LT3373B - Azole derivatives, process for preparing and using thereof - Google Patents

Abstract

Azole derivatives, which have a general formula (I):<IMAGE>where A, Z, O, R1, X, Y, Z and q have indicated meanings, their extraction method, pharmaceutical preparations and the use of these compounds, as medical substances. The azole derivatives, which have a formula (I), in which the symbols, for example, have these meanings:R<1> - (C2-C10)-alkyl,Z - azote,X, Y - independently from one another, CR<2>,Z - -CH2-,q - 0 or 1,A - biphenyl residue, in which there is a substitute, for example, R<15>,R<2> - halogen or hydrate,R<15> - SO2-NH-CO-R<6> andR<6> - phenylare very effective antagonists of angiotensin-II-receptors.

Description

wherein A, Z, O, R ¹ , X, Y, Z and q have the meanings given, the process for their preparation, pharmaceutical preparations and their use as a medicament. Azole derivatives of formula (I) wherein the symbols have the following meanings:

R ¹ - (C 2 -C 10) alkyl,

Z - nitrogen,

X, Y - independently of each other, CR ² ,

Z is CH 2 -, q is O or 1,

A is a biphenyl residue substituted with, for example, R ¹⁵ ,

R ² is halogen or hydrogen,

R ¹⁵ - SO 2 -NH-CO-R ⁶ and

R ⁶ -phenyl is a very potent angiotensin-II receptor antagonist.

i

The invention relates to azole derivatives and to the production of novel angiotensin-II receptor antagonists of increasing importance.

From European patent no. A-28834 known 1-benzyl-substituted imidazole derivatives, from European Patent Nos. A-353310 and no. A-0401030 known imidazole derivatives having a dialkylcarboxylic acid residue are disclosed in European patent no. A-323841 known pyrazole and triazole derivatives, from European patent no. A-0409332 known triazole derivatives having a diarylcarboxylic acid residue and from European patent no. A-324377 discloses imidazole derivatives having a diaryl-tetrazolyl group and describes the use of these compounds as angiotensin-II receptor antagonists.

In addition, German patent no. A 4010797 (corresponding to U.S. Patent No. 07/679233) describes substituted azoles having a sulfinylurea group.

Novel azole derivatives having a sulfonylurea, sulfonylurethane or sulfonylsulfonamide structure have been found which are highly potent angiotensin-II receptor antagonists both in vitro and in vivo.

The invention relates to compounds of formula (I) wherein the radicals have the following meanings:

(a) X, Y and Z are the same or different and are N or

CR

b) R ¹ is

1. (C ₂ -C ₁₀ ) alkyl,

2. (C ₂ -C ₁₀ ) -alkenyl,

3. (C ₃ -C ₁₀ ) -alkynyl,

4. -OR ³ ,

5. (C ₃ -C ₈ ) -cycloalkyl,

6. (C ₄ -C ₁₀ ) -cycloalkylalkyl,

7. (C ₅ -C ₁₀ ) -cycloalkylalkenyl, θ · (C ₅ -C ₁₀ ) -cycloalkylalkinyl,>

9. - (CH ₂ ) _m -B- (CH ₂ ) _n -R ⁴ ,

10. benzyl,

The substituent described in 11 (b) (1), (2), (3) or (9) containing one CO ₂ R ³ group,

The substituents described in 12 (b) (1), (2), (3) or (9), wherein the hydrogen is 1 to all substituted by fluorine, or

13. The point b) described in paragraph 10. The substituent of the phenyl ring by 1 or 2 identical or different substituents is halogen, (C _l -C ₄₎ alkoxy and nitro, r> ²

R is

1. hydrogen,

c)

2. halogen,

3. nitro group,

4. C _v F _{2v +} x,

5. pentafluorophenyl,

6. cyano group

7. -OR ⁶

8. phenyl,

9. phenyl- (C _r C3) -alkyl,

10. (C 1 -C 10) alkyl,

11. (C ₃ -C ₁₀ ) -alkenyl,

12. phenyl- (C ₂ -C ₆ ) -alkenyl,

13. 1-imidazolil- (CH _{2) m} 14. 1, 2, 3-triazolil- (CH _{2) n} 15 tetrazolil- (CH _{2) m} 16 - (CH _{2) o} _ ₁ -CHR ⁷ -0R ⁵ ,

17 - (CH _{2) o} -0-C0-R ^3,

18 - (CH _{2) o} -SR ^6,

19. -S (O) _r -R ¹⁹ ,

20. -CH = CH- (CH ₂ ) _m -CHR ³ -OR ⁶ ,

21. -CH = CH- (CH ₂ ) _m -CO-R ⁸ ,

22. -CO-R ⁸ ,

23. -CH = CH- (CH ₂ ) _m -O-CO-R ⁷ ,

24. - (CH ₂ ) _m -CH (CH ₃ ) -CO-R ⁸ ,

25 - (CH _{2) o} -C 0-R ^8,

26 - (CH _{2) o} -0-C-NH-R ^9,

II

W

27. - (CH ₂ ) 0 -NR ⁷ -C- _O R ⁹ ,

II

W

28 - (CH _{2) o} NR ⁷ -CONHR ^9,

29. - (CH ₂ ) _o -NR ⁷ -SO ₂ R ⁹ ,

30. - (CH ₂ ) _O -NR ⁷ -CR ⁹ ,

II

W

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 ⁵ R ⁷ ,

36. Phthalimido- (CH ₂ ) _n LT 3373 B

37.

38.

39.

40.

41.

42.

43.

44.

45.

46th

.

.

t

- (CH ₂ ) _n -SO ₂ NR ⁷ -CS-NR ⁶ R ⁹ ,

- (CH ₂ ) _n -SO ₂ -NR ⁷ -CO-NR ⁶ R ⁹ ,

- (CH ₂ ) _o S ⁰ ₂ R ^{9 a} substituent described in paragraph 8 or c) having 1 or 2 substituents on the phenyl group which are hydroxy, methoxy, trinodine or halogen, fluoromethyl, CO ₂ R ³ and phenyl, substituents described in c) 10, 11 or 19, wherein the hydrogens 1 to all of the substituents are replaced by fluorine, substituents described in c) 14) having 1 or 2 identical or different residues such as methoxycarbonyl and (C ₁ -C ₄ ) alkyl,

d)

e)

f)

49. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CO-R ⁶ ,

50. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CS-R ⁶ ,

R ³ is present

1. hydrogen,

2. (C ₁ -C ₈ ) alkyl,

3. (C ₃ -C ₈ ) cycloalkyl,

4. phenyl,

5. benzyl or

6 (d) (2), wherein the hydrogens are 1 to all fluorine;

R is

1. hydrogen,

2. (C 1 -C 4 alkyl,

3. (C ₃ -C ₆ ) -cycloalkyl,

4. (C ₂ -C ₄ ) -alkenyl or

5. (C ₂ -C ₄ ) -alkynyl;

R is

1. hydrogen,

2. (C 1 -C 8) -alkyl, substituent, substitution

3. (C ₃ -C ₈ ) -cycloalkyl,

4. phenyl or

5. benzyl;

g) R ⁶ , R ⁹ - the same or different

1. hydrogen,

2. (C _x -C ₆ ) -alkyl which may be substituted

1-3 residues from (C _x -C ₆₎ -alkoxyl sequence which, in turn, may have 1 to 3 residue such as hydroxyl, (C₁-C₆)-alkoxy, amino, mono (C ₁ -C ₆ ) -alkylamino, di (C ₁ -C ₈ ) -alkylamino, (C ₂ -C ₁₀ ) -alkenyl, hydroxyl, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, (C _x -C ₆₎ -alkoksikarbonilaminogrupė (C ₆ -C ₁₂₎ -aryl- (C _x -C ₄₎ alkoksikarbonilaminogrupė, (C ₆ -C ₁₀₎ -aryl, (C ₆ -C ₁₀₎ -aryl- ( C ₁ -C ₃₎ -alkyl, (C _l -C ₉₎ -heteroaryl, carboxyl and (C _x -C ₄₎ alkoxycarbonyl;

3. (C ₃ -C ₆ ) -cycloalkyl, the cycloalkyl moiety of which may also have 1-3 moieties, such as (C _x -C ₄ ) alkyl and (C ₂ -C ₄ ) -alkenyl;

. (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₆ ) -alkyl,

5. (C ₆ -C ₁₂ ) -aryl, preferably phenyl,

6. (C ₆ -C ₁₀ ) aryl- (C _x -C ₄ ) alkyl,

7. (C _x - C ₉ ) - he teroari 1 as may be partially or fully hydrogenated,

8th

(g) 5, 6, 7, 9, 15, 16, 17, 19,

A substituent described in paragraph 20 or 21 which contains one or two identical or different substituents selected from the group consisting of halogen, hydroxy, (C _x -C ₄ ) alkyl, methoxy, nitro, cyano, CO ₂ R ³ , trifluoromethyl, -NR ¹¹ R ¹² and

-IT

- (CH _{z) q}

D,

9th

(C _x -C ₉ ) -heteroaryl- (C _x -C ₃ ) -alkyl, the heteroaryl moiety of which may be partially or fully hydrogenated, (C _x -C ₆ ) -alkyl, whose hydrogens are substituted with 1 to all fluorine , (C ₂ -C ₁₀ ) -alkenyl, (C ₂ -C _X0 ) -alkenoyl or (C ₂ -C _X0 ) -alkadienyl, (C ₃ -C ₈ ) -cycloalkenyl, (C ₃ -C ₈ ) -cycloalkenyl - (C _x -C ₃ ) -alkyl, bi- and tricyclic (C ₄ -C _xo ) -cycloalkenyl (C _x -C ₄ ) -alkyl, which may also contain 1-3 (C _x -C ₄ ) -alkyl residues, (C ₆ -C ₁₀₎ -aryl- (C _x -C ₄₎ -alkyl, (C ₆ -C _X0) -aryl- (C ₃ -C ₆₎ -alkenyl, (C _x -C ₉₎ - heteroaryl- (C ₃ -C ₆ ) -alkenyl, (C ₃ -C ₆ ) -alkinyl, (C ₆ -C ₁₀ ) -aryl- (C ₃ -C ₆ ) -alkynyl,. (C ₁ -C ₉ ) -heteroaryl- (C ₃ -C ₆ ) -alkynyl,

R ⁶ , R ⁹ , together with the N-atom contained therein, form a heteroaryl, which may also be partially or fully hydrogenated;

h) R ⁷ is present

1. hydrogen,

2. (C 1 -C 8) 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 8) -heteroaryl;

and it is

1. hydrogen,

2. (C ₁ -C ₆ ) alkyl,

3. (C ₃ -C ₆ ) -cycloalkyl,

4. phenyl (CH ₂ ) _q -,

5. OR ⁶ ,

6. NR ⁿ R ¹² or / -

7. -N D, \ _ / io

j) R ¹⁰ is cyano, nitro or CO ₂ R ⁷ ;

k) R ¹¹ and R ¹² are the same or different and are

1. hydrogen,

2. (C ₁ -C ₄ ) alkyl,

3. phenyl,

4. benzyl or

5. α-methylbenzyl;

l) D is R ¹³ , O or CH ₂ ;

m) R ¹³ is hydrogen, (C _l -C ₄₎ -alkyl or phenyl;

n) A is a biphenyl residue which may be substituted by 4, preferably 2 identical or different residues R ¹⁴ or R ¹⁵ , wherein A may be optionally substituted by at least the residue described in p) 44 or 45;

\ r. ^14th

o) R is

1. halogen,

2. nitroso group,

3. nitro group,

4. amino group,

5. cyano group,

P)

6. hydroxyl,

7. (C 0 -C 8) -alkyl,

8. (C ₁ -C ₄ ) -alkonoyl,

9. (C _x -C ₄ ) alkanoyloxy,

10. CO ₂ R ³ ,

11. Methanesulfonylamino

12. trifluoromethanesulfonylamino,

13. -CO-NH-OR ⁹ ,

14. -SO ₂ -NR ⁶ R ⁷ ,

15. -CH ₂ -OR ⁷ ,

16. (C ₃ -C ₉ ) -heteroaryl- (CH ₂ ) _q -, preferably 1-tetrazolyl,

17. (C ₇ -C ₁₃ ) -aryl, / „λ

18. -CH ₂ -U_

19. - (CH ₂ C) ₀ —J Q or n v / o

20. (C ₆ -C ₁₂ ) -aryl;

R ¹⁵ is present

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 ) -aryl,

6. (C ₁ -C ₄ ) alkoxyl,

7. (C ₁ -C ₄ ) -alkanoyloxy,

8. (C 1 -C 8) -heteroaryl,

9. CO ₂ R ³ ,

10. halogen,

11. cyano group,

12. nitro group,

13. NR ⁶ R ⁷ ,

14. hydroxyl,

15. -CO-NH-CHR ⁵ -CO ₂ R ³ ,

16. sulpho group,

17. -SO ₃ R ³ ,

18. -SO ₂ -NR ⁷ -CO-NR ⁶ R ⁹ or -SO ₂ -NR ⁷ -CS-NR ⁶ R ⁷ ,

19. -no ⁷ -co-nr ⁶ -so ₂ -ch ₂ -r \

20. -C (CF ₃ ) ₂ OH,

21. phosphonooxy group,

22. -PO ₃ H ₂ ,

23. -NH-PO (OH) ₂ ,

24. -S (O) _r R ⁶ ,

25. -CO-R ⁸ ,

26. -CONR ⁶ R ⁹ ,

27. -CR ²⁰ (OH) -PO (OH) ₂ ,

The residue described in point 28 (c) (20),

-SO ₂ -NH to ©, 8

30th

-NH-CO

5-Tetrazolyl-NH-CO33

-CO-NH-NH-SO ₂ CF ₃ ,.

C0 ₂ H

HO,

35.

A / N

40. -CONH-SO ₂ R ¹⁹ ,

41. -SO ₂ -NH-CO-R ⁶ or

The residue of item 42 (p) (4) having from 1 to 2 the same or different substituents selected from the group consisting of halogen, cyano, nitro, NR ^e R ⁷ and hydroxyl,

43. R ¹⁵ together with R ¹⁴ represents -CO-NH-SO ₂ -,

44. -SO ₂ -NH-CO-OR ⁶ ,

45. -SO ₂ -NH-SO ₂ -NR ⁶ R ⁹ ,

46. -SO ₂ -NH-SO ₂ -R ⁶ ;

q) B is 0, NR ⁷ or S; r) W is 0 or S; s) z is (C 1 -C ₃ ) -alkanediyl;

v) R ¹⁶ is CH 2 CO 2 R ³ or _two R ^3;

u) R ¹⁷ is hydrogen, halogen, (C ₁ -C ₄ ) alkyl or (C ₁ -C ₄ ) alkoxyl;

v) R is hydrogen, (C 1 -C 4) alkyl or phenyl;

w) R ¹⁹ is present

1. (C1-C8) -alkyl,

2. (C ₃ -C ₈ ) -cycloacyl,

3. phenyl,

4. benzyl or

5. A residue as described in (w) 1. wherein the hydrogen is 1 to all substituted by fluorine;

x) T is

1. single connector,

2. -CO-,

3. -CH ₂ -,

4. -0-,

5. -S-,

6. -NR ²¹ -,

7. -CO-NR ²¹ -,

8. -NR ²¹ -CO-,

9. -OCH ₂ -,

10. -ch ₂ -o-,

11. -s-ch ₂ -,

12. -CH ₂ -S-,

13. -NH-CR ² ° R ²² -,

14. -NR ²¹ -SO ₂ -,

15. -SO ₂ -NR ²¹ -,

16. -CR ²⁰ R ²² -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 ³ ) -,

24. -CH (OCOR ⁵ ) -,

25. -C- or

II

NR ²³

26. R ²⁴ -C ^x oa ²⁵

22nd

y) R and R are the same or different and are hydrogen, (C _x -C ₅ ) -alkyl, phenyl, allyl or benzyl;

z) R ²¹ is hydrogen, (C 1 -C 8) alkyl, benzyl or allyl;

R ²³ is 1. no ²⁰ r ²¹ , 2. urea group, 3. thiourea group, 4. toluene-4-sulfonyl or 5. benzenesulfonylamino group;

b ') R ²⁴ and R ²⁵ are the same or different and are (C _x C ₄ ) alkyl or both are - (CH ₂ ) _q -;

c ') Q is CH ₂ , NH, O or S;

d ') m is an integer from 0 to 5;

e ') n is an integer from 1 to 5;

f ') o is an integer from 1 to 10;

g ') q is O or 1;

h ') r is 1 or 2, or i') v is an integer from 1 to 6, and their physiologically acceptable salts with the exception of the compounds of formula L

V '

Alkyl, alkenyl and alkynyl may have a linear or branched chain. The same is true for residues containing alkyls such as alkonoyl or alkoxyl.

Cycloalkyls include alkyl-substituted rings.

(C ₆ -C ₁₂ ) -aryl is, for example, phenyl, naphthyl or biphenyl, preferably phenyl. This also applies to residues containing aryl such as aroyl or arylalkyl.

(C ₃ -C ₉₎ -heteroaryl is in particular residues, which result from a phenyl or naphthyl group or one or more CH-groups replacing N, and / or wherein at least two adjacent CH-groups (to form penkianariam aromatic ring) substituted with S, NH or O, Then one or both atoms at the point where the bicyclic moiety is attached (as in indolizinyl) may also be N-atoms.

Particularly suitable as heteroaryl are furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridazinyl, isoquinolinyl, pyridyl, indolyl, phthalazinyl, chinolinyl, chinolinyl, choline, .

If necessary, the resulting stereocenters may have both (R) - and (S) - configurations.

A is attached via an alkanediyl Z bridge; preferably when it is a methylene group.

Preferably, the methylene group is linked directly to the biphenyl residue.

The physiologically acceptable salts of the compounds of formula (I) include both organic and inorganic salts, which are described in Renington's Pharmaceutical Science (17th edition, page 1418, 1985). Based on the physicochemical stability and solubility data in the presence of acidic compounds. the groups most suitable are, among others, the sodium, potassium, calcium and ammonium salts, and in the case of basic groups, among others, hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic or sulfuric acid such as acetic, citric, benzoic , salts of maleic, fumaric, tartaric and ptoluenesulphonic acids.

Most preferred are compounds of formula I wherein

a) X is N, Y is CR ² and Z is CR ² ;

b) X is CR ² , Y is CR ² and Z is N; or

c) X, Y and Z are N respectively.

Further preferred are compounds of formula I wherein the symbols have the following meanings:

is N, Y is CR ² and Z is CR ² ; is CR ² , Y is N and Z is CR ² ; is CR ² , Y is CR ² and Z is N or

X, Y and Z are N, respectively;

(a) R ¹ is present

1. (C ₂ -C ₁₀ ) alkyl,

2. (C ₃ -C ₁₀ ) -alkenyl,

3. (C ₃ -C ₁₀ ) -alkynyl

4. (C ₃ -C ₈ ) -cycloalkyl,

5. benzyl or

6. benzyl which is substituted as described above (b 13.);

b) R ² is present

1. hydrogen,

2. halogen,

3. nitro group ,. C _v F _2v _ in,

5. pentafluorophenyl,

6. cyano group,

7. -0-R ^6,

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 ) ₀ -,

15. tetrazolyl- (CH ₂ ) _m -,

16. - (CH ₂ ) _{O 1} -CHR ⁷ -OR ⁵ ,

17 - (CH _{2) o} -0- C0R ³

18. -COR ⁸ ,

19 - (CH _{2) o} -C 0-R ^8,

20. -S (O) _r R ¹⁹ ,

21. -CH = CH- (CH ₂ ) _m -CHR ³ -OR ⁶ ,

22. -CH = CH- (CH ₂ ) _m -COR ⁸ ,

23. - (CH ₂ ) ₀ -NH-CO-OR ⁹ ,

24 - (CH _{2) o} -NH-S0 ₂ -R ^9,

25. - (CH ₂ ) _n F,

26 - (CH _{2) o} -S0 ₃ R ^9,

27. - (CH ₂ ) _n -SO ₂ -NH-CO-NR ⁶ R ⁹ ,

28. - (CH ₂ ) _n -SO ₂ -NH-CS-R ⁹ or a residue of (b) 8, 9, 10, 11 or described which has the residue of (c) 46, 47 or the residues indicated,

14. in the part above

In Part 48.

30. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CO-R ⁶ ,

31. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CS-R ⁶ ;

c) R ⁸ is vanldenyl, (C ₁ -C ₅ ) alkyl, OR ⁶ , NR ⁷¹ R ¹² or a morpholine residue;

d) T is

1. single connector,

2. -CO-,

3. -CONR ²¹ -,

4. -CH ₂ -CH ₂ -,

5. -NR ²¹ -CO-,

6. -O-CH ₂ -,

7. -CH ₂ -O-,

8. —S — CH ₂ -,

9. -CH ₂ -S-,

10. -nh-ch ₂ -,

11. —CH ₂ —NH— or

12. -CH = CH-, and other residues and variables are as described above.

Particularly suitable are compounds of formula I wherein:

X is N, Y is CR ² and Z is CR ² ;

X is CR ² , Y is N, and Z is CR ² ;

X is CR ² , Y is CR ² and Z is N or

X, Y and Z are respectively N,

a) R ¹ is (C ₂ -C ₇ ) -alkyl, (C ₃ -C ₇ ) -alkenyl or (C ₃ -C ₇ ) -alkynyl;

b) R ² is present

1. chlorine,

2. bromine,

3. C _v F _{2v + 1} , where v = 1, 2 or 3,

4. pentafluorophenyl,

5. OR ⁶ ,

6. -S (O) _r R ¹⁹ ,

7. - (CH ₂ ) _{O 1} -CHR ⁷ -OR ⁵ ,

8 - (CH _{2) o} -0-C0-R ^3,

9. -COR ⁸ ,

10 - (CH _{2) o} -C 0-R ^8,

11. -ch ₂ -nh-co-r ⁹ ,

12 - (CH _{2) o} -NHS0 ₂ R ^9,

13. -ch = ch-chr ³ -or ⁶ ,

14. tetrazolyl- (CH ₂ ) _m -,

15. - (CH ₂ ) _n -SO ₂ -NH-CO-NR ⁶ R ⁹ ,

16 - (CH _{2) o} R ⁹ -S0 ₃ or where appropriate substituted by a hydroxy (C _l -C ₆₎ alkyl, preferably hydroxymethyl;

c) R ³ is hydrogen, (C 1 -C 4) alkyl or benzyl;

d) R ⁶ , R ⁹ are the same or different and are:

1. hydrogen,

2. (C ₁ -C ₈ ) -alkyl, which may have from 1 to 3 residues of the (C ₁ -C ₆ ) - (I-xoxyl) order which in turn may have from 1 to 3 residues of hydroxyl, (C ₁ -C ₈ ). -alkoxy, amino, mono (C ₁ -C ₈ ) -alkylamino, di- (C ₁ -C ₁₀ ) -alkylamino, (C ₂ -C ₁₀ ) -alkenyl, hydroxyl, amino, mono LT 3373 B (C ₁ -C ₈ ) -alkylamino, di- (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈ ) -alkoxycarbonylamino, (C ₈ -C ₁₂ ) -aryl (C _x -C ₄ ) -alkoxycarbonylamino, (C ₆ -C ₁₀ ) aryl, (C C ₆ -C ₁₀ ) -aryl- (C _x -C ₃ ) -alkyl, (C _x -C ₉ ) heteroaryl, carboxyl and (C 1 -C ₆ ) alkoxycarbonyl,

3. (C ₃ -C ₆ ) -cycloalkyl,. (C ₃ -C ₆ ) -cycloalkyl- (C _x -C ₃ ) -alkyl,

5. phenyl,

6. phenyl (C ₁ -C ₃ ) alkyl,

7. (C _x -C ₇ ) -heteroaryl, which may be partially or fully hydrogenated,

8. (g) 5., 6., 7. or 9. 14-16. and

18-20. a residue having one or two identical or different substituents selected from halogen, hydroxy, (C _x -C ₄ ) alkyl, methoxyl, nitro, cyano, CO ₂ R ³ ,

12 sequences of trifluoromethyl, -NR R and - * ^ 0.

9. (C ₁ -C ₉ ) -heteroaryl- (C _x -C ₃ ) alkyl wherein the heteroaryl moiety may be partially or fully hydrogenated,

10. (C 1 -C 8) -alkyl wherein the hydrogens, 1 to all, are replaced by fluorine,

11. (C ₂ -C ₄ ) -alkenyl or (C ₃ ) -alkenoyl,

12. (C ₃ -C ₆ ) -cycloalkenyl,

13th (C ₃ -C ₆₎ cycloalkenyl- (C _l -C ₃₎ -alkyl, 14th bi- and tricyclic (C ₄ -C ₁₀ ) -cycloalkenyl- (Οχ-Ο ₄ ) -alkyl, which may also be substituted with 1-3 (Οχ-Ο ₄ ) -alkyl, 15th C ₆ -aryl- (Οχ-Ο ₃ ) -alkyl, 16th C ₆ -aryl- (C ₃ ) -alkenyl, 17th (Οχ-Ο ₆ ) -hetaryl- (C ₃ ) -alkenyl, 18th C ₃ alkynyl, 19th C ₆ -aryl- (C ₃ ) -alkynyl, 20th (Οχ-Ο ₆ ) -hetaryl- (C ₃ ) -alkynyl, 21st R ⁶ , R ⁹ together with the N-atom to which they are attached form a hetaryl which may also be partially or fully hydrogenated; e) R ⁷ is hydrogen, (Οχ-Ο ₄ ) -alkyl, (Οχ-Ο ₉ )

roaryl or (C ₆ -C ₁₂ ) -aryl- (Οχ-Ο ₄ ) -alkyl;

6th

f) R is hydrogen, (Ο _χ- Ο ₄ ) -alkyl, OR, or a morpholine residue;

\ n ¹⁴ g) R is 1. (Οχ-Ο ₄ ) alkyl, 2. (Οχ-Ο ₄ ) -alkoxyl, 3. cyano group, 4. amino group,

h)

5. nitroso group,

6. nitro group,

7. fluorine,

8. chlorine,

9. bromine,

10. (Cy-Cg) -heteroaryl-CH ₂ 11. (C ₁ -C ₄ ) -alkanoyloxy

12. (C ₁ -C ₄ ) alkanoyl,

13. benzoyl,

14. -NH-CO-R ⁷ or

15. tetrazolyl;

R ¹⁵ is present

First (C _l -C ₄₎ -alkyl,

2. (C ₆ -C ₁₂ ) -aryl,

3. (C 1 -C 4) - alkanoyloxy,

4. (C ₁ -C ₄ ) -a 1 -coke group,

5. (C 1 -C 8) -heteroaryl, preferably 5-tetrazolyl,

6. cyano group,

7. nitro group,

8. hydroxyl,

9. -S (O) _r R ⁶ ,

10. -SO ₃ R ³ ,

11. chlorine,

12. bromine,

13. benzoyl,

14. -CO ₂ R ³ ,

15. -CO-NH-R ⁶ ,

16. -CO-R ⁰ ,

17. -SO ₂ -NR ⁶ R ⁷ ,

18. -SO ₂ -NH-CO-NR ⁶ R ⁹ ,

19. -PO ₃ H,

20. -CO-CHR ⁵ -CO ₂ H,

21. -nh-co-nh-so ₂ -ch ₂ -r ⁵ ,

22. 5-Tetrazolyl-NH-CO-,

HO;

-T

27. -CO-NH-SO ₂ - (CH ₂ ) _n or

The residue described in paragraph 28 (h) (2) having the same substituents as above (see p) (42),

29. R ¹⁵ together with R ¹⁴ are -CO-NH-SO ₂ -,

30. -SO ₂ -NH-COO-R ⁶ ,

31. -so ₂ -nh-so ₂ -nr ⁶ r ⁹ ,

32. -SO ₂ -NH-SO ₂ -R ⁶ ;

i) R ¹⁸ is hydrogen, methyl or ethyl;

j) T is a single bond, -O-, -CO-, -NHCO-, or k) q = O and L = methylene, and other residues and variables are as described above.

In addition, azole derivatives of formula (I) wherein Z is a nitrogen atom and Y and X independently of one another are CR, and the other symbols are as particularly preferred, are particularly suitable.

The following are particularly suitable azole derivatives having the general formula (I) in which the symbols have the following meanings:

Z is nitrogen,

X, Y are, independently of one another, CR ² ,

R ¹ is (C ₂ -C ₇ ) -alkyl, (C ₃ -C ₇ ) -alkenyl or (C ₃ -C ₇ ) -alkynyl,

R is hydrogen, perfluoroalkyl, (C ₃ -C ₁₀ ) -alkenyl, -OR ⁶ , halogen, nitro, (C _x -C ₃ ) cyano, (C ₁ -C ₁₀ ) -alkyl, -CH ₂ OR ⁵ , -S (O) _r -R ¹⁹ , -CO-R® or

R ⁵ is hydrogen or (C _x -C ₆ ) alkyl,

R ⁶ , R ⁹ are present

1. hydrogen,

2. (C _x -C ₆ ) -alkyl which may have from 1 to 3 substituents, such as (C _x -C ₆ ) -alkoxyl, which in turn may have from 1 to 3 substituents on hydroxyl, (C _x - C ₆₎ -alkoxyl, amino, mono (C₁-C₆) alkylamino, di- (C ₁ -C ₆₎ -alkylamino, (C _x -C ₆₎ alkoxycarbonylamino, (C ₆ -C ₁₂₎ -aryl (C _x- C ₄ ) -alkoxycarbonylamino; (C ₆ -C ₁₀₎ aryl, (C ₆ -C ₁₀₎ -aryl- (C _x -C ₃₎ -alkyl, _(Ο χ -Ο ₉₎ heteroaryl, carboxyl and (C _x -C ₄₎ alkoxycarbonyl;

3. (C ₃ -C ₈ ) -cycloalkyl,. (C ₃ -C ₆₎ cycloalkyl- _(C, -C ₃₎ -alkyl,

5.

6th

7th

8th

(C ₆ -C ₁₂ ) -aryl, preferably phenyl, (C ₆ -C ₁₀ ) -aryl- (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₉ ) -heteroaryl, which may be partially or fully hydrogenated , (C ₁ -C ₉ ) -heteroaryl- (C ₁ -C ₈ ) -alkyl wherein the heteroaryl moiety may be partially or fully hydrogenated,

9th

the residues described in paragraphs 5, 6, 7 and 8 above which may have 1 or 2 identical or different substituents such as halogen, hydroxy, (C ₁ -C ₄ ) -alkyl, methoxy, nitro, cyano, CO ₂ R ³ , trifluoromethyl, NR ¹¹ R ¹² and (C ₁ -C ₈ ) -alkyl, where the hydrogens, 1 to all, are replaced by fluorine, (C ₂ -C ₆ ) -alkenyl or (C ₃ -C ₆ ) -alkenyl , (C ₃ -C ₆ ) -cycloalkenyl, (C ₃ -C ₆ ) -cycloalkenyl- (C ₁ -C ₁₀ ) -alkyl, (C ₆ -C ₁₀ ) -aryl- (C _x -C ₄ ) -alkyl, ( C ₆ -C ₁₀ ) -aryl- (C ₃ -C ₆ ) -alkenyl, (C ₆ -C ₈ ) -hetaryl- (C ₃ -C ₆ ) -alkenyl, (C ₃ -C ₆ ) -alkynyl,. (C ₆ -C ₁₀ ) -aryl- (C ₃ -C ₆ ) -alkynyl,. (C ₁ -C ₉ ) -hetaryl- (C ₃ -C ₆ ) -alkynyl,

20. R ⁶ , R ⁹ together with the N-atom to which they are attached are heteroaryl which may also be partially or fully hydrogenated,

R ⁷ is hydrogen,

6th

R is hydrogen or -OR,

R ¹¹ , R ¹² are independently hydrogen or (C _x -C ₄ ) alkyl,

D is NR ¹³ , -O or -CH ₂ ,

R ¹³ is hydrogen or (C ₁ -C ₄ ) alkyl

A is a biphenyl residue which is substituted with R ¹⁵ ,

R ¹⁵ is -SO 2 -NR ⁷ -CO-NR ⁶ R ⁹ , -SO 2 -NH-COO-R ⁶ , -SO ₂ -NHSO ₂ -N ⁶ and ⁹ ,

-SO ₂ -NH-CO-R ⁶ or -SO ₂ -NH-SO ₂ -R ⁶ ; or

R ¹⁴ and R ¹⁵ together may form -CO-NH-SO ₂ -,

Z is -CH ₂ -, q is O and r is O, 1 or 2;

and their physiologically acceptable salts.

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

wherein R ¹ , X, Y and Z have the meanings given above, are alkylated with compounds of formula (III),

UZ- (O) _q -A (III) wherein Z, A and q have the meanings given above, and U is a leaving group, optionally deprotecting, if necessary, the resulting protecting groups of formula (I), the resulting urethanes of formula (I) are optionally converted to the sulfonylureas of formula (I) and the resulting compounds of formula (I) are optionally converted into their physiologically acceptable salts.

Suitable leaving groups are preferably nucleophilic groups (see Angew. Chem. 72, 71 (1960)) such as halogen, o-toluenesulfonate, mesylate or triflate.

Preliminary steps for the preparation of compound (II) are known, inter alia, from U.S. Pat. European Patent No. 4,356,044; A-324 377; A-323,841.

Other methods of preparation are described by G. Z'abbe (Chem. Rev., 69, 345 (1969)), T. Srodsky (The Chemistry of the

Azido Group, Wiley, New York, 1971, p. 331), H. Wanehoff (Comprehensive Heterocyclic Chemistry), and S. Katritzky Ed., Pergamon Press, New-York (1984).

Another process for the preparation of compounds of formula II is the use of 2-oxim-1-cyanoglyoxylic acid derivatives as starting materials which, after reduction of the oxime with known reducing agents and the use of suitable protecting groups in the nitride group, to imidazoles. The cyclization step includes, inter alia, a mixture of PC1 ₅ and dimethylaminopyridine (DMAP), POC1 ₃ and SOC1 ₂ and mixtures thereof with DMAP.

The oxidation of thio compounds of formula I having R = S (O) _r R where r = O or 1 is carried out using the appropriate acid such as dichloromethane to the corresponding sulfones and sulfoxides.

For the alkylation of the azoles of formula II, for example, the corresponding benzyl halides, tosylates, mesylates or triflates, or corresponding alkyl halides, tosylates, mesylates or triflates are used.

Alkylation is generally carried out in known ways according to analogous procedures.

The introduction of the metal into the azole derivatives of formula II is effected, for example, in the presence of a base. Most preferred are metal hydrides of the formula MH such as lithium hydride, sodium hydride or potassium hydride, using solvents such as dimethylformamide or dimethylsulfoxide, or metal alkoxides of the formula MOP where P is methyl, ethyl, tert. -butyl, and the reaction is carried out in the appropriate alcohol, dimethylformamide or dimethylsulfoxide. The azole salts thus obtained are dissolved in an aprotic solvent such as dimethylformamide or dimethylsulfoxide and mixed with the required amount of alkylating agent.

Alternative deprotonation of azole derivatives is, for example, the use of potassium carbonate in dimethylformamide or dimethylsulfoxide.

The reaction is carried out at temperatures below room temperature to the reflux temperature of the reaction mixture, preferably between 20 ° C and the reflux temperature of the reaction mixture; the reaction is carried out for 1 to 10 hours.

Biphenyl derivatives can be synthesized, for example, by removal of arylboronic acid by treatment with substituted aryl halides, and by the use of transition metals, in particular palladium catalysts. Corresponding reactions are described in R.B. Miller et al. (Organometallics, 1984, 3, 1961) or A. Zuzuki et al. (Synthetic Commun. 11 (7), 513 (1981).

The sulfonylurethanes of formula I can be prepared from the corresponding sulfonamides of formula I by treatment with chloro-carbonic acid esters in inert, high-boiling solvents such as toluene at about 100 ° C using solvents having such a boiling point.

Similarly, sulfonyl sulfonamides can be obtained from the corresponding sulfonamides by treatment with sulfuric anhydrides or sulfamoyl chlorides.

The sulfonamide residue can be obtained, if necessary, by leaving the amino group by means of the Meyernein reaction. To this end, the amine hydrochloride is initially diazotized and then treated with sulfur dioxide in glacial acetic acid in the presence of a copper catalyst. This is followed by treatment with ammonia to give the sulfonamide group.

Alternatively, the corresponding thiophenol is oxidized with chlorine and subsequently treated with ammonia to form the sulfonamide.

The compounds of formula (I) exhibit antagonistic activity at the angiotensin-II receptor and can therefore be used in the treatment of angiotensin-II-dependent hypertension. Other applications include: heart failure, cardioprotection, myocardial infarction, cardiac hypertrophy, atherosclerosis, nephropathy, renal failure, as well as cerebrovascular diseases such as transient ischemic attacks and bleeding into the brain.

Renin is a proteolytic enzyme from the class of aspartyl proteases that undergoes a variety of stimuli (volume depletion, sodium deficiency, β-receptor stimulation) in mixed agglomerated kidney cells. There, it releases an angiotensin decapeptide, angiotensin-I, from the liver. The latter is converted to angiotensin-II by the action of an angiotensin converting enzyme (ACE). Angiotensin-II plays an essential role in the regulation of blood pressure; it directly raises blood pressure by causing angiospasm. In addition, it stimulates aldosterone secretion from the adrenal glands, thereby increasing the volume of extracellular fluid by inhibiting the excretion of sodium, which in turn promotes an increase in blood pressure.

Post-receptor effects include, but are not limited to, stimulation of phosphoinositide alterations (Ca ²⁺ release), activation of protein kinase C, and c-AMP-dependent receptors.

The affinity of the compounds of formula (I) for angiotensin II receptors can be determined by measuring the receptor displacement of ¹²⁵ jangiotensin or ³ H-angiotensin in the membranes of the large horned adrenal glomerulosa. For this purpose, the prepared membranes are suspended in a pH 7.4 buffer.

Aprotinin is added to stop radioligand degradation during incubation An additional indicator (peptidase inhibitor) is added. about 14,000 cpm isotopic relative activity is

TBq / mmol (Amerscham Buchler Braunschweig, Germany) and the amount of receptor protein that binds 50% of the isotope indicator. The reaction is initiated by adding 50 μΐ of membrane suspension to 100 μΐ of buffer and aprotinin mixture; 50 μΐ of buffer with or without angiotensin-II or receptor antagonist and 50 μΐ of isotopic indicator. 60 minutes for the incubation period at 25 ° C, the bound and free radioligand were separated by filtration through Whatman® GF1C filters using a Skatron® cell harvester.

Non-specific binding is avoided by treating the filters with 0.3% polyethyleneimine (Sigma, # 3143) at pH = 10. Radioactivity is measured by gamma-scintillation counter; the intensity of radioligand displacement by the receptor is determined. IC ₅₀ values which represent the concentration of inhibitor required to displace 50% of the ligand are determined by J. Inor. Biol., 59, 253 (1970). For compounds of formula (I) are, 10.1 ⁴ - 1.10 ^"9 M range.

Alternative affinity for compounds of formula I. . · The 125 detection option for tenzin-II-receptors is to measure the displacement of jangiotensin-II or ³ H-angiotensin-II receptors from various organs (liver, lung, adrenal gland, brain, etc.).

For this purpose, the preparative membranes were suspended in 135 mmol NaCl, 5 mmol glucose, albumin, 0.3 mmol incubation buffer.

7.4,

0.2% (20 mmol Tris, pH 10 mmol KCl, 10 mmol MgCl ₂ , coarse horn serum protease inhibitor FMSF and 0.1 mmol bacitration) and incubated with radiolabeled angiotensin-II at various concentrations of test compounds for 90 min. . At 25 ° C. The bound and free radioligand are then separated by filtration through a microfibre filter (CF ₅₁ , Schleicher-Schull) using a cell harvester (Skatron).

radioligand receptor

By measuring the radioactivity of the bound receptor on the filter using beta-gamma spectrometers, the degree of receptor displacement due to exposure to the test compounds is determined. The radioligand ejection intensity due to exposure to the test compounds is described as IC ₅₀ , the concentration of inhibitor that displaces 50% of the radioligand-bound receptor. IC _{50 is} deducted using PC-mathematical provision (LIGAND, CA McPhersen, 1985, Elsivier-BIOSOFT, 68 Hills Road. Cambridge CB 2 LLA, UK). IC ₅₀ values for compounds of formula I are 1.10 ⁵ to 1.10 ¹¹

M (see table below for IC ₅₀ values of the compounds of the invention).

table

An example IC ₅₀ , 1 5000 2 8000 3 1100 4 1100 5 16000 22nd 2000 24th 800 25th 1400 29th 1.1 30th 2030.0 31st 153.0 32 3, 5 33 34.0 34 1.0 35 50.0 36 16.0 37 1.1 38 8.8 56 4, 6 57 1100 58 3, 0

An example IC ₅₀ , nM 59 1.3 60 2.2 61 1.1 62 3, 6 63 1.3 64 0.5 65 1.8 66 6.9 67 0, 91 68 12.0 69 3.2 70 4.4 71 2.2 73 2.5 76 9.5 79 5.8 80 0, 69 81 0.79 83 0, 96 84 4.3 85 3.9 89 1.1 90 0, 69

An example IC50 / 92 280.0 93 3, 3 95 CD V. «“ H 98 1.4 99 26, 6 100 68.5 101 2.4 102 2.3 105 3, 0 107 2.5 108 0, 95 109 0, 6 110 0.5 111 2.9 112 1.5 113 0.3 115 0.9 116 2.4 117 1.2 124 1.8 125 2.8 127 3.0 128 5, 6

An example IC 50, nM 129 1.5 134 180.0 135 5, 6 138 1.7 139 2.8 140 8.2 141 4.4 144 5.3 146 40.0 151 0.4 152 1.5 153 0, 88 154 1.8 155 6, 0 156 4.7 157 1.4 159 8.7 160 0, 73 161 57.0 162 3.9 163 3.7 164 0, 86 165 2, 3

An example IC ₅₀ , nM 166 1.2 167 4.0 168 7.0 169 2.9 170 2.7 171 0.7 172 0, 48 174 5.1 179 2.6 181 1.0 183 1.7 185 5.9 186 6.5 187 1.2 190 22.0 191 21, 4 194 21.7 195 3, 0

To determine the antagonistic effect of the compounds of formula (I), their effect on angiotensin-II induced increase in blood pressure can be measured using anesthetized Speague-Dawley rats. The drug used is Na-thiobarbital (Trapanal®, Buck Gulden, Germany, trademark) at a dose of 100 mg / kg administered intraperitoneally. For intravenous use, it is injected into the conjunctival vein. Blood pressure is measured in the carotid artery. Initially, the animals are treated with pentoline tartrate (10 mg / kg intramuscularly) to achieve lower blood pressure (ganglion block). Intravenous injection 0.1 ml / 100 g ANG-II (CIBA hypertension) every 10 minutes. The dose is 0.5 mg / kg. The compounds of the formula I are dissolved in distilled water and administered intravenously at doses of 0.1 to 1.0 mg / kg or duodenum at doses of 10 to 100 mg / kg.

The compounds of formula I are particularly effective in the dosage range of 0.1 to 100 mg / kg, preferably 0.1 to 3 mg / kg.

The invention also relates to pharmaceutical compositions comprising the compounds of formula I and other active ingredients, such as, for example, urinary or non-steroidal anti-inflammatory active ingredients. The compounds of the formula I may also be used as diagnostic agents for the renin-angiotensin system.

Pharmaceutical formulations contain an active ingredient of the Formula I and optionally other active ingredients in association with an inorganic or organic pharmaceutically acceptable carrier. The drug may be administered by the nose, intravenously, subcutaneously, or orally. The dose of the active substance depends on the type of warm-blooded animal, body weight, age and route of administration.

The pharmaceutical preparations of the present invention are prepared by known methods of dissolving, mixing, granulating, or making a dragee.

The active compounds in the oral dosage form are mixed with customary additives such as carriers, stabilizers or inert solvents for the purpose and formulated in conventional manner such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. Inert carriers include, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose, magnesium stearyl fumarate or starch, in particular maize starch. The dosage form can be made from dry or wet granulate. Oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous use, the active ingredient, or a physiologically acceptable salt thereof, is optionally mixed with suitable excipients, such as solvents, emulsifiers or other excipients, to form solutions, suspensions, or emulsions. Solvents include water, saline or alcohols such as ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol, or mixtures thereof.

List of abbreviations:

DMF N, N-dimethylformamide

NBS N-Bromosuccinimide

AIBN α, α-azobis-isobutyronitrile

EI impact electron

DCI desorption - chemical ionization

RT room temperature EE ethyl acetate (EtCOAc) DIP diisopropyl alcohol MTB methyl tert-butyl ether L.t. melting point HEP n-heptane DME dimethoxyethane FAB bombardment of stable CH ₂ Cl ₂ dichloromethane

The invention is illustrated by the following examples

Synthesis of 1- (2-phenylaminocarbonylaminosulfonyl-biphenyl-4-yl) methyl / -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde

a) Preparation of 4-methylbiphenyl-2-amine

To a solution of 23.9 g (0.112 mol) of 4'-methyl-2-nitrobiphenyl (RB Muller, S. Dugar, Organometallics, 1984, 3, 1261) was added 3 g of Rhenium nickel in 50 ml of methanol and hydrogenated under normal pressure at room temperature. theoretical amount of H ₂ . The catalyst is filtered off and the filtrate is evaporated. Chromatograph over SiO ₂ (500 g) using EE / HEP (1/6) as solvent. 19 g (92.5%) of the desired product are obtained in the form of an oil.

R _f (EE / HEP 1/4) = 0.3, MS (EI) = 183 (M ⁺ ).

b) Preparation of 4'-methyl-biphenyl-2-ammonium hydrochloride A solution of the compound in 50 mL of 6 N HCl and 100 mL of dioxane. Distillation of the solvent yields the desired compound which is used without further purification.

c) Preparation of 4'-methylphenyl-2-sulfonamide

To a suspension of 31 g (140 mmol) of compound lb in 200 mL of 6 N HCl at -10 ° C was added 7.9 g (114 mmol) of sodium nitrite; the solution becomes clear. This solution is added to a solution of 200 ml of glacial acetic acid saturated with SO ₂ , 17 g of CuCl ₂ .H ₂ O and 25 ml of H ₂ O at OC temperature. The solution is then allowed to warm to room temperature and stirred for 2 hours. 250 ml of EE are added, the layers are separated, and the organic layer is dried over magnesium sulfate. Evaporation of the solvent gives an oil which is dissolved in 300 ml of acetone, 150 ml of 25% ammonia are added and stirred for 2 hours. Evaporate, add 500 mL EE, wash EE once with water, dry over MgSO _4, and evaporate the solvent. Chromatography over SiO ₂ using EE / HEP (1/1) as eluant gives the title compound (4.6 g).

R _f (EE / HEP) = 0.25; MS (DCI) = 248 (M @ ⁺ + H). Mp: 122 ° C.

d) Preparation of 4'-methylbiphenyl-2-N, N-dimethylaminoformylsulfonamide

4.6 g (18.6 mmol) of compound 1c and 2.5 g (19.3 mmol) of N, N-dimethylformamide dimethylacetal in 30 ml of DMF are stirred for 2 hours at room temperature, 100 ml of H ₂ O are added and the precipitate is suctioned off, air dried to give 4.2 g of the title compound.

R _f (EE / HEP 1/1) = 0.2; MS (DCI) = 303 (M + H).

e) Preparation of 4'-Bromomethylbiphenyl-2-, N -dimethylamino-formylsulfonamide

To 3.76 g (13.5 mmol) of compound ld and 2.4 g (13.5 mmol) of NBS in 50 ml of chlorobenzene are added 150 mg of benzoyl peroxide. The mixture was refluxed, evaporated and 50 mL EE was added. The EE layer is washed once with 10% Na ₂ SO ₃ and once with H ₂ O, dried over Na ₂ SO ₄ and chromatographed over SiO ₂ . 1.2 g of the title compound are obtained.

R _f (EE / HEP 2/1) = 0.23; MS (DCI) = 381.383 (M ⁺ + H).

f) Preparation of 2-n-butyl-4-chloro-5-formylimidazole

To a solution of 20 g (0.106 mol) of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (obtained according to European Patent No. A 253 310) in 30 ml of glacial acetic acid is slowly added 305 ml of 1 M (10-15 ° C). NH ₄ ) ₂ Ce (NO ₃ ) _{6 in} H ₂ O. The solution is kept at room temperature for 2.5 hours and adjusted to pH = 4 by the addition of 2 N KOH (the temperature when the alkali is added is 20 ° C). The mixture is then extracted with 4 x 500 mL of CH ₂ Cl ₂ , the combined organic extracts are washed with 3 x 300 mL of saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ and the solvent is evaporated. The title compound is obtained as a colorless solid (18 g, 92%).

Lt: 90 ° C; R _f (DIP / MTB 1/1) = 0.5.

g) Preparation of 1- (2'-N, N-dimethylaminoformylsulfonamidobiphenyl-4-yl) methyl t -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde

690 mg (1.98 mmol) of compound le, 370 mg (1.98 mmol) of compound lf and 270 mg (1.98 mmol) of potassium carbonate in 10 mL of DMF are stirred at room temperature for 2 hours. 50 ml of EE are then added and the mixture is washed twice with H ₂ O. The organic layer is dried (Na ₂ SO ₄ ) and evaporated. Chromatography over SiO ₂ using EE / HEP (2/1) as the eluent gave the title compound (380 mg, 40%).

R _f (EE / HEP 2/1) = 0.15; MS (DCI) = 487 (M @ ⁺ + H).

h) Preparation of 1- (2'-sulfonamidobiphenyl-4-yl) methyl-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

280 mg (0.58 mmol) of compound Ig 7 ml of methanol and 14 ml _of H ₂ O are mixed with 110 mg (2.88 mmol) of sodium hydroxide and heated to boiling for 4 hours. Cool to room temperature, adjust pH to 6 with 4 N HCl and extract with 3 x 30 mL EE. The EE extracts were dried (NaSO ₄ ), evaporated the solvent to give 190 mg of the title compound.

R _f (EE / HEP 2/1) = 0.45; MS (DCI) = 432 (M ⁺ + H).

i) Preparation of 1- / 2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl / -2'-butyl-4-chloro-imidazole-5-carboxaldehyde

730 mg (1.69 mmol) of compound lh is heated in 10 mL of phenyl isocyanate to 80 ° C. After 4 hours, evaporate and chromatograph over SiO ₂ (EE / HEP eluent (2/1)). 400 mg of the title compound are obtained.

R _f (EE / HEP 2/1) = 0.15; MS (DCI) = 551 (M @ ⁺ + H).

Another method for the preparation of compound ld (4'-methyl-2-Ν, N-dimethylaminoformylsulfonamide)

To 11 g (37.9 mmol) of 2-N, N-dimethylaminoformylsulfonamido-bromobenzene (obtained from 2-bromoaniline according to the procedure described in 1b-ld), 1 g of triphenylphosphine, 8 g of Na ₂ CO ₃

To 150 ml of toluene and 40 ml of H ₂ O under argon are added 420 mg of Pd (OAc) ₂ followed by 5.66 g (41.9 mmol) of 4-toluoylboronic acid in 100 ml of ethanol and heated for 4 hours before boiling. The reaction mixture is evaporated and 500 ml of ethyl acetate and 500 ml of water are added. The precipitate formed is the desired compound. The ethyl acetate layer was separated, dried (Na ₂ SO ₄ ) and evaporated. Chromatography over SiO ₂ (eluent ethyl acetate) afforded the title compound (7.6 g, 66% overall). Another procedure for the preparation of 2-bromobenzenesulfonamide (analogous to intermediate lc)

4.7 g of 2-bromothiophenol are introduced into 60 ml of H ₂ O over a period of 30 minutes at a temperature of 0 to 10 ° C by the addition of gaseous Cl ₂ . Stir for 30 minutes at 0 ° C and then purge with air for 30 minutes without freezing. Add 60 ml of acetone, cool again to 0 ° C and slowly add 10 ml of a saturated solution of NH ₄ OH. Leave for another 30 minutes and adjust to pH = 3 with 4 N HCl. Filter off the precipitate to give the desired product.

Yield 4.5 g (77%); M.p .: 190-191 ° C.

example

Synthesis of 1- (2'-n-propylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl / -2-n-butyl-4-chlorimidazole-5-carboxaldehyde

The compound is prepared according to the procedure described in Example 1.

R _f (EE) = 0.6; MS (FAB) = 517 (M @ ⁺ + H).

Example 3

Synthesis of 1 - [(2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

a) Preparation of 1- [(2'-ethoxycarbonylaminosulfonylbiphenyl-4-yl) methyl] -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

To 1.1 g (2.5 mmol) of compound lh and 0.78 g (5.6 mmol) of potassium carbonate in 20 ml of dry DME are added 0.48 ml (5.1 mmol) of ethyl chloroformate. After 1 hour, the solution is cooled to room temperature and mixed with 50 ml of 10% KH ₂ PO ₄ solution. The mixture was extracted with EE, dried over Na ₂ SO ₄ and the solvent evaporated. Chromatography on SiO ₂ (eluent EE / HEP 2/1) gives 840 mg of the title compound.

R _f (EE / HEP 2/1) = 0.32; MS (DCI) = 504 (M @ ⁺ + H).

b) Preparation of 1- (2'-pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) methyl / -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

150 mg (0.3 mmol) of Compound 3a and 28.5 mg (0.3 mmol) of 2-aminopyridine were heated in 8 mL of dry toluene for 2 hours before boiling, evaporated and chromatographed over SiO ₂ (eluent EE). 34 mg of the title compound are obtained.

R _f (EE / methanol 10/1) = 0.4; MS (FAB) = 552 (M @ ⁺ +1).

The compounds of Example 39 can be synthesized according to the procedure described in the Example.

The following compounds have the general formula (A):

table

Example substituents MS location (FAB, M ⁺ H) (16) 553

3 '(2') (17) 543

3 '(2') (18) 558

3 '(2') (19) 559

3 '(2')

(20) 597

3 '(2')

-u (21) 541

3 '(2') (22) 596

3 '(2') \ O / '' z.

(23) 596

3 '(2') (24) 569

3 '(2')

Continuation of Table F

Tables 2 continuation 55 An example MS (EAB, M ⁺ + H) Alternate location R 34 595 2 ' 35 565 2 ' 36 565 2 ' 37 579 2 ' 38 583 2 '' 39 589 2 ' ' ^(s > CH \ - CO ₂ CHj

example

Synthesis of 1- (2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl / -2-n-butyl-4-chloro-5-hydroxymethylimidazole

100 mg (0.18 mmol) of compound 1 are dissolved in 5 mL of ethanol and mixed with 10 mg (0.27 mmol) of sodium borohydride at room temperature. After 20 hours, 10 mL of 5% sodium bisulfate was added and extracted 3 times

EE. The organic layer was dried over Na ₂ SO ₄ and evaporated. Chromatography on SiO ₂ (eluent EE / HEP 3/1) gives 55 mg of the title compound.

R _f (EE / HEP 3/1) = 0.25; MS (DCI) = 553 (M + H).

The compounds of Examples 54 are synthesized according to the procedure described in Example 40 from the compounds described in Examples 2, 3 and 16 to 27. Compounds of formula (B) are obtained (Table 3).

table

Example MS (FAB, M * + H)

519

554

555

545 Propyl

57 Continuation of Table 3 Example MS (FAB, M ⁺ H) R 45,560 46,561 47,599 48,543 -n- % 49,598 50,598 NO, 51,571 -fe 52,571 53,633 ~ @ H ^CF 3 54,633

Example - ((2'-Allylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl) -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

730 mg (1.69 mmol) of compound lh is heated in 10 ml of allyl isocyanate to 80 ° C. After 4 hours, evaporate and chromatograph over SiO ₂ (EE / HEP 2/1 eluent). 400 mg of the title compound are obtained.

R _f (EE / HEP 2/1) = 0.15; MS (FAB) = 515 (M @ ⁺ + H).

example

Synthesis of 1- (2'-allylaminocarbonylaminosulfonylbiphenyl-4-yl) methyl / -2-n-butyl-4-methylthiimidazole-5-carbonic acid

a) Preparation of 2-amino-2-cyanoacetic acid ethyl ester

To 35 g (0.246 mol) of ethyl 2-cyanoglyoxylic acid ethyl ester 2-oxime in 350 ml of H ₂ O and 280 ml of saturated sodium bicarbonate solution are added 119 g of sodium dithionate in portions at room temperature (15 minutes). After heating for 1 hour to 35 ° C, the solution was saturated with NaCl and extracted 5 times with dichloromethane. The solution is dried over calcium chloride and evaporated. 11.8 g of the title compound are obtained in the form of an oil.

R _f (CH ₂ Cl ₂ / CH ₃ OH 9/1) = 0.6.

b) Preparation of 2-cyano-2-n-butylcarbonylaminoacetic acid ethyl ester

To a solution of 3.6 g (28.09 mmol) of 56a in 50 mL of dry CH ₂ Cl ₂ and 2.3 mL (28.09 mmol) of pyridine is added 3.39 mL of chloride in 5 mL of CH ₂ Cl ₂ . After stirring for 1 hour

At -5 to 0 ° C (28.09 mmol), the valeroyl reaction mixture was stirred at room temperature, the organic layer was washed 3 times with H ₂ O and once with saturated NaCl solution, dried over calcium chloride and evaporated. Recrystallization from DIP gives 1.7 g of the title compound.

R _f (CH ₂ Cl ₂ / CH ₃ OH 9/1) = 0.35; Lt: 87 ° C.

c) Preparation of 3-amino-2-n-butylcarbonylamino-methylthioacrylic acid ethyl ester

To a mixture of 2.9 g (13.67 mmol) of 56b, 0.19 mL (1.36 mmol) of triethylamine and 60 mL of absolute ethanol is added 2 mL (27.26 mmol) of condensed methylmercaptan at room temperature. After 3 days, another 0.5 ml methylmercaptan was added. After a further 24 hours at room temperature, a further 0.5 ml methylmercaptan is injected and

0.19 ml of triethylamine and the reaction mixture were stirred for a further 24 hours at room temperature. After evaporation of the solvent, the residue is crystallized from DIP. 2.4 g of the title compound are obtained.

R _f (CH ₂ Cl ₂ / EE 4/1) = 0.3; Lt: 120 ° C.

d) Preparation of 2-n-butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester

4.17 g (20.0 mmol) of phosphorus pentachloride in 20 mL of CH ₂ Cl _{2 are} added dropwise at -78 ° C to 2.44 g (20.0 mmol) of 4-dimethylaminopyridine in 12 mL of CH ₂ Cl ₂ . The mixture was allowed to warm to room temperature and 30 mL of CH ₂ Cl _{2 was added} . After 2 hours under ice-cooling, 300 ml of 1 N sodium bicarbonate solution are added and stirred for 1 hour. The layers are separated, the aqueous layer is extracted 3 times with EE, and the extract and organic layer are combined and dried over calcium chloride. Chromatography over SiO ₂ (eluent:

CH ₂ Cl ₂ / EE 9 / L).

R _f (CH ₂ Cl ₂ / EE 9/1) = 0.6; MS (DCI) = 243 (M @ ⁺ + H)

e) Preparation of 1 - [(2'-sulfonamidobiphenyl-4 -) - methyl] -2-n-butyl-4-methylthiimidazole-5-carboxylic acid ethyl ester

To 1.35 g (2.5 mmol) of 1 - [(2'-dimethylaminoformylsulfonamido-biphenyl-4-yl) -methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid ethyl ester (obtained from 56d) and le according to the procedure described in Ig) Add 30 ml of methanol to 15 ml. HCl. The mixture was refluxed for 90 minutes, cooled to room temperature and adjusted to pH 5-6 with 2 N NaOH. It is then extracted with 3 x 100 ml of EE, the organic extracts are dried over Na ₇ SO ₄ and the solvent is evaporated.

The desired compound is obtained in the form of a foam which is used in the next step without further purification.

R _f (EE / HEP) 1/1) = 0.2; MS (FAB) = 488 (M @ ⁺ + H).

(f) The title compound of Example 56 is obtained by the following formula:

120 mg of ethyl 1- (2'-allylaminocarbonylaminosulfonyl-biphenyl-4-yl) -methyl--2-n-butyl-4-methylthioimidazole-5-carboxylic acid (prepared according to the procedure described in Example 55) in 10 ml of ethanol and The mixture was stirred at room temperature for 4 days, then evaporated, H ₂ O was added and 1 N HCl was adjusted to pH = 4. After precipitation, the desired compound was filtered off.

R _f (EE / MeOH 101) = 0.1; MS (FAB) = 543 (M @ ⁺ + H).

example

1- / (2 ¹ 2--piridiletil aminokarbonilaminosulfonilbifenil4-yl) -methyl / -2-n-butyl-4-metiltioimidazol 4karboksilinės acid A mixture of

a) Preparation of 1 - [(2'-Ethoxycarbonylaminosulfonylbiphenyl-4-ii) methyl] -2-n-butyl-4-methylthiimidazole-5-carboxylic acid ethyl ester

1.21 g (2.5 mmol) of compound 56e and 0.78 g (5.6 mmol) of potassium carbonate in 20 mL of dry DME are heated to reflux, 0.48 mL (5.1 mmol) of chloroformic acid ethyl are added. of ester and heated for 1 hour. It is then cooled to room temperature and 50 ml of 10% KH ₂ PO ₄ solution are added. The mixture was extracted with EE, dried over Na ₂ SO ₄ and evaporated. Chromatography over SiO ₂ (eluent EE / HEP 2/1) gives 840 mg of the title compound.

R _f (EE / HEP 2/1) = 0.5; MS (DCI) = 559 (M @ ⁺ + H).

b) Preparation of 1- (2'-pyridylethyl-2-aminocarbonylaminosulfonylbiphenyl-4-yl) -methyl--2-n-butyl-4-methylthioimidazole-5-carboxylic acid ethyl ester

168 mg (0.3 mmol) of compound 57a and 37 mg (0.3 mmol) of 2- (2-aminoethyl) pyridine at reflux are plotted over SiO _{2 of the} title compound.

ml of toluene is heated for 2 hours

The chromate is then evaporated off (eluent EE); 34 mg are obtained

R _f (EE) = 0.15; MS (FAB) = 636 (M @ ⁺ + H).

c) The title compound of Example 57 is obtained according to the procedure described in 56 f.

R _f (EE / MeOH 5/1) = 0.1; MS (FAB) = 608 (M @ ⁺ + H).

By the method described in the example, compounds of formula (C) given in Table 4 can be synthesized

(Table O (C)

Pavyz- MS R dys (EAB, M * + H)

R '

571

C ₂ H ₅

-ch ₂ 59

585

599

583

CH ₂

611

668 (CH ₂ )

continuation of the table

Pavyz- MS R dys (EAB, M ++ H)

R '

541 H -CH, -s-H

636 C ₂ H ₅ - (CH ₂ ) ₂

Λ / - ⁷

635 C ₂ H ₅ - (CH ₂ ) ₂

607 H - (CH ₂ ) ₂

659 C, H

2 ⁿ 5

Cn i

(S,

H-ę'C0 ₂ CH ₃

645 C, H

2 „5 ^K ' ^c ' cii ^CH \ ₄₎ » IS) H ' ^C i ^ CO ₂ CH ₅

657 C, H

2 ⁿ 5 hc-co, Ch,

I ¹ v (5)

603 C ₂ H ₅ -CH ₂ -CO ₂ -CH ₃

693 C, H

2 ⁿ 5 Continuation of the tfC-COjCHj table

Pavyz- MS R R 'R *' dys (FAB, Μ »+ Η)

continuation of the table

Pavyz-MS R dys (FAB, M ++ H)

R '

635

- (CH ₂ )

623

651

651

H

C ₂ H c ₂ h

627 c ₂ h

-ch ₂ - ©

611 c ₂ h —ch ₂ -

-CH ₂ -

635 c ₂ h ^CH 2- <0> -ocw,

653

623

H

-CH,

Continuation of Table H

Pavyz- MS R dys (EAB, M ++ H)

R '

639

681

623

611

635

625

561

H -CH ₂ -CO ₂ H

651

607

Continuation of Table C, H

Pavyz-MS R dys (FAB, M ++ H)

100 625 C, H

2 '5

101,597 H

102 579 H

103 677 C, H

2 ⁿ 5

104,649 H

105 573 C ₂ H ₅ - (CH ₂ ) ₂ -CH ₃

106,545 H - (CH ₂ ) ₂ -CH ₃

107,616

H - (CH ₂ ) ₂ -WO V_ /

108 614 H

- (CH ₂ ) ₂

Continuation of Table L

Pavyz- MS R dys (FRB, M ⁺ + H)

R '

109 557 H -CH,

110 585 C ₂ H ₅ -CH ₂

111,642

H - (CH ₂ ) ₂

HA

-O

112,594 H —CH ₂

113 594 H -CH ₂

114 638 C ₂ H ₅ - (CH ₂ ) ₂ _ ^ ⁼⁼⁼ ^

115,594 H

116,628

H - (CH ₂ ) ₃ -A <J

117 628 C ₂ H ₅ -CH ₂

O ^h continuation of the table

Pavyz- MS R dys (FAB, M * + H)

R '

118 628 C ₂ H ₅ - (CH ₂ ) ₂

-d

119,644

C ₂ H ₅ - (CH ₂ ) ₂ _ / 7 q H k- /

120 600 H - (CH ₂ )

O ^h

121 642 C ₂ H ₅ - (CH ₂ ) ₂

122 614 H

123 651 C, H

2 ⁿ 5

124 623 H

125 623 H

126 661 C ₂ H ₂ n ₅

A /

CH>

(ch ₂ ) ₂ -ΖΛ fru ^ch ^ oh ^h

C $) TT

CM ^Z CH ^ _OW

^k 0H

CH.iO CH = CH _Z H ^X CH ^Z i

continuation of the table

Pavyz- MS R dys (EftB, M ⁺ + H)

R '

127,633

CH ^Z i

128,665

C, H

2 ⁿ 5 ^c i <VCH _z OH

129,637

CH i

130,600

- (CH ₂ ) ₂

- * o

131,642

C, H

2 ⁿ 5

- (CH ₂ ) ₂ -W

132,665

C, H

2 ⁿ 5

- (CH ₂ ) ₂ KO Λ Orte

133,637

- (ch ₂ ) ₂

134,667

C ₂ H ₅

135,639

-ch ₂

-ch ₂ -Gi Continuation of Table ¹

Pavyz-MS R dys (FAB, M ++ H)

R '

136 664 C ₂ H ₅ -CH ₂ H

137 636 H -CH ₂ H

The compounds of Table 5 can be synthesized according to the procedure described in Example 5 57.

These compounds have the formula (D)

table

An example MS, FAB, M ⁺ + H R R 138 581 c ₂ h ₅ -G 139 553 H CI 140 601 c ₂ h ₅ -Λ / 0 v? 141 585 c ₂ h ₅ -O 142 557 H - »□ 143 573 H -N 0 144 617 C ₂ H ₅ / - \ -N S v_y 145 603 c ₂ h ₅ / X - / V S 146 714 c ₂ h ₅ / - \, h -H-N-C-O \ --T U 0 147 589 H 148 689 H - / v ~ y «-c-o ϋ 149 575 H V /

Example 150 1- {[(2'-Benzoyloxycarbonylaminosulfonyl) -biphenyl-4yl] -methyl} -2-n-butyl-4-chloroimidazole-5-carbaldehyde

This compound is obtained by stirring a mixture of 71.3 μΐ (0.5 mmol) of the ester and 70 mg (anhydrous) of the solvent for 1.5 hours in 100 ml of EE, solution and 40 ml of NaCl solution by refluxing 215 mg (0.5 mmol) of compound lh, chloroformic acid benzyl (0.5 mmol) in K ₂ CO _{3 in} 10 mL of DMF was then evaporated, washed with 40 mL of NaHSO ₄ organic layer dried over Na ₂ SO ₄ and evaporated the solvent on a rotary evaporator. Chromatography on (MTB eluent) afforded 120 mg (42%) of the title compound.

Lt: 56 ° C; R _f (MTC) = 0.20; MS (FAB) = 566 (M ⁺ + H).

The compounds of Table II can be synthesized according to the procedures described in Examples 150 or 57a.

The following compounds have the formula (E):

table

Pavyz- dys MS FAB, M ⁺ + H R R ' R '' 151 674 -OC ₂ H ₅ -CH ₂ -CH-Ph -SMe 152 646 -OH -CH ₂ -CH ₂ -Ph -SMe 153 558 -OH -CH ₂ -CH ₂ -CH = CH ₂ -SMe 154 556 -OH -CH ₂ -CH ₂ -C = CH -SMe 155 558 -OH -ch ₂ - <] -SMe 156 618 -OC ₂ H ₅ -CH ₂ -CH ₂ -Oi-Pr -SMe 157 590 -OH -CH ₂ -CH ₂ -Oi-Pr -SMe 158 666 -OC ₂ H ₅ -CH ₂ -CH ₂ -O-CH ₂ -Ph -SMe 159 628 -oc ₂ h ₅ -ch ₂ -SMe

160 600 -O H -ch ₂ - </ -SMe 161 648 -OC ₂ H ₅ -CH ₂ -CH = CH-Ph -SMe 162 620 -OH -CH ₂ -CH = CH-Ph -SMe 163 628 -OC ₂ H ₅ -ch ₂ -z y. -SMe

continuation of the table

Pavyz- dys MS EAB, M * + H R R ' R '' 164 600 -OH ^CH2 <> -SMe 165 572 -OH -CH ₂ -CH = C (CH ₃ ) ₂ -SMe 166 558 -OH -ch ₂ -c (CH ₃ ) = ch ₂ -SMe 167 572 -OH -ch ₂ -ch ₂ -ch ₂ -ch = ch ₂ -SMe 168 598 -OH - ^ch * XD -SMe 169 556 -OH -ch ₂ -c = c-ch ₃ -SMe 170 560 -OC ₂ H ₅ -ch ₂ -ch ₃ -SMe 171 532 -O H -ch ₂ -ch ₃ -SMe 172 638 -OH -CH ₂ -CH ₂ -O-CH ₂ -Ph -SMe 173 600 -OH -ch ₂ -0 -SMe 174 584 -OC ₂ H ₅ -ch ₃ -SMe 175 556 -OH -ch ₃ -SMe 176 611 -H ^CH2 ^ —C1 177 612 -H - _C K ₂ - © - "o * -C1

Example 178 - / ⁽¹ -dimetilsulfamoilaminosulfonil 2-biphenyl-4-yl) methyl / -2-n-butyl-4-methylthio-imidazo1-5-carboxylic acid ethyl ester

This compound is obtained by refluxing

244 mg (0.5 mmol) of compound 56e, 108 μΐ (1.0 mmol) of sulfamoyl chloride and 140 mg (1.0 mmol) of K ₂ CO _{3 in} 10 mL of DMF (anhydrous) for 5 days. The reaction mixture was then diluted with 50 mL EE, washed with 50 mL KHSO ₄ / H ₂ SO ₄ (pH = 1.0), the organic layer dried over Na ₂ SO ₄ and the solvent evaporated on a rotary evaporator.

Chromatography (eluent EE) afforded 69 mg (23%) of a colorless oil.

R _f (EE) = 0.15; MS (FAB) = 617 (M @ ⁺ + H).

Example 179

Synthesis of 1- [1- (2'-Dimethylsulfamoylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthiimidazole-5-carboxylic acid

mg (84 μΜ) of the compound of Example 178 and 0.84 mL of 1 N NaOH are dissolved in 3 mL of ethanol and stirred for 2 days at room temperature. The ethanol is evaporated and the pH adjusted to 2 with HCl. The precipitate is washed

2 x 1 mL water and vacuum dried. 33 mg (70%) of a colorless powder are obtained.

R _f (EE / methanol 5/1) = 0.11; MS (FAB) = 567 (M @ ⁺ + H).

Example 180

Synthesis of 1 - [(2'-Allyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthiimidazole-5-carboxylic acid ethyl ester

244 mg (0.5 mmol) of compound 56e, 106 μΐ (1.0 mmol) of K ₂ CO _{3 in} chloroformic acid (1.0 mmol) are heated under reflux for one hour with 140 mg of ester. 50 ml of 10% KHSO ₄ solution are then added and the extract is dried x 50 ml of Na ₂ SO ₄ and

EE. The organic layer is evaporated off the solvent.

Chromatography on (MTB / DIP 1/1 eluent) gives 115 mg (40%) of a colorless oil.

R _f (MTB / DIP 1/1) = 0.15; MS (FAB) = 572 (M + H) @ +.

Example 181

Synthesis of 1 - [(2'-allyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid mg (0.17 mmol) of compound 180 is saponified according to the procedure described in Example 179. 30 mg (33%) of a colorless foam are obtained.

R _f (EE / MeOH 10/1) = 0.1; MS (FAB) = 544 (M ^+).

Example 182

Synthesis of ethyl 1- (2'-benzyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl / -2-n-butyl-4-methylthioimidazole-5-carboxylic acid

This compound is prepared according to the procedure described in Example 180.

R _f (MTB / DIP 1/1) = 0.15; MS (FAB) = 622 (M @ ⁺ + H).

Example 183

Synthesis of 1- (2'-benzyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl / -2-n-butyl-4-methylthioimidazole-5-carboxylic acid

This compound is prepared according to the procedure described in Example 181.

R _f (EE / MeOH 10/1) = 0.1; MS (FAB) = 594 (M @ ⁺ + H).

Example 184

Synthesis of 1- (2 * -alylaminocarbonylaminosulfonyl) -biphenyl-4-yl / methyl-2-n-butyl-4-methoxyimidazole-5-carbaldehyde

a) Preparation of 1- (2'-sulfonamidobiphenyl-4-yl) methyl / -2-n-butyl-4-methoxyimidazole-5-carbaldehyde

215 mg (0.5 mmol) of compound lh and 1.5 mL of 1N NaOH were refluxed for 19 hours. The methanol is then evaporated in a rotary evaporator, the pH is adjusted to 2 with NaHSO ₄ solution and extracted with 3 x 50 ml.

EE. The organic layer is dried Well _? The solvent is evaporated off with SO ₄ and a rotary evaporator. Chromatography (MTB / DIP 1/1 eluent) afforded 170 mg (80%) of the title compound.

Mp: 189 ° C; R _f (MTB / DIP 1/1) = 0.19; MS (DCI) =

426 (M ⁺ + H)

b) The compound of Example 184 is obtained by refluxing 150 mg (0.33 mmol) of 184a and 3 ml of allyl isocyanate for 5 hours. It is then evaporated on a rotary evaporator and chromatographed (eluent EE). 60 mg (34%) of a colorless foam are obtained.

R _f (EE) = 0.34; MS (FAB) = 511 (M ⁺ + H).

Example 185

Synthesis of 1- (2-ethoxycarbonylaminosulfonyl) -biphenyl-4-yl / methyl-2-n-butyl-4-methoxyimidazole-5-carbaldehyde

lt

Dissolve 1.0 g (2.34 mmol) of 184a in 50 ml of anhydrous acetone, add 650 mg of K ₂ CO ₃ , bring to boiling and slowly add 0.45 ml of chloroformic acid ethyl ester at this temperature. The mixture is refluxed for 4 hours, then evaporated on a rotary evaporator. The solution is acidified to pH = 2 with NaHSO ₄ solution, extracted with 3 x 100 ml EE, dried over Na ₂ SO ₄ , evaporated on a rotary evaporator and chromatographed (MTB / DIP / HOAc 15/83/2 eluent). Recrystallization of the resulting oil from ethyl ether gives 550 mg of colorless crystals.

Mp: 134 ° C; R _f (MTB) = 0.24; MS (FAB) = 500 (M ⁺ + H).

Example 186

Synthesis of 1- (2-benzyloxycarbonylaminosulfonyl) -biphenyl-4-yl / methyl-2-n-butyl-4-methoxyimidazole-5-carbaldehyde

This compound is synthesized according to the procedure described in Example 185.

R _f (MTB) = 0.16; MS (FAB) = 562 (M ⁺ + H).

Example 187

Synthesis of ethyl 1 - {[(2'-benzylaminocarbonylaminosulfonyl) -biphenyl-4-yl] -methyl} -2-n-butylimidazole-5-carboxylic acid

A catalytic amount of 150 mg (0.24 mmol) of compound 73 dissolved in 50 mL of MeOH and 5 mL of HOAs was added under stirring at room temperature in a PD / C and H ₂ atmosphere for 12 hours. It is then evaporated on a rotary evaporator and chromatographed (eluent EE). 30 mg (22%) of a colorless foam are obtained.

R _f (EE) = 0.42; MS (FAB) = 575 (M @ ⁺ + H).

Example 188 l- {/ (2 ¹ -etoksikarbonilaminosulfonil) -biphenyl-4-yl / methyl} -2-n-butyl-imidazol-5-carboxylic acid ethyl ester

0 £ t

To 300 mg (0.5 mmol) of compound 57a dissolved in 10 ml of ethanol is added about 200 mg of Renew nickel, refluxed for 10 hours, another 200 mg of Renew nickel added and refluxed for 5 hours.

The catalyst is filtered off and the solvent is evaporated off on a rotary evaporator. The residue is chromatographed (MTB eluent) to give 50 mg (18%) of a colorless foam.

R _f (EE) = 0.27; MS (FAB) = 514 (M ⁺ + H).

Example 189 l- {/ (2 ¹ - (2-tienilsulfonilaminosulfonil) -biphenyl-4-yl) methyl} -2-n-butyl-4-metiltioimidazol-5-carboxylic acid ethyl ester

244 mg (0.5 mmol) of sulfonamide 56a are dissolved in 10 ml of diethylene glycol dimethyl ether (anhydrous)

345 mg (2.5 mmol) of K ₂ CO ₃ and 81 mg (0.5 mmol) of 2-thienylsulfonyl chloride were refluxed for 2 hours. The reaction mixture was cooled, poured into 50 mL of 5% NaHSO ₄ solution and extracted with 3 x 50 mL EE. The extract was dried over Na ₂ SO ₄ , evaporated in a rotary evaporator and chromatographed (eluent EE). 310 mg of slightly yellow crystals are obtained.

L. t. Mp: 120-122 ° C; R _f (EE) = 0.24; MS (FAB) = 634 (M @ ⁺ + H).

Example 190

Synthesis of 1- {2 '- (2-thienylsulfonylaminosulfonyl) -biphenyl-4-yl / methyl} -2-n-butyl-4-methylthio-imidazole-5-carboxylic acid

Saponification of Compound 189 according to the procedure described in Example 56f affords this compound.

R _f (EE / MeOH 5/1) = 0.13; MS (FAB) = 606 (M ⁺ + H).

The compounds of Table I can be synthesized according to the procedures described in Examples 189 or 190 (or 56f).

O

Table (F)

An example MS FAB, M ⁺ + H R R ' 191 673 C ₂ H ₅ 4-nitrophenyl 192 645 H 4-nitrophenyl 193 579 c ₂ h ₅ C ₂ H ₅ 194 634 c _? h ₅ 2-thienyl

195 Example

1- / (2 ¹ -metilaminokarbonilaminosulfonil-biphenyl-4-yl) methyl / -2-n-butyl-4-methylthio-imidazol-5-carboxylic acid ethyl ester

In an autoclave containing 1 g of sulfonylcarbamate 57a in 50 ml of toluene was added methylamine for 5 minutes at 80 ° C, followed by heating at 80 ° C for 8 hours. The reaction mixture is evaporated in vacuo and the residue is chromatographed on silica gel (eluent EE / HEP 2/1). The title compound is obtained in the form of an amorphous powder.

R _f (EE / HEP 2/1) = 0.1; MS (FAB) = 545 (M @ ⁺ + H).

The compounds of Table 8 may be synthesized according to the procedure described in Examples 195 or 56f (also the compound described in Example 195).

The following compounds have the formula (C):

table

An example MS FAB, M ⁺ + H R R ' 195 545 -c ₂ h ₅ -ch ₃ 196 517 H -ch ₃ 197 559 -C ₂ H ₅ -c ₂ h ₅ 198 531 H -c ₂ h ₅ 199 ^x 619 -c ₂ h ₅ -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -OH 200 ^x 591 H -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -OH ^x Compounds are synthesized according to 57

methodology.

Claims (11)

DEFINITION OF INVENTION 1. hydrogen, 1. (C _x -C ₄ ) alkyl, 2. _(Cg-C12) -aryl, 3. (C _r -C ₃₎ -alkanoiloksigrupė, 4. (C 1 -C 4) -alkoxy. 5. (C ₁ -C ₉ ) -heteroaryl, preferably 5-tetrazolyl, 6th cyano group, 7th nitro group, 8th hydroxyl, 9th -S (O) _r R ⁶ , 10th -so ₃ r ³ , 11th chlorine, 12th bromine, 13th benzoyl, 14th -COR ³ , 15th -CO-NH-R ⁶ , 16th -CO-R ⁸ , 17th -so _? -NR ⁶ R ^7, 114 18. -so ₂ -nh-co-nr ⁶ r \ 19. -PO ₃ H, 20. -CO-CHR ⁵ -CO ₂ H, 21. -NH-CO-NH-SO-CH ₂ R ⁵ , 22. 5-Tetrazolyl-NH-CO-, -SO ₂ -NH-bO% The residue described in point 28 (h) (2) having the substituent described above, 29. R ¹⁵ together with R ¹⁴ is -CO-NH-SO ₂ -, 30. -SO ₂ -NH-COO-R, 31. -SO ₂ -NH-SO ₂ -NR ⁶ R ⁹ ' 32. -SO ₂ -NH-SO ₂ -R ⁶ ; 115 i 18 i) R is hydrogen, methyl or ethyl; j) T is a single bond, -O-, -CO-, -NHCO- or -OCH ₂ -; k) q = O and Z are methylene and the other residues and variables are the same as in claim 1 and also the physiologically acceptable salts of these compounds. 1. hydrogen, 1. chlorine, 2. bromine, 3. ^c v ^F 2v + i where v = 1, 2 or 3, 4. pentafluorophenyl, 5. OR ⁶ , 6th -S (O) _r R ¹⁹ , 7th - (CH3 ^ -CHR'-OR ⁵ , 8th - (CH _{2) o} -0-C0-R ^3, 9th -COR ⁸ , 10th - (CH ₂ ) o-co-r®, 11th -ch ₂ -nh-co-r ⁸ , 12th - (CH _{2) o} -NH-SO ₂ -R ^9, 13th -ch = ch-chr ³ -or ⁶ , 14th tetrazolil- _{(CH?) m} -, 15th - (CH ₂ ) _n -SO ₂ -NH-CO-NR ⁶ R ⁹ , 16th - (CH ₂ ) _o -SO ₃ R ⁹ or 110 is optionally substituted with hydroxy (C _x -C ₆ ) alkyl, preferably hydroxymethyl; c) R ³ is hydrogen, (C _x -C ₄ ) alkyl or benzyl; d) R ⁶ , R ^{8 9} are the same or different and are 1. single connection, 108 1. hydrogen, 1. (C ₂ -C ₁₀ ) alkyl, NR ² ° R ²¹ , is or or a urea group 104 1. single connector, 1. (Cy-C ₆ ) alkyl, 1. halogen, 2. nitroso group, 3. nitro group 4. amino group, 5. cyano group, 6th hydroxyl, 7th (C _x -C ₆ ) alkyl, 8th (C _x -C ₄ ) alkanoyl, 9th A (C ₁ -C ₄ ) alkanoyloxy group, 10th • co ₂ r ³ , 11th methanesulfonylamino, 12th trifluoromethanesulfonylamino, 13th -CO-NH-OR ⁹ , 14th -so ₂ -no ⁶ r ⁷ , 15th -ch ₂ -or ⁷ , 16th (C 8 -C 8) -heteroaryl- (CH ₂ ) _q zolyl, 17th (C 1 -C ₁₃ ) -aryl, 18th / - \ -CH ₂ ~ _, Q, 19th - (CH ₂ C) _o ~ N ^ or 20th (C ₆ -C ₁₂ ) -aryl; R ¹⁵ is 1. hydrogen 2. (C 1 -C 8) alkyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 4. (C ₆ -C ₁₂ ) -aryl, 5. (C ₇ -C ₁₃ ) -aryl, 6th (C _x -C ₄ ) alkoxyl, 7th (C _y -C) -alkanoyloxy 8th (C ₃ -C ₈ ) -heteroaryl, 9th co ₂ r ³ , 10th halogen, best 1-tetraLT 3373 B 11th cyano group, 12th nitro group, 13th NR ⁶ R ⁷ , 14th hydroxyl, 15th -CO-NH-CHR ⁵ -CO ₂ R ³ , 16th sulfa group, 17th -so ₃ r \ 18th -SO ₂ -NR ⁷ -CO-NR ⁶ R ⁹ or -SO ₂ -NH ₇ -cs-nr ⁶ r 19th ^-7 # -co-# ⁶ -so ₂ -ch ₂ -r ⁵ , 20th -C (CF ₃ ) ₂ oh, 21st phosphonooxy group, 22nd -PO ₃ H ₂ , 23rd -NH-PO (OH) ₂ , 24th -S (O) _r R ⁶ , 25th -CO-R ⁸ , 26th -conr ⁶ r ⁹ , 27th -CR ²⁰ (OH) -PO (OH) ₂ , 28th (c) (20) remains 100 29. -SO ₂ -NH-®5®, ^X E ⁸ 32. 5-Tetrazolyl-NH-CO-, 33. -CO-NH-NH-SO ₂ CF ₃ , N - N 40. -CO-NH-SO ₂ R ¹⁹ , 101 41. -SO ₂ -NH-CO-R ⁶ or The residue of item 42 (p) (4) having 1 or 2 substituents, the same or different, selected from the group consisting of halogen, cyano, nitro, NR ⁶ R ⁷ and hydroxyl, 43. R ¹⁵ together with R ¹⁴ is -CO-NH-SO ₂ -, 44. -SO ₂ -NH-CO-OR ⁶ , 45. -SO ₂ -NH-SO ₂ -NR ⁶ R ⁹ , 46. -SO ₂ -NH-SO ₂ -R ⁶ ; q) B is O, NR ⁷ or S; r) W is O or S; s) Z is (C 1 -C 4) -alkanediyl; v) R ¹⁶ is CH 2 CO 2 R ³ or _two R ^3; u) R ¹⁷ is hydrogen, halogen, (C _x -C ₄₎ -alkyl or (C _l -C _4)-alkoxy; 1Θ v) R is hydrogen, (C 1 -C 1) alkyl or phenyl; w) R is 1. hydrogen, 1. hydrogen, 1. hydrogen, 1. hydrogen, 1. hydrogen, 1. hydrogen, 1. hydrogen, 1, 2, 3. all of which are substituted with fluorine or the hydrogens described in Part 9, from 1 to, or The substituent described in 13 (b) (10) having 1 or 2 identical or different substituents on the phenyl ring and being halogen, (C 1 -C 6) alkoxy or nitro, c) R ² is present As described in Parts 1, 2, 3 or 9 containing one CO _Z R ³ group, alternatives to b), 1. (C ₂ -C ₁₀ ) alkyl, 1. Azole derivatives of formula (I) (o) <f A wherein the symbols have the following meanings: (a) X, Y and Z are the same or different and are N or CR ² , b) R ¹ is 2. (Cy-C ₆ ) -alkyl, which may have 1-3 residues, such as (Cy-C ₆ ) -alkoxyl, which in turn may have 1-3 residues, such as hydroxyl, (Cy-C 6). ₆ ) -alkoxy, amino, mono- (Cy-C ₆ ) -alkylamino, di (C ₁ -C ₆ ) -alkylamino, (C ₂ -C ₁₀ ) -alkenyl, hydroxyl, amino, mono- (Cy-C ₆₎ ) -alkylamino, di- (Cy-C ₆ ) -alkylamino, (Cy-C ₆ ) alkoxycarbonylamino, (C ₆ -C ₁₂ ) -aryl- (C _x -C ₄ ) alkoxycarbonylamino; (C ₆ -C ₁₀ ) -aryl, (C ₆ -C ₁₀ ) -aryl- (Cy-C ₃ ) -alkyl, (Cy-C ₉ ) -heteroaryl, carboxyl and (Cy-C ₄ ) -alkoxycarbonyl, 2. (C ₁ -C ₆ ) -alkyl which may have from 1 to 3 substituents on the (C _x -C ₆ ) -alkoxyl group, which in turn may have from 1 to 3 residues such as hydroxyl, (C _x -C ₆ ) -alkoxyl, amino, mono- (C _x -C ₆ ) -alkylamino, di (C _x -C ₆ ) -alkylamino, (C ₂ -C ₁₀ ) -alkenyl, hydroxy, amino, mono- (C) _x -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, (C _x -C ₆ ) alkoxycarbonylamino, (C ₆ -C ₁₂ ) -aryl- (C _x -C ₄ ) alkoxycarbonylamino, (C) C ₆ -C ₁₀ ) -aryl, (C ₆ -C _X0 ) -aryl- (C _x -C ₃ ) -alkyl, (C _x -C ₉ ) -heteroaryl, carboxyl and (C _x -C ₄ ) -alkoxycarbonyl; 2. -CO-, 2. halogen, 2. (C ₃ -C 10 _Q ) -alkenyl, Azole derivatives of formula (I) according to claim 1 wherein: 105 a) X is N, Y is CR ² and Z is CR ² , b) X is CR ² , Y is N and Z is CR ² , c) X is CR ² , Y is CR ² and Z is N or d) X, Y: and Z is N and their physiologically acceptable salts. 2. -CO-, 2. (C ₃ -C _e) cycloalkyl, phenyl, 102 2. (C ₁ -C ₆ ) alkyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 4. phenyl (CH ₂ ) _q -, 5. OR ⁶ , 6th NR ^1X R ¹² , or 7th / ^CH 2> q -ND; \ _ / j) R ¹⁰ is cyano, nitro or CO ₂ R ⁷ ; k) R ¹¹ and R ¹² are the same or different and are 1. hydrogen, 2. (C 1 -C 6) alkyl, 3. phenyl, 4. benzyl or 5. α-methylbenzyl; l) D is NR ¹³ , O or CH ₂ ; m) R ¹³ is hydrogen, (C 1 -C ₄ ) alkyl or phenyl; n) A is a biphenyl residue which may be substituted up to 4, preferably up to 2 identical or different R ¹⁴ or R ¹⁵ residues, where A is necessarily substituted at least by the residue described in paragraph 44 or 45 of p); o) R ¹⁴ is present 2. (C _x -C ₆ ) alkyl, 2. (C 1 -C 8) -alkyl which may be substituted with 1 to 3 residues of the (C 1 -C 8) -alkoxyl group which in turn may have 1 to 3 residues such as hydroxyl, (C 1 -C 8) -alkoxy, amino, mono- (C ₁ -C ₆ ) -alkylamino, di (C ₁ -C ₆ ) -alkylamino; (C ₂ -C ₁₀₎ -alkenyl, hydroxyl, amino, (C₁-C₆) -alkoksikarbonilaminogrupė (C ₆ -C ₁₂₎ -aryl- (C ₁ -C ₄₎ -alkoksikarbonilaminogrupė (C ₆ -C ₁₀₎ -aryl, (C ₆ -C ₁₀₎ E 3373 B aryl- (C _x -C ₃₎ -alkyl, (C _r -C ₉₎ -heteroaryl, carboxyl and (C _x -C ₄₎ alkoxycarbonyl; 2. (C 1 -C 8) alkyl, 2. (C ₁ -C ₆ ) alkyl, 2. (C 1 -C 8) alkyl, 2. halogen, 2. (C ₃ -C ₁₀ ) - alkenyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 3. (C ₃ -C ₆ ) -cycloalkyl, 3. -CONR ²¹ -, 3. nitro group, 3. (C ₃ -C ₁₀ ) -alkynyl, Azole derivatives of formula (I) according to claim 1, wherein the symbols have the following meanings: X is N, Y is CR ² , Z is CR ² ; X is CR ² , Y is N, Z is CR ² ; X is CR ² , Y is CR, Z is N or X, Y and Z are N; (a) R ¹ is present 3. thiourea group, 3. -CH ₂ -, 3. (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl, the cycloalkyl moiety of which may also have 1-3 moieties, such as (C _x -C ₄ ) -alkyl and (C ₂ -C ₄ ) -alkenyl; 3. (C ₃ -C ₈ ) -cycloalkyl, 3. (C ₃ -C ₈ ) -cycloalkyl, 3. (C ₃ -Cg) - how many 1 o 1 1 i 1, 3. nitro group, 3. (C ₃ -C ₁₀ ) -alkynyl, 4. (C ₃ -C ₆ ) -cycloalkyl- (Cy-C ₃ ) -alkyl, 4. (C ₃ -C ₆ ) -cycloalkyl- (C _x -C ₃ ) -alkyl, Azole derivatives of the general formula (I) according to claim 1, wherein the symbols have the following meanings: X for N, Y for CR ² and Z for CR ² , X for CR ² , Y for N and Z for CR ² , X is CR ² , Y is CR ² and ZN or X, Y and Z are n; 109 a) R ¹ is (C ₂ -C ₇ ) -alkyl, (C ₃ -C ₇ ) -alkenyl or (C ₃ -C ₇ ) -alkynyl; b) R ² is present 4. -CH ₂ -CH ₂ -, 4. C _v F _{2v + 3} , 4. (C ₃ -C ₈ ) -cycloalkyl, 4. a toluene-4-sulfonyl group or 4. -0-, 4. benzyl or 4 (C ₆ -C _X2) -aryl- (C _x -C ₆₎ alkyl, preferably benzyl, 4. (C ₃ -C ₈ ) -cycloalkyl- (C ₁ -C ₃ ) -alkyl, 4. phenyl or 4. (C ₂ -C ₄ ) -alkenyl or 4. phenyl, 4. C _v F _{2v +} i, 4. -OR ³ , 5. (Cg-Cy ₂ ) -aryl, preferably phenyl, Azole derivatives of the general formula (I) according to claim 1 wherein Z is nitrogen and Y and X are independently CR ² and the remaining symbols have the meanings described in claim 1 and the physiologically acceptable salts thereof. 5. phenyl, 5. -NR ²¹ -CO-, 5. pentafluorophenyl, 5. benzyl or 5; 5; 5. benzenesulfonylamino group; b ') R ²⁴ and R ²⁵ are the same or different and are (C 1 -C ₄ ) alkyl or both are - (CH ₂ ) _q -; C ') Q. is CH ₂ , NH, d ') m is hello e ') n is hello f ') o is hello g ') q is 0 or ' h ') r is 1 or: i ') v is hello and their physiological formula L O or S; number from O to number 1 to number 1 to r and a number between 1 and. suitable salts, 5. -S-, Hydrogen, as described in point 5 (w) (1), from 1 to all, x) T is 5. phenyl or 5. (C ₆ -C _{X 2} ) -aryl, preferably phenyl, 5. benzyl; g) R ⁶ , R ⁹ - the same or different and are 5. (C ₂ -C ₄ ) -alkynyl; f) R ⁵ is 5. benzyl or 5. pentafluorophenyl, 5. (C ₃ -C ₈ ) -cycloalkyl, 6. (C ₆ -C ₁₀ ) -aryl- (Cy-C ₄ ) -alkyl, Compounds of general formula (I) according to claim 1, wherein the symbols have the following meanings: Z is nitrogen, X, Y independently of one another are CR ^{2 *} , R ¹ is (C ₂ -C ₇ ) -alkyl, (C ₃ -C ₇ ) -alkenyl or (C ₃ -C ₇ ) -alkynyl, R is hydrogen, halogen, nitro, (C ₁ -C ₃ ) perfluoroalkyl, cyano, (Cx-C ₁₀ ) -alkyl, (C ₃ -C ₁₀ ) -alkenyl, -CH ₂ OR ⁵ , -S (O) _r -R ¹⁹ , -CO-R ⁸ or -OR ^{6 *} , R ⁵ is hydrogen or (0 _: -0 ₆ ) -alkyl, 116 R ⁶ , R ⁹ are present 6. phenyl (C _x -C ₃ ) alkyl, 6. -O-CH ₂ -, 6. cyano group, 6. benzyl, substituted; which has the one described in item 1 106 b) R ² is present 6, excluding compound, (L) 6. -NR ²¹ -, 6. (C _x -C ₉ ) -heteroaryl; »N8 and it is 6 (C ₆ -C _X0) -aryl- (C _x -C ₄₎ -alkyl, The substituent described in point 6 (d) (2) substituted with fluorine from 1 to all hydrogen, e) R ⁴ is present 6. cyano group, 6. (C ₄ -C ₁₀ ) -cycloalkylalkyl, 7. A process for the preparation of azole derivatives of the general formula (I) according to one of claims 1 to 6 and its physiologically acceptable salts, characterized in that the compounds of the formula (II) (ii) wherein R ¹ , X, Y and Z has the meanings described in claim 1, alkylating with compounds of formula (III) UZ- (O) _q -A, (III) wherein Z, A and q have the meanings described in I, and U is a leaving group, then optionally releasing the protecting groups introduced and the resulting 119 The sulfonamides of formula (I) are converted into the urethanes of formula (I) and the resulting sulfonamides of formula (I) and the resulting urethanes of formula (I) into the sulfonylureas and, where appropriate, converting the compounds of formula (I) obtained into their physiologically acceptable salts. 7. (C y-C g) - he t θ r o a r i 1 a s, which may be partially or fully hydrogenated, 7. (C _x -C ₇ ) -heteroaryl, which may be partially or fully hydrogenated, 7. -CH ₂ -O-, 7. -OR ⁶ , 7. -CO-NR ²¹ -, 7. (C _x -C ₉ ) -heteroaryl which may be partially or fully hydrogenated 7. -OR ⁶ , 7. (C ₅ -C ₁₀ ) -cycloalkylalkenyl, Compounds according to one of claims 1 to 6 for use in therapy. 8 (Cy-Cg) -heteroaryl- (Cy-C ₃₎ -alkyl, wherein the heteroaryl portion may be partially or completely hydrogenated, The residue described in paragraph 8 (g) (5), (6), (7) or (9), (14) to (16) and (18) having 1 or 2 identical or different substituents such as 111 halogen, hydroxy, (C _l -C ₄₎ alkyl, methoxy, nitro, cyano, CO ₂ R, trifluoromethyl, -NR ¹² R and ^ \> \ CHX 8. -S-CH ₂ -, 8. phenyl, 8. -NR ²¹ -CO-, 8th (g) the substituent described in paragraphs 5, 6, 7, 9, 15, 16, 17, 19, 20 or 21, wherein one or two of the same or different substituents are halogen, hydroxyl, C _x -C ₄₎ alkyl, methoxy, nitro, cyano, CO ₂ R ^3, Trif luormetilas, -NR ¹² R and ^ri -N o. 8. phenyl, 8. (C ₅ -C ₁₀ ) -cycloalkylalkinyl, Compounds according to one of claims 1 to 6 for use as a medicament for the treatment of hypertension. 9. a residue as described in points 5, 6, 7 and 8 above, having one or two identical or different substituents, such as halogen, (Cy-C ₄ ) -alkyl, hydroxy, methoxy; 117 nitro group, cyano group, CO ₂ R ³ , trifluoromethyl, NR ⁿ R ¹² and Sch ₂ ) ^ ' 9. (C ₁ -C ₈ ) -heteroaryl- (C ₁ -C ₃ ) -alkyl in which the heteroaryl moiety may be partially or fully hydrogenated, 9. -CH ₂ -S-, 9. phenyl (C ₁ -C ₃ ) alkyl, 9. -O-CH ₂ -, 9th (C _x -C ₉ ) -heteroaryl-alkyl, in which the heteroaryl moiety may be partially or fully hydrogenated, 9. phenyl- _(Ο χ -Ο ₃₎ -alkyl, 9. - (CH ₂ ) _m -B- (CH ₂ ) _n -R ⁴ , 10. A pharmaceutical dosage form based on the active ingredient and additives, characterized in that the active ingredient uses a compound according to any one of claims 1 to 6. 10. (C 1 -C 8) -alkyl whose hydrogens are 1 to all substituted with fluorine; 11. (C ₂ -C ₆ ) -alkenyl or (C ₃ -C ₆ ) -alkenoyl, 12. (C ₃ -C ₈ ) -cycloalkenyl, 13th (C ₃ -C ₈ ) -cycloalkenyl- (C ₁ -C ₃ ) -alkyl, 14th (C ₆ -C ₁₀₎ -aryl- (C _l -C ₄₎ -alkyl, 15th (C ₆ -C ₁₀ ) -aryl- (C ₃ -C ₆ ) -alkenyl, 16th (C 1 -C ₉ ) hetaryl - (C ₃ -C ₆ ) alkenyl, 17. (C ₃ -C ₆ ) alkynyl, 18th (C ₆ -C ₁₀ ) -aryl- (C ₃ -C ₆ ) -alkynyl, 19th (C ₁ -C ₆ ) -heteryl- (C ₃ -C ₆ ) -alkynyl, 20. R ⁶ and R ^9, along with their N-atom, form a heteroaryl, which may be partially or completely hydrogenated, R ⁷ is hydrogen, 0 6 R is hydrogen or -OR, 11 12 R, R independently of one another are hydrogen or (C _x -C ₄ ) alkyl; D is -NR ¹³ , -O- or -CH ₂ -; 118 R ¹³ is hydrogen or (C 1 -C 4 alkyl; A is a biphenyl residue substituted with R ¹⁵ or R ¹⁴ and R ¹⁵ taken together as a substituent; R ¹⁵ is -SO 2 -NR ⁷ -CO-NR ⁶ R ⁹ , -SO 2 -NH-COO-R ⁶ , -SO 2 -NH-SO 2 -NR ⁶ R ⁹ , -SO 2 -NH-CO-R ⁶ or -SO _2- NH-SO ₂ -R ⁶ ; or R ¹⁴ and R ¹⁵ together are -CO-NH-SO ₂ -; Z is -CH ₂ -; q is O and r is O or 2 and the physiologically acceptable salts of these compounds. 10. (C 1 -C 8) -alkyl in which the hydrogens, 1 to all, are replaced by fluorine; 11. (C ₂ -C ₄ ) -alkenyl or (C ₃ ) -alkenoyl, 12. (C ₃ -C ₆ ) -cycloalkenyl, 13th (C ₃ -C ₅₎ cycloalkenyl- ₍₃ Ο -Ο ₃₎ -alkyl, 14. bi- or tricyclic (C ₄ -C ₁₀ ) -cycloalkenyl (C ₁ -C ₄ ) -alkyl, which may be substituted with 1 to 3 (C ₁ -C ₄ ) -alkyl, 15. Cg aryl- (C ₁ -C _j) -alkyl, 16. C ₈ -aryl- (C ₃ ) -alkenyl, 17th (C ₁ -C ₈ ) -heteryl- (C ₃ ) -alkenyl, 18. C ₃ alkynyl, 19. Cg aryl- (C ₃₎ -alkynyl, 20th _(C-C₈) -hetaril- (C ₃₎ -alkynyl, 21. R ⁶ , R ⁹ together with the N-atom which they contain form a heteroaryl which may be partially or fully hydrogenated; 112 e) R ⁷ is hydrogen, (Cl ~ _C4) -alkyl, (Cl ~ C ₉₎ heteroaryl, or (C ₆ -C ₁₂₎ -aryl- (Cl-C ₄₎ -alkyl; f) R ⁸ is hydrogen, (Cl ~ _C4) alkyl, OR ⁶ or morpholino residue; g) R ¹⁴ is 1. (C ₁ -C ₄ ) alkyl, 2. (Cl ~ _C4) -alkoxyl 3. cyano group, 4. amino group, 5. nitroso group, 6th nitro group, 7th fluorine, 8th chlorine 9th bromine, 10th (C χ-C ₉ ) —he terror 1 - CH ₂ -, 11th (Cl ~ _C4) -alkanoiloksigrupė, 12th (Cl ~ _C4) alkanoyl, 13th benzoyl, 14th . NH-CO-R ⁷ or 113 15. tetrazolyl; (h) R ¹⁵ is 10. -NH-CH ₂ -, 11. -CH ₂ -NH- or 12. -CH = CH and the other residues described in claim 1, and the physiologically acceptable salts thereof. sizes are the same as for these compounds 10. (Οχ-Ο 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-triazolil- (CH _{2) o} -, 15. tetrazolyl- (CH ₂ ) _m -, 16 - (CH _{2) o} _ ₁ -CHR ⁷ -0R ⁵ 17 - (CH _{2) o} -0- C0R ³ 18. -COR ⁸ , 107 19 - (CH _{2) o} -C 0-R ^8, 20. -S (O) _r R ¹⁹ , 21. -CH-CH- (CH ₂ ) _m -CHR ³ -OR ⁵ , 22. -CH = CH- (CH ₂ ) _m -CO-R ⁸ , 23 - (CH _{2) o} -NH-C0-0R ⁹ 24. - (CH ₂ ) _o -NH-SO ₂ -R ⁹ , 25. - (CH ₂ ) _n F, 26. - (CH ₂ ) _o -SO ₃ R ⁹ , 27. - (CH ₂ ) _n -SO ₂ -NH-CO-NR ⁶ R ⁹ , 28. - (CH ₂ ) _n -SO ₂ -NH-CS-NR ⁶ R ⁹ or The residue described in paragraph 29 (b) 8, 9, 10, 11 or 14 and described in paragraph (b) 8, 9, 10, 11 or 14 above and in paragraph (c) 46 ., 47, or 48 have such residues replaced, 30. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CO-R ⁶ , 31. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CS-R ⁶ ; c) R ⁸ is hydrogen, (Ο _χ- Ο ₅ ) -alkyl, OR ⁶ , NR ¹¹ R ^12, or a morpholine moiety; d) T is 10; 10. -ch ₂ -o-, 11. -s-ch ₂ -, 12. -CH ₂ -S-, 13. -NH-CR ² ° R ²² -, 14. -NR ²¹ -SO ₂ -, 15. -SO ₂ -NR ²¹ -, a residue substituted by fluorine; 103 16. -CR ² ° R ²² -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 ³ ) -, 24. -CH (OCOR ⁵ ) -, 25. -C- or II ₂₃ NR 26. —C— / \ R ²⁴ O OR ²⁵ y) R and R are the same or different and hydrogen, (C ₁ -C ₅ ) alkyl, phenyl, benzyl; z) R is hydrogen, (C 1 -C 4 alkyl), benzyl allyl; a ') R ²³ is present 10. (C _x -C ₆ ) -alkyl whose hydrogens are substituted with 1 to all fluorine; 11. (C ₂ -C ₁₀ ) -alkenyl, (C ₂ -C ₁₀ ) -alkenoyl or (C ₂ -C ₁₀ ) -alkadienyl, 12. (C ₃ -C _s) -cycloalkenyl 13th (C _3-C₈) cycloalkenyl- (C _x -C ₃₎ -alkyl, 14. bi- or tricyclic (C ₄ -C _x0) cycloalkenyl- (C _x C ₄₎ -alkyl, which may be 1-3 (C _x -C ₄₎ alkyl moieties, 15th (C ₆ -C _X0) -aryl- (C _x -C ₄₎ -alkyl, 16. (C ₆ -C _{X 0} ) -aryl - (C ₃ -C ₆ ) -alkenyl, 17th (C _x -C ₉ ) -heteroaryl- (C ₃ -C ₆ ) -alkenyl, 18. (C ₃ -C ₆ ) alkynyl, 19th (C ₆ -C _x0) -aryl - (C ₃ -C ₆₎ -alkynyl, 20th (C _x -C ₉ ) -heteroaryl- (C ₃ -C ₆ ) -alkynyl, R ⁶ , R ⁹ , together with the N-atom contained therein, form a heteroaryl, which may also be partially or fully hydrogenated; h) R ⁷ is present 10. (C 1 -C 6) alkyl 11. (C ₃ -C ₁₀ ) -alkenyl, 12. phenyl- (C ₂ -C ₆ ) -alkenyl, 13. 1-imidazolyl- (CH ₂ ) _m -, 14. tetrazolil- (CH _{Z) m} ~ 15. 1,2,3-triazolyl- (CH ₂ ) _n -, 16. - (CH ₂ ) _{O 1} -CHR ⁷ -OR ⁵ , 17 - (CH _{2) o} -0-C0-R ^3, 18 - (CH _{2) o} -SR ^6, 19. -S (O) _r -R ¹⁹ , 20. -CH = CH- (CH ₂ ) _m -CHR ³ -OR ⁶ , 21. -CH = CH- (CH ₂ ) _m -CO-R ⁸ , 22. -CO-R ⁸ , 23. -CH = CH- (CH ₂ ) _m -O-CO-R ⁷ , 24. - (CH ₂ ) _m -CH (CH ₃ ) -CO-R ⁸ , 25 - (CH _{2) o} -CO-R ^8, 26. - (CH ₂ ) _o -OC-NH-R ⁹ , II W 27 - (CH _{2) o} -NR ⁷ C-OR ⁹ II W 28 - (CH _{2) o} NR ⁷ -C0NHR ⁹ 29. - (CH ₂ ) - NR ⁷ -SO ₂ R ⁹ , 30 - (CH _{2) o} -NR ⁷ -CR ⁹ II w 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 = NNR ⁵ R ⁷ , 36. phthalimido (CH ₂ ) _n -, H - H 37. (CH ₂ ) _n in / O // iN 38. - <CH ₂ ) _n ~ ^ _n ^ ^CF S ' M OCH; 41. phenyl-SO ₂ -NH-N = CH-, H 43. - (CH ₂ ) _r -SO ₂ -NR ⁷ -CS-NR ^ft R ⁹ , 44. - _{(CH?) N} -SO ₂ -NR ⁷ -CO-NR ^f 'R ^9, 45 - (CH _{2) o} -S0 ₂ R ^9, The substituent described in 46 (c) (8) or (9), wherein the phenyl group has 1 or 2 identical or different substituents selected from the group consisting of halogen, hydroxyl, methoxy, trifluoromethyl, CO ₂ R ³ and phenyl, The substituents described in paragraph 47 (c) (10), (11) or (19), in which hydrogen is substituted with 1 to all fluorine, The substituent described in 48. (c) (14) having 1 or 2 moieties, the same or different, such as methoxycarbonyl and (C ₁ -C ₄ ) alkyl, 49. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CO-R ⁶ , 50. - (CH ₂ ) _n -SO ₂ -NR ⁷ -CS-R ⁶ , R ³ is present 10. benzyl, substitution in (b), 11. A process for the preparation of a pharmaceutical dosage form according to claim 10, characterized in that a suitable administration form is prepared from a compound of formula (I) according to claim 1 together with a physiologically harmless carrier and, if necessary, other additives or excipients.