Azole derivatives, process of their preparation and their use

Field of the Invention (Aarsov, λΖΉίνΚ'λΛ 3ad avyn

The invention relates to novel azole derivatives, their production and their use, in particular as angiotensin II receptor antagonists.

BACKGROUND OF THE INVENTION Art. . i θ

6 o OOO í

<img file="CS9200010A3_D0001.tif" />

The development of new angiotensin II receptor antagonists is of increasing importance. They are known from PP-A-28S34

1-benzyl-substituted imidazole derivatives, EP-A-253310 and SP-A-00401030 imidazole derivatives with diaryl carboxylic acid function, EP-A 323841 pyrazole and triazole derivatives and EP-A-0409332 triazole derivatives with diaryl carboxylic acid function and az EP-A-324377 imidazole derivatives with a diaryl-tetrazolyl group and their use as angiotensin II reeptor antagonists.

. Further; are disclosed in DE-A-4010797 (corresponding to US Patent Application No. 07/679233) substituted azoles containing a sulfonylurea group.

We have now found novel azole derivatives having a novel sulfonylurea, sulfonylurethane or sulfonylsulfonamide structure and are highly potent angiotensin II receptor antagonists both in vitro and in vivo.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I

<img file="CS9200010A3_D0002.tif" />

L- / 0 / -A q in which the symbols have the following meanings:

and / X, Y and Z are the same or different and are N or. CR²,

<td></td><td>b / R¹ 1.</td><td>/C₂-C_l0t -alkyl,</td>

<td></td><td> 2.</td><td> /^C3”^G1 0/-^8liíenyl&gt;</td>

<td></td><td> 3.</td><td>[Cn-Ci] -alkynyl,</td>

<td></td><td> 4.</td><td>-STEED³,</td>

<td></td><td> 5.</td><td>(C 1 -C 8) cycloalkyl,</td>

<td></td><td> 6..</td><td>(C 1 -C 6) cycloalkylalkyl,</td>

<td></td><td> 7.</td><td>(C 1 -C 4) cycloalkyl alkenyl,</td>

<td></td><td> 8.</td><td>(C 1 -C 6) cycloalkylalkynyl,</td>

<td></td><td> 9.</td><td>- (CH3) -3- (CH3) -R⁴, 2 tn 2 n '</td>

<td></td><td> 10.</td><td>-benzyl,</td>

<td></td><td>Ií.</td><td>the residue defined under b / 1, 2, 3 · or 9 which</td>

<td></td><td></td><td>is monosubstituted by CO₂fí \</td>

<td></td><td> 12.</td><td>the residue defined under b / 1., 2., 3. or 9. in which 1 to all H atoms are replaced by fluorine,</td>

<td></td><td></td><td>or</td>

<td></td><td> 13.</td><td>the residue defined under b / 10, which is on the phenyl</td>

<td> +</td><td></td><td>substituted with 1 or 2 same or different radicals from the group consisting of halogen, (C1-C4) -alkoxy and nitro,</td>

<td></td><td>c / R² 1,</td><td>hydrogen,</td>

<td></td><td> 2.</td><td>halogen,</td>

<td></td><td> 3.</td><td>nitro,</td>

<td></td><td> 4.·</td><td>^Cin^F2v + 1 '</td>

-35.

6.

7.

8.

pentsfluorophenyl, cyano, -O-R⁶, bitches¹.»..

9.

10. 11 .

12.

13.

14.

15.

feny1- / C₁-C 1-6 -alkyl, (C 1-6) -alkyl;

/C₃-C₁t -alkenyl, phenyl- (C)₂-C 1 -alkenyl, 1 -icaidszolyl - CH₂/ -,

1,2,3-triazolyl- / CH₂/_n-,

t.

6. 17.

15.

19.

20 May 2'Γ.

22.

23.

24.

25. ·

26.

tetr azdyl-ZCH / - -, - / ch /_O_₁-chr⁷-0r⁵j - / ch₂/_O-o-cor³,

- (CH) -SR⁶, -s- (o) -R¹⁹-CH = CH- / CH_O/ -CHR³-STEED⁽

L Π o

= CH- / CH 2 -co-1,2,2 m 2

-CC®,

-GH = CH - (CH 2) -O-CO-R⁷, 2 mo

- / CH₂/_ía-CH /^CH3/-^c0-R^O,

- / CH /_O-CO-R⁸,

- / ch /_O-oc-nh-r⁹,

27.

28.

29.

30.

31.

32.

WW

- / CH /_O-NR⁷-C-CR⁹,. - (CH 2) o -NR⁷-CO-KHR⁹, - / ch2 /₀-nr⁷-so₂r⁹,

- (CH) -NR⁷-CR⁹, u _H

-/^CH2/_nF,

- (CH 2 -O-KO)

33. -FEELING₂-N₃,

34. - / CH₂/_n-NO₂,

35. -ck = n-nr⁵r⁷,

-4x 'h' ΜιΛϊ * - '/, Y4r ςν' τ

36. phthalimido- / CH_C/ -, 2 El ⁷

- / CH₂/_n

<img file="CS9200010A3_D0003.tif" />

<img file="CS9200010A3_D0004.tif" />

<img file="CS9200010A3_D0005.tif" />

Wo-1

40.

41.

<img file="CS9200010A3_D0006.tif" />

'OCH.

phenyl-3O₂-NH-N = CH- ^J

<img file="CS9200010A3_D0007.tif" />

/ - / CH₂/_n-S0₂-NR⁷-CS-NR⁶R⁹,

44. - / CH₂/_n-SO₂-NR⁷-CO-NR⁶R⁹,

45. - / CH₂/_O-S0₂R⁹, .

46. or a residue as defined in (8) or (9) which is substituted on the phenyl by 1 or 2 identical or different substituents from the group consisting of halogen, hydroxy; methoxy, trifluoromethyl, COgR^and ^^enyl&gt;

47. the residue defined under c / 10., 11. or 19 that he has. to, all H-atoms replaced by fluorine,

48. a radical as defined in C 14-14 which is substituted by 1 or 2 with the same or different substituents from the group consisting of methoxycarbones 1 and (C 1 -C 4) -alkyl,

49. - / CH₂/_n-SO₂-NR⁷-CO-R⁶,

-550. - / CH₂/_n-SO₂-NR⁷-CS-R⁶, d / R³ 1. hydrogen; 7

2. /C₁-C8 -alkyl,

3. /C₃-C_Gt -cycloalkyl,

4. phenyl,

5. benzyl.or. .

A 6 * radical as defined in d / 2, wherein 1 to all H-atoms are replaced by fluorine, e / 1. hydrogen,

2. /C_]-C 8 -alkyl, (C 1 -C 8) cycloalkyl,

4. /C₂--C 1-6 alkenyl or

5. (C 8 -C 6) -alkynyl, (R 6) hydrogen,

2. (C1-C6) -alkyl,

3. /C₃-C8 -cycloalkyl,

4. phenyl or

5. benzyl, 6 gg / R, R⁷ they are the same or different and represent '1. hydrogen,' '' ··. ··. -,

2, (C 1 -C 8) -alkyl, which may be substituted by 1-3 radicals from the group consisting of (C 1 -C 8) -alkoxy, which may itself be substituted by 1-3 radicals from the group consisting of hydroxyl,₁-Cg / -alkoxy, ^{= i} amino, mono- (C 1 -C 8) -alkylamino, di- (C 1 -C 8) -alkyl-amino, followed by (C 6 -C 8) -alkenyl, hydroxy, amino, mono- (C 1 -C 8) -alkylamino, di- (Cp) C 6 -C 6 -alkyl amino, (C 8 -C 8) alkoxycarbonylamino, (C 8 -C 6 Aeryl-ZC 8 C 6) alkoxycarbonylamino; (C8-C8-6-aryl);_{1 Q}(aryl- (C 1-4) -alkyl, (C 1-6)₁-C (1) -heteroaryl, carboxy and (C (O) 2) -alkoxycarbonyl,

-63 ·. (C 1 -C 8) cycloalkyl, wherein the cycloalkyl moiety may still be substituted with 1-3 radicals of the group consisting of (C 1 -C 4) -alkyl and (C 1 -C 4) -alkenyl,

4. (CyCg) -cycloalkyl-C₁--C 1-6 alkyl,.

5. [C] -C₁₂t -aryl, preferably phenyl, ^δ· ^/C6^C1 -C₄Aalkyl »

7 * / C ^-C_G- heteroaryl, which may be partially or fully hydrogenated,

8. the residue defined under g / 5., 6., 7 «, 9., 15.,

16., 17o, 19., 20. or 21. substituted with 1 or 2 of the same or different radicals from the group consisting of halogen, hydroxy,₁-C 1-4 alkyl, methoxy, nitro, cyano, CO 2₂R ^_} trifluoromethyl, -NR¹¹R¹^ a

-N 'D \ _ /

9. (C 1 -C 8) -heteroaryl- (C 1 -C 6) -alkyl wherein heteroaryl. part may be partially or fully hydrogenated,

10. /C₁-C 8 -alkyl, wherein 1 to all H-atoms are replaced by fluorine,

11. /C₂-C₁₀(-alkenyl);_Q/ -alkenoyl or /^C2~^C10-alkadienyl,

12. (C1-C6Acycloalkenyl, *) C1-C6Acycloalkenyl- (C1-C6Aalkyl),

14. bi- or tricyclic (C 1 -C 4) acycloalkenes of 1- (C 1 -C 4) alkyl, which may still be substituted by 1,3 (C 1 -C 6) -alkyl radicals,

15 Dec (C 8 -C 6 Aeryl -) -, - alkyl,

16. / Cg-Cj₀(-aryl) - (C 1 -C 8) alkenyl,

7. /C₁ -C8 -heterolyl- (C)₃-Cg / -sikenyl,

18. (C 1 -C 8) alkynyl,

19 Dec / Cg-C₁θAaryl- / C₃-Cg / -alkynyl,

20 May /C₁ -C_G(-he t aryl-) CyCg A alkynyl,

-Ί6 9

21. R and R together with the nitrogen atom to which they are attached form hetaryl, which may also be partially or completely hydrogenated, h / rP 1, hydrogen,

2. /C_r^C6-alkyl,

3. (C 1 -C 8) cycloalkyl,

4. / Cg-C₁[-aryl-] C₁-C 8 -alkyl, especially benzyl,

5. phenyl or

6. C, -C₀heteroaryl, -.

i / R⁸ 1. hydrogen,

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

3. / CjC_Gt -cycloalkyl,

4. phenyl- / CH_O/ 5. -CR⁶,&gt;- .....'

6. NR * 'or /' / CH₀AND

7. \ ² /^D 'j / r10 cyano, nitro or COgR',

1119 k / R and R are the same or different and mean

1. hydrogen, · ·· -. -

2. (C1-C4) -alkyl,

3. phenyl.

4. benzyl or

5. 4-methylbenzyl,

1 / D is NR¹· ^, O or CHg,

7 m / R ^J represents hydrogen, (C1-C4) alkyl or phenyl; n / A represents a biphenyl radical which may be substituted by up to 4, preferably up to 2, the same or different radicals R; ⁴ or R, wherein A is. but substituted by at least one of p / 44 or 45,

-8*&gt;··*.

, .ϊ o / R¹⁴ 1 .

2.

3.

4.

5.

6.

7.

8. 9.

10*. 11. 12.

13.

14.

15.

16.

17.

18.

halogen, .... - - ........

nitro, nitro,

- »f.

amino, cyano, hydroxy, (C 1 -C 6) -alkyl, (C 1 -C 6) -alkanoyl, (C 1 -C 6) -alkanoyloxy,

C0₂R³, aethanesulfonylamino, trifluoromethanesulfonylamino, -CC-NH-OR⁹,

-SO_?-NR⁶R⁷,

-CH₂-STEED⁷, /C^-Cg/-heteroaryl./CH₂/_q-, in particular 1 zolyl, · / C_?-C₁₃/ -aroyl / \

-ch₉- NQ, ² \ _y

-tetra19.

- (CH.C) -NQ ^{2 0} \_!

or

20 May /C₆-C₁₂/ -aryl, p / R¹5 1. hydrogen,

2. /C_]-C8 -alkyl,

3. (C 1 -C 8) cycloalkyl,

4. / Cg-C₁₂/ -ar, yI,

5. / Cy-C₁₃/ -aroyl,

6. (C 1 -C 6 alkoxy, * 7)₁-C₄/ -alkanoyloxy,

8. /C₁-Cg / -heteroaryl,

-99.

10. 1 1 . 12.

13.

14.

15. 1 6. 17.

8.

19.

20. 21. 22.

23.

24.

25.

26.

27.

28. 29.

what₂r³, .

halogen, cyano, nitro, nr⁶r⁷,.

hydroxy,

-cc-nk-chr⁵-what₂r³, sulfo,

-SO-jR³,

-3O₂-NR⁷-WHAT NO⁶R^and? or -SO₂-RR⁷-CS-NR⁶R^WITH,

-kr⁷-co-nr⁵-so₂-ch₂-r⁵,

-C / GF₃/₂OH, phosphonooxy,

-after₃h₂'-nh-po / oh /₂,

-S / O / R

-CO-R⁸,

-CO-NR^ER⁹,

-cr²⁰/ oh / -po / W₂, the residue defined under o / 20.

• i. ...

A ^ .R⁶

-SCL-NH-SO

?. . ^ R⁸

30.

-NH-CQ o₂h,

31.

-O- (CH 2) n.

<img file="CS9200010A3_D0008.tif" />

&gt;

32.

33.

5-Tetrazolyl-NH-CO-

-co-nh-nh-so₂cf₃,

<img file="CS9200010A3_D0009.tif" />

-1140. -CO-NH-SO8-R¹⁹

41. -SO 2 -NH-CO-R⁶ or.

42. the radical mentioned under p / 4, substituted with 1 or 2 of the same or different radicals from the group, includes a halogen, cyano, nitro, NRR and hydroxy group,

43. r15 together i is -CO-NH-SO4 -,

44. -SO₂-NH-CO-OR^O,

45. -3O₂-NH-3O₂NR ° N⁹,

46. -3C-NH-3O-R⁰, q / 3 stands for NR or S, r / W stands for O or 3, s / L stands for (C 1 -C 4) alkanediyl, t / R¹⁶ CQgR³ or CHgCOgR³, u / R¹? hydrogen, halogen, (C 1 -C 4) -alkyl or (C 1 -C 4) -alkoxy, v) hydrogen, (C 1 -C 4) -alkyl₄t -alk, yl or phenyl, w / R¹⁹ 1 ./C_rC₆t -alkyl,

2. /C₃-C_G/ -cycloelkyl,

3. phenyl,

4. benzyl or

5-. a radical as defined in w / in which one to all K-atoms are substituted by fluorine, x / T 1. a single bond,

2. -CO-,

3. -CH₂-,

4. -0-,

<img file="CS9200010A3_D0010.tif" />

7. -CO-NR²¹-,

8. -NR²¹-CO-129. -O-CH₂-,

10. -CH₂-0-,

11. -S-CH₂-·,

12. -CH₃-WITH-,.

13. -NH-CR%²²-· ,

14. -NR²¹-SO₂-,'

15 Dec SCL-NR²¹-,

16. -CR²⁰R²²-NH-

17. -CH = CH-,

18. -CF = CF-

19 Dec -CH = CF-,

20 May -CF = CH-

21. -CH₂-CH₂-,

22nd -CF₂-CF₂-,

23. -CHORUS³/-,

24. -CH / OCCR⁵/-,

25. -C— or

26. -Cr²⁴O^of W³

22nd y / R and R are the same or different;

2 / S modified hydrogen, (C1-C6) alkyl, benzyl or allyl,

S * / R²³ 1. NR²⁰R²¹

2. ureido,

3. thioureiao,

4. toluene-4-sulfonyl or

5. benzenesulfonylamino

3 * / R²⁴ and R²are the same or different and represent (C1-C6) -alkyl or together - (CH)₂/_q-,

-13c7 Q CH₂, 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 0 or 1, h * / r is 0,1 or 2 or i * / v is an integer from 1 to 6, as well as their physiologically acceptable salts, with the exception of the compound of the general formula. ... - · “~ -

CH,

<img file="CS9200010A3_D0011.tif" />

OCH / 3 /

-14alkyl, alkenyl. and alkynyl may be straight or branched. The same applies to radicals derived therefrom such as alkanoyl or alkoxy.

'Come on. the term cycloalkyl also means alkyl-substituted rings.

(C 1 -C 4) -aryl is, for example, phenyl, naphthyl or biphenylyl, preferably phenyl. The same applies to radicals derived therefrom such as aroyl or aralkyl.

Po (C 1 -C 8) -heterolyl especially includes residues derived from phenyl or naphthyl in which one or more CH groups are not substituted by N and / or in which at least two adjacent CH groups are formed to form a five-membered aromatic ring (S, NH or Further, one or both of the condensation site of the bicyclic moiety (as in indolizinyl) may also be N,

Heteraroyl includes, but is not limited to, furanoyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolinyl, phthalinyl, phthalinyl, phthalinyl;

Possible stereocenters can be in both the / 3 / and / S / - configuration.

The coupling by A is carried out by an alkanediyl bridge L, which is preferably a methylene group.

The methylene group is preferably attached directly to the biphenyl moiety.

Physiologically acceptable salts of the compounds of formula (I) are understood to mean both their organic and non-organic salts. ions, how. see Emington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). From the viewpoint of physical and chemical stability and solubility, sodium, potassium, calcium and ammonium salts are preferred for acidic groups, hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic or sulphonic acid salts such as, for example, basic groups are preferred. eg. is acetic, citric, benzoic, maleic, fumaric, tartaric and p-toluenesulfonic acid.

Preferred are compounds of formula I wherein ε / N is H, Y CR² and Z CR², b / X is CR², Y 'and Z CR², c / X represents CR², Y CR² and ZN or d · / X, Y and Z. mean .. always .N., ........ ....... .....

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

XN, YCR² and Z CR²,.

X CR², Y To Z CR²,

X.CR², Y CR² and Z N, or.

X, Y and Z always N, ..... - -. -,,. .

a / R¹ 1. / C₂-C₁₀t -alkyl,

2. / CyC ₁₍₎/ -alkenes 1,

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

4 · / C 1 -C 8 -cycloalkyl,

5. benzyl or

6. benzyl which is substituted as described above for (b 13) (jb) R² 1. hydrogen,

2. halogen,

3. nitro,

-165·

6.

7.

8. 9.

. 11.

12.

13.

14.

15 Dec Ιό.

17.

18.

19.

20. 21. 22.

23.

24.

25. .26.

27.

fentafluorfeny1, ky yes,

-STEED⁶, phenyl ,.

phenyl- (O) - (N) -alkyl, (C 1 -C 6) -alkyl_r-C₁₀t-alkyl, / -C-t₁₀t -alkenyl, phenyl- (C) ₂-C 8 -alkenyl 1-imidazolyl- (CH 2)_[n- ,

1,2,3-triazolyl- / CH₂/_Otetrazolyl- / CH₂/_n-, - (C 1 H 3 -CH 2 OR 2)⁵, - / ch₀/.-o-cor³,

-COR

2 °, 8

28.

29.

30.

31.

- / CH_O/ -CO-R

-S / C /_rR¹⁹,.

-CH = CH- / CH_O/ -CHR -GR^C £ ul * Q

-CH₀= CH- / CH₉/ -CO-R

2 nt q '

- / CH3 -NfiCO-OR *,

- (CH 1) -NH-SOx-R⁹,

- / CH₂/_nF,

- / ch₂/_O-so₃r⁹,

- / CH₂/_n-SO-NH-CO-NR⁶R⁹.

- (CHp) -S0_O-NH-CS-NR⁶R⁹, or the residue defined under b / 8., 9 ·

14., which is substituted as either c / 46., 47., or 48.,

- / CH₂/_n-S0₂-NR⁷-WHAT_TR ^

- / CH_O/ -S0_O-NR⁷-CS-R 0, n 2 ', 10, 11, or as described above c / R⁸ hydrogen, C 1 -C 4 -alkyl, OR⁶, NR¹¹R¹² or morpholino, d / Τ 1. single bond, 2 - CO 3. -CO-NR²¹4. -CH₂-CH₂- .

-175. -NR²¹-CO6. -O-CH₂7. -CH₂-08. -S-CH 9. -CHg-S-.

10. -nh-ch₂11. -CH₂-NH- or

12. -CH = CH- and other residues and variations as defined above.

Particularly preferred are compounds of formula I wherein X is Y, CR² and CR²,

X CR², Y Ra Z CR²,

X. CR², Y CR² and Z. N or .X., "Y", and "Z" are always. , N, ........ . ________ a / r1 / C₂-C 1-6 -alkyl, (C 1 -C 6) -alkenyl or (C 1 -C 6) -alkynyl, b / R² 1. chlor

2. bromine,

3. ^Cin^F2v + 1 ' ^{where v = 1,2 or 3}’ '

4 .. pentafluorophenyl, ..... ..,

5. 0-R⁶, -S / O /_rR¹⁹,

7. [C] - (CH3) -OR³, .

8. [CH.] -O-CC-R³,

9. -COR, that. - / CH₂/_O-CO-R⁸, tt. -ch₂-nh-co-r⁸,

12. - / ch₂/₀-kh-so₂-r⁹,

13. -ch = ch-chr³-steed⁶,

14. tetrazolyl- / CH₂/_m15 Dec - / CH₂/_nSO₂-NH-CO-NR⁶R⁹,

-1816. - (CH 2) q -SO 2 R 2_Nob₀ optionally substituted by hydroxyl₁-C 8 H -alkyl, preferably hydroxymethyl;³ d / R⁶R, hydrogen (C1-C4) -alkyl or benzyl, are the same or different

1. hydrogen, and mean

2. (C1-C6) -alkyl, which may be substituted by 1-3 residues of the group consisting of (C1-C6) alkoxy, which itself may be substituted by 1-3 residues of the group consisting of hydroxy, (C1-C6) -alkoxy, amino, mono / C₁-C 8 -alkylamino, di- (C 8 -C 8) -alkylamino; /C₂-C 1-6 -alkenyl, hydroxy, amino, monoC 1 -C 6 -alkyl amino, di-C 1 -C 6 -alkyl amino, (C 1 -C 6) alkoxycarbonylamino, (C 6 -C 6) ₂(-aryl- (C 1 -C 6) -alkoxycarbonylamino, (C 6 -C 6) -aryl- (C 1 -C 6) -alkyl)₆-C₁₀(-aryl), (C 1 -C 6) -heteroaryl, carboxyl and (C 1 -C 6) -alkoxycarbonyl,

3. (C 1 -C 8) Cycloalkyl,

4. /C₃-C8 -cycloalkyl- (C)._]-C₃t -alkyl,

5. phenyl,

6. phenyl- (C1-C4) -alkyl,

7. (C 1 -C 6) -heteroaryl, which may be partially. or completely hydrogenated,

8. the residue mentioned above under g / 5., 6., 7. or 9.,

14.-16. and 18-20, substituted with 1 or 2 of the same or different radicals from the group consisting of: halogen, hydroxy, C 1 -C 6 alkyl, methoxy, nitro, acid, CO 2, trifluoromethyl,

-19-Nr ”r¹² and -ND \ /

9. (C 1 -C 4) -heteroaryl- (C 1 -C 4)₃n-alkyl, wherein the hetero aryl moiety may be partially or fully hydrogenated,

10. /C₁-C8 -alkyl, in which 1 to all H-atoms are replaced by fluorine,

11. (C8-C8) -alkenyl or (C8-Aalkenoyl),

121 (C 1 -C 8) cycloalkenyl, 1j. /C₃"C8-Cycloalkenyl- (C 1 -C 4) -alkyl"

14. bi- or tricyclic (C 1 -C 4) cycloalkenyl-ZC 4

C1-4alkyl, which may still be substituted by 1-3-3C alkyl radicals,

15 Dec C8-aryl-ZC1 -C4 -alkyl,

16. C8-aryl-₃Alkenyl, 1.7

18. C 1-4 -alkynyl,

19 Dec C8-aryl-₃/ -alkynyl,

20 May / C ^ -CgAhetaryl-AjAelkinyi,

21. R⁸, R⁹ together with the nitrogen atom to which they are attached form hetaryl, which is also partially or fully hydrogenated, e / R⁷ hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) -heteroaryl, or (C 6 -C 6) -alkyl ₂Aeryl- / Calkyl,

QA (R) is hydrogen, (C1-C4) alkyl, OR or morpholino, g (R)¹⁴ 1. / C₁-C₄t -alkyl,

2. C, -C₄/ -alkoxy,

3. cyano,. 4. amino,

5. nitroso,

6, nitro,

-20 '. 7 *. fluorine:

8, chlorine,. 9. bromine,

10. (C 1 -C 4 Aheteroaryl-CH 3),

11. (C1-C4) AlalkaneDyloxy ,.

12. (C 1 -C 4) alkanoyl,

13. benzoyl,

14. -NH-CO-R⁷ or

15 Dec tetrazolyl, b / R¹⁵ 1, (C1-C6) -alkyl,

2. /C₅-C₁₂/ -aryl,

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

4. (C 1 -C 4) -alkoxy,

5. /C₁ -C 1-4 Aheteroaryl, preferably 5-tetrazoles,

6. cyano,

7. nitro,

8. hydroxy,

9. -S / O /_rR⁶,

10. -SO.R³,

11. chlorine,

12 »bromine,

13 · benzoyl,. 14. -CO₂R³,

15 Dec -CO-NH-R⁶,

16. -CO-R⁸,

17. -SO₂-NR⁶R⁷,

18. -so₂-nh-co-nr⁶r⁹,

19 Dec -AFTER₃H,

20 May -CO-CHR⁵-WHAT₂H,

21. -NH-CO-NH-SO₂-CH₂-R⁵,

22nd 5-Tetrazolyl-NH-CO-

-21-yR

23. -SO 2 -NH-SO

24. -CO-N χ / L ^ y co₂h

25. HOgC

R '

26,

<img file="CS9200010A3_D0012.tif" />

or

28 ^ residue defined as h / 2. substituted as above (see p / 42),

29. R¹⁵ and R¹⁴ together form -CO-NH-SO₂~

30. -S0₂- NH - C00 - R⁶, ...... .......

31. -so₂-nh-so₂-nr ° r^with,

32. -SO₂-NH-SO₂-R⁶, i / R represents hydrogen, methyl or ethyl, j / T represents a single bond, -O-, -CO-, -NHCO- or

-och₂-_} k / q = 0 and L = methylene, and other residues and variations as defined above.

Especially preferred are. from the azole derivatives of the formula I, those in which Z represents a nitrogen atom and Y and X independentlyo means CR and other symbols have. as defined above.

Particularly suitable are furthermore the azole derivatives of the general formula I, wherein the general symbols have the following meaning;

From nitrogen,

X, Y are independently CR,

R¹ (C 1 -C 6) -alkyl, (C 1 -C 6) alkenyl or (C 1 -C 6) alkynyl, R 2² hydrogen, halogen, nitro, (C1-C4) Aperfluoro alkyl, acid, /^Cr^CJ0^{/ _slky1}’ ^^C3~^CÍ (/ '^alkenyl, -CH₂-CO-IT *

OR, -S / O /_r-R¹⁹, or -OR,

R @ 1 is hydrogen or (C1 -C6) - alkenyl,

H⁶,_R5 '⁶ rt

1. hydrogen,

2. (C 1 -C 8) -alkyl, which may be substituted with 1-3 radicals of the group consisting of (C 1 -C 8) -alkoxy, which itself may be substituted with 1-3 radicals of the group comprising hydroxy, (C 1 -C 6) - alkoxy, amino, mono (C 1 -C 8) -alkylamino, di- (C 1 -C 8) -alkylamino, hereinafter "C"₂-C₁q) -alkenyl, hydroxy, amino, mono- (C1-C6) alkylamino, di-C1-C6-alkylamino, (C1-C6) alkoxycarbonylamino, (C6-C8)_{1 2}[-aryl-] C₁-C 1-4 alkoxycarbonylamino; / Cg-C₁₀(A-C 1 -C 6) aryl-C 1 -C 6 -alkyl, (C 1 -C 6) -heteroaryl, carboxy and (C 1 -C 6) alkoxycarbonyl,

3. / C8-C8Acycloalkyl,

4. (C8-C8) -cycloalkyl-₃t -alkyl,

5. [Cg-C]₂t -aryl, preferably phenyl,

6. (C 8 -C 6 Aaryl-N 4 -C 4 alkyl),

7. (C 1 -C 8) heteroaryl, which may be partially or fully hydrogenated,

-238. (C 1 - (N) - heteroaryl-C 1 -C 4) -alkyl, wherein the heteroaryl moiety may be partially or fully hydrogenated, ...

9. a residue as defined under 5, 6, 7, and 8 substituted with 1 or 2 same or different radicals from the group consisting of halogen, hydroxy, (C 1 -C 3) alkyl, methoxy, nitro, cyano , CCLR, trifluoromethyl, -NRR and a group of formula

-ND λ_ /

10, (C 1 -C 8) -alkyl, wherein 1 to all H-atoms can be replaced by fluorine;

11 «/ C₂-CgAalkenoyl or / C 1 -C 8Aalkenoyl,

12. (C 1 -C 8 -cycloalkenyl),

13 * / C₃"C 8 -cycloalkenyl- (C 1 -C 6) alkyl"

14. (C 8 -C 8 Aaryl) C 4 -C 8 -alkyl; .

15 Dec / Cg-C »! ₀[-aryl-] C₃-C8 -alkenyl,

16. (C 1 -C 4 Z-hetaryl-ZC 1 -C 8 Alkenyl)

17. (C 1 -C 8) -alkynyl,

18. / Cg-C₁₀(-sryl-) C₃-Cg / -alkynyl,

19 * / C₁- (-) - Hetaryl- (C)₃-Cg / -alkynyl,

20 May R ^ _and r9 _WITHthe nitrogen atom array to which they are attached is hetaryl, which may also be wholly or partially hydrogenated,

R? hydrogen, hydrogen or -OR 4

12

R, R ^ώ independently of one another are hydrogen or (C1-C6) -alkyl,

D -NR¹³, -O or -CH₂

R¹³ hydrogen or (C 1 -C 4) alkyl

A biphenyl radical which may be substituted with R radical¹or together R^lzl and R¹^,

-24R¹⁵ -SO 2 -NR⁷-CO-NR⁶R⁹, -SO 2 -NH-COO-R⁶, -SO₂-NH-so₂-nr⁶r⁹ ,

-SO-NH-CO-R⁶ or -SCL-NH-SO 4 -R⁶ or.

&lt;J «AW £

R ⁴ and R ⁷ together may form -CO-NH-SO₂-,

L -CH₂q, zero and zero, 1 or 2, as well as their physiologically acceptable salts. .

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

ZY

<img file="CS9200010A3_D0013.tif" />

N_X

H wherein r 1, X, Y and Z are as defined above, alkylated with compounds of formula III

Wherein L, A and q are as defined above and U is a leaving group, or the previously introduced protecting groups are cleaved again, the resulting sulfonamides of the formula I are optionally converted to urethanes of the formula I, the obtained sulfonamides of the formula I or the obtained urethanes of the formula I are optionally converted to the sulfonylureas of the formula I and the obtained compounds of the formula I are optionally converted into their physiologically acceptable salts.

Preferred leaving groups U are preferably nucleofug / srv groups. Aigew.Chem.72 / 1960/71 /

<img file="CS9200010A3_D0014.tif" />

&gt;4

-25 halogen: o-toluenesulfonate, mesylate or triflate. Methods for preparing the starting compounds of formula (II) are known, inter alia, from US 4355044, EP-Ar324377 and EP-A323841.

<img file="CS9200010A3_D0015.tif" />

(1969 //, T, Srodsky / The Chemistry of the Azido Group, Wiley, New York, 1971, p. 331), H. Hamhoff / Comprehensive Heterocyclie. Chemistry (and S. atritzky Ed., Pergamon Press, New York (1984)).

Another process for the preparation of the compounds of formula (II) starting from 1-oxyglyoxylic acid-2-oxime derivatives is carried out by reduction of the oxime with reducing agents known from the literature and by the addition of mercury and the compound of the formula III. s-kupin using appropriate protecting groups in the intermediate steps which can be cyclized to imidazoles under water cleavage conditions. Mixtures of PCl4 and dimethylaminopyridine (DMAP), POC-1 ^ and SOCl4 and mixtures thereof with DMAP may be used for the cyclization step.

<img file="CS9200010A3_D0016.tif" />

The sulfones and sulfoxides are preferably carried out with peracids in suitable solvents such as dichloromethane.

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

The alkylation is carried out analogously to known methods.

. ih '·

-26 ... Azoles. derivatives of the formula (II) with metal, e.g. in the presence of a base; Preferred bases are metal hydrides of the formula MH such as lithium, sodium or potassium hydride, e.g. in DMF or DMSO as a solvent or metal alkoxide of the formula MOR, wherein R is methyl, ethyl, tert-butyl, and the reaction is carried out in the corresponding alcohol,

DMF or DMSO. The thus formed azole salts are dissolved in the aprotic solvent (as in DMF or DMSO) and reacted with an appropriate amount of alkylating agent.

An alternative possibility of deprotonation of the esol derivatives is, for example, reaction with potassium carbonate in DMF or DMSO.

The reactions are carried out at a temperature below room temperature up to the boiling point of the reaction mixture, preferably between + 20 ° C and the boiling point of the reaction mixture for about 1 to 10 hours.

For example, biphenyl derivatives can be synthesized from arylboronic derivatives. acids by coupling with substituted aryl halides to. the presence of transition metal non-catalysts, in particular palladium. Corresponding reactions have been described

SBMiller.a spol. (Organometallics 1984,3,1261) or

A. Zuzuki et al. Synthetic Commun. 11/7/513 (1981) // «

The sulfonylurethanes of formula (I) may be obtained from the corresponding sulfonamides of formula (1) by reaction with chlorocarbon esters in inert high boiling solvents such as toluene at temperatures of from about 100 ° C to about 100 ° C. the boiling point of the corresponding solvent.

Analogously, sulfonyl sulfonamides can be prepared from the corresponding sulfonamides by reaction with sulfonic acid chlorides or sulfamoyl chlorides.

The sulfonamide moiety can be prepared, if desired, starting from an amino group and proceeding with a Meerwein reaction. Therefore, the amine hydrochloride is first diazotized and then reacted in the presence of a copper-based catalyst with sulfur dioxide in glacial acetic acid. Subsequent treatment with ammonia leads to a sulfonamic group.

Alternatively, the corresponding thiophenol can be converted by oxidation with chlorine and finally by treatment with ammonia to give the sulfonamide.

The compounds of the formula I according to the invention have an antagonistic effect on the angiotensin II receptors and can therefore be used for the treatment of angiotensin-dependent hypertension and can also be used for the treatment of angiotensin II-dependent hypertension. cardioprotection, myocardial infarction, cardiac hypertrophy, arteriosclerosis, nephropathy, renal failure as well as vascular brain diseases such as transitoric ischemic attacks and stroke.

Renin is a proteolytic enzyme from the class of aspartyl proteases which, due to various stimuli (volume depletion, sodium deficiency, stimulation of β-receptors), is secreted from the juxtaglomerular kidney cells into the bloodstream, the lam cleaves from angiotensinogens secreted from the liver. angiotensin converting enzyme / .ACE converts to angiotensin II. Angiotensin-II plays an important role in the regulation of blood pressure, since it directly increases blood pressure by contracting blood vessels. In addition, it stimulates aldosterone secretion from the adrenal glands and in this way increases the volume of extracellular fluid due to inhibition of sodium secretion, contributing to an increase in blood pressure.

The antagonistic effects are, among other things, stimuli . conversion of phosphoinositol (Ca-release), activation of protein kinase C) and facilitation of c-AMP hormone dependent receptors.

The affinity of the compounds of formula (I) for angiotensin II receptors can be screened by measuring suppression of 125

J-angiotensin-II- or ^JK-angiotehsin-II receptors on bovine adrenal glomerulosis membranes. The prepared membranes are then suspended in a buffer at pH 7.4,

Aprotinin, a peptidase inhibitor, is added to prevent radioligend degradation during incubation. In addition, about 14,000 cpm trscers with a specific activity of 74 TBq / mmol (available from Amersham Buchler, Braunschweig, Germany) and a protein receptor in an amount that binds 50% of the tracer are used. The reaction is started by adding 50 µl of the membrane suspension to a mixture of 100 µl of buffer + aprotinin; 50 µl buffer with or without angiotensin-II or receptor antagonists and 50 µl tracer. Incubate for 60 minutes at 25 ° C with bound and free radioligand. isolate by filtering the R-i test with Whatmann C-FIC filters on a Skatron cell harvester^E. '

Non-specific binding is prevented by treating 0.3% polyethyleneimine filters at pH = 10 (Sigma, # 3143). By measuring the radioactivity in the gamma-scintillation counter, the potency of radioligand receptor suppression is determined. IC 50 values ​​representing the concentration of inhibitor required to suppress 50% of the ligand were determined by JAheor.

Biol., 52, 253 (1970). It lies in the range from 1.10^-4 to 1.10 ~⁹ M.

Alternatively, the affinity of the compounds can be determined

<img file="CS9200010A3_D0017.tif" />

¹ h ' ^fc

<img file="CS9200010A3_D0018.tif" />

;^J·· ί

{

J ί

of formula I to angiotensin II receptors. by measuring 1

125 Suppression of J-angiotensin-II- or H-angiotensin-II in receptor / liver, lipid-derived receptor preparations;

ce, adrenal glands, brain etc./.

To this end, the prepared membranes were suspended in incubation buffer / 20 mM Tris, pH 7.4, containing 135 mM NaCl, 10 mM KCl, 10 mM MgClg, 5 mM glucose, 0.2% bovine serum albumin, and PM3F protease inhibitors 0 , 3 mM and bacitracin 0.1 mM / a were incubated together with radiolabeled sngiotensin II and various concentrations of test compounds for 50 min at 25 ° C. Finally, bound and free radioligs are separated by filtration through a glass microfiber filter (GF51, Schleicher and Schtt11) on a cell collector (SKATRON).

Measurement of receptor-bound radioactivity on filters by beta- or gamms spectrometers is determined

In step, suppression of receptor radioligands by test compounds. The potency of suppression of receptor radioligands by test compounds is assessed by IC50, ie, the concentration of inhibitor that suppresses 50% of the bound receptor radioligand. Calculation of hodnoty hodnoty θ values ​​is performed using PCsoftware / LIGAND, G.'A.McPherson 1985, Slsevier-BIOSCFT, 68. Hills Ho ad, Csmbridge CB 2 1LA, UX /. Rro of the compound of formula I measured Ι0ε_Λ values ​​range from

-5 -11 x 10 to 1 x 10 M / cf. The following Table 1 summarizes the IC50 values ​​for the compounds of the invention.

-30Table 1

Example - -. -. ΙΟ ^ θ / ηΜ / · -. . . . ...., ........,^{1 5000}

8000

1100 . 1100

16000

To determine the antagonist effect of the compounds of formula I, their effect can be measured by sngiotensin II induced blood pressure elevation in sprained-rat Sprague-Dawley rats. ^όε&gt; ο narcotic, serves sodium thiobsrbital / Trapanal, 3yk Gulden / at a dose of 100 mg / kg ip. IV application is done to the vein jugularis. Blood pressure is measured in A. carotis. First, the animals are pretreated with pantolinium tartrate (10 mg / kg im) to obtain a lower blood pressure level (ganglion blockade). ANG II (Hypertensin CIB4) is administered iv at a volume of 0.1 ml / 1,000 g. At 10 minute intervals. The dose is 0.5 / Ug / kg. The compounds of formula I are dissolved in distilled water and injected intraduodenally at doses of 10 to 100, 0.1 to 1.0 mg / kg intravenously.

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

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

The pharmaceutical preparations contain an effective amount of an active compound of the formula I and optionally further active compounds together with inorganic or organic pharmaceutically acceptable carriers. The use can be performed intranasally, intravenously, subcutaneously or orally. Dosage. -30eShouting table 1

<td>Example</td><td>IC₅₀ [nM]</td>

<td> 22</td><td> 2000</td>

<td> 24</td><td> 800</td>

<td> 25</td><td> 1400*</td>

<td> 29</td><td> 1,1</td>

<td> 30</td><td> 2030,0</td>

<td> 31</td><td> 153,0</td>

<td> 32</td><td> 3,5</td>

<td>³³ &lt; .</td><td> 34,0</td>

<td> 34</td><td> 1,0</td>

<td> 35</td><td> 50,0</td>

<td> 36 *</td><td> 16,0</td>

<td> 37</td><td> 1,1</td>

<td> 55</td><td> 8,8</td>

<td> 56</td><td> 4,6</td>

<td> 57</td><td> 1100</td>

<td> 58</td><td> 3,0</td>

<td> 59</td><td> . . ....... . . , ...1,3.'.,</td>

<td> 60</td><td> 2,2</td>

<td> 61</td><td> 1,1 </td>

<td> 62</td><td> 3,6 _</td>

<td> 63</td><td> 1,3 '</td>

<td> 64- </td><td> 0,5</td>

<td> 65</td><td> 1,8 </td>

<td> 66</td><td> 6,9 ,</td>

<td> 67.....</td><td> 0,91</td>

<td> 68</td><td> 12,0</td>

<td> 69</td><td> 3,2</td>

<td> 70</td><td> 4,4</td>

<td> 71</td><td> 2,2</td>

<td> 73</td><td> 2,5 .</td>

<td> 76</td><td> 9,5</td>

<td> 79</td><td> 5,8</td>

<td> 80</td><td> 0,69</td>

<td> 81. ’</td><td> 0,79</td>

-30 bCake tables ϊ

<td>Spin '</td><td>ic_5o [nM]</td>

<td> 83</td><td> 0,96</td>

<td> 84 . . .</td><td> - 4,3</td>

<td> 85</td><td> 3,9</td>

<td> 89</td><td> 1,1</td>

<td> 90</td><td> 0,69</td>

<td> 92</td><td> 280,0</td>

<td> 93</td><td> 3,3</td>

<td> 95</td><td> 1,8</td>

<td> 98</td><td> 1,4</td>

<td> 99</td><td> 26,6</td>

<td> 100</td><td> 68,5</td>

<td> 101</td><td> 2,4</td>

<td> 102</td><td> 2,3</td>

<td> 105</td><td> 3,0</td>

<td> 107</td><td> 2,5</td>

<td> 108</td><td> 0,95</td>

<td> 109</td><td> 0,6</td>

<td> 110</td><td> 0,5</td>

<td> 111</td><td> 2,9</td>

<td>¹¹²</td><td> 1,5</td>

<td> 113</td><td> 0,3</td>

<td> 115</td><td> 0,9</td>

<td> 116</td><td> 2,4</td>

<td> 117</td><td> 1,2</td>

<td> 124</td><td> 1,8</td>

<td> 125</td><td> 2,8.</td>

<td> 127</td><td> 3,0</td>

<td> 128</td><td> 5,6</td>

<td> 129</td><td> 1,5'</td>

<td> 134</td><td> 180,0</td>

<td> 135</td><td> 5,6</td>

<td> 138</td><td> 1,7</td>

<td> 139</td><td> 2,8</td>

<td> 140</td><td> 8,2</td>

-30c-

<td colspan="3">- C3 · ^ u '% ιει&gt; ιυ. *. Ν</td>

<td colspan="2">-'sayEo</td><td>IC₅₀ fnMj</td>

<td>¹⁴¹</td><td></td><td> 4,4</td>

<td> 144</td><td></td><td> 5,3</td>

<td> 146</td><td></td><td> 40,0</td>

<td> 151</td><td></td><td> 0,4</td>

<td> 152</td><td></td><td> 1,5</td>

<td> 153</td><td></td><td> 0,88</td>

<td> 154</td><td></td><td> 1,8</td>

<td> 155</td><td></td><td> 6,0</td>

<td> 156 .</td><td></td><td> 4,7</td>

<td> 157</td><td></td><td> 1,4</td>

<td> 159</td><td></td><td> 8,7</td>

<td> 160</td><td></td><td> 0,73</td>

<td> 161</td><td></td><td> 57,0</td>

<td> 162</td><td></td><td> 3,9 </td>

<td> 163</td><td></td><td> 3,7</td>

<td> 164</td><td></td><td> 0,86</td>

<td> 165' ' ' ' </td><td></td><td> ..... 2,3......</td>

<td> 166</td><td></td><td> 1,-2</td>

<td> 167</td><td></td><td> 4,0</td>

<td> 168</td><td></td><td> 7,0</td>

<td> 169</td><td></td><td> 2,9</td>

<td> 170</td><td></td><td> 2,7</td>

<td> 171</td><td></td><td> 0,7</td>

<td> 172</td><td></td><td> 0,48 .</td>

<td> ,174</td><td></td><td> 5,1</td>

<td> 179</td><td></td><td> 2,6</td>

<td> 181</td><td></td><td> 1,0</td>

<td> 183</td><td></td><td> , 1,7</td>

<td> 185</td><td></td><td> 5,9</td>

<td> 186</td><td></td><td> 6,5</td>

<td> 187</td><td></td><td> 1,2</td>

<td> 190</td><td></td><td> 22,0</td>

<td>¹⁹¹</td><td></td><td> 21,4</td>

<td> 194</td><td></td><td> 21,7</td>

<td> 195</td><td></td><td> 3,0</td>

The active ingredients depend on the species of warm-blooded animal, body weight, age and mode of administration.

The pharmaceutical preparations of the present invention may be prepared by known methods of dissolution, mixing, granulation or coating.

For oral use, the active compounds are admixed with excipients such as carriers, stabilizers or inert diluents and are then formulated, by conventional methods, into suitable dosage forms such as tablets, dragees, push-fit capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. For example, Arabic can be used as inert carriers. gum, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose, magnesium stearyl fumarate or starches, in particular corn starch, can be obtained in the form of dry or wet granules. Suitable oily carriers are, for example, vegetable or animal oils such as sunflower oil and fish oil (the same examples also apply to solvents).

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, optionally together with the auxiliaries commonly used for these purposes, such as solubilizers, emulsifiers or other auxiliaries, are formulated as solutions, suspensions or emulsions, Suitable solvents are, for example, water, physiological saline solution or alcohols such as ethanol, propenediol or glycerin. as well as sugar solutions such as glucose or mannitol solutions or mixtures of said solvents.

List of shortcuts:

D 1 F N, h -dimethylformamide

- 32 NSS N-br omsuccinioid

AISN. (R) -azobis-isobutyronitrile

EX electron. impact

DCI desorption. chemical ionization

RT room temperature

ES ethyl acetate (EtOAc)

DIP diisopropyl ether

MT3. methyl tert-butyl ether

mp melting point

HEP n-heptane.

DME dimethoxyethane

FAB Past Atom.Bombardment

CH 2 Cl 2 dichloromethane

The invention is illustrated in more detail by the following non-limiting examples.

EXAMPLES OF THE INVENTION ·

Example 1

Synthesis 1 -^-of^/2. * - Phenylaminocarbonylaminosulfonyl-biphenyl-4-yl-methyl-7-n-butyl-4-chloroimidezole-5-carboxaldehyde

K — i “Cl

<img file="CS9200010A3_D0019.tif" />

-33a / Production of 4 * -methyibiphenyl-2-amine - ··· ....... ......

. To 23.9 g (0.112 mol) 4'-methyl-2-nitrobiphenyl (S).

B. Mttller and S.Dugar, Organometallics 1984, 3, 1261) in 50 ml of methanol are added 3 g of Raney-nickel and hydrogenated at normal pressure at room temperature until the theoretical amount of H2 is consumed. the filtrate is concentrated. Chromatography on SiO2 (500 g) with EE (HEO) (1) as eluent gave 19 g of the title compound as an oil (92.5%).

R_F (EE / HEP 1/4) = 0.3 MS (EI) = 133 / M⁺/ b / 4.^- -Me thy1-biphenyl-2-ammonium hydrochloride g of compound 1 a / is dissolved in 50 ml of 6N HCl and

10.0 ml dioxane. Distilling off the solvent gave the title compound which was used without further purification.^Řcis-4-Methyl biphenyl-2-sulfonamide.

To a suspension of 3.1 g (140 mmol) of compound 1 b) in 200 mL

6N HCl was added at -10 ° C to 7.9 g (14 mmol) of sodium nitrite * to give a clear solution. T_entc is added at 0 ° C to a solution prepared from 20.0 ml of glacial acetic acid, saturated with Sp, 17 g of CuGlg · H 2 O._and The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. 250 ml of EE are added, the phases are separated and the organic phase is dried over magnesium sulphate. Evaporation gave an oil which was dissolved in 300 mL of acetone. Finally, 150 ml is added. 25% ammonia and stirred for 2 hours. The mixture is concentrated, 500 ml of EE are added. The EE phase was washed once with water, dried over magnesium sulfate and evaporated. Chromatography on SiO2 with EE (HEP) (1) affords the title compound (4.6 g). R_F / EE / HEP '1/1 / = 0.25 WDCIA 248 At⁺+ H /

mp: 122 ° C.

vd / 4'-Methylbiphenyl-2-N, Ν-dimethylaminoformylsulfonamide

4.6. g./18.6 mmol (compound 1c) and 2.5 g (19.3 mmol)

The N, N-dimethylformamide dimethyl acetal in 30 mL of DME was stirred

-342 hours at room temperature, then added. 100 ml water. The resulting precipitate was filtered off with suction and air dried to give 4.2 g of the title compound.

H_F (EE / HEP 1/1) = 0.2 MS (DCI) -303 '/ M⁺+ H / e / 4 '* - Brooethylbiphenyl-2-N, N-dimethylamino-formylsulfonamide

To 3.76 g (13.5 mmol) of 1d and 2.4 g MBS (13.5 mmol) in 50 ml of chlorobenzene were added 150 mg of benzoyl peroxide. After 4 hours at reflux, the mixture is acidified, 50 ml of EA are added. and EE-phase. se. washed 1x with 10% solution; Na 2 SO 4 and 1x. water ,. Po.sušení. The mixture is concentrated and chromatographed on SiO2 (eluent EE / HEP 2/1). It is obtained

1.2 g of the title compound.

(B)_F (EE / HEP 2/1) - 0.23 MS (DCI) = 381, 383 / &amp;⁺+ K / $ / 2-nr.3uyl-4-chloro-5-formyl-imidazole

To 20 g (0.106 mol) of 2-tert-butyl-4-chloro-5-hydroxymethylimidazole (produced according to EP-A 253310) in 350 ml of ice. of acetic acid at 10-15 ° C is slowly added 305 ml

Of a 1M solution of (1 H 2 O) / water (N 2 O). After 2.5 h at room temperature, the reaction mixture was stirred at room temperature. adjusts the pH_T2H value of KOH at 4/20 ° C during. addition of base was extracted 4 times with 500 ml of CH2Cl2 each time and combined with ethereal extracts. is saturated with an aqueous sodium bicarbonate solution, dried with sodium sulphate

Evaporate to give the title compound as a colorless solid (18 g, 92%).

tt = o o ° σ fi_F (PIP / MTB '· 1/1) - 0,5 g (1-Z) 2 5-N, Ν-Dimethylsminoformylsulfonamidobiphenyl-4-yl-methyl-7'-n-butyl-4-^andchloro-imiaazole-5-carboxoleic acid. 690 mg (1.98 mmol) of compound 1e, 370 mg (1.98 mmol) of compound 1f and 270 mg (1.98 mmol) of potassium carbonate were stirred for 2 hours in DME (10 ml) at room temperature. At-..

-35It is. 50; ml._;ES and washed twice with water. The organic phase is dried (sodium sulphate) and evaporated. neSiÓg. .... help. ES / HEP (2/1) as eluent to give the title compound (380 mg, 40 (EE) / HEP / (2/2) = 0.1.5 MS (DCI) = 487 / M⁺+ H (h) 1- (2) -Sulfonamido-biphenyl-4-yl) -methyl-17-n-butyl-4-. ch o ri mi d az ol-5-k ar box al dehy d ...

280 mg (0.58 mmol) of compound (1g) in 7 mL of methanol and 14 mL of water. 110 mg (2.88 mmol) of sodium hydroxide are added and the mixture is heated at reflux for 4 h. After cooling to room temperature, the pH is adjusted to about 6 with 4N HCl and extracted with 3x30 ml. The EE-phase is dried (sulphate, sodium) and evaporated. , with the title compound.

β ^ '/ ΕΕ / ΗΕΡ2 / 1. / = Q, 45 MS / DCI /? 432 / &amp;⁺(H) (R) - (4-Penylaminocarbonyleminosulfonylbiphenyl-4-yl) -phenyl] -2-n-butyl-4-chloroimidazole-5-carboxaldehyde

730 mg (1.69 mmol) of (1h) was heated in 10 ml. phenyl, isocyanate at 80^GC. After 4 hours, evaporate and chromatograph. The eluent (EE / HIP / 2/1) afforded 400 mg of the title compound.

(BE / HEP 2/1) = b, 15 MS (DCI) = 551 (M)⁺+ fí /

Alternative_production of 1d (4y-methyl-2-N, Nd imethylaminoformsulfonamide)

K. g (37.9 mmol) of 2-N, N-dimethylaminoformylsulfoneabidobromobenzene (made from 2-bromoaniline analogously to 1b) d) g of triphenylphosphine, 8 g of sodium carbonate in 50 ml of toluene and 40 ml of water are added under argon at first 420 mg of Pd (OA2) and finally 5.66 g (41.9 mmol) of 4-tolylboronic acid. of acid in 100 ml of ethanol. It is then heated to boiling for 4 hours. Evaporate and remove into 500 ml of ethyl acetate ε 500 ml of water. The resulting precipitate is filtered off and filtered

<img file="CS9200010A3_D0020.tif" />

-36 is characterized as the title compound. The ethyl acetate phase is separated, dried (sodium sulfate) and evaporated; Chromatography on SiO₂ ethyl acetate gave a longer fraction of the title compound (total 7.6 g = 66%).

Alternative production of 2-bromobenzenesulfonamide (analogous to step 1c) to 4.7 g of 2-bromothiophenol in 60 ml of water is introduced at 0-10 ° C for 30 minutes with chlorine gas. It is then stirred for 30 minutes at 0 ° C and then air is bubbled through the solution for 30 minutes without cooling. After addition of 60 ml of acetone and cooling again to 0 [deg.] C., 10 ml of a saturated NH4OH solution are slowly added dropwise. After a further 30 min, the pH of the solution is adjusted to 3 with 4 N HCl and the product is obtained by filtration.

Yield: 4-, 5- g- / 77-% / &lt;........ ........... - - tt = 190-191 ° CR_F(EE / H 1/1) = 0.4

Example 2._: ......

3-Methyl-2-n-propyl-amino-carbonylamino-phenyl-biphenyl-4-yl-methyl-7-n-butyl-4-chloro-imidazole-5-carboxaldehyde was carried out analogously to Example 1

R_F (EE) = 0.6 MS (FAB) = 517 Å⁺+ H /

- -...... ..... 0. , .. .

<img file="CS9200010A3_D0021.tif" />

-37Example 3..Synthesis1^and-/^-(2'-Pyridyl-2-aminocarbonylaminosulfonylbiphenyl-4-cyl) methyl-7-2-n-butyl-4-chloroimidazole-5-carboxaldehyde h₃c / -ch₂/₃

<img file="CS9200010A3_D0022.tif" />

€1

<img file="CS9200010A3_D0023.tif" />

SO8-NH-C-NH and (1'-Z) -2'-Ethoxycarbonylaminosulfonylbiphenyl-4-yl} -methyl-2-n-butyl-4-chloroimidazole-5-carboxaldehyde

To 1.1 g (2.5 mmol) of compound 1h and 0.78 g (5.6 mmol) of potassium carbonate in 20 ml of dried DME was added 0.48 ml (5.1 mmol) of ethyl chloroformate. . After 1 hour, it is allowed to cool to room temperature and 50 ml of a 10% potassium dihydrogen phosphate solution are added. After extraction with EE, it is dried over sodium sulphate and concentrated. Chromatography on 10 µg using EE (HEP / 2/1) as eluent gave 840 mg of the title compound.

(EE / HEP 2/1) = 0.32 MS (DCI) = 504 / M⁺+ H /

8/2-Z '/ 2 * -Pyridyl-2-thiaminocarbonylaminosulfonylbiphenyl-4-yl-methyl-7-n-butyl-4-chloro-imidazole-5-carboxaldehyde

150 mg / 0.3 mmol / Compound 3® / 8 28.5 mg / 0.3 mmol /

The 2-aminopyridine is stirred under boiling in 8 ml of dry toluene for 2 hours. It was then concentrated and chromatographed on 10g (eluent EE) to give 34 mg of the title compound.

R_F (EE) methanol 10 (1) = 0.4 M 3 (PAS) = 552 / M⁺+1/

The compounds of Examples 4-39 were synthesized in analogy to Example 3.

These compounds have the following general formula A

<img file="CS9200010A3_D0024.tif" />

/IN

0'

Μ

SOgNHC-HR

Η

Table 2.

Example MS position

<img file="CS9200010A3_D0025.tif" />

h ^ⁿ

6/18/558 3 72 V

<img file="CS9200010A3_D0026.tif" />

7/19/ 559 372 7 /20 597 3727

9/21/ 541 3727

<img file="CS9200010A3_D0027.tif" />

<img file="CS9200010A3_D0028.tif" />

-39All ice (22) (23) (24) (25) (26) (27) δ ··· 29

MS

FAB; M⁺+ H)

596

596

569

569

631

631

552

580

586

584 complete substitution

3’ (2')

3' (2')

3' (2’)

3’ (2')

3' (2*)

3' (2’) '

2' '

'

<img file="CS9200010A3_D0029.tif" />

u&gt;.

-40Continuation of half 2

Př.íkied

MS

FAB; M⁺+ H) half fat

572 2'

581 2'

595 2 '

565 2 ' .565 2'

579 2'

583 . 2'

589 2'

<img file="CS9200010A3_D0030.tif" />

^ CH-CO₂CH₃ (£)

-41Example 4.0 - -.......... ..............

Synthesis of 1- (2'-phenylaminocarbonylaminosulfonylbiphenyl-4-yl) -methyl-7-n-butyl-4-chloro-5-hydroxymethylimide azole

100 ALIGN! Compound 1 mg (0.18 mmol) was dissolved in ethanol (5 ml) and treated with sodium borohydride (10 mg, 0.27 mmol) at room temperature. After 20 hours, 10 ml of 5% sodium bisulfate solution was added and extracted 3x with EE. The organic phase was dried over sodium sulfate and evaporated. Chromatography on SiO₂ EE (HEP / 3/1) gave 55 mg of the title compound.

R_F (EE / HEP // 3/1) = 0.25 MS (DCI) = 553 (M)⁺+ H /

The compounds (Formula B) of Examples 41-54 were synthesized in analogy to Example 40 of the compounds of Examples 2, and 16-27 (Table 3).

Table 3 ^h3c- / ch₂7^

Cl —CH₂OH

<img file="CS9200010A3_D0031.tif" />

SO₂NHC-NH-S

II / B /

<img file="CS9200010A3_D0032.tif" />

Example MS / FAB; M⁺+ R /

519 n-propyl

554 // Λ

-42&gt;.

Continue tcbulk 'r? L ni aci

K5

FAB; M⁺+ H)

555

545

560

<img file="CS9200010A3_D0033.tif" />

561

<img file="CS9200010A3_D0034.tif" />

599

<img file="CS9200010A3_D0035.tif" />

543

X NH

598

598

<img file="CS9200010A3_D0036.tif" />

no₇ b

Ř.

-43Continuation Table 3

-Example - MS / FAB, M⁺+ H / ...... - —R

<img file="CS9200010A3_D0037.tif" />

Example 55

Preparation of 1 - [- (2-allylaminocarbonylaniinosulfonylbiphenyl-4-yl) -methyl] -2-n-butyl-4-chloro-imidazole-5-carboxaldehyde

<img file="CS9200010A3_D0038.tif" />

-44., 730 mg. (1.69 mmol) of compound 1h) was heated in 80 ml of allyl isocyanate to 80 ° C. After 4 hours, evaporate and chromatograph. to SiO 2 (eluent EE / HEP / 2/1) to give 400 mg of the title compound,

R_F[EE / HEP2 / 1] = 0.15 MS (FAB) = 515 (M)⁺+ H /

Example 56

Produce both 1- (2 ') - 2-allylaminocarbonylamino with ulphonylbiphenyl-4-yl-methyl 17-2-n-butyl-4-methylthioimide azole-5-carboxylic acid

<img file="CS9200010A3_D0039.tif" />

a) 2-Amino-2-cyano-acetic acid ethyl ester. Ke, 35 g (0.246 mol) of 2-cyanoglyoxylic acid 2-oxime (as ethyl ester) in 350 ml of water and 280 ml of saturated sodium bicarbonate solution are added. 119 g of sodium dithionite was added portionwise at room temperature (15 min). It is then heated at 35 ° C for 1 hour and then extracted after saturation with NaCl 5x: dichloromethane. After drying over calcium chloride, the organic phase is evaporated. 11.8 g of the title compound are obtained as an oil.

R_F / CH₂NO. 1₂/ CH₃OH 9/1 = 0.6.

-45 j-b / 2-Cyano-2-n-butylcarbonylaminoacetic acid ethyl ester * - * v / piny

Ke 3.6 g? (28.09 mmol) of compound 56a / τ 50 ml dried. of CH 3 Cl 2 and 2.3 ml (28? 09 mmol) of pyridine are added dropwise at -5 ° C to 0 ° C.₂NO. 1₂. Then. is stirred for 1 hour at room temperature. The organic phase was then washed 3x with water and 1x with saturated NaCl solution, dried. and evaporated.

Crystallization from DIP afforded 1.7 g of the title compound.

R_F / CH₂NO. 1₂/ CH₃OH 9 (1) = 0.35 mp: 87 ° C c) 3-Amino-2-n-butylcarbonylamino-methylthioacrylic acid ethyl ester

To 2.9 g (13.67 mmol) of 56b and 0.19 ml (1.36 mmol) of triethylamine in 60 ml of absolute ethanol was added, at room temperature, 2 ml (27.26 mmol) of condensed methyl mercaptan. After 3 days, 0.5 ml of methalmercaptine was added. After a further 24 hours at room temperature, 0.5 ml of methyl mercaptan was added via syringe. and 0.19 ml of triethylamine and stirred at room temperature for a further 24 hours. Finally, the solvent was distilled off and the residue was crystallized from DIP, leaving 2.4 g of the title compound.

R_F / CH₂NO. 1₂[EE 4/1] = 0.3

mp: 120 ° C d) 2-n-Butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester

4.17 g (20.0 mmol) of phosphorus pentachloride in 20 ml of CH₂NO. 1₂ 2.44 g (20.0 mmol) of 4-dimethylaminopyridine in 12 ml of CH 2 Cl 2 are added dropwise at -78 ° C. After 5 min, 2.42 g (10.0 mmol) of 56c in 25 mL of CH 2 Cl 2 was added dropwise. The temperature is. The mixture was allowed to warm to room temperature and diluted with 30 mL of CH₂NO. 1₂After 2 hours 300 ml of TN sodium bicarbonate solution are added under ice-cooling and stirred for 1 hour. The phases were then separated, and the aqueous phase was extracted with 3xEE

-46a combined, organic phase. is dried with calcium chloride. Chromatography on SiO₂ CH 2 Cl 2 (EE) (9/1) gave the title compound.

/ Cff₂Cl₂/ EE 9/1 / -0.6. MS (DCI) = 243 / M⁺+ H / e / Ethyl ester 1 - ^ '/ 2 * -_sllIfonamidobiphenyl-4-yl / “methyl-7-n-butyl-4-methylthioimidazole-5-carboxylic acid • To 1.35 g (2.5 mmol) of 1-Z” / 2 * -N, N-dimethylaminoformamyl sulfonamido-biphenyl-4-yl / methyl 17-2-n-butyl-4-methylthio-imidazole-5-carboxylic acid ethyl ester produced from Example 56d and Example; (E) (analogously to Example 1 g) in 30 ml of methanol, 15 .mu.l of conc. HCl. After 90 min under reflux, the mixture was allowed to cool to room temperature and the pH was adjusted. 2N. NaOH solution to 5-6. Extract each time with 100 ml of EE 3x, dry the organic extracts with sodium sulfate; and evaporated, the title compound precipitated as a foam and was used without further purification for the next reaction step.

R_F (EE / HEP, 1/1) = 0.2 MS (FAB) = 488 (M + H) +. The title compound 56 was obtained by taking 120 mg of ethyl ester. 1 - /^?(2 * -allylaminocarbonylamino-sulfonyl-biphenyl-4-yl) -methyl-7-n-butyl-4-methylthio-imidazole-5-carboxylic acid (obtainable according to Example 55) in 10 ml of ethanol. and 1 ml of 2N sodium hydroxide solution, stirred at room temperature for 4 days. It is then evaporated, water is added and the pH is adjusted to 4 with 1N HCl, whereby the title compound precipitates and is isolated by filtration.

(EE / MeOH 10/1) = 0.1 MS (FA 3) = 543 (M + H)

Example 57

Synthesis of 1- (R) -2-n-Ethylethyl-2-amino: carbonyl amino sulfonylbiphenyl-4-yl / methyl 17-2-n-butyl-4-methylthioimidazole-4-carboxylic acid

<img file="CS9200010A3_D0040.tif" />

<img file="CS9200010A3_D0041.tif" />

<img file="CS9200010A3_D0042.tif" />

jSO₂-NH-C-NH-CH₂-CH₂

<img file="CS9200010A3_D0043.tif" />

a) 1- (2-ethoxycarbonylamino-sulfonylbiphenyl-4-yl) methyl-7-n-butyl-4-methylthioimidazole-5-carboxylic acid ethyl ester, 21 g (2.5 mmol) of compound 56e and 0.78 g (5), 6 mmol of potassium carbonate in 20 ml of dried DME is heated to boiling and 0.48 ml (5.1 mmol) of ethyl chloroformate are added. After 1 hour, the mixture was allowed to cool to room temperature and 50 ml of 10% potassium dihydrogen phosphate solution was added. After extraction with EE, it is dried over sodium sulfate and evaporated. Chromatography on SiO₂ EE / HEP (2/1) gave 840 mg of the title compound.

(EE / HEP 2/1) = 0.5 MS (DCI) = 559 7M⁺+ H / b / 1- (N ') - (2'-Pyridyl-ethyl-2-aminocarbonylaminosulfonyl-biphenyl-4-yl) -methyl-2-n-butyl-4-methyl-thioimidazolo-5-carboxylic acid ethyl ester

168 mg / 0.3. mmol (Compound 57a) and 37 mg (0.3 mmol)

2- (2-Aminoethyl) -pyridine was heated to boiling in 8 ml of dried toluene for 2 hours. It was then evaporated and chromatographed on SiO2 (eluent EE) to give 34 mg of the title compound. ,

R_F (EE) = 0.15 MS (FAB) = 636 (M)⁺+ H (c) The title compound 57 was obtained analogously 56f).

R_F (EE / MeOH 5/1) = °, 1 MS (FAB) = 608 (M + H) + - 4

-, .. -48TlJ * '· * »' * '

In a manner analogous to Example 57, the compounds shown in Table 4 can be synthesized.

These compounds have the following formula C.

<img file="CS9200010A3_D0044.tif" />

<td>Example</td><td>MS FAB, M⁺+ H '</td><td>Ή R</td><td>R -</td>

<td> 58' ' '-*·</td><td> '571 '</td><td>C₂h₅ .....- CH₂—# ‘</td><td>H '</td>

<td> 59</td><td> 585</td><td>- o</td><td>H</td>

<td> 60 ,</td><td> ' 599</td><td>H -CH₂&lt;)</td><td>H</td>

<td> 61</td><td> 583</td><td>H ~ CH₂—</td><td>-ch₂—</td>

<td> 62</td><td> 611</td><td>H - / CH₂/-£)</td><td>H</td>

<td> 63.</td><td> 668</td><td>H - / CH₂/₂- \ OV^N° 2 If⁷</td><td>H-</td>

<td>Example</td><td>MS FAB; M⁺+ H</td><td>R</td><td>R '</td><td>R</td>

<td> 64</td><td> 541</td><td>'H</td><td>-CH₂-eH</td><td>H</td>

<td> 65</td><td> 636</td><td>^C2^H5</td><td></td><td>H</td>

<td> 66</td><td> 635 '/</td><td>C₂h₅</td><td>- (. Y₂/£&gt;</td><td>H</td>

<td> 67</td><td> 607</td><td>H</td><td></td><td>H</td>

<td> 68</td><td> 659</td><td>^C2^H5</td><td rowspan="2">Γ H ^ I ^ OO ^ CH,² 3 (S)</td><td>H</td>

<td></td><td></td><td></td><td></td>

<td> 69</td><td> 645</td><td>C₂h₅</td><td>^H3^C -CH · '' i</td><td>H</td>

<td></td><td></td><td></td><td>H 2 O 2₂CH₃(WITH)</td><td></td>

<td> 70</td><td> 657</td><td>^C2^H5</td><td></td><td>H</td>

<td> 71</td><td> 603</td><td>C₂h₅</td><td>Hf — CO-O-¹ (WITH) -ch₂-what₂ch₃</td><td>H</td>

<td> 72</td><td> 693</td><td>^C2^H5</td><td>í θ! CHo and ¹ ÍS) ! Hj: - &lt;O2C^H3</td><td>H</td>

<td> 73</td><td> 621</td><td>C₂h₅</td><td>-ra₂_θ</td><td>H</td>

<td> 74</td><td> 703</td><td>^C2^H5</td><td>- &lt;α₂)₂- (ο \ σ₃</td><td>H</td>

Fokračovční tabulky 4

Example

NS

FAB; M⁺+ H

<img file="CS9200010A3_D0045.tif" />

51tabulkj

MS

FAB; M

651

627.

⁶¹¹

635

653

623

639

681

623

611

R '

R + H ^C2 ^H5 ^C2^H5

<img file="CS9200010A3_D0046.tif" />

C₂h₅ - CH₂-CH₂-í ^ ^C2^H5 ⁰ of^-001? H

<img file="CS9200010A3_D0047.tif" />

^C2^H5 '2ⁿ5

<img file="CS9200010A3_D0048.tif" />

OCH.

h3&gt;

H -CH, ^ A) ·¹

H -CK-X O) -F.

-52Pokr ε

Tebulk.y &lt;

-d

MS

FAB; M⁺+ H

R ”

100

101

102

103

104

635

625

561

651

607

625

597

579

677

649 ^C2^H5 ^C2^TO5 C₂h₅^C2^H5

<img file="CS9200010A3_D0049.tif" />

<img file="CS9200010A3_D0050.tif" />

&lt;°)-^F

- @ - F &lt;D

-0-j

53Fokra ·;

Filing Tables 4

2d 'MS R' R '. R

FAB; M⁺+ H

105

106

107

108

109

110

111

112

113

114

573

545

616

614

557

585

642

594

594 C₂h₅ - (ch₂).₂-ch₃

H - {CH₂)₂-CH₃^H -^(CH2&gt; 2-O

Η - ^₂)₂-Ο

N

AND

CH₃^H -^CHrXj ^C2 «5 - -CH ^ -

<img file="CS9200010A3_D0051.tif" />

<img file="CS9200010A3_D0052.tif" />

^C2 »5 - (CH) -ON

638

-54MC

R '

R υ ?.

7? -ⁱⁿ- «&lt;&gt; 2. £ ž

FAB; Μ + H

115

594

116

628

117

628

118

628

- - 14-0&lt; -6-44

120 '600

121

642

122

614

123

651

124

623

<img file="CS9200010A3_D0053.tif" />

-55Baptism Ο '.' Ϊ́

Example of a table

MS RR '

FAB; M⁺+ H

R

125

126

127

128

129

130

131

132

133

134

623

661

633

665

637

600

642

665

637

667

H

<img file="CS9200010A3_D0054.tif" />

CH

2\.

CH

<img file="CS9200010A3_D0055.tif" />

H

- {Ο ^ ς ^C2^H5 ^C2^H5 ^C2^H5

-⁽®2&gt;2

-O ί-θ ·

- (CH₂)₂- (O) -CMe

-QMe

-56 • -'j

Example sd 'i-; s

-, tr

FAB; Μ + H

135 639

H -CH.

136 664

137 636, -0-ΝΙ

2ⁿ5 ^ 2Λ ^at y-IN (CH₃)₂ H

CoHq —CH

H -CH₂- ^ O ^ -N (CH₃,₂

57 The compounds of the following Table 5 can be synthesized in analogy to Example 57.

These compounds have the following formula D:

<img file="CS9200010A3_D0056.tif" />

Table 5

Get MS. RR *

FAB, M + + H.

<img file="CS9200010A3_D0057.tif" />

-58If ον

Exercise 5

MS

FAB; M⁺+ H

R '

144

145

146

147

148

149

617

603

714

583

686

575 C₂h₅.

^C2^H5 ^C2^TO5

IN

-N ^ S _ 7 ^{Z AK}

-N -NCOH \ __ S H * o

-N ε v_ /

-N ^ S

-59Example 150., .... ·· ......

Production of 1- (2-Behzoylcarbonylaminosulfonyl) -biphenyl-4-yl7 **^methyl-2-n-butyl-4-chloro-imidazole-5-carb aldehyde

<img file="CS9200010A3_D0058.tif" />

The title compound 150 was obtained by taking 215 mg (0.5 mmol) of compound for 1 h, 71.3 (U1) (0.5 mmol) of chloroformic acid benzyl ester and 70 mg (0.5 mmol) in 10 ml of DMF. (anhydrous) 1.5 h under reflux. Concentrate, add 100 ml of EE and wash each time with 1 x 40 ml of sodium hydrogen sulphate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated on a rotary evaporator. Chromatography with MTB afforded 120 mg (42%) of the title compound 150%. mp 56 ° C.

R_F [MTC] = 0.20 MS (FA3) = 566 (M)⁺The compounds of the following Table 6 were synthesized in analogy to Example 150 and Example 1, respectively. 57a.

These compounds have the following general formula (E):

-60 • ffl

<img file="CS9200010A3_D0059.tif" />

Table 6

MS RR example *

FAB; M⁺+ H '' '⁴- - · R

151

152

153

154

155

156'

157

158

159

674

646

558

556

558

618

590

666

628

-OC₂H₅ -CHg-CHg-Ph-SMe

-OH -CH₂-CH₂-Ph -SMe

-OH -CH₂-CH₂-CH = CH₂ -SMe

-OH -CH₂-CH₂-e = CH. -SMe

-OH -CH,

-SMe

-OC₂H₅ -CH₂-CH₂-O-i-Pr -SMe

-OH -CHg-CHg-Oi-Ex-SMe

-OC₂H₅ -CH₂-CH₂-O-CH₂-Ph -SMe.

-oc₂h₅ -ch₂-I {33

-SMe

-61P ckr č b í p tpbu 1 k .v 6

Example MS R

FAB; M⁺+ H

R '

R ”

<td> 160</td><td> 600</td><td>-OH</td>

<td> 161</td><td> 648</td><td>-oc₂:</td>

<td> 162</td><td> 620</td><td>-OH</td>

<td> 163</td><td> 628 ·</td><td>-oc₂:</td>

<td></td><td> -</td><td></td>

<td> 164</td><td> 600 .</td><td>-OH</td>

<td> 165</td><td> 572</td><td>-OH</td>

<td> 166</td><td> 558</td><td>-OH</td>

<td> 167</td><td> 572</td><td>-OH</td>

<td>16S</td><td> 598</td><td>-OH</td>

<td> 169</td><td> 556</td><td>-OH</td>

<td> 170</td><td> 560</td><td>-oc₂</td>

<td> 171</td><td> 532</td><td>-OH</td>

<img file="CS9200010A3_D0060.tif" />

-CH₂-CH = CH-Ph

-CH₂-CH = CH-Ph

<img file="CS9200010A3_D0061.tif" />

-CH₂-CH = C (CH₃)₂.

-ČH₂(CH₃) = CH₂

-ch₂-ch₂-ch₂-ch = ch₂

-CH?

-CH 2 -C = C-ch₃

-ch₂-ch₃

-ch₂-ch₃

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-SMe

-62Pokrr-jovar-l ·. 1 n.buiL, · e? * · *! 1 * J C ..

MS

FAB; M⁺+ H

R '

172

173

174

175

638

600

584

556·

OH -CH₂-CH₂-O-CH₂-Ph • oc₂h₅

176 611

177 612

-OH -CH.

<img file="CS9200010A3_D0062.tif" />

CH-OH-CH-H

-H

<img file="CS9200010A3_D0063.tif" />

R

-SMe

-SMe

-SMe

-SMe

Cl

WHOSE

-63'1

I •₍ Example 78

Ethylester. 1- [2'-Dimethylsulfamoylaminosulfonylbiphenyl-4-yl] -methyl-7-n-butyl-4-methylthiimidazole-5-carboxylic acid_inacids

<img file="CS9200010A3_D0064.tif" />

<img file="CS9200010A3_D0065.tif" />

<img file="CS9200010A3_D0066.tif" />

The title compound 178 was obtained by 244 mg (0.5 mmol) of compound 56e. 108 [mu] l (1.0 mmol) of sulfamoyl chloride and 140 mg (1.0 mmol) of potassium carbonate in 10 ml of DME (anhydrous) were heated to reflux for 5 days. It is then diluted with 50 ml. EE. a. wash with 50 ml KHSO 4 (H 2 SO 4) (pH = 1.0). Organic. the phases are dried. over sodium sulfate and evaporated on a rotary evaporator. Chromatography with EE yielded 69 mg (23%) of a colorless oil.

(ES) = 0.15 MS (FAB) = 6.17 (M)⁺+ Na /

Example 179

Preparation of 1- [1- (2-dimethylsulfamoylaminosulfonylbiphenyl-4-yl) -methyl] -2-n-butyl-4-methylthioimidazole-5-carboxylic acid

<img file="CS9200010A3_D0067.tif" />

mg (84 yumol) of the title compound of Example 178 and 0.84 ml of 1N NaOH. Dissolve in 3 mL of ethanol and stir at room temperature for 2 days. Ethanol is distilled off, 5 ml of water are added and the pH is adjusted to 2 with HCl. The precipitate is washed. 2.times.1 ml of water and dried in vacuo. 33 mg (70%) of a colorless powder are obtained.

WITH_F (EE) methanol (5: 1) = 0.11 MS (FAB) = 567 (M)⁺+ H / Example 180

1- (2'-Allyloxycarbonylaminosulphonyl-biphenyl-4-yl) methyl-7-n-butyl-4-methylthiimidazole-5-carboxylic acid ethyl ester ·

<img file="CS9200010A3_D0068.tif" />

ii fi i!

£

Íí

Cj i

\

-65.244 mg (0.5 mmol) of compound. 56 e), 106 µl (1.0 mmol) of allyl chloroformate and 140 mg (1.0 mmol) of potassium carbonate were boiled under reflux for 1 h. Then 50 ml of 10% potassium hydrogen sulphate solution are added and extracted 3 times with 50 ml of EE each time. The organic phase is dried over sodium sulphate and evaporated. Chromatography with MTB / DIP 1: 1 gave 115 mg (40%) of a colorless oil.

R_F (MTB / DIP // 1: 1) = 0.15 MS (FAB): 572 (M)⁺+ H7

Example. 181

The 1- (2'-allyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl-7-n-butyl-4-methylthioimidazole-5-carboxylic acid sythesis of mg (0.17 mmol) of compound 180 is saponified. as described in Example 179. 30 mg (33%) of a colorless foam are obtained. R_F (EEA nOH 10: 1) = 0.1. MS (FA 3) = 544

Example 182

1- (2'-Benzyloxycarbonylaminosulfonyl-biphenyl-4-yl) -methyl-7-n-butyl-4-methyl-thiimidazole-5-carboxylic acid ethyl ester

<img file="CS9200010A3_D0069.tif" />

The title compound was synthesized in analogy to Example 180. Rf_F./MTB/DIP 1: 1 / = 0.15 MS (FA 3) = 622 / M⁺+ H /

<img file="CS9200010A3_D0070.tif" />

-66&lt;

í i

»

EXAMPLE 183 2- (2-Benzyloxycarbonylaminosulfonyl-biphenyl-4-yl) methyl

2-n-butyl-4-methylthiimidazole-5-carboxylic acid

N&gt; —— S-HR

<img file="CS9200010A3_D0071.tif" />

The title compound was synthesized in analogy to Example 181.

(EE / MeOH 10: 1) = 0.1 MS (FAB) = 594 / M⁺+ H /

Example 184

- 2 • * - Allyl aminocarbonyl aminosulfonyl / -biphenyl-4-ylmethyl} -2-tert-butyl-4-methoxy-imidazole-5-carbonyl aldehyde

<img file="CS9200010A3_D0072.tif" />

-βίο (1,2'Sulfonamidobiphenyl-4 * yl) -methyl] -2-n-butyl-4-methoxy-imidazole-5-carb aldehyde

5‘ _{; j} 215 mg (0.5 mmol) of compound (1 h) and 1.5 mol of 1N NaOH were boiled in 10 ml of methanol for 19 h under reflux. Then. methanol is distilled off on a rotary evaporator?, the pH is adjusted to 2 with? sodium sulfate and extracted with 50 ml of EE 3 times. The organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. Chromatography with MTB (DIP) (1: 1) afforded 170 mg (30%) of the title compound.

mp = 189 ° C, Rt_F [Alpha] DB / DIP 1: 1 / = 0.19 MS / DCI = 428 / M⁺+ H (b) The title compound 184 was obtained by boiling 150 mg (0.35 mmol) of compound 184a and 3 ml of allyl acetate for 5 h. at reflux temperature. Finally, it is concentrated on a rotary evaporator and chromatographed with EE. 60 mg (34%) of a colorless foam are obtained.

R_F (EE) = 0.34 MS (FAB) = 511 / M⁺+ H /

Fřlklad, 185

1- (trans) -2-Ethoxycarbonylaminosulfonyl-biphenyl-4-yl-methyl-2-n-butyl-4-methoxy-imidazole-5-carbaldehyde

<img file="CS9200010A3_D0073.tif" />

O

<img file="CS9200010A3_D0074.tif" />

<img file="CS9200010A3_D0075.tif" />

-681.0 g: (2.34 mmol) of compound 184a) is dissolved in 50 ml of water and dried in vacuo. of acetone (anhydrous) was added 650 mg. The reaction mixture was heated to reflux temperature, then 0.45 ml of ethyl chloroformate was added slowly via syringe._t whose. Heat for an additional 4 hours. and then evaporated on a rotary evaporator. Using a hydrogen sulphate solution. The pH is adjusted to 2 with sodium, the mixture is extracted 3 times with 100 ml. each of it is dried over sodium sulphate and evaporated on a rotary evaporator.

MTB / DIP / HO Ac (15: 83: 2) chromatographed. The oil obtained may be crystallized from diethyl ether. 550 mg of colorless crystals are obtained, mp 134 ° C.

R_F (MTB) = 0.24 MS (FA 3) = 500 / M⁺+ H /

Example: .186 *

<img file="CS9200010A3_D0076.tif" />

<img file="CS9200010A3_D0077.tif" />

Example 186 was synthesized analogously to Example. 185. R_F (MTB) = 0.16 MS (FAB) = 562 (M)⁺+ H /

-69Translate. 187 .,

Ethylester ^C 1-tert-2-Benzyl aminocarbonylmino-sulfonyl-1-biphenyl-4-yl-7-methyl-4-n-butyl-imidazole-5-carboxylic acid

<img file="CS9200010A3_D0078.tif" />

To 150 mg (0.24 mmol) of the compound of Example 73 dissolved in 50 mL of MeOH and 5 mL of HQAc was added catalytic amounts of Pd / C. The mixture was stirred under a hydrogen atmosphere for 12 h at room temperature. The mixture was then rotary evaporated and chromatographed with EE. 30 mg (22%) of a colorless foam are obtained.

(EE) - 0.42 MS (FAB) = 575 (M)⁺+ H /

Rříklaď188

Ethyl ester 1 - ^ $ * "^Etboxycarbonylaminosulfonyl / -biphenyl-4-yl-7-methyl-2-n-butyl-imidazole-5-carbonic acid

-70v

<img file="CS9200010A3_D0079.tif" />

To 300 mg (0.5 mmol) of Compound 57 and dissolved in 10 mL of EtOH was added about 200 mg of Raney nickel. Heat under reflux for 10 h, add an additional 200 mg of Raney-nickel and re-heat at reflux. ..Catalyst. The mixture was filtered and the solvent evaporated on a rotary evaporator. The residue was chromatographed with MTB to give a 50 mg (18%) colorless foam. Rf (EE) = 0.27 MS (FAB) = 514 (M)⁺+ H /

Example. 189 ..

1- [N- (2 * - (Thienylsulfonylaminosulfonyl) -biphenyl-47-yl] -methyl] -2-n-butyl-4-methylthiimidazole-5-carboxylic acid ethyl ester. ...

<img file="CS9200010A3_D0080.tif" />

-71244 mg (0.5 mmol). of the sulfonamides of Example 56e are dissolved in 10 ml of diethylene glycol dimethyl ether (anhydrous). 346 mg (2.5 mmol) of KgCO3 and 81 mg (0.5 mmol) are then added.

Of 2-thienylsulfonyl chloride. The reaction mixture is poured onto a cooled reaction mixture into 50 ml of 5% sodium hydrogen sulphate solution and extracted 3 times with 50 ml of EE each time. 310 mg of pale yellow crystals were obtained, mp = 120-122 ° C.

R_F(EE) = 0.24 MS (FAB) = 634 (M)⁺+ H /

Example: 190

1- [2 * - 12-Thienylsulfonylaminosulfonyl-1'-biphenyl-4-yl] methyl7-2-n-butyl-4-methylthioimidazole-5-carboxylic acid

<img file="CS9200010A3_D0081.tif" />

Saponification of the ethyl ester from Example 189 of Example 56f '

R_F [EE] (MeQH 5: 1) = 0.13 MS (FAB) =

The compounds in the following table are performed analogously

606 / M⁺+ H] can be synthesized in analogy to Example 189 and Example 189, respectively. Example 190 / resp. 56f /.

These compounds have the following formula F:

<img file="CS9200010A3_D0082.tif" />

Table 7

MS / FAB /

Example M⁺+ HR

<td> 191</td><td> .673</td><td>4-nitrophenyl</td>

<td> 192</td><td> 645</td><td>H.</td>

<td> 193</td><td> 579</td><td>^C2^TO5 ^C2^H5</td>

<td> 194 ' </td><td> 634 '</td><td>2-thienyl ·</td>

<td colspan="3">Priklaď 195 1- / 2'-Methylaminocarbonylaminosulfonylbiphenyl- 4-yl-methyl-2-n-butyl-4-methylthioimidazole-5-carboxylic acid acid</td>

<td>To v 50. ml warms up</td><td>autoclave to toluene at 80 to 80 R c for 8 h.</td><td>1 g of the sulfonylcarbamate of Example 57 ° C was introduced with methylemine for 5 min. It is then evaporated under vacuum and the residue is chromatographed.</td>

“73matograph. on. silica gel. (EE) n-HEP 2 (1), the title compound precipitated as. amorphous powder.

R_F[EE] n-HEP2 (1) = 0.1 MS (FAB) = 545 (M)⁺+ H /

Analogously to Example 195 or FIG. of Example 56f, the compounds in the following Table 8 / compounds of Example 195 can be synthesized. also listed.

These compounds have the general formula C k₃c - / ch₂/ j ^

<img file="CS9200010A3_D0083.tif" />

/C/

SO 2 NHCl 2: - rt - rt 0

<img file="CS9200010A3_D0084.tif" />

-74Table 8

<td>Example</td><td>MS (FAB) M;⁺+0</td><td>R</td><td>R *</td><td>P</td>

<td> 195</td><td> 545</td><td> -^C2^H5</td><td>-ch₃</td><td> (</td>

<td> 196</td><td> 517</td><td>H</td><td> -ch₃</td><td></td>

<td> 197.</td><td> 559</td><td>^C2^H5</td><td> “^C2^H5</td><td></td>

<td> 198 </td><td> 531</td><td>H</td><td></td><td></td>

<td> 199*</td><td> 619</td><td>^C2^H5</td><td>-ch₂-ch₂-q-ch₂-ci £ Oh</td><td></td>

<td> 200*</td><td> 591 .</td><td>H.</td><td>-CH₂-CH₂-O-CH₂-CH₂-OH</td><td></td>

Compounds were synthesized in analogy to Example 57 / Example