amiloride, triamterene, spironolactone; the cardiac glycosides digoxin, digitoxin, strophantin; the antiarrhythmics amiodarone, sotalol, bretylium, flecainide; the nitrate glycerol trinitrate; the K⁺ (ATP) openers Cromakalim, Lemakalim, Nocorandil, Pinacidil, Minoxidil; the inhibitors of the veratridine-activated Na⁺ channel.

An example of such a particularly advantageous combination partner with NCBE inhibitors are blockers of the non-inactivating sodium channel (veratridine-ak activatable sodium channel). The combinations of an NCBE inhibitor with a Blocker of the non-inactivating sodium channel (veratridine-activatable Sodium channel) is suitable for infarct and re-infarct prophylaxis and the Treatment of infarction and for the treatment of angina pectoris and inhibition ischemically induced cardiac arrhythmias, tachycardia and development and Maintenance of ventricular fibrillation, the combinations of one  NCBE inhibitor with a blocker of the non-inactivating sodium channel also preventive the pathophysiological processes when ischemically induced Inhibit or greatly reduce damage. Because of their enhanced protective May have effects against pathological hypoxic and ischemic situations the combinations according to the invention of an NCBE inhibitor with a blocker of the non-inactivating sodium channel due to increased inhibition of Na⁺-Ein flows into the cell as a medicine to treat all acute or chronic damage caused by ischemia or thereby primarily or secondary induced diseases can be used. This affects their use as a medicine for surgical interventions, e.g. B. in organ transplants, the Combinations of an NCBE inhibitor with a blocker of the non-inactivating Na trium channel both for the protection of the organs in the donor before and during the Removal, for the protection of removed organs, for example also from their Storage in physiological bath fluids, as well as in the transfer to the Receiver organism can be used. The combinations of one NCBE inhibitors with a non-inactivating sodium channel blocker are also valuable, protective drugs when performing angioplasty surgical interventions, for example on the heart as well as on peripheral vessels. According to their protective effect against ischemically induced damage the combinations of an NCBE inhibitor with a blocker of the non-in activating sodium channel also as a medicine for the treatment of ischemia of the nervous system, particularly the central nervous system are suitable for the treatment of stroke or brain edema. About that the combinations of an NCBE inhibitor according to the invention are also suitable with a blocker of the non-inactivating sodium channel Treatment of forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition to use as a fixed combination, the invention also relates to simultaneous, separate or staggered use of NCBE inhibitors with NHE inhibitors and / or an additional active substance from one another class of cardiovascular agents for the treatment of the above Diseases.  

The invention further relates to a pharmaceutical preparation containing a) an NCBE inhibitor and an NHE inhibitor and / or their physiological tolerable salts; or b) an NCBE inhibitor and an active one Substance from another cardiovascular agent class and / or their physiologically acceptable salts; or c) an NCBE inhibitor, one NHE inhibitor and also an active substance from another cardiovascular effect substance class, and / or their physiologically tolerable salts.

Preferred pharmaceutical preparations are those which contain a compound of formula I. and / or contain their physiologically acceptable salt as an NCBE inhibitor.

The combined application can have the effect of a combination partner are potentiated by the respective other partner, d. that is, the effect and / or The duration of action of a combination or preparation according to the invention is stronger or lasting than the effect and / or duration of action of the individual components (synergistic effect). In the case of a combined application, this leads to a Reduction of the dose of the respective combination partner compared to the Single application. The combinations and preparations according to the invention therefore have the advantage that the amounts of active ingredient to be administered significantly reduced and undesirable side effects eliminated or strong can be reduced.

The invention further relates to a commercial pack containing pharmaceutical Active ingredient a) an NCBE inhibitor and an NHE inhibitor and / or their physiologically acceptable salts; or b) an NCBE inhibitor and additionally one active substance from another cardiovascular agent class and / or their physiologically acceptable salts; or c) an NCBE inhibitor, one NHE inhibitor and also an active substance from another cardiovascular effect substance class and / or their physiologically tolerable salts in each case together with instructions for the use of these ingredients in combination for simultaneous, separate or staggered use in treatment or prophylaxis of the above clinical pictures, especially for Treatment of cardiovascular diseases.  

Commercial packs containing the compounds of the formula I are preferred NCBE inhibitors included.

The pharmaceutical preparations according to the invention can, for example be made by either intensely powdering the individual components mixes, or by placing the individual components in the appropriate solvent such as a lower alcohol and dissolves the solvent then removed.

The weight ratio of the NBCE inhibitor to the NHE inhibitor or the heart circulatory active substance in the combinations and Preparations are advantageously 1: 0.01 to 1: 100, preferably 1: 0.1 to 1:10.

The combination and preparations according to the invention contain a total preferably 0.5-99.5% by weight, in particular 4-99% by weight of these active ingredients.

When used according to the invention in mammals, preferably in For example, people move the cans of different Active ingredient components in the range of 0.001 to 100 mg / kg / day.

List of abbreviations:
Bn benzyl
CH ₂ Cl ₂ dichloromethane
DCI Desorption-Chemical Ionization
DIP diisopropyl ether
DMA dimethylacetamide
DME dimethoxyethane
DMF N, N-dimethylformamide
EE ethyl acetate (EtOAc)
EI electron impact
eq equivalent
ES electrospray ionization
Et ethyl
FAB Fast Atom Bombardment
HEP n-heptane
HOAc acetic acid
Me methyl
MeOH methanol
mp melting point
MTB methyl tertiary butyl ether
NCBE sodium-dependent chloride / bicarbonate exchanger
NHE sodium / hydrogen exchanger
NMP N-methylpyrrolidone
RT room temperature
THF tetrahydrofuran
TMU N, N, N ', N'-tetramethyl urea
Tol toluene
CNS central nervous system.

General instructions for the preparation of sulfonyl cyanamides from sulfonamides

The sulfonamide starting material is dissolved in 10 ml / mmol of anhydrous acetonitrile, 3 molar equivalents of K ₂ CO ₃ and one molar equivalent of a 5 N solution of BrCN in acetonitrile are added dropwise and the mixture is heated under reflux until conversion is complete (typical reaction time 1-6 Hours). The reaction mixture is then chromatographed on silica gel without further working up.

example 1

2-Butyl-5-methylsulfanyl-3- (2'-cyanaminosulfonyl-biphenyl-4-ylmethyl) -3H-imi dazole-4-carboxylic acid ethyl ester

975 mg 1 - [[2 '- (aminosulfonyl) (1,1'-biphenyl) 4-yl] methyl] -2-butyl-4- (methylthio) -1-H-imi dazol-5-carboxylic acid ethyl ester ( J. Med. Chem. 1995, 38, 2357) were dissolved in 10 ml of anhydrous acetonitrile, then 276 mg of K ₂ CO ₃ and 2 ml of a 1N cyanogen bromide solution in acetonitrile were added and the mixture was heated under reflux for 4 h. The reaction mixture was chromatographed on silica gel with EA / MeOH 10: 1, and 780 mg of a colorless amorphous solid was obtained, crystallizing on standing and decomposing.
mp 111 ° C with decomposition,
R _f (EE / MeOH 10: 1) = 0.20; MS (FAB): 513 (M + H) ⁺.

Example 2

2-Butyl-5-methylsulfanyl-3- (3'-cyanaminosulfonyl-biphenyl-4-ylmethyl) -3H-imi dazole-4-carboxylic acid ethyl ester

• a) 3-bromo-N-dimethylaminomethylene-benzenesulfonamide
  20.3 g of 3-bromo-benzenesulfonamide were dissolved in 120 ml of DMF and 57 ml of dimethylformamide-dimethylacetal were added dropwise at RT. The mixture was stirred at RT for 5 h and left to stand at RT for 3 days. The reaction mixture was then poured onto 1.2 l of water, stirred for 90 minutes and the white precipitate was filtered off. The product was dried in vacuo at 50 ° C., and 20.5 g of white crystals were obtained,
  mp 122 ° C.
  R _f (EE) = 0.59; MS (DCl): 291 (M + H) ⁺.
• b) 4'-methyl-biphenyl-3-sulfonic acid dimethylaminomethylene amide
  2.9 g of 3-bromo-N-dimethylaminomethylene-benzenesulfonamide, 1.5 g of p-tolylboronic acid, 112 mg of Pd (II) acetate and 224 mg of triphenylphosphine were dissolved in 60 ml of toluene and 17 ml of ethanol, 10 ml of a 2 N aqueous Na ₂ CO ₃ -Solution added and boiled under reflux for 7 h. The reaction mixture was taken up in 150 ml of a saturated aqueous Na ₂ CO ₃ solution and 150 ml of water and extracted 3 times with 200 ml of EA each time. It was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with MTB gave 1.8 g of a colorless foam.
  R _f (EE / HEP 2: 1) = 0.22; MS (DCl): 302 (M + H) ⁺.
• c) 4'-Bromomethyl-biphenyl-3-sulfonic acid-dimethylaminomethylene amide
  1.7 g of 4'-methyl-biphenyl-3-sulfonic acid dimethylaminomethylene amide were dissolved in 30 ml of chlorobenzene and 1.0 g of N-bromosuccinimide and 10 mg of benzoyl peroxide were added at 130 ° C. and the mixture was refluxed for 30 minutes. The reaction mixture was taken up in 150 ml of EA and washed twice with 150 ml of an 8: 1 mixture of saturated aqueous Na ₂ CO ₃ and saturated aqueous Na ₂ SO ₃ solution. The aqueous phase was then extracted twice with 150 ml of EA each time. The combined organic phase was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with MTB gave 1.6 g of a pale yellow oil.
  R _f (EE) = 0.59; MS (DCl): 291 (M + H) ⁺.
• d) 2-Butyl-3- [3 '- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-ylmethyl] -5- (methylsulfanyl) -3H-imidazole-4-carboxylic acid ethyl ester
  1.6 g of 4'-bromomethyl-biphenyl-3-sulfonic acid-dimethylaminomethylenamide, 990 mg of 2-butyl-5-methylsulfanyl-3H-imidazole-4-carboxylic acid ethyl ester (J. Med. Chem. 1995, 38, 2357) and 570 mg K ₂ CO ₃ were stirred in 12 ml DMF at RT for 4 h and left to stand overnight. The mixture was then stirred for a further 6 h at RT, then the reaction mixture was poured into 125 ml of a saturated aqueous NaHCO ₃ solution and 125 ml of water and extracted 3 times with 200 ml of EA each time. It was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with EA / HEP 2: 1 gave 1.1 g of a colorless oil.
  R _f (EE / HEP 1: 1) = 0.10; MS (ES): 543 (M + H) ⁺.
• e) 2-Butyl-5-methylsulfanyl-3- (3'-sulfamoyl-biphenyl-4-ylmethyl) -3H-imidazol-4-carbonic acid ethyl ester
  1.1 g of ethyl 2-butyl-3- [3 '- (dimethylaminomethylene-sulfamoyl) -biphenyl-4-ylmethyl] -5- (methylsulfanyl) -3H-imidazole-4-carboxylate were dissolved in 20 ml of methanol and 10 ml added a saturated aqueous HCl solution. The mixture was heated under reflux for 4 h, then adjusted to pH = 5-6 with an aqueous 6 N NaOH solution, diluted with 50 ml of water and extracted 3 times with 150 ml of EA each time. It was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with EA / HEP 1: 1 gave 950 mg of a colorless foam.
  R _f (EE / HEP 1: 1) = 0.38; MS (ES): 488 (M + H) ⁺.
• f) 2-Butyl-5-methylsulfanyl-3- (3'-cyanaminosulfonyl-biphenyl-4-ylmethyl) -3H-imi-azole-4-carboxylic acid ethyl ester
  720 mg of 2-butyl-5-methylsulfanyl-3- (3'-sulfamoyl-biphenyl-4-ylmethyl) -3H-imidazol-4-carbonic acid ethyl ester were reacted according to the general procedure for the preparation of sulfonylcyanamides from sulfonamides, and one received 550 mg of an amorphous solid.
  R _f (EE / MeOH 10: 1) = 0.38; MS (ES): 513 (M + H) ⁺.

The title compounds of Examples 3-9 were synthesized analogously to Example 2:  

Example 3 2-butyl-5-methylsulfanyl-3- (4'-cyanaminosulfonyl-biphenyl-4-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 244 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.17; MS (ES): 513 (M + H) ⁺.

Example 4 2-butyl-5-methylsulfanyl-3- (2'-cyanaminosulfonyl-biphenyl-3-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 118 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.19; MS (ES): 513 (M + H) ⁺.

Example 5 2-butyl-5-methylsulfanyl-3- (3'-cyanaminosulfonyl-biphenyl-3-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 112 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.15; MS (ES): 513 (M + H) ⁺.

Example 6 2-butyl-5-methylsulfanyl-3- (4'-cyanaminosulfonyl-biphenyl-3-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 120 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.36; MS (ES): 513 (M + H) ⁺.

Example 7 2-butyl-5-methylsulfanyl-3- (2'-cyanaminosulfonyl-biphenyl-2-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 105 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.23; MS (ES): 513 (M + H) ⁺.

Example 8 2-butyl-5-methylsulfanyl-3- (3'-cyanaminosulfonyl-biphenyl-2-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 108 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.27; MS (ES): 513 (M + H) ⁺.

Example 9 2-butyl-5-methylsulfanyl-3- (4'-cyanaminosulfonyl-biphenyl-2-ylmethyl) -3H-imi dazol-4-carboxylic acid ethyl ester

mp 116 ° C with decomposition
R _f (EE / MeOH 10: 1) = 0.23; MS (ES): 513 (M + H) ⁺.

The title combination 03903 00070 552 001000280000000200012000285910379200040 0002019741636 00004 03784ndung of Example 10 was analogous to Example 2 from 2-cyclopropyl-5-me thysulfanyl-3- (4'-sulfamoyl-biphenyl-2-ylmethyl) -3H-imidazole-4-carboxylic acid ethyl ester (J. Med. Chem. 1995, 38, 2357).

Example 10 2-Cyclopropyl-5-methylsulfanyl-3- (2'-cyanaminosulfonyl-biphenyl-4-yl methyl) -3H-imidazole-4-carboxylic acid ethyl ester

mp <260 ° C
R _f (EE / MeOH 10: 1) = 0.30; MS (ES): 497 (M + H) ⁺.

Example 11  4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sul fonylcyanamide

• a) 4 '- (4-Chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonic acid di methylaminomethylene amide
  2.1 g 4-chloro-5-formyl-2-phenyl-imidazole (Chem. Pharm. Bull. 1976, 24 (5), 960), 3.8 g 4'-bromomethyl-biphenyl-2-sulfonic acid-dimethylaminomethylene amide (J. Med Chem. 1995, 38, 2357) and 2.8 g of K ₂ CO ₃ were stirred in 50 ml of DMF at RT for 30 h. The reaction mixture was poured into 500 ml of water and extracted twice with 250 ml of EA each time. The organic phase was then washed with 100 ml of water, dried over MgSO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with MTB gave 1.9 g of a white, crystalline powder, mp 193 ° C.
  R _f (MTB) = 0.19; MS (ES): 507 (M + H) ⁺.
• b) 4 '- (4-Chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide
  1.9 g of 4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonic acid dimethylaminomethylene amide were dissolved in 20 ml of ethanol and 20 ml of a saturated aqueous HCl solution were added. The mixture was heated under reflux for 2 hours, then the volatile constituents were removed in vacuo, taken up in 200 ml of water, adjusted to pH = 7 with aqueous NaOH solution, stirred for 1 hour and the precipitate was filtered off with suction. The product was dried in vacuo to give 1.7 g of a colorless solid, mp 215 ° C. with decomposition.
  R _f (MTB) = 0.57; MS (FAB): 452 (M + H) ⁺.
• c) 4 '- (4-Chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonylcyanamide
  800 mg of 4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide were reacted according to the general procedure for the preparation of sulfonylcyanamides from sulfonamides, and 650 mg of an amorphous was obtained Solid.
  R _f (EE / MeOH 10: 1) = 0.18; MS (ES): 477 (M + H) ⁺.

Example 12 4 '- (4-methoxy-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sul fonylcyanamide

• a) 4 '- (4-Methoxy-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide
  700 mg of 4 '- (4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide (Example 11b) and 620 mg of NaOH were dissolved in 10 ml of methanol and heated under reflux for 1 hour . The solvent was removed in vacuo, taken up in 20 ml of water, adjusted to pH = 7 with aqueous HCl solution and the precipitate was filtered off. It was dried in vacuo to give 650 mg of a colorless solid,
  mp 188 ° C.
  R _f (DIP / MTB 1: 1) = 0.26; MS (FAB): 448 (M + H) ⁺.
• b) 4 '- (4-methoxy-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonylcyanamide
  650 mg of 4 '- (4-methoxy-5-formyl-2-phenyl-imidazol-1-ylmethyl) biphenyl-2-sulfonamide were reacted according to the general procedure for the preparation of sulfonylcyanamides from sulfonamides, and 600 mg of an amorphous were obtained Solid.
  R _f (EE / MeOH 10: 1) = 0.18; MS (ES): 472 (M + H) ⁺.

Claims (19)

1. Compounds of the formula I
in which the symbols have the following meaning:
R1 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C _a H _2a phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or (C ₁ -C ₄ ) alkyl;
a zero, 1 or 2;
or
R1 -C _b H _2b - (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or (C ₁ -C ₄ ) alkyl;
b zero, 1 or 2;
or
R1 -C _d H _2d - (C ₃ -C ₇ ) cycloalkyl;
d zero, 1 or 2;
R2 and R3
independently of one another hydrogen, F, Cl, Br, I, CF ₃ , -C∼N, -NO ₂ , CH ₂ OR17, CO-R6 or O-R7;
R17 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
R6 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or (C ₁ -C ₄ ) alkyl;
R30 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or (C ₁ -C ₄ ) alkyl;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or (C ₁ -C ₄ ) alkyl;
or
R2 and R3
independently of one another alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _g H _2g -phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or (C ₁ -C ₄ ) alkyl;
g zero, 1 or 2;
or
R2 and R3
-C ₁ H ₂₁ - (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or (C ₁ -C ₄ ) alkyl;
l zero, 1 or 2;
or
R2 and R3
SO _n -R22;
n zero, 1 or 2;
R22 alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _S H _2s -phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of group F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
independently of one another H or (C ₁ -C ₄ ) alkyl;
s zero, 1 or 2;
R4 and R5
independently of one another hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO-R23 or O-R24;
p zero, 1 or 2;
R16 alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or (C ₁ -C ₄ ) alkyl;
R23 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR25;
R25 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or (C ₁ -C ₄ ) alkyl;
as well as their physiologically acceptable salts. 2. Compound of formula I according to claim 1, in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or -C _a H _2a phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or methyl;
a zero or 1;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or methyl;
or
R1 -C _d H _2d - (C ₃ -C ₇ ) cycloalkyl;
d zero or 1;
R2 and R3
independently of one another hydrogen, F, Cl, Br, CF ₃ , -C∼N, -NO ₂ , CH ₂ OR17, CO-R6 or O-R7;
R17 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or methyl;
R30 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or methyl;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or methyl;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _g H _2g -phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or methyl;
g zero or 1; or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or methyl;
or
R2 and R3
SO _n -R22,
n zero, 1 or 2;
R22 alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C _S H _2s -phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
selected from the group consisting of H or methyl;
s zero or 1;
R4 and R5
independently of one another hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO-R23 or O-R24;
p zero, 1 or 2;
R ¹⁶ alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
that is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or methyl;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or methyl. 3. A compound of formula I according to claim 1, in which:
R1 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (8) R (9);
R (8) and R (9)
independently of one another H or methyl;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (10) R (11);
R (10) and R (11)
independently of one another H or methyl;
or
R1 (C ₃ -C ₇ ) cycloalkyl;
R2 and R3
independently of one another hydrogen, F, Cl, Br, CF ₃ , -C∼N, -NO ₂ , CO-R6 or O-R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (31) R (32);
R (31) and R (32)
independently of one another H or methyl;
R30 is hydrogen or alkyl having 1, 2 or 3 carbon atoms,
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (12) R (13);
R (12) and R (13)
independently of one another H or methyl;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (14) R (15);
R (14) and R (15)
independently of one another H or methyl;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (18) R (19);
R (18) and R (19)
independently of one another H or methyl;
or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ , methoxy, hydroxy and NR (20) R (21);
R (20) and R (21)
independently of one another H or methyl;
or
R2 and R3
SO _n -R22;
n zero or 2;
R22 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 with 1-2 substituents selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (34) R (35);
R (34) and R (35)
independently of one another H or methyl;
R ⁴ and R ⁵ independently of one another are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF ₃ , -C∼N, -NO ₂ , SO _p -R16, CO-R23 or O-R24 ;
p zero or 2;
R23 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or OR25;
R25 is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (28) R (29);
R (28) and R (29)
independently of one another H or methyl;
R16 alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , methyl, methoxy, hydroxy and NR (26) R (27);
R (26) and R (27)
independently of one another H or methyl. 4. A compound of formula I according to claim 1, in which:
R1 alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R1 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , CH ₃ and methoxy;
or
R1 (C ₃ -C ₇ ) cycloalkyl;
R2 and R3
independently of one another hydrogen, F, Cl, CF ₃ , -C∼N, CO-R6 or O-R7;
R6 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR30 or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R30 is hydrogen, methyl or ethyl;
R7 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R7 (C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, Br, CF ₃ , CH ₃ and methoxy;
or
R2 and R3
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
or
R2 and R3
(C ₁ -C ₉ ) heteroaryl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , CH ₃ and methoxy;
or
R2 and R3
SO _n -R22;
n zero or 2;
R22 alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R4 and R5
independently of one another hydrogen, methyl, F, Cl, CF ₃ , -C∼N, SO ₂ -R16, CO-R23 or O-R24;
R ¹⁶ alkyl with 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy;
R23 is hydrogen, methyl or OR25;
R25 is hydrogen, methyl or ethyl;
R24 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl,
which is unsubstituted or substituted with a substituent selected from the group consisting of F, Cl, CF ₃ , methyl and methoxy. 5. Use of a compound of the formula
in which mean:

• a) X, Y and Z
  the same or different, N or CR (102);
• b) R (1)
  1. (C ₁ -C ₁₀ ) alkyl, 2. (C ₃ -C ₁₀ ) alkenyl, 3. (C ₃ -C ₁₀ ) alkynyl, 4. -OR (103), 5. (C ₃ - C ₈ ) cycloalkyl, 6. (C ₄ -C ₁₀ ) cycloalkylalkyl, 7. (C ₅ -C ₁₀ ) cycloalkylalkenyl, 8. (C ₅ -C ₁₀ ) cycloalkylalkynyl, 9. (CH ₂ ) _m -B- (CH ₂ ) _n -R (104), 10. -Benzyl, 11. a radical as defined under b) 1., 2., 3. or 9. which is monosubstituted with CO ₂ R (103) , 12. a radical as defined under b) 1., 2., 3. or 9., in which 1 to all H atoms are substituted by fluorine, or 13. the radical defined under b) 10., which is at the phenyl 1 or 2 identical or different radicals from the series halogen, (C ₁ -C ₄ ) alkoxy and nitro is substituted,
• c) R (102)
  1. hydrogen, 2. halogen, 3. nitro, 4. C _v F _{2v + 1} , 5. pentafluorophenyl, 6. cyano, 7. -OR (106), 8. phenyl, 9. phenyl- (C ₁ -C ₃ ) -alkyl, 10. (C ₁ -C ₁₀ ) alkyl, 11. (C ₃ -C ₁₀ ) alkenyl, 12. phenyl- (C ₂ -C ₆ ) alkenyl, 13. 1-imidazolyl- (CH ₂ ) _m -. 14. 1,2,3-triazolyl- (CH _{2) n} -, 15. tetrazolyl _{(CH2) m} -, 16. - _{(CH2) o-1} -CHR (107) -OR (105), 17 . - (CH ₂ ) _o -O-CO-R (103), 18. - (CH ₂ ) _o -SR (106), 19. -S (O) _r -R (119), 20. CH = CH - (CH ₂ ) _m -CHR (103) -OR (106), 21. CH = CH- (CH ₂ ) _m -CO-R (108), 22. -CO-R (108), 23. -CH = CH- (CH ₂ ) _m -O-CO-R (107), 24. (CH ₂ ) _m -CH (CH ₃ ) -CO-R (108), 25. - (CH ₂ ) _o -CO- R (108), 26. - (CH ₂ ) _o -O- [C = W] -NH-R (109), 27. - (CH ₂ ) _o -NR (107) - [C = W] -OR (109), 28.- (CH ₂ ) _o -NR (107) -CO-NHR (109), 29.- (CH ₂ ) _o -NR (107) -SO ₂ R (109), 30.- ( CH ₂ ) _o -NR (107) - [C = W] -R (109), 31. - (CH ₂ ) _n F, 32. (CH ₂ ) _n -O-NO ₂ , 33. -CH ₂ - N ₃ , 34. - (CH ₂ ) _n -NO ₂ , 35. -CH = N-NR (105) R (107), 36. phthalimido (CH ₂ ) _n -,
  41. phenyl-SO ₂ -NH-N = CH-,
  43. - (CH ₂ ) _n -SO ₂ -NR (107) -CS-NR (106) R (109), 44. - (CH ₂ ) _n SO ₂ -NR (107) -CO-NR (106) R (109), 45. - (CH ₂ ) _o -SO ₂ R (109), 46. a radical as defined under c) 8th or 9th, the phenyl with 1 or 2 identical or different radicals from the series Halogen, hydroxy, methoxy, trifluoromethyl, CO ₂ R (103) and phenyl is substituted, 47. a radical as defined under c) 10th, 11th or 19th, in which one to all H atoms are substituted by fluorine, 48 the residue defined under c) 14, which is substituted by 1 or 2 identical or different residues from the series methoxycarbonyl and (C ₁ -C ₄ ) alkyl, 49. - (CH ₂ ) -SO ₂ -NR (107 ) -CO-R (106), 50. - (CH ₂ ) _n -SO ₂ -NR (107) CS-R (106),
• d) R (3)
  1. hydrogen, 2. (C ₁ -C ₈ ) -alkyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 4. phenyl, 5. benzyl, 6. the radical defined under d) 2., wherein 1 to all H atoms are substituted by fluorine;
• e) R (104)
  1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₂ -C ₄ ) al kenyl or 5. (C ₂ -C ₄ ) Alkynyl;
• f) R (105)
  1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. phenyl or 5. benzyl;
• g) R (106) and R (109)
  identical or different 1. hydrogen, 2. (C ₁ -C ₆ ) alkyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of (C ₁ -C ₆ ) alkoxy, which in turn is substituted with 1- 3 radicals from the series hydroxy, (C ₁ -C ₆ ) -alkoxy, amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino can be substituted, (C ₂ -C ₁₀ ) -Al kenyl, hydroxy, amino, mono- (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkoxycarbonylamino, (C ₆ -C ₁₂ ) aryl- (C ₁ -C ₄ ) alkoxycarbonylamino; (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₃ ) alkyl, (C ₁ -C ₉ ) -heeroaryl, carboxy and (C ₁ -C ₄ ) - Alkoxycarbonyl; 3. (C ₃ -C ₈ ) cycloalkyl,
  wherein the cycloalkyl part is unsubstituted or substituted with 1-3 substituents selected from the group consisting of (C ₁ -C ₄ ) alkyl and (C ₂ -C ₄ ) alkenyl;
  4. (C ₃ -C ₈ ) cycloalkyl- (C ₁ -C ₃ ) alkyl, 5. (C ₆ -C ₁₂ ) aryl, preferably phenyl, 6. (C ₆ -C ₁₀ ) aryl- ( C ₁ -C ₄ ) alkyl, 7. (C ₁ -C ₉ ) heteroaryl,
  which can be partially or fully hydrogenated,
  8. a radical as defined under g) 5th, 6th, 7th, 9th, 15th, 16th, 17th, 19th, 20th or 21st, substituted with 1 or 2 identical or different radicals from the Range halogen, hydroxy, (C ₁ -C ₄ ) alkyl, methoxy, nitro, cyano, CO ₂ R (103), trifluoromethyl, NR (111) R (112) and
  9. (C ₁ -C ₉ ) heteroaryl- (C ₁ -C ₃ ) alkyl, where the heteroaryl part can be partially or completely hydrogenated,
  10. (C ₁ -C ₆ ) alkyl, in which 1 to all H atoms are substituted by fluorine, 11. - (C ₂ -C ₁₀ ) alkenyl, (C ₂ -C ₁₀ ) alkenoyl or (C ₂ -C ₁₀ ) alkadienyl, 12. (C ₃ -C ₈ ) cycloalkenyl, 13. (C ₃ -C ₈ ) cycloalkenyl (C ₁ -C ₃ ) alkyl, 14. bi- or tricyclic (C ₄ -C ₁₀ ) cycloalkenyl- (C ₁ -C ₄ ) alkyl,
  which can still be substituted with 1-3 (C ₁ -C ₄ ) alkyl radicals;
  15. (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₄ ) alkyl, 16. (C ₆ -C ₁₀ ) aryl- (C ₃ -C ₆ ) alkenyl, 17. (C ₁ - C ₉ ) -Hetaryl- (C ₃ -C ₆ ) alkenyl, 18. (C ₃ -C ₆ ) alkynyl, 19. (C ₆ -C ₁₀ ) aryl- (C ₃ -C ₆ ) alkynyl , 20. (C ₁ -C ₉ ) hetaryl- (C ₃ -C ₆ ) alkynyl, 21. R (106) and R (109) together with the N atom carrying them are a hetaryl,
  that can also be partially or fully hydrogenated;
• h) R (107)
  1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₆ -C ₁₂ ) aryl (C ₁ -C ₆ ) alkyl , preferably benzyl, 5. phenyl or 6. (C ₁ -C ₉ ) -he teroaryl;
• i) R (108)
  1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. phenyl- (CH ₂ ) _q , 5. OR (106), 6. NR (111 ) R (112) or 7.
  
• j) R (110)
  Cyano, nitro or CO ₂ R (107);
• k) R (111) and R (112)
  identical or different, 1. hydrogen, 2. (C ₁ -C ₄ ) -alkyl, 3. phenyl, 4. benzyl, or 5. α-methylbenzyl;
• l) D NR (113), O or CH ₂ ;
• m) R (113)
  Hydrogen, (C ₁ -C ₄ ) alkyl or phenyl;
• n) A biphenylyl,
  that is unsubstituted or substituted with 1-4, preferably 1 to 2 identical or different substituents R (114) or R (115);
• o) R (114)
  1. halogen, 2. nitroso, 3. nitro, 4. amino, 5. cyano, 6. hydroxy, 7. (C ₁ -C ₆ ) alkyl, 8. (C ₁ -C ₄ ) alkanoyl, 9. (C ₁ -C ₄ ) alkanoyloxy, 10.CO ₂ R (103), 11. methanesulfonylamino, 12. trifluoromethanesulfonylamino, 13. -CO-NH-OR (109), 14. -SO ₂ -NR (106) R (107), 15. -CH ₂ -OR (107), 16. (C ₁ -C ₉ ) -Heteroaryl- (CH ₂ ) _q -, preferably 1-tetrazolyl, 17. (C ₇ -C ₁₃ ) - Aroyl,
  or
  20. (C ₆ -C ₁₂ ) aryl;
• p) R (115)
  1. hydrogen, 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) cycloalkyl, 4. (C ₆ -C ₁₂ ) aryl, 5. (C ₇ -C ₁₃ ) - Aroyl, 6. (C ₁ -C ₄ ) alkoxy, 7. (C ₁ -C ₄ ) alkanoyloxy, 8. (C ₁ -C ₉ ) heteroaryl, 9. CO ₂ R (103), 10. halogen , 11th cyano, 12th nitro, 13th NR (106) R (107), 14th hydroxy, 15th -CO-NH-CHR (105) -CO ₂ R (103), 16th sulfo, 17th - SO ₃ R (103), 18. -SO ₂ -NR (107) -CO-NR (106) R (109) or -SO ₂ -NR (107) -CS-NR (106) R (109), 19th -NR (107) -CO-NR (106) -SO ₂ -CH ₂ -R (105), 20. -C (CF ₃ ) ₂ OH, 21. Phosphonooxy, 22. -PO ₃ H ₂ , 23. -NH-PO (OH) ₂ , 24. S (O) _r R (106), 25. -CO-R (108), 26. -CO-NR (106) R (109), 27. -CR ( 120) (OH) -PO (OH) ₂ , 28. the radical defined under o) 20.,
  32. 5-tetrazolyl-NH-CO-, 33. -CO-NH-NH-SO ₂ -CF ₃ ,
  40. -CO-NH-SO ₂ -R (119), 41. -SO ₂ -NH-CO-R (106) or 42. the radical defined under p) 4., substituted with 1 or 2 identical or different radicals from the series halogen, cyano, nitro, NR (106) R (107) and hydroxy; 43. R (115) together with R (114) means -CO-NH-SO ₂ -, 44. -SO ₂ -NH-CO-OR (106), 45. -SO ₂ -N H-SO ₂ -NR (106) R (109), 46. -SO ₂ -NH-SO ₂ -R (106);
• q) BO, NR (107) or S;
• r) WO or S;
• s) L (C ₁ -C ₃ ) alkanediyl;
• t) R (116)
  CO ₂ R (103) or CH ₂ CO ₂ R (103);
• u) R (117)
  Hydrogen, halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxy;
• v) R (118)
  Hydrogen, (C ₁ -C ₄ ) alkyl or phenyl;
• w) R (119)
  1. (C ₁ -C ₆ ) alkyl, 2. (C ₃ -C ₈ ) cycloalkyl, 3. phenyl, 4. benzyl or 5. the radical defined under w) 1., wherein one to all H atoms are substituted by fluorine,
• x) T 1. a single bond, 2. -CO-, 3. -CH ₂ -, 4. -O-, 5. -S-, 6. -NR (121) -, 7. -CO-NR (121 ), 8. -NR (121) -CO-, 9. -O-CH ₂ -, 10. -CH ₂ -O-, 11. -S-CH ₂ -, 12. -CH ₂ -S, 13. -NH-CR (120) R (122), 14. -NR (121) -SO ₂ , 15. SO ₂ -NR (121) -, 16. -CR (120) R (122) -NH, 17. -CH = CH-, 18. -CF = CF-, 19. -CH = CF-, 20. -CF = CH-, 21. -CH ₂ -CH ₂ -, 22. -CF ₂ -CF ₂ -, 23. -CH [OR (103)] -, 24. -CH (OCOR (105)) -, 25. -C [N = R (123)] - or 26.- [R (124) O] -C - [OR (125)] -
• y) R (120) and R (122)
  identical or different, hydrogen, (C ₁ -C ₅ ) alkyl, phenyl, allyl or benzyl:
• z) R (121)
  Hydrogen, (C ₁ -C ₆ ) alkyl, benzyl or allyl;
• a ') R (123)
  1. NR (120) R (121), 2. ureido, 3. thioureido, 4. toluene-4-sulfonyl or 5. benzenesulfonylamino;
• b ') R (124) and R (125)
  identical or different, (C ₁ -C ₄ ) -alkyl or together (CH ₂ ) _q -;
• c ') Q CH ₂ , NH, O or S;
• d ') m 1, 2, 3, 4 or 5;
• e ') n 1, 2, 3, 4 or 5;
• f ') o 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
• g ') q zero or 1;
• h ') r zero, 1 or 2;
• i ') v 1, 2, 3, 4, 5 or to 6;
  and their physiologically tolerable salts for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions or for the manufacture of a medicament for the treatment of disturbed respiratory drive.

6. Use of a compound of formula I according to claim 1 and of its physiologically acceptable salts for the manufacture of a medicament for Treatment or prophylaxis of ischemic conditions Diseases or for the manufacture of a medicament for the treatment of disturbed Breath drive. 7. Use of a compound of formula I according to claim 1 for the preparation a drug for the treatment or prophylaxis of ischemic  Conditions caused diseases. 8. Use of a compound of formula 1 according to claim 1 for the preparation a medication to treat or prevent myocardial infarction. 9. Use of a compound of formula I according to claim 1 for the preparation a medication to treat or prevent angina pectoris. 10. Use of a compound of formula I according to claim 1 for the preparation a drug for the treatment or prophylaxis of ischemic conditions of the heart. 11. Use of a compound of formula I according to claim 1 for the preparation a drug for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and stroke. 12. Use of a compound of formula I according to claim 1 for the preparation a drug for the treatment or prophylaxis of ischemic conditions peripheral organs and limbs. 13. Use of a compound of formula I according to claim 1 for the preparation a drug used to treat shock. 14. Use of a compound of formula I according to claim 1 for the preparation a drug for use in surgical operations and Organ transplants. 15. Use of a compound of formula I according to claim 1 for the preparation a medication for the preservation and storage of grafts for surgical measures. 16. Use of a compound of formula I according to claim 1 for the preparation a drug used to treat diseases in which cell proliferation  is a primary or secondary cause. 17. Use of a compound of formula I according to claim 1 for the preparation a medication to treat or prevent breathing disorder. 18. Medicament, characterized by an effective content of a compound of formula I according to one or more of claims 1 to 4. 19. Medicament according to claim 18, characterized in that it additionally an effective amount of an NHE inhibitor and / or an effective substance another class of cardiovascular agents, or their physiologically acceptable Contains salts.