Method of obtaining novel derivatives of azole

The present invention relates to a process for the production of new azole derivatives with pharmacological properties

The development of new angiotensin II receptor antagonists is of increasing importance. Caenzyl-substituted im6 derivatives are known from EP-A-28834

168 887 dazole, imidazole derivatives with diarylcarboxylic acid function are known from European patents EP-A-253310 and EP-A-0401030, known from European patent specification _n / inoQ2o .............

0-409332 are known triazole

Ll 1 1 Vł,

PnronpicViPon r \ r \ icn mtAntmrAfTfi ...... l) ivj | jUWiłł »» v ^ jL '* triazole derivatives with diarylcarboxylic acid function and from European patent specification EP-A-324377 imidazole derivatives with a diaryl-tetrazobiic group are known and their use as angiotensin II receptor antagonists.

In addition, German Patent No. DE-A-4010797 (corresponding to US Patent No. 07/679233) describes substituted azoles containing a sulfonylurea group.

New azole derivatives containing new sulfonylurea, sulfonylurethane or sulfonylsifonamide structures have been found to be highly active angiotensin II receptor antagonists both in vitro and in vivo.

The invention relates to compounds of the formula I in which the symbols have the following meanings: a / X, Y and Z are identical or different and represent N or CR², b / Ri is the 1st / C2-Ci <0 -alkyl group, 2nd / C3-C1-alkenyl group, 3rd / C3-C10 / alkynyl group, 4. -ORA 5. group / C3-C8 / -cykioalkllową. 6. group / C4-Clo / -cycloalkylalkyl, 7. group / C5-Cιl / -cykoalkylalkenyl, 8. group 9. group / CH2 / mB- / CH2 / "~ R4 10. benzyl group, 11. group specified in point b / 1., 2., 3. or 9. monosubstituted CO2R group³, The 12th group specified in b / 1., 2, 3 or 9, in which from one to all hydrogen atoms are replaced with fluorine, or the 13th group specified in b / 10, which on the phenyl radical is substituted 1 or 2 identical or different groups from a series of halogen atoms, (C 1 -C 4) -oxyl and nitro groups, c / R2 is 1. hydrogen, 2. halogen, 3. nitro, 4. group C_vF2v + 1, 5. pentafluorophenyl group, 6. cyano group, 7. -OR group, 8. phenyl group, 9. phenyl- / Cl-C3 / -alkyl group, 10. group / Cl-Cl (0-alkyl, 11. group / C3-C10-alkene, 12. phenyl / C2-C6 group^/-alkenyl, 13. group 1- ~ midazolyl- / CH2 / m-, 14. group 1,2,3- ~ riazole:) lilo- / CH2n-, 15. graphene tetπ: olyl- / CH2 / m-, 16 group - CH2 / oi-CHR⁷-OR⁵, 17. group -CH2 / 0-O-CO-R3, 18. group --CRU-R⁶, 19. group -S / O / rR! 20. -CH = CH- / CH2m-CHR3-OR group⁶, 21. group -CH2 = CH- / CH2 / m-CO-R⁸, 22nd group -CO-R⁸, 23. -OH = CH- / CH2 / mO-CO-R group⁷, 24th group —ΟΙΕ / πΓΟΙΗ / ΟΗν-ΟΟΑ, 25th group - / CH2 / o-CO-R8, 26th group of formula 4, 27th group of formula 5.28. a group of formula - CH2 / 0-NR7-CO-NHR⁹29. - / CH2 / o-NR7-SO2R group⁹,thirty. group of formula 6, 31. group -CHnE, 32. group - / CH2 / n-0-NO2, 33. group -Clis-ZN, 34. group --0Η2 /_η-02, 35. group -CH = N-NR5r7, 36. group of phthalimido- / CH2 / n ~, 37. group of formula 7, 38. group of formula 8, 39. group of formula 9. 40 group of formula 10 , 41. phenyl-SO2-NH-N = CH-, 42. group of formula 11.43. grupę9 - CH2 / n-SO2-NR7-CS-NR⁶R⁹, 14. group - / CH2 / n-SO2-NR7-CO-NR k9 45. group --CH2 / o-SO2R9, 46th group specified in c / 8. or 9. which in the phenyl radical is substituted with 1 or 2 identical or different groups from a number of halogen atoms, hydroxyl, methoxy, trifluoromethyl, CO2R³ and phenyl, 47th group specified in c / 10., 11. 19. in which one to all hydrogen atoms are replaced by fluorine, 48th group specified in c / 14. which is substituted with 1 or 2 identical or different groups from a series of methoxycarbonyl and / C1-C4 / dldl groups, 49th group / CH2 / n-SO2-NR7-CO-R6, 50th group -CI ^ r ^ -NR-CS-R⁶, d / R³ means 1. hydrogen atom, 2. (C1-C8) -alkyl group, 3. ^ -ν ^ ΜοΟύ ^^ group

4. a phenyl group, a 5th benzyl group or a 6th group as defined in point d / 2, in which 1 to all hydrogen atoms is replaced by fluorine, e / R4 is. 1. hydrogen atom, 2. (C1-C6) -alkyl group, 3. (C3-C8) -cycloalkyl group,

4. a / C2-C4 / alkenyl group or a / C2-C4 / alkalkyl group, f / R5 is the 1st hydrogen atom, the 2nd / C1-C ^ group, the 3rd / grupę3-θ8 / ^ group ΜοαΠύ ^^

4. phenyl group or 5. benzyl group, g / R⁶ and R9 are identical or different and represent 1. hydrogen, 2. radical / C1-6, which may be substituted by 1-3 residues, such as a / C1-C-alkoxy group, which in turn may be substituted by 1-3 residues from a number of hydroxyl, / C1-C6-alkoxy, amino, mono- / C1-C6-alkylamino, di-C1-C6-alkylamino groups, hereinafter such as the C2-C11 / alkenyl, hydroxyl, amino group, mono-AC-alkylamino, όί-ΑΤ-Ο © 168 887 alkylamino, / Ci-C6 / alkoxycarbonylamino, / C <, - Ci₂/ -aryl- / C 1 -C 4 -alkoxycarbonylamino, / C 6 -C 10 -aryl group, / C 6 -C 10 / -aryl- / C 1 -C 3 -alkyl, / C 1 -C 9 / -heteroaryl, carboxylic acid and / or ^ t1-Z-alkoxycarbonyl, 3.

groups / C1-C8-cycloalkyl, wherein the cycloalkyl part may still be substituted by 1-3 residues from a series of / C1-C4 / -alkyl and / C2-C4 / -alkenyl, 4. groups / C3-C8 / -cycloalkyl - / Ci-C3 / -alkyl, 5. groups / C6-Ci₂/ -aryl, preferably phenyl, 6. (C6-C10) aryl (C1-C4) alkyl groups, (C1-C9) heteroaryl groups which may be partially or fully hydrogenated, 8. groups defined in point g /

5., 6., 7., 9., 15., 16., 17., 19., 20. or 21., substituted with 1 or 2 identical or different residues from a series of halogen atoms of hydroxyl groups, / Ci-CZ- alkyl, methoxy, nitro, cyano, CO₂R \ trifluoromethyl, -NR^hR¹² and groups of formula 12. 9. (C 1 -C 9) heteroaryl / C 1 -C 3 alkyl groups, whereby the heteroaryl portion may be partially or fully hydrogenated, 10 C 1 -C 6 alkyl groups in which to all hydrogen atoms it is replaced by fluorine, 11. / C2-C10 / alkenyl, / C groups₂-Cio / -alkenoyl or / C₂Cio / -alkadienyl, 12. / C3-C8 / -cycloalkenyl groups, 13. / C3-C6 / -cycloalkenyl- / CiC3 / -alkyl groups, 14. Di- or tricyclic groups / C4-C10 / -cycloalkenyl- / Ci -C4 / -alkyl, which may still be substituted by 1-3 (C 1 -C 4) -alkyl groups, 15. C 6 -C 10 / -aryl- / C 1 -C 4 / -alkyl groups, 16 / C 6 -C 10 groups (-aryl- / C3-C6) -alkenyl, 17. / C1-C8-heteroaryl- / C3-C6 / -alkenyl groups, 18. / C3-C6 / -alkynyl groups, 19. / C6-Cio groups - aryl- / C3-C6 / alkynyl. twenty. / Ci-C9 / -heteroaryl - / C3-C6 / -alkynyl groups, 21. Ri R⁹ together with the N atom binding them they represent a heteroaryl group, which can also be partially or completely hydrogenated, h / R⁷ is hydrogen, 2. radical / C1-C6 -alkyl, 3. group / C3-C6 / -cycloalkyl, 4. group / C6-Ci₂/ -aryl- / C 1 -C 6 -alkyl, preferably benzyl, 5. phenyl group or 6. (C 1 -C 9) heteroaryl, and / R⁸ means 1. hydrogen atom, 2. (C1-C6) alkyl group, 3. (C3-C8) cycloalkyl group, 4. phenyl / CH2 / group_q-, 5th OR group⁶, 6th group NRⁿR¹² or 7. group of formula 12, j / R¹⁰ is cyano, nitro or CO2R⁷, k / R¹¹ and R¹² are the same or different and are 1. hydrogen, 2. C1-C4 / alkyl, 3. phenyl, 4. benzyl or 5. a-methylbenzyl,

1 / D means NR¹³, Ó or ĆH2, m / R¹³ is hydrogen, / C 1 -C 4 -alkyl or phenyl, n / A is biphenyl, substituted with R¹⁵ or together with R residues¹⁴ and R¹⁵,

O / R¹⁵ is the group -SO2-NR-CO-NR⁶R⁹, -SO2-NH-COO-R⁶, -SO2-NH-SO2-NR⁶R⁹, -SO2-NH-CO-R⁶ or -SO2-NH-SO2-R⁶or R¹⁴ and R¹⁵ together they represent the group -CO-NH-SO2,

P / w is O or S, q / L is a / C 1 -C 3 -alkanediyl group, r / R¹⁹ means 1. group / C1-CZ-alkyl, 2. group ACi-C6Acycloalkyl, 3. phenyl group, 4. benzyl group, or 5. group specified in point w / 1 in which one to all hydrogen atoms is replaced by fluorine,

S / m is an integer 0.5, t / n is an integer 1-5, u / o is an integer 1-10, v / q is 0 or 1, w / r is 0, 1 or 2, or x / v is an integer 1-6. and their physiologically acceptable salts, except for the compound of formula 1 a.

Alkyl, alkenyl and alkynyl groups can be straight or branched. The same applies to groups derived therefrom, such as alkanoyl or alkoxy groups.

Cycloalkyl groups should also be understood as rings substituted with alkyl radicals.

The (C6-C12) aryl group is, for example, a phenyl, naphthyl or biphenyl, preferably phenyl group. Tg itself relates to groups derived from it, such as an aroyl or aralkyl group.

068 887

The term "/ C1-C9 / -hetero2a-yl" means groups derived from a phenyl or kerosene group! in which one or more CH groups are replaced by N _____ GTT and / or in which at least one piece of the five aromatic ring / are replaced by S, NH or O. In addition, either or both the condensation positions of bicyclic residues (as in the indolizinyl group) may be N and ^ N atoms.

Heteroyl groups include, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pirarolyl, triazohl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, ithiazolyl, pyridyl, pyrazinyl, pyridinyl, indilidyl, pyridinyl, isochipolyl, phthalazinyl, quinoxalipyl, linyl, cypclipyl.

Any stereometry centers that may be present may have both the / R7 and / S / configurations.

Binding A occurs via the L-alkapodiyl bridge, which preferably represents a methylene group.

The methylene group is preferably directly linked to the diphenyl group.

As physiologically acceptable salts of the compounds of formula 0 are considered both organic and inorganic salts such as those described in Remington © Pharmaceutical Sciences / 07 Edition, p. 0408/0985 //. Because of the physical and chemical stability and solubility for acid groups, sodium, calcium, potassium and ammonium salts are preferred, for basic groups, among others, salts of hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic or sulfonic acids, such as e.g. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p- / oluenossfonic acid.

Compounds of formula 0 are preferred, wherein a / X is N, Y is Cr2, and Z is CR2 b / X is CR2, Y is N and Z is CR2, c / X is CR2, Y is CR2, and Z is N or d / X, Y and Z are each N.

In addition, compounds of formula I are preferred wherein the symbols have the following meanings:

X is N, Y is CR2 and Z is CR2,

X is CR2, Y is N and Z is CR²,

X is CR2, Y is CR2 and Z is N, or

X, Y and Z are in each case N, and R1 is 0. group / C2-Cι // - a1kyl, 2. group / C3-Cl // - a1kenyl, 3. group ^ / C3-Co /// alkynyl, 4. / C3-C8 / -cycloalkyl group, 5. benzyl group or 6. benzyl group which is substituted as described in b / 03., b / R2 is 0. hydrogen, 2. - halogen atom, 3. group nitro, 4th group C_vF2_V+0, 5. peptafluorofepyl group, 6. cyano group, 7. -OR group, 8. phenyl group, 9. phenyl- / Cl-C3 / -a1-kilyl group, 1 /. / CrC10 / - ^ H ^ ii (^^ ą, 10. / C3-Ci // - aakenyl group, 12. phenyl- / C2-C6 / - / dkepy1 group, 03. l-imidazohlo- / CH2 group / m-, 04. group 0,2,3-triazol1lo- / CH2 /> /, 05. grapa teίr; azolilO '· / CH2 / m / 06. grapa a / CH2oa-CHR7 · OR5, 07. -CH2 group // - O-COR3, 08. group -COR8 09. group -CH-o / CO ^, 2 /. Group -S / O /_rR1⁹, 20th group -CH = CH- / CH2 /_m-CHR3OR6 22. group -CH2 = CH- / CH2 / m-CO-R8, 23. group - / CH2 / o-NH-CO-OR9, 24. group ^ -CH-₀NH-SO2-R9 25. group / CH2 / Pf 26. group - CH2 // - SO3R9. 27. group - / - CH2 / n-SO2-NH-CO-NR⁶R9, 28th group - CH2 / n-SO2-NH-CS-NR⁶R9 or 29th group specified in point b / 8.,

9., 0 /., 0 0. or 04., which is in each case substituted as described for such a group in item c / 46., 47., or 48, 3 /. the - / CH2n-SO2-NR7-CO-R6 group, 30. - / CH2n-SO2-NRR-CS-R6 group, c / r8 is a hydrogen atom, a radical / Cl-Cs / ai1ki1owy, OR6 group, NRr12 or morpholip group.

Particularly preferred are compounds of formula 0. wherein X is N, Y is CR2 and Z is CR2,

X is CR2, Y is N and Z is CR,

Q 2

X is CR, Y is CR and Z is N, or

168 887

X, Y and Z are each N and a / R¹ means a group / C2-C7 / -alkyl, / C3-C7 / -alkenyl or / C3-C7 / - dkinyl, b / R^from means 1. chlorine, 2. bromine, 3. group C_vF2v + 1, iiioa _, _Λ . ics ~ \ 6 x _ o / f \ / τ * »19 where v is 1,2 or 3,4. pentauuoroicinyl group, 5th group o ^ r, group -o / o / R,

7. group / CH9 / ci-CHR⁷-OR⁵, 8. group / CH2 / o-0-COR³, 9. group -COR⁸, 10th group - / CH2 / 0-COR⁸, 11. group -CH2-NH-CO-R8, 12. group - CH20-NH-SO2-R9. 13. group -CH ^ HC ^ -OR⁶

14. tetrazolyl- / CH2m- group, 15.GG2 / nSO2-NH-CO-NR6R9 group, 16.CH / CH26-SO3R 'group or optionally substituted with a hydroxyl group radical / C1-C0, / -' alkyl, preferably hydroxymethyl , c / R³ is a hydrogen atom, a group,^/Cl-C4 / -alkyl or benzyl, d / r6 and r9 are the same or different and represent 1. hydrogen atoms, 2. alkyl radicals, optionally substituted with 1-3 groups, such as a / C1-C / -aOoxy group which in turn, it can be substituted by 1-3 groups from a number of hydroxyl, / C1-0 (, / - hydroxy, amino, mono- / C1-C6 / alkylamino, di- / C1-C6 / alkylamino groups, hereinafter / C2-CiO-: dkenyl, hydroxyl, amino, mono- / C1-C6 / alkylamino, di- / C1-C6 / alkylamino. / Cl-O6 / '- alkoxycarbonylamino, / C6-Cl2 / -aryl- / Cl-C4 / -alkoxycarbonylamino, / C6-Cιl / aryl, / C6-Cl0-aryl - Cl-C3 / -alkyl, / Cl-C9 / -hetero; α-acrylic, carboxy and / Cl-C4 / -alkoxycarbonyl, 3. groups / C3-C6 / -cycloalkyl, 4. groups / O3-C6 / aykloalkyl- / ClC3 / -alkyl, 5. phenyl groups , 6. phenyl / C 1 -C 3 -alkyl groups, 7. (C 1 -C 7) heteroaryl groups which may be partially or completely hydrogenated, 8. the group described above under g / 5, 6, 7. or 9., 14.-16. and 18-20, substituted with 1 or 2 identical or different residues from a series of halogen atoms, hydroxyl, / C1-C4 / alkyl, methoxy, nitro, cyano, CO2R³, trifluoromethyl, -NRⁿRH and groups of formula 12, 9. / C1-C9 / -heteroaryl- / C1 - ^ / - ΙΙ.ιΙΙ'Ι groups, whereby the heteroaryl portion may be partially or completely hydrogenated, 10. groups / Cl-C6 // alkyl, in which 1 to all hydrogen atoms is substituted by fluoro, 11. / C2-C4 / ^^ h ^ <^ and ^: yl or / CO-aikenoyl, 12, / C3-C6 / -cycloalkenyl groups , 13. (C 3 -C 6) -cycloalkenyl / C 1 -C 3 -alkyl groups, 14. bicyclic or tricyclic / C4-Cl0-cycloalkenyl- / 01-C4 / -alkyl groups which may be further substituted by 1-3 (C1-C4) -alkyl groups, 15. C6-aryl / Cl-C3 / -alkyl groups , 16. C6-aryl / C3 / alkenyl groups, 17. Cl / C6 // aeteroaryl-C3 // alkenyl groups, 18. C3-6 akinyl groups, 19. C6-aryl / C-3 / groups -alkynyl, 20. / Cl-C6 / -heteroaIyl- / C3 / -alkynyl groups, 21. R⁶ and R⁹ together with the N atom which binds them, they represent a heteroarquine group, which may also be partially or completely hydrogenated, e / r7 represents a hydrogen atom, a / CrC © -! ^^^, / Cl-C9 / -heteroaryl or / 'C6-C12 / group aryl- / Cl-C4 / alkyl, f / r8 Means hydrogen atom, / C1 - C / - ^ Ucilyl group, OR6 or morpholino group, g / q is O and L is methylene, and other residues and variables are of higher significance given.

Particularly preferred are azole derivatives of the general formula I, in which Z is nitrogen, and Y and X are, independently of each other, a CR group, and the other symbols are as defined above.

Particularly preferred are azole derivatives of the general formula (I), in which the symbols have the following meanings: Z is nitrogen, X and Y are CR2 independently of each other, R1 is (C2-C7) -alkyl, / Cr, -07 / -1-enyl or / C3-C7 -alkynyl, r2 is hydrogen, halogen, nitro, / C1-C3 / perrluoroalkyl, cyano, / C1-C1H-kilo / C3-CίO-alkenyl, - CHLOR ", -S / O / rR'9 -CO-R or -0-R⁶, R⁵ is hydrogen or radical / Cl-C6 / alkia; R6 and R9 are 1. hydrogen, 2. (C1-C6) -alkyl radicals that can be substituted with 1-3 residues, such as a / C1-C6 / alkoxy group, which in turn can be substituted with 1-3 groups from a series of hydroxyl groups, / C1-C6 / -alkoxy, amino, mono / C1-C6 / alkylamino, C1- / C1-C6 / alkylamino, further such as / C2-Cι0-alkenyl, hydroxyl, amino, mono- / Cl-C66 / alkylamino, dl-- Cl-C66-alkylamino, / Cl-C <6 -alkylcarbonylamino, / C6-Cl2 / aryl- / Cl-C4 / alkoxycarbonylamino. / C6-C10-aryl, / C6-Cl0-aryl- / Cl-C3 / -alkyl, / C1-C9 / -heteroaryl, carboxylic 1 / Cl-C4 / -alkoxycarbonyl, 3rd group 4th group / C3-C6 / - cycloalkyl - Cιa / -alkyl, 5th / C6-Cl2 / aryl, preferably phenyl, 6th group

168 887 / C6-Cl0-aryl - Cl-C4 / -atkyl, 7. (Cl-C9) -hethetoaryl group which may be partially or completely hydrogenated, 8. Cl / C9 / heteroaryl- / Cl-C3 group / -katkyl, where the heteroarya part may be partially or completely homogenized, 9. g and above mentioned in items 5, 6, 7 and 8 .. substituted with 1 or 2 identical or different groups from a series of halogen atoms, hydroxyl groups , / C1-CV-alkyl, methoxy, nitro, cyano, CO2R3, mfluoromethyl, -NH groups^hR1- and groups of formula 12, 10.CrC / acyl group in which - to all hydrogen atoms is substituted by fluorine, -. a / C2-C6 / alkenyl or / C-C6 group^/- injectable. 2. a / C3-C8-cycloalkenyl group, a 13. / C3-C & apos; -cycloalkenyl- / C1-C3 / aikii group, -4. a / C-C10-7O-C-C4-alkyl group, a / C6-C10-aryl / C3-C6 / -aakenyl group, -6. a / C1-C9 / -hetetoaryl- / C3-C6 / -alkenyl group, 17. / C3-C6 / alkynyl group, -8. /C6-Cll./- aryl-/C3-C66/alkynyl group, -9. gmpa / Cl-C9 / -hethtoaryl- / C3-C6 / alkynyl, 20. R6 and R9 together with the N atom binding them are a heteroaryl group which may also be partially or completely hydrogenated, R7 is a hydrogen atom, R⁸ represents a hydrogen atom or a group -OR6, R^h and R-² independently of each other are hydrogen atoms or C1-C1 / - alkyl radicals, D is the group -NR-³, -O or CH2, R-³ is hydrogen or radical '¹⁵ or together. . , -SO2-NH or R-⁴ and R- 'together represent a (C1-C4) -atkyl group A is a biphenyl group which is substituted with a group R group R-4 and R1⁵, R-⁵ is the group -SOo-N ^ -CO-MUrY -SO2-NH-COO-R⁶S0₂NR6r9, SO2-NH-CO-R6 or -SO2-NH-SO2-R6

-CO-NH-SO2, R-9 is a radical

- / C1-C6 / alkyl / C3-C8 / cycloalkyl phenyl benzyl or a group as defined in - where one of all hydrogen atoms is substituted with fluorine, L is a group -CH2-q is zero, and s is zero, 1 or 2 and their physiologically acceptable salts.

According to the invention, the method for preparing compounds of formula 1 and their physiologically acceptable salts is that compounds of formula 2 in which R-, X, Y and Z are as defined above, are alkylated with compounds of formula 3 in which L , A and q are as defined above, and U is a leaving group, again splits any temporarily introduced protective groups, the obtained sulfonamides of formula - optionally converts to urethanes of formula -, the obtained sulfonamides of the formula - or the obtained urethanes of the formula are optionally converted into sulfonylureas of the formula - and the obtained compounds of the formula - optionally converted into their physiologically acceptable salts.

Suitable U-leaving groups are preferably nucleofugic groups (Angew. Chem. 72/1960) 71), such as halogen, o-too-sulfonate, methanesulfonate or trifluoromethanesulfonate.

Methods for preparing the starting compounds of Formula 2 are, among others, known from U.S. Patent No. 4,355,044 - from EP-A-324377 and EP-A-323841.

Other methods are described by G. L'abbe / Chem. Rev. 69, 345/1969 //, T. Srodsky / The Chemistry of the Azido Group^{1 1}, Wiley, New York, - 97-, p. 33 - /, H. Wamhoff / Comprehensive Heterocyclic Chemistry / and S Katritzky Ed. Pergamon Press, New York / -984 //.

Another method for preparing compounds of formula 2 is derived from 2-oxime derivatives - cyanoglyoxy-acid - after oxime reduction by means of reduction agents known from the literature and addition of mercapture compounds to the nitrile group using appropriate protective groups, which results in starting compounds which under water splitting conditions can be cyclized to imidazoles. Mixtures of PCI5 and dimethylaminopyridine / DMAP /, POCI3 and SOC1 can be used for the cyclization process₂ and mixtures thereof with DMAP.

Oxidation of thi compounds of the formula - in which r 2 is the group -S / O / R-, in which r is zero or -, to the corresponding sulfones and sulfoxides is preferably carried out with the help of peroxy acids in suitable solvents such as e.g. dichloromethane.

168 887

For the alkylation of the azoles of formula II, for example, suitable benzyl halides, toluenesulfonates, methanesulfonates or benzyl trifluoromethanesulfonates, or the corresponding 1.2 ____ IC 2 ~ 2 are used. _Λ . l..V 'Π. _ _. ir · · n ·, not halides, toluenesonates, methanesunoates or alkyl unsubstituted mononucleates.

Alkylation is carried out analogously to generally known methods.

Azole derivatives of formula II are metallised, e.g. in the presence of a base. Preferred bases are metal hydrides of formula MH, such as e.g. lithium, sodium or potassium hydride, using e.g. dimethylformamide or dimethyl sulfoxide as a solvent or metal alkoxides of the formula MOR, wherein R is a methyl, ethyl, t-butyl radical. and the process is carried out in the appropriate alcohol, dimethylformamide or dimethyl sulfoxide. The azole salts thus obtained are dissolved in an aprotic solvent such as dimethylformamide or dimethyl sulfoxide and treated with an appropriate amount of an alkylating agent.

Another possibility to deprotonate azole derivatives is, for example, by reacting with potassium carbonate in dimethylformamide or dimethyl sulfoxide.

The reactions are carried out at a temperature below room temperature to the boiling point of the reaction mixture, preferably from + 20 ° C to the boiling point of the reaction mixture for about 1--0 hours.

Biphenyl derivatives can be prepared, e.g., from arylboronic acid derivatives by coupling with substituted aryl halides in the presence of transition metal catalysts, especially palladium. Appropriate reactions are described by RB Miller et al. / Organometallics 1984, 3, 1261 / or A. Zuzuki et al. Synthetic Commun. 11/7 /, 513/1981 //.

The sulfonylurethanes of formula 1 can be obtained from the corresponding sulfonamides of formula 1 by reaction with chlorocarbonic acid esters in inert high boiling solvents, e.g. toluene, at a temperature of about 100 ° C or at the boiling point of suitable solvents.

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

The sulfonamide group, if necessary, can be obtained starting from an amino group by a Meerwein reaction. For this purpose, the amine hydrochloride is first subjected to diazotization, and then reacted with sulfur dioxide in glacial acetic acid in the presence of a copper catalyst. The subsequent treatment with ammonia results in a sulfonamide group.

The corresponding thiophenol can also be converted by chlorine oxidation and subsequent ammonia treatment to sulfonamide.

The compounds of the formula I obtained according to the invention have an antigenic effect on angiotensin II receptors and can therefore be used to treat angiotensin-dependent hypertension. They can also be used for heart failure, cardiac protection, myocardial infarction, cardiac hypertrophy, arteriosclerosis, nephropathy, renal failure, and for vascular brain disorders such as transient ischemic attacks and stroke.

Renin is a proteolytic enzyme from the class of γ1α and γ2-proteases, which, as a result of various stimulating factors / excessive volume loss, lack of sodium, stimulation of Preceptors / is secreted from the pericellular renal cells into the bloodstream. There he decontaminates decapeptide angiotensin I from the liver secreted from the liver, angiotensinogen, which is converted into angiotensin II by the angiotensin converting enzyme (ACE). Angiotensin II plays an important role in regulating blood pressure because it directly raises blood pressure due to vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal gland and thus increases by suppressing the secretion of sodium the extracellular liquid volume, which in turn contributes to an increase in blood pressure.

Postreceptor activities include, among others, stimulating phosphoinositide transformation / Ca release⁺2, activating protein / kinase C / and piling c-AMP-dependent hormone receptors.

The affinity of compounds of formula I for angiotensin II receptors can be determined by measuring the displacement of H2j-angiotensin II or ³H-angiotensin II from receptors to the membranes of the wife

168 887 bovine adrenal glomerulosa. To this end, the membrane preparations are suspended in a buffer at pH 7.4.

To prevent radioligand degradation during incubation, add _ CIO IO and aprotinin, a peptidase inhibitor, is added. In addition, approximately 14,000 cpm of tag with specific activity of 74 TBq / mmol / commercially available from Amersham Buchler, Braunschweig, Germany / and the amount of receptoroprotein that binds 50% of the tag is added. The reaction is started by adding 50 μί membrane suspension to a mixture of 100 µl buffer with aprotinin. 50 pl buffer with or without angiotensin II or receptor antagonists and 50 pl label. Incubation is carried out for 60 minutes at 25 ° C, after which the bound and free radioligand are separated by means of a filter set with Whatmann GFIC filters on a Skatron cell harvester.

Non-specific binding is prevented by treating the filter with 0.3% polyethyleneimine pH 10 (Sigma No. 3143). By measuring radioactivity in the gamma counter, the displacement power of the radioligand from the receptor is determined. The IC50 value denoting the concentration of inhibitor needed to displace the 50% ligand period ligation according to J. Theor. Biol. 59.253 / 1970 /. For compounds of formula I, they are from 1.10- 1.10'9m.

The affinity of compounds of formula 1 for dngioreneyin II receptors can also be determined by measuring the displacement of nj-angiotensin II or ³H-angioteneyna II from preparations of receptors from various organs / liver, lungs, adrenal glands, brain etc. /.

For this purpose, membrane preparations are suspended in incubation buffer / 20 mM Tris, pH 7.4, containing 135 mM NaCl, 10 mM KCl, 10 mM MgCh, 5 mM glucose, 0.2% bovine serum albumin and PMSF 0 protease inhibitors. 3 mM and Bacitracin 0.1 mM / i together with radioactively labeled angiotensin II and various concentrations of test compounds are incubated for 90 minutes at 25 ° C. The bound and free radioligand are then separated by filtration through a glass fiber microfilter / GF51, Schleicher & Schull / on a cell harvester / SKATRON /.

By measuring the radioactivity of bound receptors on filters using a beta and gamma spectrometer, the extent of radioligand displacement from the receptor by the compounds tested is determined. The strength of displacement of radioligand from the receptor by test compounds is given by means of IC50, i.e. the concentration of the inhibitor that displaces 50% of bound radioligand from the receptor. Calculation of IC50 values ​​is carried out using PC-Software / LIGAND, GA McPherson 1985, Elsevier-BIOSOFT, 68 Hills Road, Cambridge CB 2 1LA, Great Britain2. The IC50 values ​​measured for compounds of Formula 1 are ^ 10- to 1x O '¹¹ / compare the following table 1, in which the IC50 values ​​of the compounds of the invention are summarized /.

Table 1

<td>Relationship No.</td><td>IC5o / nM /</td><td>Relationship No.</td><td>IC50 / nM /</td><td>Relationship No.</td><td>IC50 / nM /</td>

<td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td>

<td> 1</td><td> 5000</td><td> 34</td><td> 1,0</td><td> 64</td><td> 0,5</td>

<td> 2</td><td> 8000</td><td> 35</td><td> 50,0</td><td> 65</td><td> 1,8</td>

<td> 3</td><td> 1100</td><td> 36</td><td> 16,0</td><td> 66</td><td> 6,9</td>

<td> 4</td><td> 1100</td><td> 37</td><td> 1,1</td><td> 67</td><td> 0,91</td>

<td> 5</td><td> 16000</td><td> 55</td><td> 8,8</td><td> 68</td><td> 12,0</td>

<td> 22</td><td> 2000</td><td> 56</td><td> 4,6</td><td> 69</td><td> 3,2</td>

<td> 24</td><td> 800</td><td> 57</td><td> 1100</td><td> 70</td><td> 4,4</td>

<td> 25</td><td> 1400</td><td> 58</td><td> 3,0</td><td> 71</td><td> 2,2</td>

<td> 29</td><td> 1,1</td><td> 59</td><td> 1.3</td><td> 73</td><td> 2,5</td>

<td> 30</td><td> 2030,0</td><td> 60</td><td> 2,2</td><td> 76</td><td> 9,5</td>

<td> 31</td><td> 153,0</td><td> 61</td><td> 1,1</td><td> 79</td><td> 5,8</td>

<td> 32</td><td> 3,5</td><td> 62</td><td> 3,6</td><td> 80</td><td> 0,69</td>

<td> 33</td><td> 34.0</td><td> 63</td><td> 1,3</td><td> 81</td><td> 0,79</td>

168 887 c. Table 1

<td> 1</td><td> 2</td><td> 1</td><td> 2</td><td> 1</td><td> 2</td>

<td> 83</td><td> 0,96</td><td> 117</td><td> 1,2</td><td> 161</td><td> 57,0</td>

<td> 84</td><td> 4,3</td><td> 124</td><td> 1,8</td><td> 162</td><td> 3,9</td>

<td> 85</td><td> 3,9</td><td> 125</td><td> 2,8</td><td> 163</td><td> 3,7</td>

<td> 89</td><td> 1-1</td><td> 127</td><td> 3,0</td><td> 164</td><td> 0,86</td>

<td> 90</td><td> 0,69</td><td> 128</td><td> 5,6</td><td> 165</td><td> 2,3</td>

<td> 92</td><td> 280,0</td><td> 129</td><td> 15</td><td> 166</td><td> 1,2</td>

<td> 93</td><td> 3,3</td><td> 134</td><td> 180,0</td><td> 167</td><td> 4,0</td>

<td> 95</td><td> 1,8</td><td> 135</td><td> 5,6</td><td> 168</td><td> 7,0</td>

<td> 98</td><td> 1,4</td><td> 138</td><td> 1,7</td><td> 169</td><td> 2,9</td>

<td> 99</td><td> 26,6</td><td> 139</td><td> 2,8</td><td> 170</td><td> 2,7</td>

<td> 100</td><td> 68,5</td><td> 140</td><td> 8,2</td><td> 171</td><td> 0,7</td>

<td> 101</td><td> 2,4</td><td> 141</td><td> 4,4</td><td> 172</td><td> 0,48</td>

<td> 102</td><td> 2,3</td><td> 144</td><td> 5,3</td><td> 174</td><td> 5,1</td>

<td> 105</td><td> 3,0</td><td> 146</td><td> 40,0</td><td> 179</td><td> 2,6</td>

<td> 107</td><td> 2,5</td><td> 151</td><td> 0,4</td><td> 181</td><td> 1,0</td>

<td> 108</td><td> 0,95</td><td> 152</td><td> 1,5</td><td> 183</td><td> 1,7</td>

<td> 109</td><td> 0,6</td><td> 153</td><td> 0,88</td><td> 185</td><td> 5,9</td>

<td> 110</td><td> 0,5</td><td> 154</td><td> 1,8</td><td> 186</td><td> 6,5</td>

<td> 111</td><td> 2,9</td><td> 155</td><td> 6,0</td><td> 187</td><td> 1,2</td>

<td> 112</td><td> 1,5</td><td> , 156</td><td> 4,7</td><td> 190</td><td> 22,0</td>

<td> 113</td><td> 0,3</td><td> 157</td><td> 1,4</td><td> 191</td><td> 21,4</td>

<td> 115</td><td> 0,9</td><td> 159</td><td> 8,7</td><td> 194</td><td> 21,7</td>

<td> 116</td><td> 2,4</td><td>j 160</td><td> 0,73</td><td> 195</td><td> 3,0</td>

To determine the antagonistic activity of the compounds of Formula 1, their effect on angiotensin II elevated blood pressure induced in dormant Sprague Dawley rats can be measured. As a sleeping agent, sodium thiobarbital derivative (TrapanaiR trademark Byk Gulden, RFn) is used at a dose of 100 mg / kg ip. Intravenous administration is via the zygomatic vein. Blood pressure is measured in the carotid artery. First, animals are pretreated with pentolin tartrate (10 mg / kg intramuscularly) so as to obtain a lower blood pressure level (ganglion blockage). Angiotensin II (Hypertensin CIBA) is administered in an amount of 0.1 ml / 100 g intravenously at 10-minute intervals. The dose is 0.5 μg / kg. Compounds of formula 1 are dissolved in distilled water and applied at a dose of 0.1-1.0 mg / kg intravenously or 10-100 mg / kg intraduodenally. Compounds of formula 1 are active, especially in the range of 0.1-100 mg / kg, preferably 0.1-3 mg / kg.

The compounds of formula I may be used together with other active substances in pharmaceutical preparations such as, e.g. diuretics or non-steroidal anti-inflammatory active substances. The compounds of formula I can also be used as diagnostic agents for the renin-angiotensin system.

The pharmaceutical preparations contain the active amount of the active substance of the formula I and optionally other active substances together with an inorganic or organic pharmaceutically acceptable carrier. The agents can be used intranasally, intravenously, subcutaneously or orally. The dosage of the active substance depends on the type of warm-blooded, body weight, age and type of administration.

Pharmaceutical preparations containing the compounds of the invention are prepared according to known methods of dissolving, mixing, granulating or coating.

To obtain an oral form for use, the active compounds are mixed with conventional additives such as carriers, stabilizers or inert diluents and converted by known methods into suitable administration forms, such as tablets, dragees, hard capsules,

168 887 aqueous alcohols or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose, magnesium stearate, or starch, especially corn starch, are considered. The preparation can be made in the form of dry or wet granules. As oily carriers or solvents, for example, vegetable and animal oils such as sunflower oil and liver tan are used.

For subcutaneous or intravenous administration, the active compounds or their physiological acceptable salts. optionally together with suitable substances such as solubilizers, emulsifiers or other auxiliaries are converted into solutions, suspensions or emulsions. As solvents, e.g. water, physiological saline or alcohols such as ethanol, propanediol or glycerin, and sugar solutions such as glucose or mannitol solution or mixtures of these solvents.

The following is a list of abbreviations used in the examples:

DMF = N, N-dimethylformamide

NBS = N-brornosumco-b ^ id

AIBN = α, α-azobis-isobutyronitrile

El = collision elekteon (or

DCI == j onization of Ceesrpcyyno-fhhmiczza

RT - room temperature

EE = ethyl acetate / EtOAc /

DIP = left diisopropm ether

MTB = methyl-IΠ-futyl ether mp = topdicaia temperature

HEP = n-heptane

DME = dimethoxyethane

FAB = Comba / powanie pprd ^ d ^^ ic / omdmi

CH2Cl2 = dichloromethane.

The invention is illustrated by the following examples.

Example I.

l [/ D-fenyloaminϋkarbonyiodmidssu] dnyyiob (nenfl-F-yiof meyyiof-fn-tertbutyl-4-_Chl_ABOUTIΌ -imldαnold-5-ka / boksaldahyd of formula 27 / compound No. 1 / a / 4'-methylbifanyld-2-amine

Into 23.9 g / 0.112 mol / 4'-matyl-2-C-biphenyl / RB Muller and S. Dugar, Organomelaillics, 1984, 3, 1261 / in 50 ml of methanol, 3 g of Raney nickel are introduced and hydrogenation under normal pressure at temperature room until the theoretical amount of hydrogen is taken up. Then the catalyst is filtered off and the filtrate is concentrated. The chromatograph on 500 g SiO2 using EE / HEP / 1: 6 / as the agent gives 19 g / 92.5% of the title compound.

Rf / EE / HEP 1: 4 / = 0.3

MS / EE m 183 / M⁺/ b / 4'-mεtyl-biphenyl-2-f / potassium hydrochloride g of compound I / Ronpusnyza in 50 ml of 6N HCl and 100 ml of dioxane. Distillation of the solvent by distillation gives the title compound which is used ealan without further isolation.

c / 4'-methyl-biphenyl-2-phosphonamide

7.9 g / 114 mmol / sodium nitrite are added to the suspension of 31 g / 140 mmol / compound 1b / in 200 ml of 6N HCl at -10 ° C, resulting in a clear solution. This solution is introduced at a temperature of 0 ° C into a solution consisting of 200 ml glacial acetic acid saturated with SO2.17 g CuCO2 and 25 ml H2O. The solution was then brought to room temperature and stirred for 2 hours at this tamperatur. Then 250 ml EE are added, the phases are separated and the organics phase is dried over magnesium sulfate. After concentration, an oil is obtained, which is dissolved in 300 ml of acetone. Then 150 ml 25% ammonia 1 is added and stirred for 2 hours. Then it is concentrated again and 500 added

068 887 ml EE. The EE phase is washed once with water, dried with magnesium sulfate and concentrated. Chromatography on SiO2 with EE / HEP 0: 0 / gives 4.6 g of the title compound, with ______ ιωπ ° γ

LCiiipdatuiz-ν ιχ / ρπινηια i4.z. vz.

R_f/ EE / HEP 1: 1 / = /, 25

MS / DCI / = / M + + H / d / 4'-methylBlphenyl-2-N, N-dimethylaminoformylsulfonamide

4.6 g / 18.6 mmol / compound 0c and 2.5 g / 39.3 mmol / N, N-dimethylformamide dimethylacetal in 3 / ml DMF are stirred for 2 hours at room temperature, followed by 0 / / ml water and sucked off the formed precipitate and air dried. 4.2 g of the title compound are obtained.

Rf / EE / HEP 0 0 / = /, 2

MS / DCI / = 3/3 / M⁺+ H / e / 4'-bbomomethylbiphenyl-2-N, N-aimetocamino-acetylsulfonamide.

To 3.76 g / 13.5 mmol / compound Id and 2.4 g / 03.5 mmol / NBS in 5 / ml chlorobenzop are introduced 15 / mg benzoyl peroxide. After 4 hours of refluxing the mixture is concentrated, 5 / ml EE is added and the phase is washed once with 00% Na2SCb solution and once with water. After drying over sodium sulfate, the mixture is concentrated and chromatographed on SiO2 using EE / HEP 2: 0 as a developing agent. 1.2 g of the title compound are obtained.

Rf / EE / HEP 2: 1 / = /, 23

MS / DCI / = 381, 383 / M ++ H / f / 2-p-butyl-4-chloro-5-aol · myl-imidazole

Into 2 / g //, 006 mol / 2-n-autoyl-α-chloro-5-5-hydroxytrlethylimidazole / prepared according to the European patent EP-A-253 31 // in 35 / ml glacial acetic acid is fed in at 5 13/5 ml 0 M solution / NH — zCe / NO — s in water. After 2.5 hours maintaining the mixture at room temperature, the pH is adjusted with 2 N KOH to 4, maintaining the temperature at 2 / ° - during the addition of the base. Then it is extracted 4 times with 50 ml portions of CH2Cl2 and the combined organic extracts are washed 3 times with 30 ml portions of saturated aqueous NaHCO3 solution, dried over sodium sulfate and concentrated to give 08 g / 92% of the title compound as a colorless solid with a melting point of 9 / ° C.

Rf / DIP / MTB 1: 1 / = /, 5 g / l - [/ 2'-N, N-dimethylaminoCrmlylouulCpnnmidobiPenyl4aI-o (α / -methyl / -an-butyl-4-chloro-imidazole-5-carboxaldehyde

690mg / 0.98 mmol / compound 0e /, 370mg / 0.98mmol / compound lf / i270mg / 1.98mmol / potassium carbonate are stirred in 1 / ml DMF at room temperature for 2 hours. Then 5 / ml EE is added and washed twice with water. The organic phase is dried over sodium sulfate and concentrated. The SiO2 chromatograph using eE / HEP / 2: 0 / as developing agent gives 38 / mg / 4 /% / of the title compound.

Rf / EE / HEP 2: 0 / = /, 05

MS / DCI / = 487 / M + H / h / 1 - [/ 2'-sulfonamidobiphenyl-ayl-methyl] -2-p-butyl-4-chloro-imidazole-5-carboxaldehyde.

28 / mg //, 58 mmol / compound Ig / in 7 ml methanol and 04 ml water are mixed with 10 / mg / 2.88 mmol / sodium hydroxide and heated for 4 hours to reflux. After cooling to room temperature, the pH is adjusted to approximately 6 with 4 N HCl and

Extracted 3 times with 3 / ml EE each, the EE phases are dried over sodium sulfate and concentrated to give 09 / mg of the title compound.

ΐΡ / ΈΕ / ΉΕΡ / 2: 00 = /, 45

MS / DCI / = 432 / M ++ H /

O / l - [/ 2'-aenyylaminoocarbonylammonylCinylobiPenal-α-yl / -methyl) -2-p-butyl-4-chloro-c- / billionazolc-5-carboxaldehyde.

168 887

ΤΞΊ2 / ΤΎΓ7Γ) Ζ'Ί. 1 /;

730 mg / 1.69 mmol / compound 1 h / is heated in 10 ml phenyl isocyanate to 80 ° C. After 4 hours, the mixture is concentrated and chromatographed on SiOa as a developing agent to give 400 mg of the title compound.

Rf / EE / HEP 2: 1 / = 0.15 MS / DCI / = 551 / M ++ H /

Compound 1d, i.e. 4'-meeylbiphenyl-2-N, N-dimeyloominool-mylsulfonamide, can also be obtained as follows:

To 11 g / 37.9 mmoles / 2-N, N-dίmeeylaminofoomylsulfonamidobromobenzene / prepared from 2-bromoaniline analogously 1b-1d), 1 g triphenylphosphine, 8 g Na2CO3 in 150 ml toluene and 40 ml water are introduced under argon first 420 mg Pd / DAc / 2 followed by 5.66 g / 41.9 mmol / 4-olyboronic acid in 100 ml ethanol. It is then heated to reflux for 4 hours, then concentrated and the residue is taken up in 500 ml of ethyl acetate and 500 ml of water. The resulting precipitate is filtered off and characterized as the title compound. The ethyl acetate phase is separated, dried over sodium sulfate and concentrated. Chromatography on SiO2 with ethyl acetate gives a further amount of the title compound, a total of 7.6 g (66%).

2-Bromobenzene.oulphone (analogue intermediate to 1c) can also be prepared as follows.

Chlorine gas is introduced into 4.7 g of 2-bromothiophene in 60 ml of water over a period of 30 minutes. The mixture is then stirred for 30 minutes at 0 ° C. and then air is blown through the solution without cooling for 30 minutes. After adding 60 ml of acetone and re-cooling to 0 ° C, 10 ml of saturated NH 4 OH solution are slowly added dropwise. After a further 30 minutes, the pH of the solution is adjusted to 3 with 4 N HCl and the product is filtered off. 4.5 g / 77% / product are obtained, m.p. 90-191 ° C.

Rf / EE / H 1: 1 / = 0.4

Example II Compound of formula 28 / compound No. 2 /.

and ~ [(2'-n-pro-aminoaminocarbonylaminosulene-Noborene)] -4-yl / -methyl--2-n-butyl-4-chloro-imidazooo-5-carboxaldehyde is prepared analogously to Example 1.

Rf / EE / = 0.6

MS / FAB / = 517 / M + + H /

Example III. 1 / [/ 2'-pyridyl-2- / minocarbonylaminosiphonylbenzyl-4-yl / methyl] -2 - / - / ytyl-4- (haloimidία.olo-5-carboxaldehyde of formula 29 / compound No. 3 / a / i ~ [ / 2'-eeoksykarbonyloaminosulOnnylobineno ~ o - / - yl / -melylo ~ -2-n-butyl-4-chloroim ^ c ^ C until about - 5-carboxaldehyde.

To 1.1 g / 2.5 mmol / compound 1h / and 0.78 g / 5.6 mmol / potassium carbonate in 20 ml dry DME are added 0.48 ml / 5.1 mmol / ethyl chloroformate. After 1 hour, it is cooled to room temperature and 50 ml and 10% KH2PO4 solution are added. After extraction with EE, it is dried over sodium sulfate and concentrated. Chromatography on SiO2 using WE / HEP / 2: 1 / as a developing agent gives 840 mg of the title compound. Rf / EE / HEP 2: 1 / = 0.32

MS / DCI / = 504 / M + + H / b / 1 ~ [/ 2'-pyridyl - / - / minocarbonylamino-sulfoyl-biphenyl / 1-4-yl / -melyl ~ -2-nn-butyl-4-chloro-midazole-5- kairoksaldeeiyd

150 mg / 0.3 mmole / compound 3a / and 28.5 mg / 0.3 mmole / 2-aminopyridine is heated to reflux in 8 ml of dry toluene for 2 hours. Then it is concentrated and chromatographed on SiO2 using EE as a developing agent to obtain 34 mg of the title compound. Rf / EE / methanol 10: 1 / = 0.4

MS / FAB / = 552 / M⁺= I /.

Compounds Nos. 4-39 can be prepared in analogy to Example 3. These compounds are represented by the formula 30 and are listed as compounds / AJ in Table 2.

168 887

Table 2

<td>Relationship No.</td><td>MS / FAB, M + + H /</td><td>Substitution position</td><td>R</td>

<td> 4/16/</td><td> 553</td><td> 3' /2’/</td><td>model 31</td>

<td> 5/17/</td><td> 543</td><td> 3’ /27</td><td>formula 32</td>

<td> 6/18/</td><td> 558</td><td> 3' /2'/</td><td>formula 33</td>

<td> 7/19/</td><td> 559</td><td> 3’/2/</td><td>formula 34</td>

<td> 8/20/</td><td> 597</td><td> 3’ /27</td><td>formula 35</td>

<td> 9/212</td><td> 541</td><td> 3’ /2 /</td><td>formula 36</td>

<td> ^0/22/</td><td> 596</td><td> 3’ /27</td><td>formula 37</td>

<td> 1 1/23/</td><td> 596</td><td> 3’ /2’/</td><td>model 38</td>

<td>zz / ult /</td><td> 569</td><td> 3’ /2’/</td><td>model 39</td>

<td> 13^^25/</td><td> 569</td><td> 3’ /2’/</td><td>formula 40</td>

<td> 14/26/</td><td> 631</td><td> 3’ /27</td><td>formula 41</td>

<td> 15/27/</td><td> 631</td><td> 3’ /2/</td><td>formula 42</td>

<td> 28</td><td> 552</td><td> 3’</td><td>formula 43</td>

<td> 29</td><td> 580</td><td> 2’</td><td>formula 44</td>

<td> 30</td><td> 586</td><td> 2’</td><td>formula 45</td>

<td> 31</td><td> 584</td><td> 2’</td><td>model 46</td>

<td> 32</td><td> 572</td><td> 2’</td><td>formula 47</td>

<td> 33</td><td> 581</td><td> 2’</td><td>formula 48</td>

<td> 34</td><td> 595</td><td> 2’</td><td>model 49</td>

<td> 35</td><td> 565</td><td> 2’</td><td>formula 50</td>

<td> 36</td><td> 565</td><td> 2’</td><td>model 51</td>

<td> 37</td><td> 579</td><td> 2’</td><td>model 52</td>

<td> 38</td><td> 583</td><td> 2’</td><td>formula 53</td>

<td> 39</td><td> 589</td><td> 2’</td><td>formula 54</td>

Example IV ll [/ 2'-lenylaminocarbonyldiminotiphonylbiphenyl-4-yl7l-mrtylol-2n-butylol-chloro-5-hhdroOtheroethylimiddkol compound No. 40 /

100 mg / 0.18 mmol / Compound 1 / are dissolved in 5 mL ethanol and 10 mg / 0.21 mmol / sodium borohydride are added at room temperature. After 20 hours, 0 ml of 5% sodium bisulfate solution is added and extracted 3 times with EE. The organic phase is dried over sodium sulfate and concentrated. Chromatography on SiO2 with EE / HEP 23: -2 gives 55 mg of the title compound.

Rf / EE / HEP 3: 1 / = 0.25

MS / DCI / = 553 / M + + H /

Compounds Nos. 41-54 are prepared analogously to Example 4 from compounds Nos. 2.3 and 16-27. These compounds are represented by the formula 55 and are listed as compounds / B / in Table 3.

Table 3

<td>Relationship No.</td><td>MS / FAB; M + + H</td><td>R</td>

<td> 1</td><td> 2</td><td> 3</td>

<td> 41</td><td> 519</td><td>n-propyl</td>

<td> 42</td><td> 554</td><td>model 56</td>

<td> 43</td><td> 555</td><td>model 31</td>

<td> 44</td><td> 545</td><td>formula 32</td>

<td> 45</td><td> 560</td><td>formula 33</td>

<td> 46</td><td> 561</td><td>formula 34</td>

<td> 47</td><td> 599</td><td>formula 35</td>

<td> 48</td><td> 543</td><td>formula 36</td>

<td> 49</td><td> 598</td><td>formula 37</td>

168 887

cd of table 3

<td> 1</td><td> 2</td><td> 3</td>

<td> 50</td><td> 598</td><td>model 38</td>

<td> 51</td><td> 571</td><td>model 39</td>

<td> 52</td><td> 571</td><td>formula 40</td>

<td> 53</td><td> 633</td><td>formula 42</td>

<td> 54</td><td> 633</td><td>formula 41</td>

Example V. 1- [/ 2'-α-ylamoylcarbonylaminosulfine (o-binenal-ajyl-mineyl (-2-n-butyl-4-chloroamidazole-5-carboxaldehyde of formula 57 / compound 55)

730 mg / 1.69 mmol / compound 1h / are heated in 10 ml allyl isocyanate to 80 ° C. After 4 hours, the mixture is concentrated and chromatographed on SiCO using EE / HEP 112: 1 / as the development agent to give 400 mg of the title compound.

R_f / EE / HEP 2: 1 / = 0.15

MS / FAB / = 515 / M ++ H /

Example VI. La [/ 2'-α-ylaminoaminebebonylamino acid! Fnnyla-biennal-α-yla-methyl] -2-a-ablyl-α-meίylthioimide; azole-5-aarboxylic acid of formula 58 / compound No. 56 / a / 2- ethyl ethyl ester rmino-2 - ^; yyjano - ^ c ^ tt ^ '^ vego.

To 35 g / 0.246 mole / 2-oxime of 2-cyanoglyoxy acid ethyl ester in 350 ml of water and 280 ml of saturated sodium bicarbonate solution are added portionwise over 15 minutes at room temperature 119 g of sodium bisulfite. Then it is heated to 35 ° C for 1 hour, then saturated with NaCl and 5-C 4 (extracted with dichloromethane. After drying with calcium chloride, the organic phase is concentrated. 11.8 g of the title compound are obtained as an oil.

Rf / CH2Cl2 / CH3OH 9: 1 = 0.6 b / 2-cyano-2-n-ablylcareonylaminoacetic acid ethyl ester.

To 3.6 g / 28.09 mmol / compound 56a1 in 50 ml dry CH2Cl2 and 2.3 ml / 28.09 mmol / pyridine are added dropwise at -5 ° C to 0 ° C 3.39 ml / 28.09 mmol / valeroyl chloride in 5 ml CH2Cl2. After stirring for 1 hour at room temperature, the organic phase is washed 3 times with water and once with saturated NaCl solution, dried with calcium chloride and concentrated. Crystallization from DIP gives 1.7 g of the title compound, m.p. 87 ° C.

Rf / CH2Cl2 / CH3OH 9: 1/3 = 0.35 c / 3-amino-2-α-abtycarbonylamino-meeylthioacrylic acid ethyl ester.

Into 2.9 g / 13.67 mmol / compound 56b / and 0.19 ml / 1.36 mmol / triethylamma in 60 ml absolute ethanol are introduced at room temperature 2 ml 121. 26 mmol / concentrated methylmercaptan. After 3 days, 0.5 ml methylmercaptan is added again. After a further 24 hours at room temperature, 0.5 ml methylmercaptan and 0.19 ml triethylamine are injected again and stirred for a further 24 hours at room temperature. Then the solvent is removed and the residue crystallized from DIP, whereby 2.4 g of the title compound is obtained with a melting point of 120 ° C.

Rf / CH2Cl2 / EE4: 1 = 0.3 d / 2an-aulyl-4-1-methyloylimimaric acid ethyl ester, ol-5-aarboxyOxyl.

Up to 4.17, g / 20.0 mmol / phosphorus pentachloride in 20 ml CH2C.21 dropped in at -77? ° &lt;C 2.44 g / 20.0 mmol / 4- im &lt;RTI ID = 0.0&gt; t; ^ y ^ ^ minopyridine in 12 ml CH2Cl2. After 5 minutes, 2.42 g / 10.0 mmol / 56c / in 25 ml CH2Cl2 are added dropwise. Then it is brought to room temperature and diluted with 30 ml CH2Cl2. After 2 hours, 300 ml 1N sodium bicarbonate solution is added under ice-cooling, and stirred for 1 hour. The phases are then separated, the aqueous phase is extracted 3 times with EE and the combined organic phases are dried with calcium chloride. Chromatography on SiO2 is then carried out with CH2Cl2 / EE / 9: 1 /. Rf / CH2C12 / EE 9: 1 / = 0.6

MS / DC1 / = 243 / M⁺ + H /

168 887 e / ethyl ester of l - [/ l '- ^ ιUfonamictcb ^ other - 4-y^;t / -mtryyto-2-n-burylo-4-merylotioimldazolo-5-karboksylowngo.

Up to 1.35 g / 2.5 mmol / 1-172'-N, N-dimethylaminoformylsuffonamic acid ethyl ester biphene-4-yto-methyl-2-n-butyl-4-methyl-tt-imidazole-5-carboxylic acid [prepared from compound No. 56d / and compound No. 1e / analogously to example -g /] in 30 ml methanol, -5 ml concentrated HCl is added. The mixture is refluxed for 90 minutes, then cooled to room temperature and adjusted to pH 5-6 with a 2N NaOH solution. Then it is extracted 3 times with 100 ml EE portions. The organic extracts are dried over sodium sulfate and concentrated, the title compound being isolated as a foam which is fed to the next reaction step without further purification.

Rf / EE / HEP 1: 1 / = 0.2

MS / FAB / = 488 / M + + H / f / The title compound No. 56 is obtained in such a way that 120 mg of 0-j72 '- ^ diaminocarbonylamamino-sulfnyl-binnyl-4-yl-methylmethyl] -2-ethyl acid ester -n-butyro-4-methylthioimidazole-5-carboxylic acid (prepared analogously to Example 5) for compound 55 / in 10 ml of ethanol and 1 ml of 2 N sodium hydroxide solution is stirred for 4 days at room temperature. It is then concentrated, water added and the pH adjusted to 4 with 1 N HCl, the title compound being isolated which is collected by filtration.

Rf / EE / MeOH -0: 1 / = 0.1

MS / FAB / = 543 / M ++ H /

Example VII. 1 - [/ 2'-pylidylethyl-2-amino-carbonylaminosulfonyl-biphenyl] -4-yl / -methyl] -2-n-butyl-4-methyl-thiotimidazole-4-kb-xb-xylic acid of formula 59 / compound No. 57 / a / [/ 2 &amp; apos; -ethoxycarbonylaminosuffonotobinyl-4-yto-methyl] -2-n-butyl4-methylthioimidazole-5-carboxylic acid.

1.21 g / 2.5 mmol / compound 56e / and 0.78 g / 5.6 mmol / potassium carbonate in 20 ml dry DME are heated to reflux and 0.48 ml / 5.1 mmol / ethyl chloroformate is added. After - hours, cool to room temperature and add 50 ml 10¹% KH2PO4 solution. After extraction with EE, it is dried over sodium sulfate and concentrated. Chromatography on S1O2 with EE / HEP / 2: 1 as developing agent gives 840 mg of the title compound.

Rf / EE / HEp 2: - / = 0.5

MS / DCI / = 559 / M + + H / b / acid ethyl ester - - [[2'-pilrididylthyl-2-amino; α-carbonylaminosuffonot-bffenyl-4-yl / methyl] -2-n-bulyl-4-menetrothioinMdazolo- 5-kaaboksylowego

168 mg / 0.3 mmol / compound 57a / and 37 mg / 0.3 mmol / 2-2-aminonyl / pyridine are heated in 8 ml of dry toluene for 2 hours to reflux. It is then concentrated and chromatographed on S-O2 using EA as a developing agent to give 34 mg of the title compound.

Rf / EE / = 0.15

MS / FAB / = 636 / M + + H / c / The title compound 57 is obtained analogously to compound 56f /.

Rf / EE / MeOH 5: - / = 0.1 MS / FAB / = 608 / M + + H /

In a manner analogous to Example 7, i.e. as compound 57, the compounds collected in Table 4 can be prepared. These compounds are represented by the formula 60 and as compounds C are given in Table 4.

168 887

Table 4

<td>NTT · 1 '»Łj» ł 1 tjr-ιχ century</td><td>MS FAB: M + + H</td><td>R</td><td>R '</td><td>R</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td> 58</td><td> 571</td><td>C2H5</td><td>model 61</td><td>H</td>

<td> 59</td><td> 585</td><td>H</td><td>model 62</td><td>H</td>

<td> 60</td><td> 599</td><td>H</td><td>model 63</td><td>H</td>

<td> 61</td><td> 583</td><td>H</td><td>model 61</td><td>model 61</td>

<td> 62</td><td> 611</td><td>H</td><td>formula 64</td><td>H</td>

<td> 63</td><td> 668</td><td>H</td><td>model 65</td><td>H</td>

<td> 64</td><td> 541</td><td>H</td><td>-CH 2 - tH</td><td>H</td>

<td> 65</td><td> 636</td><td>C2H5</td><td>formula 44</td><td>H</td>

<td> 66</td><td> 635</td><td>C2H5</td><td>model 52</td><td>H</td>

<td> 67</td><td> 607</td><td>H</td><td>model 52</td><td>AT XX</td>

<td> 68</td><td> 659</td><td>C2H5</td><td>model 66</td><td>H</td>

<td> 69</td><td> 645</td><td>C2H5</td><td>model 67</td><td>H</td>

<td> 70</td><td> 657</td><td>C2H5</td><td>model 68</td><td>H</td>

<td> 71</td><td> 603</td><td>C2H5</td><td>-CH2-CO2CH3</td><td>H</td>

<td> 72</td><td> 693</td><td>C2H5</td><td>model 69</td><td>H</td>

<td> 73</td><td> 621</td><td>C2H5</td><td>pattern 70</td><td>H</td>

<td> 74</td><td> 703</td><td>C2H5</td><td>model 71</td><td>H</td>

<td> 75</td><td> 561</td><td>H</td><td>model 72</td><td>H</td>

<td> 76</td><td> 649</td><td>C2H5</td><td>model 73</td><td>H</td>

<td> 77</td><td> 663</td><td>C2H5</td><td>model 74</td><td>H</td>

<td> 78</td><td> 653</td><td>C2H5</td><td>model 61</td><td>model 62</td>

<td> 79</td><td> 675</td><td>H</td><td>formula 75</td><td>H</td>

<td> 80</td><td> 593</td><td>H</td><td>pattern 70</td><td>H</td>

<td> 81</td><td> 621</td><td>H</td><td>model 73</td><td>H</td>

<td> 82</td><td> 635</td><td>H</td><td>model 74</td><td>H</td>

<td> 83</td><td> 623</td><td>H</td><td>model 76</td><td>H</td>

<td> 84</td><td> 651</td><td>C2H5</td><td>model 76</td><td>H</td>

<td> 85</td><td> 651</td><td>C2H5</td><td>model 77</td><td>H</td>

<td> 86</td><td> 627</td><td>C2H5</td><td>model 63</td><td>H</td>

<td> 87</td><td> 611</td><td>C2H5</td><td>model 61</td><td>model 61</td>

<td> 88</td><td> 635</td><td>C2H5</td><td>model 78</td><td>H</td>

<td> 89</td><td> 653</td><td>H</td><td>model 79</td><td>H</td>

<td> 90</td><td> 623</td><td>H</td><td>model 78</td><td>H</td>

<td> 91</td><td> 639</td><td>C2H5</td><td>model 80</td><td>H</td>

<td> 92</td><td> 681</td><td>C2H5</td><td>model 79</td><td>H</td>

<td> 93</td><td> 623</td><td>H</td><td>pattern 70</td><td>H</td>

<td> 94</td><td> 611</td><td>TT H</td><td>model 80</td><td>H</td>

<td> 95</td><td> 635</td><td>C2H5</td><td>model 81</td><td>H</td>

<td> 96</td><td> 625</td><td>H</td><td>model 61</td><td>model 62</td>

<td> 97</td><td> 561</td><td>H</td><td>CH2-CO2H</td><td>H</td>

<td> 98</td><td> 651</td><td>H</td><td>model 82</td><td>H</td>

<td> 99</td><td> 607</td><td>C2H5</td><td>model 83</td><td>H</td>

<td> 100</td><td> 625</td><td>C 2H5</td><td>model 84</td><td>H</td>

<td> 101</td><td> 597</td><td>H</td><td>model 84</td><td>H</td>

<td> 102</td><td> 579</td><td>H</td><td>model 83</td><td>H</td>

<td> 103</td><td> 677</td><td>C2H5</td><td>model 85</td><td>H</td>

<td> 104</td><td> 649</td><td>H</td><td>model 85</td><td>H</td>

<td> 105</td><td> 573</td><td>C 2H5</td><td>--CH2 / 2-CH3</td><td>H</td>

<td> 106</td><td> 545</td><td>H</td><td>CH2 / CH3 2-</td><td>H</td>

168 887

cd of table 4

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td>

<td> 107</td><td> 616</td><td>H</td><td>model 86</td><td>H</td>

<td> 108</td><td> 614</td><td>H</td><td>model 87</td><td>H</td>

<td> 109</td><td> 557</td><td>H</td><td>model 88</td><td>H</td>

<td> 110</td><td> 585</td><td>C2H5</td><td>model 88</td><td>H</td>

<td> 111</td><td> 642</td><td>H</td><td>model 89</td><td>H</td>

<td> 112</td><td> 594</td><td>H</td><td>model 91</td><td>H</td>

<td> 114</td><td> 638</td><td>C2H5</td><td>model 92</td><td>H</td>

<td> 115</td><td> 594</td><td>H</td><td>model 93</td><td>H</td>

<td> 116</td><td> 628</td><td>H</td><td>model 94</td><td>H</td>

<td> 117</td><td> 628</td><td>C2H5</td><td>model 95</td><td>H</td>

<td> 118</td><td> 628</td><td>C2H5</td><td>model 96</td><td>H</td>

<td> 119</td><td> 644</td><td>C2H5</td><td>model 86</td><td>H</td>

<td> 120</td><td> 600</td><td>H</td><td>model 95</td><td>H</td>

<td> 121</td><td> 642</td><td>C2H5</td><td>model 87</td><td>H</td>

<td> 122</td><td> 614</td><td>H</td><td>model 87</td><td>H</td>

<td> 123</td><td> 651</td><td>C2H5</td><td>model 97</td><td>H</td>

<td> 124</td><td> 623</td><td>H</td><td>model 97</td><td>H</td>

<td> 125</td><td> 623</td><td>H</td><td>model 98</td><td>H</td>

<td> 126</td><td> 661</td><td>C2H5</td><td>model 99</td><td>H</td>

<td> 127</td><td> 633</td><td>H</td><td>model 99</td><td>H</td>

<td> 128</td><td> 665</td><td>C2H5</td><td>formula 100</td><td>H</td>

<td> 129</td><td> 637</td><td>H</td><td>formula 100</td><td>H</td>

<td> 130</td><td> 600</td><td>H</td><td>model 101</td><td>H</td>

<td> 131</td><td> 642</td><td>C2H5</td><td>model 102</td><td>H</td>

<td> 132</td><td> 665</td><td>C2H5</td><td>formula 103</td><td>H</td>

<td> 133</td><td> 637</td><td>H</td><td>formula 103</td><td>H</td>

<td> 134</td><td> 667</td><td>C2H5</td><td>model 104</td><td>H</td>

<td> 135</td><td> 639</td><td>H</td><td>model 104</td><td>H</td>

<td> 136</td><td> 664</td><td>C2H5</td><td>formula 105</td><td>H</td>

<td> 137</td><td> 636</td><td>H</td><td>formula 105</td><td>H</td>

In a manner analogous to Example 7, i.e. as compound 57, the compounds collected in Table 5 can be prepared. These compounds are represented by the formula 106 and as compounds / D / are given in Table 5.

Ta b e1 a 5

<td>Compound No.</td><td>MS FAB; M⁺ + H</td><td>R</td><td>R '</td>

<td> 138</td><td> 581</td><td>C2H5</td><td>model 107</td>

<td> 139</td><td> 553</td><td>H</td><td>model 107</td>

<td> 140</td><td> 601</td><td>C2H5</td><td>model 108</td>

<td> 141</td><td> 585</td><td>C2H5</td><td>model 109</td>

<td> 142</td><td> 557</td><td>H</td><td>model 109</td>

<td> 143</td><td> 573</td><td>H</td><td>model 108</td>

<td> 144</td><td> 617</td><td>C2H5</td><td>model 110</td>

<td> 145</td><td> 603</td><td>C2H5</td><td>model 111</td>

<td> 146</td><td> 714</td><td>C2H5</td><td>model 112</td>

<td> 147</td><td> 589</td><td>H</td><td>model 313</td>

<td> 148</td><td> 686</td><td>H</td><td>model 112</td>

<td> 149</td><td> 575</td><td>H</td><td>model 111</td>

168 887

Example VIII. and ~ {[(2'-benzoyloxycarbonylamiosulonyl) -butynyl-4-yl-methyl} ~ 2-n- (uyl-4- (hloorimldazole-5-carboxaldehyde of formula 114 / compound No. 150).

The title compound No. 150 is obtained in such a way that 215 mg / 0.5 mmol / compound lh /, 71.3 μ1 / 0.5 mmol / benzyl ester of chioromic acid and 70 mg / 0.5 mmol / K2CO3 in 10 ml Anhydrous DMF is heated under reflux for 1.5 hours. Then it is concentrated, 100 ml EE 1 is added, washed once with 40 ml of NaHSCO solution and once with NaCl solution. The organic phase is dried over sodium sulfate and centrifuged. Chromatography by MTB gives 120 mg / 42% of the title compound, m.p. 56 ° C.

Rf / MTC / = 0.20

MS / FAB / = 566 / M + + H /

Similarly to Example VIII or VIIa /, i.e. just like compounds Nos. 150 and 57a /, the compounds collected in Table 6 may also be obtained. These compounds are represented by the formula 115 and as compounds / E / are given in Table 6.

Table 6

<td>Relationship No.</td><td>MS FAB; M + + H</td><td>R</td><td>R '</td><td>R</td>

<td> 151</td><td> 674</td><td>-OC2H5</td><td>-CH2 -CCk-Ph</td><td>-SMe</td>

<td> 152</td><td> 646</td><td>OH</td><td>-CH2-CH2-Ph</td><td>-SMe</td>

<td> 153</td><td> 558</td><td>OH</td><td>-CH; -CH2-CH = CH₂</td><td>-SMe</td>

<td> 154</td><td> 556</td><td>OH</td><td>-CH2-CH2-CH CH</td><td>-SMe</td>

<td> 155</td><td> 558</td><td>OH</td><td>model 88</td><td>-SMe</td>

<td> 156</td><td> 618</td><td>-OC2H5</td><td>-CH2-CH2-O - Pr</td><td>-SMe</td>

<td> 157</td><td> 590</td><td>OH</td><td>-CH2-CH2-Oi-Pr</td><td>-SMe</td>

<td> 158</td><td> 666</td><td>-OC2H 5</td><td>-CH2CH2-O-CH2-Ph</td><td>-SMe</td>

<td> 159</td><td> 628</td><td>-OC2H5</td><td>model 116</td><td>-SMe</td>

<td> 160</td><td> 600</td><td>OH</td><td>model 116</td><td>-SMe</td>

<td> 161</td><td> 648</td><td>-OC2H5</td><td>-CH2-CH = CH-Ph</td><td>-SMe</td>

<td> 162</td><td> 620</td><td>OH</td><td>-CH2rCH = CH-Ph</td><td>-SMe</td>

<td> 163</td><td> 628</td><td>-OC2H5</td><td>formula 117</td><td>-SMe</td>

<td> 164</td><td> 600</td><td>OH</td><td>formula 117</td><td>-SMe</td>

<td> 165</td><td> 572</td><td>OH</td><td>-CH2-CH = C / CH3 / 2</td><td>-SMe</td>

<td> 166</td><td> 558</td><td>OH</td><td>-CH2 C / CH3 / CH2 =</td><td>-SMe</td>

<td> 167</td><td> 572</td><td>OH</td><td>-CH2-CH2-CH2CH = CH2</td><td>-SMe</td>

<td> 168</td><td> 598</td><td>OH</td><td>model 118</td><td>-SMe</td>

<td> 169</td><td> 556</td><td>OH</td><td>-CH2-C C-CH3</td><td>-SMe</td>

<td> 170</td><td> 560</td><td>-OC2H5</td><td>-CH2-CH3</td><td>-SMe</td>

<td> 171</td><td> 532</td><td>OH</td><td>-CH2-CH3</td><td>-SMe</td>

<td> 172</td><td> 638</td><td>OH</td><td>-CH2-CH2-O-CH2-Ph</td><td>-SMe</td>

<td> 173</td><td> 600</td><td>OH</td><td>model 119</td><td>-SMe</td>

<td> 174</td><td> 584</td><td>-OC2H5</td><td>CH3</td><td>-SMe</td>

<td> 175</td><td> 556</td><td>OH</td><td>CH3</td><td>-SMe</td>

<td> 176</td><td> 611</td><td>-H</td><td>model 120</td><td>these</td>

<td> 177</td><td> 612</td><td>-H</td><td>model 121</td><td>cl</td>

Example IX. 1- (2'-Dimethyl] sulfamylaminosulfonyl-biphenyls-4-yl / -methyl] -2-butyl-4-methyl-thio-1-imidazole-5-carboxylic acid ethyl ester of formula 13 / compound 178.

The title compound No. 178 is obtained in this way from 244 mg / 0.5 mmol / compound No. 56e /, 108 μ1 / 1.0 mmol / sulfamoyl chloride and 140 mg / 1.0 mmol / K₂C03 in 10 ml DME (anhydrous) and refluxed for 5 days. The mixture is diluted with 50 ml EE 1 washed with 50 ml KHSO4 / H2SO4 / pH = 1.0 /. The organic phase is dried over sulfate

168 887 sodium and centrifuged. Chromatography with EE gives 69 mg / 23% / colorless oil.

Rf / Ee / -0.15

MS / FAB / = 617 / NT + Na /

Example X. 1- (1-- 2'-Dimethylsulfamoylamine-sulfnyyla-bifnnyl-α-yl) -methyl] -2-α-autyl-α-methyltimethimidase, ol-5-carboxylic acid of formula 14 / compound No. 179 / .

mg / 84 mmol / title compound 178 of Example 9 and 0.84 ml 1N NaOH are dissolved in 3 ml ethanol and stirred for 2 days at room temperature. Ethanol is distilled off, 5 ml of water are added and the pH is adjusted to 2 with hydrochloric acid. The precipitate is washed with 2 - irDt2tiie with 1 ml of water and dried in vacuo. 33 mg / 70% / colorless powder is obtained.

Rf / EE / methanol 5: 1 / = 0.11

MS / FAB / = 567 / M + + H /

Example XI. D-^ - alloxycarbonylaminosuffonyl-biphenyl-4-yl) -methyl] -2-a-autyl-α-methyltimidimol-α-aarbarboxylic acid ethyl ester of formula 15 / compound No. 180 /

244 mg / 0.5 mmol / compound 56e / 106 pi / 1.0 mmol / allyl ester chloroformic acid and 140 mg / 1.0 mmol / K2CO3 are boiled under reflux for 1 hour. Then 50 ml 10% KHSO4 solution is added and extracted three times with 50 ml EE each. The organic phase is dried over sodium sulfate and evaporated. Chromatography with MTB / DIP 1: 1 gives 115 mg / 40% / colorless oil.

Rf / MTB / DIP 11 / = 0.15

MS / FAB / = 572 / M + + H /

Example XII. 1- // 2'-Allyloxycarbonylaminosuffony-α-bffeyyl-4-yl / -methyl] -2-n-autyl-α-methyl-t-imidazole-5-carboxylic acid / Compound No. 181 / mg / 0.17 mmol / Compound No. 180 subjected to saponification as described in Example 10 for compound 179. 30 mg / 33% / colorless foam is obtained.

Rf / EE / MeOH 10:11 = 0.1

MS / FAB / = 544

Example XIII. 1- [/ 2'-Benzyloxycarbonylaminosulfonyl-biphenyl-4-yl] -methyl] -2-a-abyl-α-methylthio-mmdaaol-α-carbarbyl ethyl ester of formula 16 (compound No. 182).

The title compound is obtained analogously to the method described in Example 11 for compound 180.

Rf / MTB / DIP 11 = 0.15 MS / FAB / = 622 / M + + H /

Example XIV. 1 ~ 1 / 2'-benzyloxycarbonylc [amίnosulf'oyyla-bif'-ynyl-α-yl-methyl] -2-α-autyl-α-mmylthyl-imidazole-5-carboxylic acid of formula 17 (compound No. 183).

The title compound is obtained analogously to the method described in Example 12 for compound 181.

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

Example XV 1- {/ 2'-allylamino carbonylaminosulfenyl / -bifnyl-4-yl] methyl} 2-n-butyl-4-methoxy-and midazol ~ 5-carbaldehyde of formula 18 / compound No. 184 / a1 1- // 2 ' -sulfonamidobffnnyl-a-yl / -melylo] -2-n-butyl-4-methoxy-lmidćZΌlo-5-carbaldehyde

215mg / 0.5mmol / compound 1h / l 1.5 molNNaOH in 10ml methanol is boiled under reflux for 19 hours. The methanol is then centrifuged, the pH value is adjusted to 2 with a NaHSCL solution and 3 x 3 (tc) is extracted with 50 ml EE portions. The organic phase is dried over sodium sulfate and centrifuged by chromatography with MTB / DIP / 1: 1/170 mg / 80% of the title compound is obtained with a melting point of 189 ° C. Rf / MTB / DIP / 11 / = 0.19

MS / DCI / = 428 / M + + H /

168 887 b / Title compound No. 184 is obtained in that way, 150 mg (0.35 mmol) of compound 184ι / and 3 ml of allyl isocyanate are boiled under reflux for 5 hours. It is then centrifuged and ch-omarog-afuJe by means of EE. 60 mg / '34% / of a colorless foam are obtained. Rf / EE = 0.34

MS / FAB / = 511 / M4 + + H /

Example XVI 1 - {[/ 2'-ethoxycarbonylammosulfinyl-bieeyyl-k-ylol-methylol-2-butyr-4kmetokeykmiddol-5-carbaldehyde of formula 19 / compound No. 185 /

1.0 g (2.34 mmol) / compound 184i / is dissolved in 50 mL anhydrous acetone and 650 mg K2CO3 are added. The tumble bulb is heated to the root under a kg-gold condenser, and 0.45 ml of ethyl chloroformate are slowly injected at this temperature. The mixture is heated for 4 hours under a Kg-gold condenser and then centrifuged. The mixture is acidified to pH 2 with NaHSO4 solution, and then extracted three times with 100 ml EE portions. Dried over sodium sulfate, then centrifuged and chromatographed with MTB / DIP / HOAc / 15: 83: 22. The oil obtained can be crystallized from diethyl ether. 550 mg of colorless crystals are obtained, m.p. 134 DEG C.

Rf / MTB / = 0.24

MS, FAB / = 5 ^ 0AM + ++ H

Example XVII. 1 - {[/ 2'-beenzγloxycarbonylaminotulfonyl7-bieenyl-4-ylol-methyl} -2-n-butyl-4-methyl-imidazole-5-ka-aldehyde of formula 20 / compound No. 186).

Compound No. 186 is obtained analogously to the procedure described in Example XVI for compound No. 185 Rf / MTB / = 0.16 MS / FAB / = 562 / M + + H /

Example XVIII. 1- {[22'-Benzylaminocarbonylamino-sulfonyl) -biphenyl-1-yl] -methyl} -2-n-butyl-imidyl-5-oxo-1-oxoic acid ethyl ester of formula 21 (compound No. 187).

To 150 mg / 0.24 mmol / compound 73 dissolved in 50 mL MeOH and 5 mL HOAc is added the catalytic amount of Pd / C. The mixture is stirred under an atmosphere of hydrogen for 12 hours at room temperature. The mixture is then centrifuged and chromatographed with EE. 30 mg / 22% / colorless foam is obtained.

Rf / EE / = 0.42

MS / FAB / = 575 / M + + H /

Example XIX. | L {[/ 2'-ethoxycarbonylaminosulfonyl-biphene | l-4-yl-O-methyl-kk-cuyl-imidazole-k-carb-ethyl acid ethyl ester of formula 22 / compound No. 188).

About 200 mg of Raney nickel are added to 300 mg / 0.5 mmol / compound n-57a / dissolved in 0 mL of EtOH. The mixture is heated under reflux for 10 hours, a further 200 mg of Raney nickel is added and heated again under reflux for 5 hours. The catalyst is filtered off and the solvent is centrifuged. The residue is chromatographed with MTB to give 50 mg / mL of colorless foam.

Rf / EE / = 0.27

MS / FAB / = 514 / M + + H /

Example XX. 1- [22 '- {2 - Reylsuthonylamino-sulfinyl-biphenyl-4-yl) -methyl] -kk-kb-yl-k-methyl-thio-imidio-o-k-kayroctyl acid ethyl ester of formula 23 / compound n-189 /

244 mg / 0.5 mmol / sulfonamide of Example VIe / No. 56e / is dissolved in 10 ml of anhydrous dimethyl ether glycol. Then 346 mg / 2.5 mmol / K2CO3 and 81 mg / 0.5 mmol / 2-lrenylsutfonyl chloride are added. The mixture is heated under reflux for 2 hours, then the cooled reaction mixture is poured into 50 ml of 5% NaHSO4 solution and extracted three times with 50 ml eE portions each time. Dried over sodium sulfate, centrifuged and chromatographed with EE. 310 mg of pale yellow crystals are obtained with a melting point of 120-122 ° C.

Rf / EE / = 0.24 MS / FAB / = 634 / M + H /

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Example XXI. Ia [/ 2 '- (2-Leenenesulfonylaminos] fonyl (-bien (-4-ylmethyl] -2-a-aulyl-a-meeylthio- (midazole-5-carboxylic acid of formula 24 / compound No. 190 / .

The saponification of ethyl ester No. 189 from Example XX is carried out analogously to the procedure of Example VIf / (compound No. 56f).

Rf / EE / MeOH 5: 1/1 = 0.13 MS / FAB / = 606 / M⁺ + H

The compounds in the following Table 7 can be prepared analogously to Example XX / compound No. 189 / or to compound XXI / compound No. 190 / or to Example VIf / / compound No. 56f /.

These compounds are represented by the formula 25 and are listed as compounds / F / in Table 7.

Table 7

<td>Compound No.</td><td>MS / FAB / M ++ H</td><td>R</td><td>R '</td>

<td> 191</td><td> 673</td><td>C2H5</td><td>4-nitrophenyl</td>

<td> 192</td><td> 645</td><td>H</td><td>4-nitrophenyl</td>

<td> 193</td><td> 579</td><td>C2H 5</td><td>C2 H5</td>

<td> 194</td><td> 634</td><td>C2H5</td><td>2-thienyl</td>

Example XXII. Ia [/ 2'-Meeylaminocarbonylammosulfonyl-polynucleic acid ethyl ester (-a-ylamino (-2-n-butyl-α-methyl-thio-thio) (midiazole-5-carboxylic acid / compound No. 195).

In an autoclave, to 1 g of sulfonyl carbamate No. 57a (from Example VIIa) in 50 ml of toluene, methylamine is introduced at 80 ° C for 5 minutes. The mixture is then heated to 80 ° C for 8 hours. It is then concentrated in vacuo and the residue is chromatographed on silica gel with EE / n-HEP 2: 1, whereby the title compound is obtained in the form of an amorphous powder.

Rf / EE / n-HEP 2: 1 / = 0.1

MS / FAB / = 545 / M + + H /

In a manner analogous to Example XXII (compound No. 195 / or example VIf / / compound No. 56f), the compounds in the following table 8 / compound No. 195 can also be prepared there. These compounds are represented by the formula 26 and as compounds C are given in Table 8.

Table 8

<td>Compound No.</td><td>MS / FAB / M ++ H</td><td>R</td><td>R '</td>

<td> 195</td><td> 545</td><td>C2H5</td><td>CH3</td>

<td> 196</td><td> 517</td><td>H</td><td>CH3</td>

<td> 197</td><td> 559</td><td>C2H5</td><td>C2H5</td>

<td> 198</td><td> 531</td><td>H</td><td>C2H5</td>

<td> 199^</td><td> 619</td><td>C2H5</td><td>-CH2-CH2-O-CH2-CH2-OH</td>

<td> 200^v</td><td> 591</td><td>H</td><td>-CH2-CH2-O-CH2-CH2-OH</td>

T7 ------- '- Compounds are prepared analogously to Example VII / compound No. 57 /.

168 887

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MODEL 12

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Walkthrough level 16

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Walkthrough level 18

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Walkthrough level 27

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Walkthrough level 32

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Walkthrough level 34

Walkthrough level 35

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

<td>Walkthrough level 40</td><td>Walkthrough level 41</td>

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Walkthrough level 46

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Walkthrough level 48

Walkthrough level 49

Walkthrough level 50

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Walkthrough level 51

Walkthrough level 52

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Walkthrough level 53

CH, CH, 3 \ / J

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Walkthrough level 55

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Walkthrough level 56

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Walkthrough level 58

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Walkthrough level 60

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Walkthrough level 61

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Walkthrough level 64

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Walkthrough level 65

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Walkthrough level 66

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Walkthrough level 67

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Walkthrough level 68

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Walkthrough level 69

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Walkthrough level 70 ^their2'2-C^CF3

Walkthrough level 71

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OH

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Walkthrough level 72 &lt;^CH2&gt;4&lt;^&gt;

Walkthrough level 74

CH₂^ p oh₃

Walkthrough level 76

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Walkthrough level 75

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Walkthrough level 77

068 887 ^CH2bQb oh₃

Walkthrough level 78

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Walkthrough level 79 ^cf2 O^f

Walkthrough level 80

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Walkthrough level 82

Walkthrough level 83

Walkthrough level 84

Walkthrough level 85

168 887 (CH₂)₂- ν

Walkthrough level 86

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ch₃

Walkthrough level 87

Walkthrough level 88

CH_and.

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168 887

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Walkthrough level 90

Walkthrough level 91

-(^ch2)₂—

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Walkthrough level 92

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- (ch₂)₃-n

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Walkthrough level 93

Walkthrough level 94

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CH

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Walkthrough level 97

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Walkthrough level 98

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Walkthrough level 99

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(S)

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Walkthrough level 100

Walkthrough level 101

168 887 (CH₂)₂-N

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Walkthrough level 102

Walkthrough level 103 ₂_® MODEL 104

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Walkthrough level 105

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Walkthrough level 106

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Walkthrough level 107

Walkthrough level 108

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Walkthrough level 109

168 887

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Walkthrough level 11 a ~ xH

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Walkthrough level 13

168 887

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Walkthrough level 114

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Walkthrough level 15

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<td>Walkthrough level 116</td><td>Walkthrough level 117</td>

<td>^CH2-O</td><td></td>

<td>pattern ne</td><td>Walkthrough level 119</td>

<td> ©</td><td>CH₂ ON °₂</td>

<td>Walkthrough level 120</td><td>Walkthrough level 121</td>

Department of Publications of the Republic of Poland. Edition of 90 copies. Price: PLN 1.50