Five-membered heterocycles with biphenylmethanol replacement drug

 

(57) Abstract:

The invention relates to the five-membered heterocycles with biphenylmethanol substitution of formula I

R1means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; CandH2A-phenyl, where a = 0, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, J, CF3, metoxygroup; CdH2d(C3-7-cycloalkyl, where d = 0; R2and R3independently from each other denote hydrogen, F, Cl, J, C=N; COR6where R6denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, OR30where R30- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; OR7where R7denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; phenyl; or R2and R3, independently of one another, denote CqH2q-phenyl, where q=0; or R2and R3independently from each other mean-SOnR22where n stands for zero, R22- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R4and R5independently of one another denote hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, J, CF3and their physiologically acceptable salts; and to medicines, inhibiting Na+dependent Cl-/HCO-3- exchange rate is toroi symbols have the following meaning:

R1 denotes hydrogen, alkyl with 1,2,3,4,5,6,7 or 8 C-atoms

or-CandH2A-phenyl,

which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(8)R(9); where R(8) R(9) independently of one another, denote H or (C1-C4) -alkyl;

a represents zero, 1 or 2,

or R1 denotes-CbH2b-(C1-C9-heteroaryl,

which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F,Cl, Br, I, CF3CH3, metoxygroup, hydroxyl and NR(10)R(11);

where R(10) R(11), independently of one another, denote H or (C1-C4)-alkyl;

or b stands for zero, 1 or 2;

R1 denotes-CdH2d- (C3-C7-cycloalkyl; where d is zero, 1 or 2;

R2 and R3, independently of one another, mean hydrogen, F, Cl, Br, I,

CF3,-C N, -NO2CH2OR17, CO-R6 or 0-R7;

where R17 denotes hydrogen or alkyl with 1,2,3,4,5,6,7 or 8 C-atoms;

R6 denotes hydrogen, alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, OR30 or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting ut H or (C1-C4)-alkyl;

R30 denotes hydrogen or alkyl 1,2,3,4,5,6,7 or 8 C-atoms;

R7 denotes hydrogen, alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(12)R(13) where R(12) R(13) independently of one another, denote H or (C1-C4)-alkyl;

or

R7 means (C1-C9-heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3CH3, metoxygroup, hydroxyl and NR(14)R(15); where R(14) R(15) independently of one another, denote H or (C1-C4)-alkyl;

or

R2 and R3, independently of one another denote alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, cycloalkyl 3,4,5,6

or 7 C-atoms or-CgH2g-phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(18)R(19); where R(18) R(19), independently of one another, denote H or (C1-C4)-alkyl;

g means zero, 1 or 2;

or

R2 and R3 denote, independently of one another, ClH2l-, ostoja from F, Cl, Br, I, CF3CH3, metoxygroup, hydroxyl and NR(20)R(21),

where R(20) R(21), independently of one another, denote H or (C1-C4) -alkali;

l is zero, 1 or 2;

or

R2 and R3 denote, independently from each other, SOn-R22; where n stands for zero, 1 or 2;

R22 denotes alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, cycloalkyl 3,4,5,6 or 7 C-atoms or-CsH2sis phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(34)R(35),

where R(34) and R(35), independently of one another, denote H or (C1-C4)-alkyl;

S stands for zero,1 or 2;

R4 and R5, independently of one another denote hydrogen, alkyl with 1,2,3,4,5,6,7 or 8 C-atoms, F, Cl, Br, I, CF3, -C N, -NO2, SOp-R16, CO-R23, or O-R24;

p denotes zero, 1 or 2;

R16 denotes alkyl with 1,2,3,4,5,6,7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F,CI, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(26)R(27); where R(26) R(27) independently of one another, denote H or (C1-C4) -alkyl;

R23 means water

R24 denotes hydrogen, alkyl with 1,2,3,4,5,6,7 or 8 C-atoms or phenyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, metoxygroup, hydroxyl and NR(28)R(23); where R(28) R(29), independently of one another, denote H or (C1-C4)-alkyl;

and their physiologically acceptable salts.

Preferred are the compounds of formula (1), in which

R1 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or-CandH2Ais phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(8)R(9);

where R(8) R(9) independently of one another, denote H or methyl,

and means zero or 1;

or

R1 means (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3CH3, metoxygroup, hydroxyl and NR(10)R(11);

R(10) R(11), independently of one another, denote H or methyl;

or

R1 denotes-CdH2d-(C3-C7-pilooski;

where d denotes zero or 1;

R2 and R3 where R17 denotes hydrogen or alkyl with 1,2,3 or 4 C-atoms;

R6 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, OR30 or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl NR(31)R(32);

where R(31) R(32), independently of one another, denote H or methyl;

R30 denotes hydrogen or alkyl with 1,2,3 or 4 C-atoms;

R7 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br,CF3, methyl, metoxygroup, hydroxyl and NR(12)R(13);

where R(12) R(13) independently of one another, denote H or methyl;

or

R7 means (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3CH3, metoxygroup, hydroxyl and NR(14)R(15);

where R(14) R(15) independently of one another, denote H or methyl;

or

R2 and R3, independently of one another denote alkyl with 1,2,3 or 4 C-atoms, cycloalkyl 3,4,5,6 or 7 C-atoms or - CqH2qis phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3

  • g means zero or 1;

    or

    R2 and R3 denote,independently from each other, (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br,CF3CH3, metoxygroup, hydroxyl and NR(20)R(21); where

    R(20) R(21), independently of one another, denote H or methyl;

    or

    R2 and R3 denote, independently from each other, SOn-R22;

    where n stands for zero, 1 or 2;

    R22 denotes alkyl with 1,2,3 or 4 C-atoms, cycloalkyl 3,4,5,6 or 7 C-atoms or-CsH2sis phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, CL, Br, CF3, methyl, metoxygroup, hydroxyl and NR(34)R(35);

    where R(34) and R(35) is chosen from the group consisting of H or methyl;

    s means zero or 1;

    R4 and R5, independently of one another denote hydrogen, alkyl with 1,2,3 or 4 C-atoms, F, Cl, Br, CF3, -C N, -NO2, SOp-R16, CO-R23 or-R24;

    p denotes zero, 1 or 2;

    R16 denotes alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, R23 means hydrogen, alkyl with 1,2,3 or 4 C-atoms or OR25;

    where R25 denotes hydrogen or alkyl with 1,2,3 or 4 C-atoms;

    R24 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(28)R(29);

    where R(28) R(29), independently of one another, denote H or methyl;

    and their physiologically acceptable salts.

    Especially preferred compounds of formula (1) in which R1 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(8)R (9);

    where R(8) R(9) independently of one another, denote H or methyl;

    or

    R1 means (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3CH3, metoxygroup, hydroxyl and NR(10)R(11);

    where R(10) R(11), independently of one another, denote H or methyl;

    or

    R1 means (C3-C7-cycloalkyl;

    R2 and R3, independently ot,3 or 4 C-atoms, OR30 or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(31) R(32);

    where R(31) R(32), independently of one another, denote H or methyl;

    R30 denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

    R7 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(12)R(13);

    where R(12) R(13) independently of one another, denote H or methyl;

    or

    R7 means (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3CH3, metoxygroup, hydroxyl and NR(14)R(15);

    where R(14) R(15) independently of one another, denote H or methyl;

    or

    R2 and R3, independently of one another denote alkyl with 1,2,3 or 4 C-atoms, cycloalkyl 3,4,5,6 or 7 C - atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(18)R(19);

    1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3CH3, metoxygroup, hydroxyl and NR(20)R(21);

    where R(20) R(21), independently of one another, denote H or methyl;

    or

    R2 and R3 denote, independently from each other, SOn-R22;

    where n means zero or 2;

    R22 denotes alkyl with 1,2,3 or 4 C-atoms, cycloalkyl 3,4,5,6 or 7 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, hydroxyl and NR(34)R(35);

    where R(34) and R(35), independently of one another, denote H or methyl;

    R4 and R5, independently of one another denote hydrogen, alkyl with 1,2,3 or 4 C-atoms, F, Cl, CF3, -C N, -NO2, SOp-R16, CO-R23 or-R24;

    where p denotes zero or 2;

    R23 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or OR25;

    where R25 denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

    R24 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, Br, CF3, methyl, metoxygroup, get alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, CL, Br, CF3, methyl, metoxygroup, hydroxyl and NR(26)R(27);

    where R(26) R(27) independently of one another, denote H or methyl;

    and their physiologically acceptable salts.

    Very particularly preferred compounds of formula (1), in which

    R1 denotes alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    or

    R1 means (C1-C9-heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3CH3and metoxygroup;

    or R1 means (C3-C7-cycloalkyl;

    R2 and R3, independently of one another, mean hydrogen, F, Cl, CF3-N, CO-R6 or O-R7;

    where R6 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, OR30 or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    and R30 denotes hydrogen, methyl or ethyl;

    R7 means waters of the constituent from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    or

    R7 means (C1-C9-heteroaryl, which is unsubstituted or substituted by one Deputy, selected from the group consisting of F, Cl, Br, CF3CH3and metoxygroup;

    or

    R2 and R3, independently of one another denote alkyl with 1,2,3 or 4 C-atoms, cycloalkyl 3,4,5,6 or 7 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    or

    R2 and R3 denote, independently of each other (C1-C9)heteroaryl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3CH - and metoxygroup;

    or

    R2 and R3 denote, independently from each other, SOn-R22;

    where n means zero or 2;

    R22 denotes alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with 1-2 substituents selected from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    R4 and R5, independently of one another, signify hydrogen, methyl, F, Cl, CF3, -C N, SO2-R16, CO-R23, or O-R24;

    where R16 denotes alkyl with 1,2,3 and the standing of F, Cl, CF3, bromide and metoxygroup;

    R23 denotes hydrogen, methyl or OR25;

    where R25 denotes hydrogen, methyl or ethyl;

    R24 denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms or phenyl, which is unsubstituted or substituted with one substituent selected from the group consisting of F, Cl, CF3, bromide and metoxygroup;

    and their physiologically acceptable salts.

    Further, preferred compounds of formula (1), in which the residues R1, R2, R3, R4 and R5 have the abovementioned meaning and biphenylyl Deputy linked as in formula (1a), (1b), (1C), (1d), (1e), (1f), (1g) and (1h):

    and their physiologically acceptable salts. Further, preferred compounds of formula (1), in which the residues R1, R2, R3, R4 and R5 have the abovementioned meaning, and R4 and R5 are not simultaneously denote hydrogen. The alkyl can be linear or branched. Under cycloalkyl see also substituted by alkyl cycles. Under (C1-C9) heteroaryl see in particular residues, which are manufactured from phenyl or naphthyl, in which one or more CH groups replaced by nitrogen and/or in which at least two adjacent CH groups (in the formation of five-membered aromatic ring) semangat be an N-atoms.

    As heteroaryl are especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnolines.

    Optionally available stereocenter can be either in (R) - and (S)-configuration.

    Under physiologically acceptable salts of the compounds of formula (1) understand how their organic and inorganic salts, which are described in Remington's Pharmaceutical Sciences [17th edition, 1418 S. (1985)]. On the basis of physical and chemical stability and solubility for acid groups are preferred, particularly sodium, potassium, calcium and ammonium salts, the main groups are preferred, in particular, salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid or p-toluensulfonate.

    The invention relates also to a method for producing compounds of formula (1), and their physiology have the above significance, these connections are either known from J. Med. Chem.,38, 2357 (1995), or get them in the same way, enter into interaction with bromine cyan.

    The reaction proceeds in a dipolar aprotic solvent which is resistant to bromine cyan, for example such as acetonitrile, dimethyl-ndimethylacetamide (DMA), N,N,N'N'-tetramethylrhodamine (TMU) or N-methyl-pyrrolidone (NMP), with a strong supporting base, which mononucleotide, as, FOR example, a2CO3or Cs2CO3. As the reaction temperature taking into account the temperature from 0° C to boiling point of the solvent used; preferably the temperature is from 60 to 120°C.

    The invention further relates to the use of compounds of formula

    in which:

    a) X, Y and Z, equal or different, denote N or CR(102);

    b) R(1) means

    1. (C1-C10)-alkyl; 2. (C3-C10) -alkenyl; 3. (C3-C10)-quinil; 4. -OR(103); 5. (C3- C8-cycloalkyl; 6. (C4-C10-cycloalkenyl; 7. (C5-C10) -cycloalkylcarbonyl; 8. (C5-C10-cycloalkylcarbonyl; 9. -(CH2)m-B-(CH1)n- R(104); 10. -benzyl; 11. the decree is, where from 1 to all H atoms replaced by fluorine; or 13. specified in paragraph (b) 10. the remainder, which in the phenyl substituted by one or two identical or different residues from the series consisting of halogen, (C1-C4)-alkoxyl and nitro;

    b) R(102) means:

    1. hydrogen; 2. halogen; 3. the nitro-group; 4. CvF2v+1; 5. pentafluorophenyl; 6. the cyano; 7. -O-R(106); 8. phenyl; 9. phenyl-(C1-C3)-alkyl; 10. (C1-C10)-alkyl; 11. (C3-C10)-alkenyl; 12. phenyl-(C2-C6)-alkenyl; 13. 1-imidazolyl-(CH2)m-; 14. 1, 2, 3-triazolyl-(CH2)n-; 15. tetrazolyl-(CH2)m-; 16. -(CH2)o-1-CHR(107)-OR(105); 17. - (CH2)o-O-CO-R (103); 18. -(CH2)o-S-R(106); 19. -S(O)r-R(119); 20.-CH=CH-(CH2)m-CHR(103)-OR(106); 21. -CH=CH-(CH2)m-CO-R(108); 22. -CO-R(108); 23. -CH=CH-(CH2)m-O-CO-R (107); 24. - (CH2)m-CH (CH3)-CO-R(108); 25. -(CH2)oCO-R(108); 26. - (CH2)o-O-[C=W]-NH-R (109); 27. - (CH2)o-NR(107) -[C=W]-CR(109); 28. - (CH2)o-NR (107)--OTHER(109); 29. -(CH2)o-NR(107)-SO2R(109); 30. - (CH2)o-NR (107)-[C=W]-R(109); 31. -(CH2)nF; 32. - (CH2)n-O-NO2; 33. -CH2-N3; 34. -(CH2)n-NO2; 35. -CH=N-NR(105)R(107); 36. phthalimide in the phenyl substituted by one or two identical or different residues from the series, consisting of halogen, hydroxyl, metoxygroup, trifloromethyl, CO2R(103), and phenyl; 47. specified in paragraph (b). 10., 11. 19. balance, where from 1 to all H atoms replaced by fluorine; 48. specified in paragraph (b).14. the residue, which is substituted by one or two identical or different residues from the series consisting of methoxycarbonyl and (C1-C4)-alkyl;

    49.-(CH2)n-SO2-NR(107)-CO-R(106); 50. - (CH2)n-SO2-NR (107) CS-R(106);

    g) R(103) means

    1. hydrogen; 2. (C1-C8)-alkyl; 3. (C3-C8-cycloalkyl; 4. phenyl; 5. benzyl; 6. specified in paragraph (g) 2. balance, where from 1 to all H atoms replaced by fluorine;

    d) R(104) means

    1. hydrogen; 2. (C1-C6)-alkyl; 3. (C3- C8-cycloalkyl; 4. (C2-C4) -alkenyl or 5. (C2-C4)-quinil;

    e) R(105) means

    1. hydrogen; 2. (1-C6) -alkyl; 3. (C3-C8-cycloalkyl; 4. phenyl; or 5. benzyl;

    W) R(106) and R(109), the same or different, mean

    1. hydrogen; 2. (C1-C6) -alkyl, which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of (C1-C6-)-alkoxyl, which, for its part may be substituted by 1-3 two of octachlorodipropyl, di(C1-C6-alkylamino; and (C2-C10-alkenyl, hydroxyl, amino, mono-(C1-C6-alkylamino, di(C1-C6-alkylamino, (C1-C6-alkoxycarbonylmethyl, (C6-C12) -aryl- (C1-C4) alkoxycarbonylmethyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C3)-alkyl, (C1-C9)-heteroaryl, carboxyl and (C1-C4)-alkoxycarbonyl; 3. (C3-C8-cycloalkyl, and cycloalkyl part unsubstituted or substituted by 1-3 two substituents selected from the group consisting of (C1-C4) -alkyl and (C2-C4-alkenyl;

    4. (C3-C8-cycloalkyl-(C1-C3)-alkyl; 5. (C6-C12)-aryl, preferably phenyl; 6. (C6-C10)-aryl-(C1-C4)-alkyl; 7. (C1-C9-heteroaryl, which may be partially or fully be gidrirovanny; 8. specified in paragraph (W) 5., 6., 7., 9., 15., 16., 17., 19., 20. or 21. the residue, substituted by one or two identical or different residues from the series consisting of halogen, hydroxyl, (C1-C4)-alkyl, metoxygroup, nitro, ceanography, CO2R(103), trifloromethyl, NR(111)R(112) and

    10. (C1-C6) -alkyl in which from 1 to all H atoms replaced by fluorine;

    11. (C2-C10)-alkenyl, (C2-C10-alkanoyl or (C2-C10)-alkadienes; 12. (C3-C8) -cycloalkenyl; 13. (C3-C8)-cycloalkenyl-(C1-C3)-alkyl; 14. bi - or tricyclic (C4-C10)-cycloalkenyl-(C1-C4)-alkyl which may be substituted 1-3-me (C1-C4)-alkyl residues; 15. (C6-C10)-aryl- (C1-C4) -alkyl; 16. (C6-C10)-aryl-(C3-C6)-alkenyl; 17. (C1-C9-heteroaryl-(C3-C6)-alkenyl; 18. (C3-C6)-quinil; 19. (C6-C10)-aryl-(C3-C6)-quinil; 20. (C1-C9-heteroaryl-(C3-C6)-quinil; 21. R(106) and R(109) together with bearing N-atom form heteroaryl, which also may be partially or fully be gidrirovanny;

    C) R(107) means

    1. hydrogen; 2. (C1-C6)-alkyl; 3. (C3-C8-cycloalkyl; 4. (C6-C12)-aryl-(C1-C6)-alkyl, preferably benzyl; 5. phenyl; or 6. (C1- C9-heteroaryl;

    I) R(108) means

    1. hydrogen; 2. (C1-C6)-alkyl; 3. (C3The) R(110) means

    a cyano, a nitro-group or CO2R(107);

    l) R(111) and R(112), the same or different, mean

    1. hydrogen; 2. (C1-C4)-alkyl; 3. phenyl; 4. benzyl; or

    5. -methylbenzyl;

    m) D NR means(113); or CH2;

    n) R(113) denotes hydrogen, (C1-C4)-alkyl or phenyl;

    Oh) And means biphenylyl, which is unsubstituted or substituted with 1-4, preferably 1-2, same or different substituents R(114) or R(115);

    p) R(114) means

    1. halogen; 2. nitrosourea; 3. the nitro-group; 4. the amino group; 5. the cyano; 6. hydroxyl; 7. (C1-C6)-alkyl; 8. (C1-C4-alkanoyl; 9. (C1-C4)-alkanoyloxy; 10. CO2R(103); 11. methanesulfonylaminoethyl; 12. triptorelin-sulfonylamino; 13.-CO-NH-OR(109); 14.-SO2-NR(106)R(107); 15. -CH2-OR(107); 16. (C1-C9-heteroaryl- (CH2)q- preferably 1-tetrazolyl; 17. (C7-C13-aroyl;

    or 20. (C6-C12)-aryl;

    p) R(115) means

    1. hydrogen; 2. (C1-C6)-alkyl; 3. (C3-C8-cycloalkyl; 4. (C6-C12)-aryl; 5. (C7-C13-aroyl; 6. (C1-C4-alkoxyl; 7. (the PU; 12. the nitro-group; 13. NR(106)R(107); 14. hydroxyl; 15. -CO-NH-CHR(105)-CO2R(103); 16. alphagroup; 17. -SO3R(103); 18. -SO2-NR(107)-CO-NR(106)R(109) or-SO2-NR(107)-CS-NR(106)R(109); 19. -NR(107)-CO-NR(106)-SO2-CH2-R(105); 20.-WITH(CF3)2HE; 21. phosphonooxy; 22. RHO3H2; 23. -NH-PO(OH)2; 24. -S(O)rR(106); 25.-CO-R(108); 26. -CO-NR(106)R(109); 27. -CR(120)(HE)-RO(OH)2; 28. specified in paragraph (p) 20. balance;

    40. -CO-NH-SO2-R(119); 41. -SO2-NH-CO-R (106); or 42. specified in paragraph (p) 4. the residue, substituted by one or two identical or different residues from the series consisting of halogen, ceanography, nitro, NR(106)R(107) and hydroxyl; 43. R(115) together with R(114) mean-CO-NH-SO2-; 44.-SO2-NH-CO-OR(106); 45. -SO2-NH-SO2-NR(106)R(109); 46. -SO2-NH-SO2-R(106);

    C) means O, NR(107) or S;

    t) W denotes O or S;

    y) L means (C1-C3)-alcander;

    f) R(116) means CO2R(103) or CH2CO2R(103);

    x) R(117) means hydrogen, halogen, (C1-C4)-alkyl or (C1-C4-alkoxyl;

    C) R(118) denotes hydrogen, (C1-C4)-alkyl or phenyl;

    h) R(119) means

    1. (C1-C6)-alkyl; 2. (C3-C8-cycloalkyl; 3. Fe is achet: 1. simple connection;

    2. -CO-. 3. -CH2-, 4. , 5. -S-, 6. -NR(121)-. 7. -CO-NR(121), 8. -NR(121)-CO-. 9. -O-CH2-, 10. -CH2, 11. -S-CH2-, 12. -CH2-S, 13. -NH-CR(120)R(122), 14. -NR(121)-SO2,15. SO2-NR(121)-, 16. -CR(120)R(122)-NH, 17. -CH=CH-, 18. -CF=CF-, 19. -CH=CF-, 20. -CF=CH-, 21. -CH2-CH2-, 22. -CF2-CF2-, 23. -CH[OR(103)]-, 24. -CH(OCOR(105))-; 25. -C[N=R(123)]- oder 26. -(R(124)O]-C-(OR(125)]-y) R(120) und R(122)

    y) R(120) and R(122), identical or different, denote hydrogen, (C1-C5)-alkyl, phenyl, allyl or benzyl;

    e) R(121) denotes hydrogen, (C1-C6)-alkyl, benzyl or allyl;

    a') R(123) means: 1. NR(120)R(121); 2. raidgroup; 3. cheoreography; 4. toluene-4-sulfonyl; or 5. benzoylphenyl-amino group;

    `b') R(124) and R(125), identical or different, mean (C1- C4)-alkyl or together denote -(CH2)q-;

    in') Q means CH2, NH, O or S;

    g' m denotes 1, 2, 3, 4 or 5;

    d') n denotes 1, 2, 3, 4 or 5;

    e') means 1,2,3,4,5,6,7,8,9 or 10;

    W') q denotes zero or 1;

    C') g denotes zero, 1 or 2,

    and') v means 1,2,3,4,5 or up to 6;

    as well as its physiologically acceptable salts for obtaining a medicinal product for treatment or prevention causes the military breathing pulse.

    Further, the invention relates to the use of compounds of formula (1) for drugs for treatment or prevention caused by coronary artery disease States; and

    to the use of compounds of formula (1) for drugs for treatment or prevention of heart attack, as well as to the use of compounds of formula (1) for drugs for treatment or prophylaxis of angina,

    and also to the use of compounds of formula (1) for drugs for treatment or prophylaxis of ischemic conditions of the heart;

    and also to the use of compounds of formula (1) for drugs for treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and of stroke,

    and also to the use of compounds of formula (1) for drugs for treatment or prophylaxis of ischemic conditions of peripheral organs and limbs;:

    and also to the use of compounds of formula (1) for drugs for treatment of shock;

    and also to the use of compounds of the Fort is the beautiful bodies;

    and also to the use of compounds of formula (1) to obtain medicines for preservation and storage of transplants for surgical measures;

    and also to the use of compounds of formula (1) for drugs for treatment of diseases in which cell proliferation represents a primary or secondary cause; and thus to use this connection to get anti-atherosclerosis, anti-diabetic late complications, against cancer, fibrocycstic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, prostate hyperplasia;

    and also to the use of compounds of formula (1) to obtain medicines for the treatment of impaired respiratory impulse;

    and a drug, characterized in that it contains an effective amount of the compounds of formula (1).

    Such proposed according to the invention compounds of formula (1) compounds are known from U.S. patent 5482957 and 5604251. However, they do not contain available according to the invention always sulfanilamidna side chain. Imidazole derivatives as antagonists of angiotensin-P t is it in U.S. patent 5281614 describes derivatives of triazole, and in international application 9220662 and in J. Med.Chem., 37(17), 2808-2824 (1994) describes derivatives of triazolinone as receptor antagonists angiotensin-P. Known compounds are antagonists of the receptor of angiotensin-P subtype AT1, which have no effect or have only a small extent by the action proposed according to the invention compounds of formula (1).

    Proposed according to the invention the compounds of formula (1) have a very good antiarrhythmic properties, which are important, for example, for the treatment of diseases arising from the effects of lack of oxygen. Because of their pharmacological properties the compounds of formula (1) is perfectly suitable as antiarrhythmic drugs with cardiotoxin component for prevention of heart attack and treatment of infarction and for the treatment of angina, and they also preventively inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced lesions, especially when ischemia-induced cardiac arrhythmias.

    Because of their protective actions against pathological hypoxic and chemico Na+-dependent mechanism of exchange of CL-/HCO-3accordingly, the sodium/bicarbonate-symport, can be used as medicines for the treatment of any acute or chronic, caused by ischemia lesions or induced as a consequence of primary or secondary disease. They protect acutely or chronically insufficient provide of oxygen to the organs by reducing or preventing ischemia-induced lesions and thus suitable as pharmaceuticals, for example, thrombosis, spasm of blood vessels, atherosclerosis or during surgery (for example, transplantation of kidney and liver, and the connections can be used to protect the organs in the donor before and during removal, for the protection of removed organs, for example, when processing with use or when stored in physiological fluids, as well as when converting to the recipient's organism) or in the case of chronic or acute renal failure. The compounds of formula (1) are also valuable, applicable protective drugs in the implementation angioplasticheskih surgical interventions, for example, in the case of the heart, as also in the case of peripheral vessels. In the quality medicines for the treatment of ischemia of the nervous system, in particular, the Central nervous system, and they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, it is proposed according to the invention the compounds of formula (1) are also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

    Moreover, it is proposed according to the invention the compounds of formula (1) have strong inhibitory effects on the proliferation of cells, such as proliferation of fibroblasts and proliferation of vascular smooth muscle cells. Therefore, the compounds of formula (1) take into account as a valuable therapeutic agents in the case of diseases in which cell proliferation represents a primary or secondary cause, and therefore they can be used as tools against atherosclerosis, agents against diabetic late complications, anti-cancer, fibrocycstic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, against hypertrophy and hyperplasia of the authorities, especially when hyperplasia, respectively, hypertrophy of the prostate.

    Discovered that inhibitors of Na+-dependent CL-/HCO-3-exchange with the chemotherapeutic drug chemoreceptors breathing. These chemoreceptor largely responsible for maintaining uniform (ordered) breathing. They are activated in the body due to hypoxia, reduced pH and elevated CO2(hypercapnia) and lead to adaptation of the minute volume of respiration. In a dream breathing is particularly sensitive to disturbances and highly depends on the activity of chemoreceptors.

    Improving respiratory pulse due to the stimulation of chemoreceptors with substances which inhibit the Na+-dependent exchange of CL-/HCO-3that leads to better breathing in the case of the following clinical conditions and disorders: impaired Central respiratory pulse (for example, the Central stop breathing during sleep, sudden death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory disorders during adaptation in the Alpine region, obstructive and mixed form stop breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia.

    Drugs, which contain the compound of formula (1), can be administered orally, parenteral clinical disease. The compounds of formula (1) can be applied individually or together with galenovye excipients, namely both in veterinary and in human medicine.

    What excipients suitable for the desired pharmaceutical form specialist known on the basis of his expert knowledge. Besides solvents, gel-forming agents, bases suppositories, auxiliary materials for the production of tablets and other carriers of active substances can be used, for example, antioxidants, dispersants, emulsifiers, antispyware, corrective unpleasant taste of the drug substances, preservatives, agents, dissolution or dyes.

    For oral forms of application of active compound is mixed with suitable for this purpose additives such as carriers, stabilizers or inert diluents, and conventional methods lead to suitable forms of applications, such as tablets, pills, detachable capsules with the medicine, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn. is as oily carriers or solvents are used, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

    For subcutaneous or intravenous administration, the active compounds in the desired case, along with the usual for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, are dissolved, suspended or emuleret with obtaining a solution, suspension or emulsion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, such as, for example, ethanol, propanol, glycerin, along with which also use the solutions of sugars, like glucose, or mannitol, or a mixture of these various solvents.

    As pharmaceutical compositions for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active substances of the formula (1) in pharmaceutically acceptable solvents, such as especially ethanol, or water, or mixtures of such solvents.

    If necessary, the finished dosage form may also contain other pharmaceutical excipients, as surface-ACTICE in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3 wt.%.

    Dosage entered active substances of the formula (1) and the frequency of administration depend on the effectiveness and duration of exposure used compounds; in addition, they also depend on the kind and severity of treatable diseases, as well as gender, age, weight and individual sensitivity of the treated mammal.

    The average daily dose of the compounds of formula (1) when the weight of the patient of approximately 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg, up to at most 10 mg/kg, preferably 1 mg/kg of body weight. In acute outbreaks, for example directly after transferring of heart attack, may also be necessary even higher and especially more frequent dosing, for example, up to 4 doses per day. Especially with intravenous administration, for example in the case of patients with heart attack in the hospital may require up to 200 mg per day.

    The compounds of formula (1) can be used as the sole active substances or in combination with other pharmacologically effective compounds.

    The compounds of formula (1) and/or their physiologically acceptable salts for the achievement of preference is disiniame for the treatment or prevention of the above diseases, in particular for the treatment of cardiovascular diseases. Preferred is the combination with inhibitors of the sodium/hydrogen exchange (NHE) and/or active substances of other classes of active substances for the treatment of cardiovascular diseases.

    The invention also relates generally to the combination of (a) NCBE inhibitors and/or their physiologically acceptable salts with NHE inhibitors and/or their physiologically acceptable salts;

    b) NCBE inhibitors and/or their physiologically acceptable salts with active substances from other classes of active substances for the treatment of cardiovascular diseases and/or their physiologically acceptable salts, as well as in) NCBE inhibitors and/or their physiologically acceptable salts with NHE inhibitors and/or their physiologically acceptable salts and active substances from other classes of active substances for the treatment of cardiovascular diseases and/or their physiologically acceptable salts. Preferred such combinations using NCBE inhibitors of General formula (1) and/or their physiologically acceptable salts.

    In the case of known and identified as NHE inhibitors active substances it comes to derivatives of guanidine, preferably about acing the and Sons, 303-341 (1983), or NHE-inhibitors listed in the Federal Republic of Germany patent 19737224.4.

    Suitable NHE inhibitors are, for example, also benzylguanine, which are described in U.S. patents 5292755, 5373024, 5364868, 5591754, 5516805, 5559153, 5571842, 5641792, 5631293; in the European patent applications 577024, 602522, 602523, 603650, 604852, 612723, 627413, 628543, 640593, 640588, 702001, 713864, 723956, 754680, 765868, 774459, 794171; patents Germany 19624178.2 and 19713427.0; ortho-substituted benzylguanine, which are described in European patent applications 556673, 791577, 794172; the patent Germany 19624178.2; ortho-aminosilane benzylguanine, which are described in European patent application 690048; isoquinolines, which are described in European patent application 590455; benzododecinium five-membered heterocycles, which are described in European patent application 639573; decylamine guanidine, which are described in European patent application 640587; acylhalides, which are described in U.S. patent 5547953; containing performanceline group phenylsilane alkyl-, respectively, alkenylboronic acid - guanidine, which are described in U.S. patent 5567734, in European patent application 688766; heteroorganic, which are described in European patent application 676395; bicyclic heteroaromatic that the patent 738712; benzyloxycarbonylglycine, which are described in European patent application 748795; containing forfinally group phenylsilane alkenylboronic acid - guanidine, which are described in European patent application 744397; substituted cinnamic acid - guanidine, which are described in European patent application 755919; sulfonylamide, which are described in European patent application 771788; benzylcarbamoyl acid - biguanidine, which are described in European patent applications 774458 and 774457; direcarmenia acid - biguanidine, which are described in European patent application 787717; substituted difenilalkilamina acid guanidine, which are described in European patent application 790245; bis-ortho-substituted benzylguanine, which are described in the patent Germany 19621319.3; substituted 1 - or 2-naphtylamine, which are described in the patents Germany 19621482.3 and 19621483.1; indonesianization, which are described in European patent application 96112175.1; phenylsilane alkenylboronic acid - guanidine, which are described in the patent Germany 19633966.9; aminopiperidin-benzylguanine, which are described in European patent application 667341; heterocyclic-benzylguanine, caloriewise patent 704431; ortho-substituted alkylbenzenes, which are described in European patent application 699660; ortho-substituted heterocyclyl-benzylguanine, which are described in European patent application 699666; ortho-substituted 5-methylsulphonyl-benzylguanine, which are described in European patent application 708088; ortho-substituted 5-alkyl-sulfonylmethane with 4-amino-substituents, which are described in European patent application 723963; ortho-substituted 5-alkylchlorosilanes with 4-mercapto-substituents, which are described in European patent application 743301; 4-sulfonyl - or 4-sulfinil-benzylguanine, which are described in European patent application 758644; alkenylbenzenes, which are described in European patent application 760365; benzoylpyridine with annulated cyclic sulfones, which are described in the patent Germany 19548708; benzoyl-, the polycyclic aroyl and heteroorganic, which are described in the international application 9426709; 3-aryl/heteroaryl-benzylguanine, which are described in the international application 9604241; 3-phenylbenzophenone with the main amidon in position 5, which are described in the international application 9725310; 3-dehalogenation or 3-dehalogenans-resolveeventhandler with defined amino substituents in position 4, which are described in the international application 9512584; amiloride-derivatives, which are described in the international application 9512592; 3-methylsulfonylmethane with defined amino substituents in position 4, which are described in the international application 9726253; indolalkylamine, which are described in European patent applications 622356 and 708091; indolealkylamine with anilinophenol additional cyclic system, which are described in European patent 787728; derivatives methylguanine, which are described in the international application 9504052; 1/4-benzoxazine-igualadina, which are described in European patent application 719766; 5-bromo-2-nattergalen, which are described in the Japan patent 8225513; quinoline-4-carbonylcyanide with the phenyl residue in position 2, which are described in European patent application 726254; cinnamoylcocaine, which are described in the Japan patent 09059245; propanolamine with naphthalene Deputy, which are described in the Japan patent 9067332; propanolamine with indole Deputy, which are described in the Japan patent 9067340; or heteroaryl-substituted acryloylmorpholine, which are described in the international application 9711055, as well as their physiologically acceptable salts.

    Examples active against cardiovascular classes of active substances, which are therapeutically preferably can be combined with NCBE inhibitors, or can optionally be combined with combinations of NCBE inhibitors and NHE inhibitors, blockers are beta-receptors, calcium antagonists, inhibitors of the angiotensin converting enzyme inhibitor angiotensin receptor common diuretics, thiazide diuretics, potassium-sparing diuretics, aldosterone antagonists, which, for example, used to lower blood pressure, and cardiac glycosides or other increases force of contraction tool in the treatment of heart failure and congestive heart failure, as well as antiarrhythmic agent of class 1-1U, nitrates, KATP-openers, TOATP-blockers, inhibitors of activated veratridine sodium channel, etc. Thus, for example, are suitable: beta-blockers - propanolol, Aten angiotensin converting enzyme - captopril, enalapril, ramipril; trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; receptor antagonists angiotensin - P-losartan, valsartan, telmisartan, eprosartan, tasosartan, capesante, irbesartan; common diuretics - furosemide, piretanide, torasemide; thiazide diuretics - hydrochlorothiazide, metolazone, indapamide; potassium-sparing diuretics amiloride, triamterene, spironolactone; cardiac glycosides digoxin, digitoxin, strophanthin; antiarrhythmic agent is amiodarone, sotalol, bretylium, flecainide; nitrate-nitroglycerin;+(ATP)-openers - chromosom, imaclim, nicorandil, pinacidil, Minoxidil; inhibitors of activated veratridine Na+channel.

    An example of such especially preferred component combinations with NCBE inhibitors are blockers mainactivity sodium channel (activated veratridine sodium channel). Combination NCBE inhibitor with a blocker of mainactivity sodium channel (activated veratridine sodium channel) suitable for prevention of heart attack and re-infarction and for the treatment of infarction and for the treatment of angina and the suppression of ischemia-induced heart is Thor mainactivity sodium channel also preventively inhibit or greatly reduce the pathophysiological processes in the occurrence of ischemia-induced lesions. Because of their enhanced protective actions against pathological hypoxic and ischemic situations proposed according to the invention combination NCBE inhibitor with a blocker of mainactivity sodium channel due to increased inhibition of Na+-influx into the cell can be used as medicines for the treatment of any acute or chronic, caused by ischemia lesions or induced as a consequence of primary or secondary disease. The same applies to their use as pharmaceuticals for surgical interventions, for example, transplant organs, and combinations NCBE inhibitor with a blocker of mainactivity sodium channel can be used to protect the organs of the donor before and during removal, for the protection of removed organs, also during storage in physiological fluids, as well as during the transfer to the recipient's organism. Combination NCBE inhibitor with a blocker of mainactivity sodium channel are also valuable, applicable protective drugs in the implementation angioplasticheskih surgical interventions, for example, in the case of the heart, as also in the case of peripheral vessels. In accordance with their protective d what about the sodium channel also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, in particular, the Central nervous system, and they are suitable for the treatment of stroke or of cerebral edema. Moreover, it is proposed according to the invention combination NCBE inhibitor with a blocker of mainactivity sodium channel is also suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

    Along with the application as a fixed combination, the invention also relates to the simultaneous, separate or stupenchataya time use NCBE inhibitors with NHE inhibitors and/or additional active substance from another class of active substances for the cardiovascular system for treatment of the above diseases.

    Further, the invention relates to pharmaceutical compositions containing (a) NCBE inhibitor and NHE inhibitor and/or a physiological acceptable salt; or b) an NCBE inhibitor and optionally the active substance from another class of active substances in relation to the cardiovascular system and/or their physiologically acceptable salts; or C) NCBE inhibitor, I-inhibitor, and optionally the active substance from another class of active substances in relation to the cardiovascular system and/or the physiological is their formula (1) and/or its physiologically acceptable salt as MSO inhibitor.

    Due to the combined method, it is possible to enhance the effect of one component of the combination for the account of the respective other component, i.e. the action and/or duration of action proposed according to the invention combination or mixture stronger, respectively, longer than the action and/or the duration of the respective individual components (Energeticheskiy effect). In the case of combined application this leads to a reduction of the dose of the corresponding component of the combination compared to the individual application. Proposed according to the invention combinations and preparations accordingly have the advantage that the insertion amount of the active substance can be significantly reduced and eliminated, respectively, greatly reduce unwanted side effects.

    The invention relates, further, to the sales package comprising as pharmaceutically active substances (a) NCBE inhibitor and NHE inhibitor and/or their physiologically acceptable salts; or b) an NCBE inhibitor and optionally the active substance from another class of active substances in relation to the cardiovascular system and/or their physiologically acceptable salts; or the cardio-vascular system and/or their physiologically acceptable salts, depending on the circumstances, together with instructions for the use of these active substances in combination for simultaneous, separate or stupinatorov time of application for the treatment or prevention of the above clinical pictures of the disease, in particular for the treatment of cardiovascular diseases. Preferred sales packaging, which contain compounds of the formula (1) as NCBE inhibitors.

    Proposed according to the invention the pharmaceutical composition can be obtained, for example, the fact that either intensively mixing the individual components in powder form, or the individual components are dissolved in a suitable solvent, as, for example, lower alcohol, and the solvent then removed.

    The mass ratio of NCBE inhibitor to NHE-inhibitor or active in relation to the cardiovascular system of the substance in the proposed according to the invention combinations and compositions expedient is from 1:0.01 to 1:100, preferably from 1:0.1 to 1:10.

    Proposed according to the invention the combination and composition contain, in General, preferably from 0.5 to 99.5 wt.%, in particular 4-99 wt.% these active substances.

    When applied according to the invention in SSA in the range from 0.001 to 100 mg/kg/day.

    A General method of obtaining sulfanilamide of sulfonamides

    The original substance of the sulfonamide is dissolved in 10 ml/mmol of anhydrous acetonitrile, add 3 mol-equivalent TO2CO3and added dropwise 1 mol-equivalent 5N Enrichment solution in acetonitrile and refluxed until complete conversion (typical reaction time is 1-6 hours). The reaction mixture was then without further processing chromatographic on silica gel.

    Example 1: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    975 mg of Ethyl ether 1-[[2'-(aminosulfonyl) (1,1'-biphenyl)-4-yl]-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylic acid (J. Med.Chem.,38, 2357 (1995)) was dissolved in 10 ml of anhydrous acetonitrile, then added 276 mg2CO3and 2 ml of 1N solution of bromine cyan in acetonitrile and boiled for 4 hours under reflux. The reaction mixture chromatographic on silica gel, elwira using a mixture of ethyl acetate with methanol in the ratio of 10:1, and obtain 780 mg of a colorless amorphous solid, crystallized upon standing with decomposition.

    So pl. 110° With PR is emer 2: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(3'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    a) 3-Bromo-N-dimethylaminoethylmethacrylate of 20.3 g of 3-Bromo-benzosulfimide dissolved in 120 ml of dimethylformamide, and at room temperature pin 57 ml of dimethylformamide-dimethylacetal. Stirred for 5 hours at room temperature and left to stand for three days at room temperature. The reaction mixture was then poured into 1.2 l of water, additionally stirred for 90 minutes and the precipitate is filtered off white color. The product is dried in vacuum at 50°C, and get to 20.5 g of white crystals.

    So pl. = 122° C; Rf (ethyl acetate) =0,59; mass spectrum (DCl): 291 (M+H)+

    b) Dimethylaminomethylene 4'-methylbiphenyl-3-sulfonic

    2.9 g of 3-Bromo-N-dimethylbenzenesulfonamide, 1.5 g of p-tolylboronic acid, 112 mg of palladium acetate-(P) and 224 mg of triphenylphosphine are dissolved in 60 ml of toluene and 17 ml of ethanol, add 10 ml of 2n aqueous solution of sodium carbonate and refluxed for 7 hours. The reaction mixture is treated with 150 ml of a saturated aqueous solution of sodium carbonate and 150 ml of water and extracted with 3 times 200 ml of ethyl acetate. The extract is dried over sodium sulfate, and the solvent is removed in vacuo. the ylacetic/n-heptane = 2:1) = 0,22; mass spectrum (DCl):302 (M+N)+

    C) Dimethylaminomethylene 4' -bromomethylbiphenyl-3-sulfonic

    1.7 g of Dimethylaminomethylene 4'-methylbiphenyl-3-sulfonic acids dissolved in 30 ml of chlorobenzene and at a temperature of 130° With add 1.0 g of N-bromosuccinimide, and 10 mg of benzoyl peroxide, and within 30 minutes, refluxed. The reaction mixture is treated with 150 ml of ethyl acetate and washed 2 times with 150 ml of a mixture in the ratio of 8:1 of saturated aqueous solution of sodium carbonate and a saturated aqueous solution of Na2SO3. The aqueous phase is then extracted with twice 150 ml of ethyl acetate. The combined organic phase is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using methyl-tert.-butyl ether to give 1.6 g of pale yellow oil.

    Rf (ethyl acetate) = 0,59: mass spectrum (DCl): 291 (M+N)+

    d) Ethyl ester of 2-butyl-3- [3'(dimethylaminomethylphenol)-biphenyl-4-ylmethyl-5-(methylsulfonyl)-3H-imidazole-4-carboxylic acid

    1.6 g of Dimethylaminomethylene 4'-bromomethylbiphenyl-3-sulfonic acids, 990 mg of ethyl ester of 2-butyl-5-methylsulfanyl-3H-imidazole-4-carboxylic acid (J. Med. Chem., 38, 2357 (1995)) and left to stand over night. Then mix the next 6 hours at room temperature, after which the reaction mixture is then poured into a mixture of 125 ml of saturated aqueous sodium hydrogen carbonate solution and 125 ml of water and extracted with 3 times 200 ml of ethyl acetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 2:1 gives 1.1 g of colorless oil.

    Rf (ethyl acetate/n-heptane = 1:1) = 0,10; mass spectrum (ES):543(M+H)+

    d) Ethyl ester of 2-butyl-5-methylsulfanyl-3-(3'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    1.1 g of Ethyl ester of 2-butyl-3- [3'-(dimethylaminomethylphenol) -4-ylmethyl]-5-(methylsulfonyl)-3H-imidazole-4-carboxylic acid was dissolved in 20 ml of methanol and add 10 ml of a saturated aqueous solution of Hcl. Refluxed for 4 hours, then with aqueous 6N NaOH solution set pH 5-6, diluted with 50 ml of water and extracted 3 times with 150 ml ethyl acetate. Dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 1:1 to give 950 mg of a colorless foam.

    Rf (this is lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    720 mg of Ethyl ester of 2-butyl-5-methylsulfanyl-3-(3'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid turn according to the General method of obtaining sulfanilamide of sulfonamides, and obtain 550 mg of an amorphous solid.

    Rf (ethyl acetate/methanol = 10:1) = 0,38; mass spectrum (ES):513 (M+H)+

    The target compounds of examples 3-9 are synthesized analogously to the method of example 2.

    Example 3: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(4'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 244° C with decomposition; Rf (ethyl acetate/methanol = 10:1)=0,17; mass spectrum (ES): 513 (M+H)+

    Example 4: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(2'-lineministries-3-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 118° C with decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,19; mass spectrum (ES): 513 (W+H)+

    Example 5: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(3'-lineministries-3-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 112° C with decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,15; mass spectrum (ES): 513 (M+H)+

    Example 6: Ethyl ester of 2-butyl-5-metilsulfate 120° With decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,36; mass spectrum (ES): 513 (M+N)+

    Example 7: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(2'-lineministries-2-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 105°C With decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,23; mass spectrum (ES): 513 (M+N)+

    Example 8: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(3'-lineministries-2-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 108° C with decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,27; mass spectrum (ES): 513 (M+N)+

    Example 9: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(4'-lineministries-2-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 116° C with decomposition; Rf (ethyl acetate/methanol = 10:1) = 0,23; mass spectrum (ES): 513 (M+N)+

    The target compound of example 10 are synthesized according to the method of example 2 of the ethyl ester of 2-cyclopropyl-5-methylsulfanyl-3- (4'-sulfamoylbenzoyl-2-ylmethyl)-3H-imidazole-4-carboxylic acid (J. Med. Chem., 38, 2357 (1995)).

    Example 10: Ethyl ester of 2-cyclopropyl-5-methylsulfanyl-3- (2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. in the-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    a) Dimethylaminomethylene 4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonic

    2.1 g of 4-Chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 24 (5) 960 (1976)), 3,8 g dimethylaminomethylene 4'-bromomethylbiphenyl-2-sulfonic acids (J. Med. Chem., 38, 2357 (1995)) and 2.8 g2CO3in 50 ml of dimethylformamide is stirred for 30 hours at room temperature. The reaction mixture is poured into 500 ml of water and extracted 2 times with 250 ml ethyl acetate. The organic phase is then washed with 100 ml of water, dried over magnesium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using methyl-tert.-butyl ether to give 1.9 grams of white crystalline powder; so pl. = 193° C; Rf (tert.-butyl ether) = 0,19;

    mass spectrum (ES): 507 (M+N)+

    b) 4'(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide

    1.9 grams of Dimethylaminomethylene 4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acids dissolved in 20 ml of ethanol and add 20 ml of a saturated aqueous solution of model HC1. Refluxed for two hours, then the volatile component parts removed in vacuo, treated with 200 ml of water, using water Raut in vacuum and obtain 1.7 g of colorless solid.

    So pl.= 215° C with decomposition; Rf (tert.-butyl ether) = 0,57; mass spectrum (FAB): 452 (M+H)+

    in) 4' -(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl) biphenyl-2-sulfanilamide

    800 mg 4'-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide of sulfonamides and obtain 650 mg of an amorphous solid.

    Rf (ethyl acetate/methanol = 10:1) = 0,18; mass spectrum (ES):477 (M+H)+

    Example 12: 4'-(4-Methoxy-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    a) 4'-(4-Methoxy-5-formyl-2-phenylimidazol-1-ylmethyl) biphenyl-2-sulfonamide

    700 mg 4'-(4-Chloro-5-formyl-2-phenylimidazol-1-ylmethyl) biphenyl-2-sulfonamida (example 11 b) and 620 mg of NaOH dissolved in 10 ml of methanol and within 1 hour and refluxed. The solvent is removed in vacuo, treated with 20 ml of water, set pH 7 with aqueous Hcl, and the precipitate is filtered off, dried in vacuum and obtain 650 mg of colorless solid. So pl. = 188° C; Rf (diisopropyl ether/methyl-tert.-butyl ether = 1:1) = 0,26; mass spectrum (FAB): 448 (M+H)+

    b) 4'-(4-Methoxy-5-formyl-2-Hairdryer who yl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide of sulfonamides, and receive 600 mg of an amorphous solid.

    Rf (ethyl acetate/methanol = 10:1) = 0,18; mass spectrum (ES): 472 (M+N)+

    Example 13: Ethyl ester of 2 - butyl-3- (2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    a) Ethyl ester 1-[[(2'-(aminosulfonyl)(1, 1'-- biphenyl)-4-yl]methyl]-2-butyl-1H=imidazole-5-carboxylic acid

    244 mg of Ethyl ether 1-[[2'-(aminosulfonyl) (1,1'-biphenyl)-4-yl]-methyl]-2-butyl-4-(methylthio)-1H-imidazole-5-carboxylic acid (J. Med. Chem., 38, 2357 (1995)) was dissolved in 10 ml of ethanol and add 200 mg of Raney Nickel. Then refluxed for 6 hours, add a further 200 mg of Raney Nickel and again refluxed for 3 hours. The residue is filtered off and the solvent is removed in vacuum. Receive 200 mg of colorless oil.

    Rf (tert.-butyl ether/diisopropyl ether = 1:1) = 0,12; mass spectrum (FAB): 442 (M+H)+.

    b) Ethyl ester of 2-butyl-3- (2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    140 mg of Ethyl ether 1-[[2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl]-methyl]-2-butyl-1H-imidazole-5-carboxylic acid turn according to the General method of obtaining solgenia; Rf (ethyl acetate/methanol =5:1) = 0,20; IR spectrum (C N): 2174,7 cm'1; mass spectrum (ES): 467 (M+N)+

    Example 14: 4'-(2-Butyl-5-cyano-4-methoxyindol-1-ylmethyl)biphenyl-2-sulfanilamide

    and) 4'-[2-Butyl-5-(gidroksilaminami)-4-methoxyindol-1-ylmethyl]-biphenyl-2-sulfonamide

    4.1 g of 4'-(4-Methoxy-5-formyl-2-phenylimidazol-1-ylmethyl)bifacil-2-sulfonamida (example 12A) is dissolved in 500 ml of methanol and added to 3.3 g of hydroxylaminopurine, and 1.2 g of 1,4-diazabicyclo-[2.2.2]octane. Stirred for 11 hours at room temperature, the mixture is then mixed with 200 ml of a saturated aqueous solution of sodium bicarbonate and 200 ml of water and extracted 6 times with 400 ml ethyl acetate. The organic phase is dried over sodium sulfate and solvents removed under vacuum. Obtain 4.5 g of colorless oil.

    Rf (tert.-butyl ether/toluene = 1:1) = 0,32

    b) 4'-(2-butyl-5-cyano-4-methoxyindol-1-ylmethyl) biphenyl-2-sulfonic-ndimethylacetamide

    210 mg 4'-[2-Butyl-5-(gidroksilaminami)-4-methoxyindol-1-ylmethyl]-biphenyl-2-sulfonamida dissolved in 4 ml of pyridine and add 4 ml of acetanhydride. Refluxed in turning 170 minutes, then poured into 200 ml okhlazhdennogo the ical phase is dried over sodium sulfate and the solvent is removed in vacuum. Obtain 230 mg of a colorless oil.

    Rf (tert.-butyl ether/toluene = 1:1) = 0,14; mass spectrum (FAB); 467 (M+N)+

    in) 4'-(2-Butyl-5-cyano-4-methoxyindol-1-ylmethyl)biphenyl-2-sulfonamide

    2.1 g of Acetylated 4'-(2-butyl-5-cyano-4-methoxyindol-1-ylmethyl)-2-sulphonic acids suspended in 40 ml of 20% aqueous solution of sulfuric acid and refluxed for 3 hours. The reaction mixture was pinned to 400 ml 2/3 M solution KN2RHO4in water and extracted 3 times with 300 ml ethyl acetate. The organic layer is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using methyl-tert.-butyl ether to give 1.6 g of colorless oil.

    Rf (tert.-butyl ether): 0,48.

    g) 4- (2-Butyl-5-cyano-4-methoxyindol-1-ylmethyl)biphenyl-2-sulfanilamide 360 mg 4'-(2-Butyl-5-cyano-4-methoxyindol-1-ylmethyl)biphenyl-2 - sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 1 hour), and receive 300 mg of white crystals.

    So pl.= 160° decomposition; Rf (ethyl acetate/methanol = 5:1) = 0,27; IR spectrum (C N): 2177,2 cm-1; mass spectrum (ES): 450 (M+H)+

    Example 15: 4'-(2-Motorbility-1-ylmethyl)biphenyl-2-sulfonamide

    10.6 g of Dimethylaminomethylene 4'-(2-butyl-4-chloro-5-formylindole-1-ylmethyl)biphenyl-2-sulfonic acids(J. Med. Chem., 38, 2357(1995)) are dissolved in 200 ml of methanol and add 100 ml of a saturated aqueous solution of Hcl. Refluxed for two hours, after cooling with 2n aqueous NaOH solution set pH 5-6 and extracted 4 times with 200 ml ethyl acetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuum.

    Gain of 9.2 g of a colorless oil. Rf (ethyl acetate/n-heptane = 2:1) = 0,46

    b) 4'-(2-Butyl-4-chloro-5-formylindole-1-ylmethyl)biphenyl-2-sulfanilamide

    160 mg 4'-(2-Butyl-4-chloro-5-formylindole-1-ylmethyl) biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time of 75 minutes) and obtain 110 mg of white crystals with so pl. =135°With decomposition.

    Rf (ethyl acetate/methanol = 5:1)= 0,28; IR spectrum (C N):

    RUB 2,176 .9 cm-1; mass spectrum (ES): 457 (M+N)+

    The target compounds of examples 16-19 are synthesized according to the method of example 1:

    Example 16: Ethyl ester of 5-methylsulfanyl-2-propyl-3-(2'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    Example 17: Ethyl ester of 2-ethyl-5-methylsulfanyl-3-(2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 94° C (decomposition); Rf (ethyl acetate/methanol = 5:1) = 0,38; IR spectrum (C N): 2173,3 cm-1; mass spectrum (ES): 485 M+H)+

    Example 18: Ethyl ester of 2-methyl-5-methylsulfanyl-3-(2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 169° C (decomposition); Rf (ethyl acetate/methanol = 5:1)=0,29; IR spectrum (C N): 2173,0 cm-1; mass spectrum (ES): 471 (M+H)+

    Example 19: Ethyl ester of 2-isopropyl-5-methylsulfanyl-3-(2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    So pl. = 276° C (decomposition); Rf (ethyl acetate/methanol = 5:1) = 0,28; IR spectrum (C N): 2178,8 cm-1; mass spectrum (ES):499 (M+H)+

    Example 20: Isopropyl ester of 2-butyl-5-methylsulfanyl-3- (2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    a) Isopropyl ester of 2-butyl-5-methylsulfanyl-3-(2'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    980 mg of Ethyl ester of 2-butyl-5-methylsulfanyl-3-(2'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazol-4 refluxed for 9 hours, and then add the following 590 µg of isopropylate tetravalent titanium. Refluxed for 8 hours, and again add 1.2 ml of isopropylate tetravalent titanium. After further boiling under reflux for 11 hours, the reaction mixture was poured into 200 ml of a saturated aqueous solution of sodium bicarbonate and diluted with 200 ml of water. Extracted 3 times with 150 ml ethyl acetate, the extract is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 1:2 produces 420 mg of colorless oil. Rf (tert.-butyl ether/n-heptane/l3= 2:1:1) = 0,36.

    b) Isopropyl ester of 2-butyl-5-methylsulfanyl-3-(2'-lineministries-4-ylmethyl)-3H-imidazole-4-carboxylic acid

    410 mg of Isopropyl ester of 2-butyl-5-methylsulfanyl-3-(2'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid turn according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours) and obtain 310 mg of white crystals; so pl. = 113° C with decomposition; Rf (ethyl acetate/methanol = 5:1) = 0,16; IR spectrum (C N), 2178,2 cm-1; mass spectrum (ES): 527 (M+H)+

    PR is 4 - carboxylic acid

    a) 4,4,5, 5-Tetramethyl-2-p-tolyl- [1.3.2] dioxaborolan

    1.4 g of p-tolylboronic acid, 1.2 g of pinecone, and a catalytic amount (about 2 mg) of p-toluenesulfonic acid are suspended three times in toluene, taking each time in 40 ml of toluene, and the volatile component parts each time removed in vacuum. Then dried in high vacuum and obtain 2.0 g of pale yellow oil.

    Rf (ethyl acetate/n-heptane= 1:1) = 0,86.

    b) 2- (4-Bromomethylphenyl) -4,4,5, 5-tetramethyl-[1.3.2] dioxaborolan

    2.0 g 4,4,5,5-Tetramethyl-2-p-tolyl-[1.3.2]dioxaborolan dissolved in 50 ml of chlorobenzene, and the temperature of the evaporating portions add 1.7 g of N-bromosuccinimide and 5 mg of benzoyl peroxide. Refluxed for 4 hours, and after cooling, diluted with 200 ml of ethyl acetate. The organic phase is washed with 2 times 100 ml of a mixture in the ratio of 8:1 of saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium sulfate, and then the aqueous phase is extracted a further 2 times 100 ml of ethyl acetate, and the combined organic phases are dried over sodium sulfate. The solvents are removed in vacuo, and chromatography on silica gel using mixtures of ethyl acetate with n-heptane in cootes b) Ethyl ester of 2-butyl-5-methylsulfanyl-3-[4-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)benzyl]-3H-imidazole-4-carboxylic acid

    1.5 g of 2-(Bromomethylphenyl)-4,4,5,5-tetramethyl-[1.3.2]-dioxaborolane, 1.2 g of ethyl ester of 2-butyl-5-methyl-effect-free remedy 3H-imidazole-4-carboxylic acid (J. Med. Chem., 38, 2357 (1995)) and 700 mg of potassium carbonate in 15 ml of dimethylformamide is stirred at room temperature for 14 hours. The reaction mixture is poured into 200 ml of a saturated aqueous solution of sodium bicarbonate, diluted with 200 ml of water and extracted 3 times with 150 ml ethyl acetate. Dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane 1:4 gives 1.4 g of colorless oil.

    Rf (ethyl acetate/n-heptane = 1:2) = 0,29; mass spectrum(FAB):

    459 (M+H)+

    d) Ethyl ester of 2-butyl-5-methylsulfanyl-3-[4-(dihydroxyaryl)benzyl]-3H-imidazole-4-carboxylic acid

    1.2 g of Ethyl ester of 2-butyl-5-methylsulfanyl-3-[4-(4,4,5,5-tetramethyl-[1.3.2]dioxaborolan-2-yl)benzyl]-3H-imidazole-4-carboxylic acid are dissolved in 50 ml of ethyl acetate and add 260 μl of diethanolamine. Stirred for 5 hours at room temperature, then for 4 hours at room temperature is treated in the bath for ultrasonic cleaning. After that add the following 260 μl of diet the aces at room temperature, and sucked off. The residue is treated with 50 ml policecontributing aqueous solution of sodium hydrosulphate and stirred for two hours at room temperature. Then extracted with 3 times 150 ml ethyl acetate, dried over sodium sulfate, and the solvent is removed in vacuum. Obtain 390 mg of an amorphous solid. Rf (ethyl acetate) = 0,62; mass spectrum (FAB. + glycerin): 433 (M+56+H)+

    d) 3-Bromo-4-methylbenzenesulfonamide

    10 g 3-Bromo-4-methylaniline suspended in 22 ml of water, and pin 22 ml of a saturated aqueous solution of model HC1. Stirred additionally for 5 minutes at room temperature, then cooled to -10° C and at this temperature, pin a solution of 4.1 g of NaNO2in 15 ml of water. The reaction mixture is additionally stirred for 45 minutes at a temperature of -15° C and at room temperature are added in several portions to a suspension of 916 mg ul2×2 H2Oh, and 92 mg of CuCl in a saturated solution of SO2in glacial acetic acid. The reaction mixture is slowly heated in a water bath until then, until the evolution of nitrogen. Then extracted with 3 times 250 ml of diethyl ether, the organic phase is washed 2 times in 80 ml of water and sinno the solution is cooled to 0°C, and at this temperature slowly pin aqueous ammonia solution until pH 10. Which results in a precipitate which is filtered off and recrystallized from methyl-tert.-butyl ether. Obtain 2.5 g of white crystals; so pl. = 156° C.

    Rf (diisopropyl ether) = 0,30; mass spectrum (DC1):250 (M+N)+

    e) 3-Bromo-N-dimethylaminomethylene-4-methylbenzenesulfonamide

    of 7.7 g of 3-Bromo-4-methylbenzenesulfonamide dissolved in 50 ml of dimethylformamide, and at room temperature pin of 20.5 ml of dimethylformamide-dimethylacetal. Stirred for 4.5 hours at room temperature, and then the product is sucked off and dried in vacuum. Obtain 9.0 g of pale yellow crystals; so pl. = 162° C.

    Rf (ethyl acetate) = 0,48; mass spectrum (ES): 305 (M+N)+

    W) Ethyl ester of 2-butyl-3-[5'-(dimethylaminomethylphenol) -2'-methylbiphenyl-4-ylmethyl]-5-methylsulfanyl-3H-imidazole-4-carboxylic acid

    390 mg of Ethyl ester of 2-butyl-5-methylsulfanyl-3-[4-(dihydroxyaryl)benzyl]-3H-imidazole-4-carboxylic acid, 288 mg of 3-bromo-N-dimethylaminomethylene-4-methylbenzenesulfonamide, 11 mg of palladium acetate-(P) and 28 mg of triphenylphosphine are suspended in a mixture of 6 ml of toluene and 1.6 ml of ethanol and add 940 μl of 2M is more in 200 ml policecontributing aqueous solution of sodium bicarbonate and extracted 3 times with 150 ml ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed in vacuum. Chromatography on silica gel gives 150 mg of colorless oil.

    Rf (ethyl acetate/n-heptane = 2:1) = 0,19; mass spectrum (ES):557 (M+H)+

    C) Ethyl ester of 2-butyl-3-[5'-sulfamoyl-2'-methylbiphenyl-4-ylmethyl]-5-methylsulfanyl-3H-imidazole-4-carboxylic acid

    140 mg of Ethyl ester of 2-butyl-3-[5'-(dimethylaminomethylphenol) -2'-methylbiphenyl-4-ylmethyl]-5-methylsulfanyl-3H-imidazol-4~carboxylic acid are dissolved in 2.5 ml of methanol, and pin 1.3 ml of a saturated aqueous solution of Hcl. The reaction mixture was then refluxed for 75 minutes, set pH 6 with 6N aqueous NaOH solution and diluted with 50 ml of water. Extracted 5 times with 50 ml ethyl acetate, dried over sodium sulfate, and the solvent is removed in vacuum. Obtain 110 mg of an amorphous solid. Rf (ethyl acetate/n-heptane = 2:1)= 0,44; mass spectrum (ES): 502 (M+H)+

    and) Ethyl ester of 2-butyl-3-(2'-methyl-5'-cyanamide-sulfonylmethane-4-ylmethyl)-5-methylsulfanyl-3H-imidazole-4-carboxylic acid

    100 mg of Ethyl ester of 2-butyl-3-[5'-sulfamoyl-2'-methylbiphenyl-4-ylmethyl]-5-methylsulfanyl-3H-imidazole-4-carboxylic cicas) and obtain 63 mg of white crystals.

    So pl. = 127° C with decomposition; Rf (ethyl acetate/methanol =5:1) = 0,09; IR spectrum (C N):2179,3 cm-1; mass spectrum (ES):527 (M+H)+

    The target compounds of examples 22-26 synthesized according to the method of example 21.

    Example 22: Ethyl ester of 2-butyl-3-(2'-methyl-4'-lineministries-4-ylmethyl)-5-methylsulfanyl-3H-imidazole-4-carboxylic acid

    So pl. = 211° C; Rf (ethyl acetate/methanol=5:1) = 0,20;

    IR spectrum (C N): 2189,9 cm-1; mass spectrum (ES): 527 (M+H)+

    Example 23: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(4'-tianmenshan-2'-triptorelin-4-ylmethyl) -3H-imidazole-4-carboxylic acid

    Amorphous substance. Rf (ethyl acetate/methanol= 10:1) = 0,20;

    IR spectrum (C N): 2184,9 cm-1; mass spectrum (ES): 581 (M+H)+

    Example 24: Ethyl ester of 2-butyl-3-(2'-methyl-5'-lineministries-3-ylmethyl)-5-methylsulfanyl-3H-imidazole-4-carboxylic acid

    So pl. = 160° C (decomposition); Rf (ethyl acetate/methanol = 10:1) = 0,18; IR spectrum (C N): 2181,3 cm-1; mass spectrum (ES): 527 (M+H)+

    Example 25: Ethyl ester of 2-butyl-3- (2'-methyl-4'-lineministries-3-ylmethyl)-5-methylsulfanyl-3H-imidazol-4-carbon,2 cm-1; mass spectrum (ES): 527 (M+H)+

    Example 26: Ethyl ester of 2-butyl-5-methylsulfanyl-3-(4'-tianmenshan-2'-triptorelin-3-ylmethyl)-3H-imidazole-4 - carboxylic acid

    So pl. = 122° C (decomposition); Rf (ethyl acetate/methanol = 10:1) = 0,27; IR spectrum (C N): 2186,1 cm-1; mass spectrum (ES): 581 (M+H)+

    Example 27: 4'-(2-Butyl-4-methylsulfonylamino-1-ylmethyl)biphenyl-2-sulfanilamide

    a) 4'(2-Butyl-4-methylsulfonylamino-1-ylmethyl)biphenyl-2-sulfonamide

    460 mg of 2-Butyl-5-methylsulfanyl-3-(2'-sulfamoylbenzoyl-4-ylmethyl)-3H-imidazole-4-carboxylic acid are dissolved in 5 ml of isopropanol, inject 220 μl of thionyl chloride and refluxed for 4 3/4 hours. Then set pH 6 with 6N aqueous NaOH solution, diluted with 100 ml of water and extracted with 3 times 100 ml ethylacetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using a mixture of ethylacetate with n-heptane in the ratio of 1:1 gives 300 mg of colorless oil.

    Rf (ethyl acetate) = 0,58; mass spectrum (FAB): 416(M+H)+

    b) 4'(2-Butyl-4-methylsulfonylamino-1-ylmethyl)biphenyl-2-sulfolene common method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours 20 minutes) and receive 50 mg of an amorphous powder.

    Rf(ethyl acetate/methanol = 5:1) = 0,19; IR spectrum (C N): 2171,8 cm-1; mass spectrum (ES): 441 (M+N)+

    Example 28: 4'-(4-Chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    a) 4'-(4-Chloro-2-phenylimidazol-1-ylmethyl) biphenyl-sulfonamid

    9.2 grams of Dimethylaminomethylene 4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acids (example IIA), 95 ml of a saturated aqueous solution of Hcl and 95 ml of ethanol is refluxed for two hours. After cooling, diluted with 500 ml of water, extracted 2 times with 500 ml ethyl acetate, and the organic phase is washed with 2 times 100 ml saturated aqueous NaCl, dried over sodium sulfate, and the solvent is removed in vacuum. The resulting mixture is recrystallized from 200 ml of ethyl acetate and obtain 6.2 g of 4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamida (see example 11b). The solvent from the mother liquor is removed under vacuum, and the residue chromatographic on silica gel using a mixture of methyl-tert.-butyl ether and diisopropyl ether in the ratio 1:1. Receive 40 mg of colorless oil.

    Rf (tert.-butyl ether/diisopropyl ether = 1:1) = 0,22; mass spectrum (ES): 424 (M+N)+

    Rf (ethyl acetate/methanol = 10:1) = 0,09; mass spectrum (ES):447 (M-H)+;

    ES: electronic sputtering, negative mode.

    Example 29: 4'-(5-Acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2 - sulfanilamide

    a) 3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

    3.0 g of 4-Chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull., 24 (5), 960 (1976)), 7,0 g 4-bromobenzylamine and 11.7 g of potassium carbonate in 200 ml of dimethylformamide is stirred for 20 hours at room temperature. Then pour the reaction mixture into 500 ml of water, the precipitate is sucked off and chromatographic on silica gel using diisopropyl ether. Gain of 3.9 g of an amorphous foam.

    Rf (diisopropyl ether) = 0,36; mass spectrum (ES): 375 (M+H)+

    b) 1-[3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]ethanol

    3.8 g of 3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde are dissolved in 50 ml of tetrahydrofuran and, at room temperature slowly introducing the solution of Grignard reagent prepared from 385 mg of magnesium shavings and 990 μl under the conditions in 50 ml of diethyl ether. Stirred for three days at room temperature, then add 200 ml of 5% aqueous solution of sodium hydrosulphate and extracted with 2 rasaut 3.7 g of colorless oil. Rf (diisopropyl ether) = 0,13; mass spectrum (DC1): 391 (M+H)+

    C) 1-[3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]alanon

    3.7 g of 1-[3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazol-4-yl]ethanol was dissolved in 20 ml of acetic acid and at a temperature of 15° With slowly mixed with a solution of 15.6 g (NH4)2CE(NO3)6in 30 ml of water. At a temperature of 10°C. additionally stirred for 30 minutes, then allowed to warm to room temperature. Diluted with 200 ml of water, set pH 5 with sodium bicarbonate, and the product is sucked off. Chromatography using once diisopropyl ether and once with methyl tert.-butyl ether gives 2.0 g of colorless oil.

    Rf (diisopropyl ether) = 0,42; mass spectrum (DC1):389 (M+N)+

    g) tert.-Butylamide 4'-(5-acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonic

    21,0 g of 1-[3-(4-Bromobenzyl)-5-chloro-2-phenyl-3H-imidazol - 4-yl]ethanone, 2.0 g of N-tert.-butyl-2-dihydroxybis-2-albenzaalbenza, 135 mg of triphenylphosphine, 58 mg of palladium acetate-(P) and 1.1 g of sodium carbonate in 50 ml of toluene and 10 ml of water is refluxed for 6 hours. The mixture is diluted with 200 ml ethyl acetate, washed with 2 times the t in vacuum. Chromatography on silica gel using diisopropyl ether gives 1.4 g of colorless oil. Mass spectrum(ES): 522 (M+H)+

    d) 4'-(5-Acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide

    1.0 g of tert.-Butylamide 4'-(5-acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acids and 230 μl of anisole is dissolved in 5 ml triperoxonane acid and incubated for 24 hours at room temperature. Volatile component parts then removed in vacuo,and the residue insist with 50 ml of heptane. Obtain 870 mg of an amorphous solid.

    Rf (tert.-butyl ether) = 0,66; mass spectrum (ES): 466 (M+H)+

    e) 4'-(5-Acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    100 mg 4'-(5-Acetyl-4-chloro-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours) and receive 30 mg of an amorphous powder.

    Rf (ethyl acetate/methanol = 10:1) = 0,20; IR spectrum (C N): 2182.0 cm-1; mass spectrum (ES-): 489 (M-N)-.

    Example 30: 4'-(5-Acetyl-4-methoxy-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    and) 4'-(5-Acetyl-4-methoxy-2-phenylimidazol-1-ylmethyl) b is g NaOH in 10 ml of methanol is refluxed for 22 hours. The solvent is then removed under vacuum, the residue is treated with 20 ml of water, set pH 6 with 10% aqueous Hcl solution and extracted with 3 times 50 ml of ethyl acetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using a mixture of methyl-tert.-butyl ether and diisopropyl ether in the ratio 1:1 give 230 mg of a viscous oil.

    Rf (tert.-butyl ether/diisopropyl ether = 1:1) = 0,31; mass spectrum (ES): 462 (M+N)+

    b) 4'-(5-Acetyl-4-methoxy-2-phenylimidazol-1-ylmethyl) biphenyl-2-sulfanilamide

    210 mg 4'-(5-Acetyl-4-methoxy-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours) and receive 181 mg of an amorphous powder.

    Rf (ethyl acetate/methanol = 10:1) = 0,14; IR spectrum (C N): 2179,7 cm; mass spectrum (ES -): 485 (M-N)-.

    Example 31: 4'-(2,4,5-Triphenylimidazole-1-ylmethyl)biphenyl-2-sulfanilamide

    a) Dimethylaminomethylene 4'-(2,4,5-triphenylimidazole-1-ylmethyl)biphenyl-2-sulfonic

    1.5 g of 2,4,5-Triphenylimidazole, 1.9 grams of dimethylaminomethylene 4'-bromomethylbiphenyl-2-Sul is the tour for 6 days. The reaction mixture is poured into 300 ml of water and extracted with 500 ml of ethyl acetate. The organic phase is washed 3 times with 250 ml of saturated aqueous NaCl, dried over sodium sulfate, and the solvent is removed and the vacuum. Obtain 2.8 g of a viscous oil. Mass spectrum (ES): 597 (M+N)+

    b) 4'-(2, 4, 5-Triphenylimidazole-1-ylmethyl) biphenyl-sulfonamid

    1.9 grams of Dimethylaminomethylene 4 -(2,4,5-triphenylimidazole-1-yl-methyl) biphenyl-2-sulfonic acids in 20 ml ethanol and 20 ml of a saturated aqueous solution of Hcl is refluxed for three hours. Volatile component parts removed in vacuum, the residue is stirred with 100 ml of water, and the product is filtered. Obtain 1.0 g of an amorphous powder.

    Rf (tert.-butyl ether): 0,47; mass spectrum (ES): 542 (M+H)+

    in) 4'-(2,4,5-Triphenylimidazole-1-ylmethyl)biphenyl-2-sulfanilamide

    1.0 g 4'-(2,4,5-Triphenylimidazole-1-ylmethyl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours), and obtain 970 mg of an amorphous powder.

    Rf (ethyl acetate/methanol 10:1) = 0,26; IR spectrum (C N): 2173,5 cm-1; mass spectrum (FAB): 567 (M+H)+

    Example 32: 3'-Chlorine-4'-(4-chloro-5-/P>

    of 7.1 g of 4-Bromo-2-chlorotoluene was dissolved in 20 ml of chlorobenzene and at a temperature of 130° With portions mixed with a mixture of 9.4 g of N-bromosuccinimide and 200 mg dibenzoylperoxide. Refluxed for 30 minutes, after cooling, diluted with 100 ml dichloromethane and washed 1 time with 50 ml of a saturated aqueous solution of PA2SO3and 100 ml of a saturated aqueous solution of NaHCO3, dried over sodium sulfate, and the solvent is removed in vacuum. Get 11,0 g of pale yellow oil.

    Rf (ethyl acetate/n-heptane = 1:8) = 0,49; mass spectrum (DCl): 283(M+H)+

    b) 3-(4-Bromo-2-Chlorobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde

    1.5 g of 4-Chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull., 24 (5), 960 (1976)), 5,8 g of potassium carbonate and 8.0 g of 4-bromo-1-methyl bromide-2-chlorobenzene in 50 ml of dimethylformamide is stirred at room temperature for 24 hours. Then diluted with 250 ml ethyl acetate and washed with 2 times 100 ml of water and 1 time with 100 ml saturated aqueous NaCl, dried over sodium sulfate, and the solvents removed in vacuo. Chromatography on silica gel using mixtures of ethyl acetate with n-heptane 1:4 gives 2.2 g of colorless oil.

    Rf (ethyl acetate/n-hepta-1-yl-methyl)biphenyl-2-sulfonic

    2.2 g of 3-(4-Bromo-2-Chlorobenzyl)-5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 2.0 g of N-tert.-butyl-2-dihydroxybis-2-albenzaalbenza (J. Med. Chem., 40, 547 (1997)), 140 mg of triphenylphosphine, 64 mg of palladium acetate-(P), and 1.2 g of sodium carbonate dissolved in a mixture of 30 ml of toluene, 10 ml of ethanol and 10 ml of water and refluxed for three hours. After cooling, add 200 ml of a saturated aqueous solution of sodium bicarbonate and extracted with 3 times 200 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel gives 1.5 g of a colorless foam.

    Rf (diisopropyl ether) = 0,25; mass spectrum (ES): 542 (M+H)+

    g) 3'-Chlorine-4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamide

    1.5 g of tert.-Butylamide 3'-chlorine-4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acids and 340 μl of anisole are dissolved in 10 ml triperoxonane acid and stirred for 24 hours at room temperature. Volatile component parts removed in vacuum, the residue is treated 2 times with 50 ml of toluene, and again remove the volatile parts in vacuum. Obtain 1.5 g of a colorless foam.

    Rf (diisopropyl ether) = 0,15; phenylcinnamic

    400 mg 3' -Chlorine-4' -(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours), and obtain 970 mg of an amorphous powder.

    Rf (ethyl acetate /methanol = 10:1) = 0,23; IR spectrum (C N): 2179,2 cm-1; mass spectrum (FAB): 511 (M+H)+

    The target compound of example 33 are synthesized according to the method of example 32.

    Example 33: 3'-Fluoro-4-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-2-sulfanilamide

    Rf (ethyl acetate/methanol = 10:1) = 0,28; IR spectrum (C N): 2177,7 cm-1; mass spectrum (ES): 493 (M-N)-

    The target compound of example 34 synthesized according to the method of example 12 from 3'-chlorine-4'-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonamida (example 32 g).

    Example 34: 3'-Chlorine-4'- (4-methoxy-5-formyl-2-phenyl-imidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    Rf (ethyl acetate/methanol = 10:1) = 0,26; IR spectrum (C N): 2177,4 cm-1; mass spectrum (ES): 505 (M-N)-

    Example 35: 3'-Chlorine-4'-(4-phenoxy-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfanilamide

    a) 3'-Chlorine-4'-(4-phenoxy-5-formyl-2-phenylimidazol-1-ylmethyl) the IDA (example 32), 116 mg of phenol and 426 mg of potassium carbonate in 10 ml of dimethylformamide is stirred for 8 hours at a temperature of 100° C. After cooling, add 100 ml of a saturated aqueous solution of sodium bicarbonate and extracted with 300 ml of ethyl acetate. The organic phase is washed with 3 times 50 ml of water, dried over sodium sulfate, and the solvent is removed in vacuum. Chromatography on silica gel using a mixture of toluene with ethyl acetate in the ratio of 2:1 gives 150 mg resinous compounds.

    Rf (toluene/ethyl acetate =2:1) = 0,39; mass spectrum (ES+): 544 (M+H)+

    b) 3'-Chlorine-4'-(4-phenoxy-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfanilamide

    145 mg 3'-Chlorine-4'-(4-phenoxy-5-formyl-2-phenylimidazol-1-ylmethyl)-biphenyl-2-sulfonamida transform according to the General method of obtaining sulfanilamide from sulfonamides (reaction time 2 hours), and receive 90 mg of foam. Rf (ethyl acetate/methanol = 10:1) = 0,35; IR spectrum (C N), 2180,4 cm-1; mass spectrum (ES-): 567(M-N)-

    The target compounds of examples 36-38 synthesized according to the method of example II.

    Example 36: 4'-[4-Chloro-5-formyl-2-(4-chlorophenyl)imidazol-1-ylmethyl]-biphenyl-2-sulfanilamide

    Rf (ethyl acetate/methanol = 10:1) = 0,28; so plil]-biphenyl-2-sulfanilamide

    Rf(ethyl acetate/methanol = 10:1) = 0,31; so pl. = 110-126° C; mass spectrum (ES): 507 (M+1)+

    Example 38: 4'-[4-Chloro-5-formyl-2-(2,6-differenl)imidazol-1-ylmethyl]-biphenyl-2-sulfanilamide

    Rf (ethyl acetate/methanol = 10:1) = 0,25; so pl.= 164-178°C; mass spectrum (ES): 513 (M+1)+

    PHARMACOLOGICAL DATA

    Inhibition of Na+-dependent CL-/HCO-3-exchange (NCBE) in human endothelial cells

    Endothelial cells (ECV-304) was isolated from the vessels for culturing using trypsin/EDTU-buffer is 0.05/0.02% in phosphate buffer) and after centrifugation (acceleration of 100 g, 5 minutes) process in buffered salt solution (115 mmol/l NaCl; 20 mmol/l NH4Cl; 5 mmol/l KCl, 1 mmol/l CaCl2; 1 mmol/l MgSO4; 20 mmol/l N-(2-hydroxyethyl)-piperazine-N'-2-econsultancy (HEPES); 5 mmol/l glucose and 1 g/l bovine serum albumin; pH 7.4). This cell suspension with 5 µm BCECF-acetoxymethyl of ester incubated for 20 minutes at 37°C. the cells are Then washed again and suspended in not containing sodium bicarbonate buffer solution (5 mmol/l HEPES; 133,8 mmol/l holdingarea; 4.7 mmol/l KCl; 1.25 mmol/l MgClthe blowing of measuring fluorescence in FLIPR (tablet reader fluorescent images) per well 96-well microtiter plate pipette introduce 100 μl of this cell suspension, accordingly, with 20000 cells, and this microtiter plate centrifuged (acceleration of 100 g, 5 minutes).

    In FLIPR now from another prepared microtiter plates are selected each time 100 μl of buffer solution and pipette contribute to each of the 96 wells plate for measurement. For 100% control, i.e., recovery of intracellular pH (pHjthrough NCBE, used containing bicarbonate and sodium buffer solution (5 mmol/l HEPES; 93,8 mmol/l NaCl; 40 mmol/l NaHCO3; 4.7 mmol/l KCl; 1.25 mmol/l CaCl2; 1.25 mmol/l MgCl2; 0.97 mmol/l Na2HPO4; 0.23 mmol/l NaH2PO4; 5 mmol/l glucose; pH 7.4) containing 50 mmol NOAH 642. For 0% of the control, i.e. where it does not restore the pH, use do not contain bicarbonate, but sodium-containing buffer solution (5 mmol/l HEPES, 133,8 mmol/l NaCl; 4.7 mmol/l KCl; 1.25 mmol/l CaCl2; 1.25 mmol/l MgCl2; 0.97 mmol/l Na2HPO4; 0.23 mmol/l NaH2PO4; 5 mmol/l glucose; pH 7.4), which also add 50 µmol NOAH 642. Proposed according to the invention compounds in different concentrations added to containing sodium and bicarbonate solution. After adding buffer solutions in the record for Aut increase in fluorescence intensity, which corresponds to the increasing pH values. The kinetic data recorded in a time interval of 2 minutes at a temperature of 35° C.

    The increase of fluorescence intensities for different concentrations proposed according to the invention compounds are referred to both controls and from this determine the inhibitory activity of the substances.

    1. Five-membered heterocycles with biphenylmethanol substitution of formulas (I)

    where R1 denotes alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; CandH2A-phenyl, where a = 0, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, J, CF3, metoxygroup; CdH2d-(C3-C7- cycloalkyl, where d = 0;

    R2 and R3,independently of one another, mean hydrogen, F, Cl, J, JV; R6, where R6 denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, OR30, where R30 is alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; OR7where R7 denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; phenyl;

    or R2 and R3, independently of one another, denote CqH2q-phenyl, where q=0;

    or R2 and R3, independently of one another, mean-SOnR22, where n stands for zero, R22 is alkyl with 1, 2, 3, 4, 5, 6, 7 or 8-is CF3,

    and their physiologically acceptable salts.

    2. Five-membered heterocycles of the formula (I) under item 1, where biphenylyl Deputy linked as in formula (Ia), (IB), (Ic), (Id), (Ie), (If), (Ig) or (Ih):

    and R4 and R5are specified in paragraph 1 values

    and their physiologically acceptable salts.

    3. Five-membered heterocycles of the formula (I) under item 1 or 2, suitable for the production of medicines for the treatment of diseases in which cell proliferation is a primary or secondary cause.

    4. Five-membered heterocycles of the formula (I) under item 3, suitable for the production of medicines for the treatment of atherosclerosis, postdialectic complications, cancer, fibrocycstic diseases, as well as hypertrophy and hyperplasia of the authorities, in particular for the treatment of cancer.

    5. The drug, inhibition of Na+dependent Cl-/HCO-3-currency, based on activitiesthese agents and conventional additives, characterized in that it contains an effective amount of the compounds of formula (I) under item 1 or 2.



  •  

    Same patents:

    The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

    The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

    The invention relates to an improved process for the preparation of compounds of formula III

    < / BR>
    where R1is hydrogen or heteroaromatic, R2is a group selected from CH2-O-aralkyl, CH2OCO-alkyl, CH2ОСОNН2CH2ОСОРh, CH2LLC-alkyl; R3- C3-alkyl; R4- dichlorophenyl, including interaction of the compounds of formula I

    < / BR>
    where R1, R2and R3such as defined above, with a compound of formula II: R4-S-Hal, where R4like is definitely above and Hal represents halogen, in the presence of a base

    The invention relates to a new use of derivatives of imidazole, to new derivatives of imidazole, the way they are received, to the new obtained intermediate products and to pharmaceutical compositions based on derivatives of imidazole

    The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

    < / BR>
    in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

    < / BR>
    in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

    < / BR>
    in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

    < / BR>
    in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
    in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

    O=C=N-R6' (XV)

    in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

    < / BR>
    in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

    < / BR>
    in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

    < / BR>
    in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

    < / BR>
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    < / BR>
    in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

    a) esterification of the acid function,

    (b) saponification functions of ester to acid functions,

    C) transforming functions of ester function acyl,

    d) transforming Sinopoli in an acid function,

    e) conversion of the acid function to an alcohol function,

    g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

    h) oxidation of the alcohol function to the aldehyde, acid or keto-function

    i) the conversion of the formyl radical in the radical carbarnoyl,

    j) turning radical carbarnoyl in the nitrile radical,

    k) converting the nitrile radical in tetrazolyl,

    l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

    m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

    n) the transformation function oxo function of thioxo,

    a) transforming radical

    < / BR>
    in radical

    < / BR>
    p) conversion of the acid function in function

    < / BR>
    q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

    r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

    s) removal of protective groups, which can protect the reaction functions,

    t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

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