Biphenylsulfonylcyanamides, method for their preparing and their applying as drugs

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

 

This invention relates to compounds of the formula

where the substituents have the following meanings:

R(1) 1. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

2. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms in which one to all hydrogen atoms replaced by fluorine;

3. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C-atoms or

4. -CnH2n-nn-Y

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is zero or 1 if nn is equal to 2;

5. -CnH2n-nn-Y

nn is zero or 2, and

n - 1, 2, 3 or 4; and n is 1 if nn

equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the remainder of the series

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

2. amino group;

3. NR(22)R(23);

4. alkoxycarbonyl;

5. COOR(16);

6. alkyl with 1, 2, 3 or 4 C-atoms;

7. (C6-C14)-aryl -(C1-C4)-alkyl-carbonyl, preferably phenylacetyl;

R(2)

1. hydrogen;

2. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

3. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms in which one to all hydrogen atoms replaced by fluorine;

4. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C-atoms;

5. quinil with 2, 3, 4, 5, 6, 7 or 8 C-atoms;

6. -CnH2n-nn-Z

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is zero or 1 if nn is equal is 2;

7. -CnH2n-nn-Z

nn is zero or 2, and

n - 1, 2, 3 or 4; and n is 1 if nn

equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the remainder of the series

1. aryl with 6, 1, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

2. amino group;

3. NR(22)R(23);

4. (C1-C4-alkoxycarbonyl;

5. COOR(16);

6. alkyl with 1, 2, 3 or 4 C-atoms;

R(3) and R(4) independently from each other hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

R(5), R(6) R(7) independently of one another hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, I, CF3, -CN, -NO2, SOq-R(8), CO-R(21) or O-R(10);

R(8) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, NR(11)R(12) or phenyl, which is unsubstituted or substituted 1, 2 or 3 identical or different residues from the series F, Cl, Br, I, CF3, methyl, methoxy-, hydroxy-group or NR(11)R(12);

R(9) and R(21) independently of each other hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or or(13);

R(10) is hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, if appropriate substituted (C1-C4-alkoxygroup; or phenyl, which is unsubstituted or substituted 1, 2 or 3 identical or different residues from the series F, Cl, Br, I, CF3, methyl, methoxy-, hydroxy-group or NR(11)R(12);

R(11)R(12), R(19) R(20) independently of one another

hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, and (C 1-C4-alkanoyl, preferably acetyl;

R(13) is hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

X is carbonyl, -CO-NH-, -CO-CO - or sulfonyl;

Y and Z independently of one another

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

2. one of the residues defined in claim 1, substituted 1, 2, 3, 4 or 5 identical or different residues from the series alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl, F, CL, Br, I, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2or CO-R(9); or two of rest together form one condensed heterocyclic residue, preferably methylenedioxy.

3. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms;

4. one of the residues defined in claim 3, substituted by 1, 2 or 3 identical or different residues from the series F, Cl, Br, I, CF3CH3, methoxy-, hydroxy-group or NR(11)R(12);

5. cycloalkyl with 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl;

6. one of the residues defined in claim 5, substituted aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

7. O-R(14);

8. O-R(17);

9. -SO2-R(14);

10. arylalkylamines, preferably phenyl-CH2-CO-;

or

11. heterocyclyl

R(14) and R(17) independently of one another

1. hydrogen;

2. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

3. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C-atoms;

4. -CnH2n-nn-phenyl,

nn is zero or 2, and

n is zero, 1, 2, 3, or 4; and n is zero or 1 if nn is equal to 2;

5. one of the residues defined in claim 4, and the phenyl part is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, I, CF3, SOqR(15), OR (16), NR(11)R(12), -CN, -NO2or CO-R(9) or R(15) and R(18) independently from each other alkyl with 1, 2, 3 or 4 C-atoms, alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3or NR(11)R(12);

R(16) 1. hydrogen

2. alkyl with 1, 2, 3 or 4 C-atoms

3. alkyl with 1, 2, 3 or 4 C-atoms, substituted (C1-C4-alkoxygroup,

4. alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3;

5. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

6. one of the residues defined in claim 5, which is substituted by 1, 2 or 3 identical or different residues from the series F, Cl, Br, I, CF3, NR(19)R(20), -CN, NO2;

R(22) R(23) independently from each other hydrogen or CO-OR(24);

R(24) is hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms or-CnH2nis phenyl and n is 1, 2, 3, and 4;

q independently of one another are zero, 1 or 2;

and their physiologically acceptable salts.

Preferred are the compounds of formula (I) with R(1)

1. alkyl with 1, 2, 3, 4 or 5 C-atoms;

2. alkyl with 1, 2, 3, 4 or 5 C-atoms, in which one to all hydrogen atoms replaced by fluorine;

3. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12

C-atoms or

4. -CnH2n-nn-Y

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is not zero

or 1 if nn is equal to 2;

5. -CnH2n-nn-Y

nn is zero or 2, and

n - 1, 2, 3 or 4; and n is 1 if nn is equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the rest of the series

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

2. amino group;

3. NR(22)R(23);

4. alkoxycarbonyl;

5. COOR(16);

6. alkyl with 1, 2, 3 or 4 C-atoms;

7. (C6-C14)-aryl -(C1-C4)-alkyl-carbonyl, preferably phenylacetyl;

R(2) 1. hydrogen;

2. alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

3. alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, in which one to all hydrogen atoms replaced by fluorine;

4. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C-atoms;

5. quinil 2, 3, 4 or 5 C-atoms;

6. -CnH2n-nn-Z

nn is zero or 2 and n is zero, 1, 2, 3, or 4; and n is not zero

or 1 if nn is equal to 2;

7.-C nH2n-nn-Z

nn is zero or 2, and

n - 1, 2, 3 or 4; and n is 1 if nn

equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the rest of the series

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;

2. amino group;

3. NR(22)R(23);

4. (C1-C4-alkoxycarbonyl;

5. COOR(16);

6. alkyl with 1, 2, 3 or 4 C-atoms;

R(3) and R(4) independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(5), R(6) R(7) independently of one another hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3, -CN, SOq-R(8), CO-R(21) or O-R(10);

R(8) alkyl with 1, 2, 3 or 4 C-atoms, NR(11)R(12) or phenyl, which is unsubstituted or substituted by 1 or 2 identical or different residues from the series F, Cl, Br, CF3, methyl, methoxy-, hydroxy-group or NR(11)R(12);

R(9) and R(21) independently of each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or or(13);

R(10) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, if needed replaced (C1-C4-alkoxygroup; or phenyl, which is unsubstituted or substituted by 1 or 2 identical or different residues from the series F, Cl, Br, CF3, methyl, methoxy-, hydroxy-group or NR(11)R(12);

R(11)R(12), R(19) R(20) independently of one another hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, or (C1-C4-alkanoyl, preferably acetyl;

R(13) in the location or alkyl with 1, 2, 3 or 4 C-atoms;

X is carbonyl, -CO-NH-, -CO-CO - or sulfonyl;

Y and Z independently of one another

1. phenyl, 1-naphthyl or 2-naphthyl;

2. one of the residues defined in claim 1, substituted 1, 2, 3, 4 or 5 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, phenyl, 1-naphthyl or 2-naphthyl, F, Cl, Br, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, or CO-R(9);

or two of rest together form one condensed heterocyclic residue, preferably methylenedioxy;

3. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms;

4. one of the residues defined in claim 3, substituted by 1 or 2 identical or different residues from the series F, Cl, Br, CF3CH3, methoxy-, hydroxy-group or NR(11)R(12);

5. cycloalkyl with 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl;

6. one of the residues defined in claim 5, substituted phenyl, 1-naphthyl or 2-naphthyl;

7. O-R(14);

8. O-R(17);

9. -SO2-R(14);

10. arylalkylamines, preferably phenyl-CH2-CO - or

11. heterocyclyl;

R(14) and R(17) independently of one another

1. hydrogen;

2. alkyl with 1, 2, 3 or 4 C-atoms;

3. alkenyl 2, 3, 4, 5 or 6 C-atoms;

4. -CnH2n-nn-phenyl,

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is not zero

or 1 if nn is equal to 2;

5. one of the residues defined what the R in claim 4, and the phenyl part is substituted by 1, 2 or 3 identical or different radicals from the series alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3, SOqR(15), OR(16), NR(11)R(12), -CN, or CO-R(9) or R(15) and R(18) independently of one another

alkyl with 1, 2, 3 or 4 C-atoms, alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3or NR(11)R(12);

R(16) 1. hydrogen;

2. alkyl with 1, 2, 3 or 4 C-atoms;

3. alkyl with 1, 2, 3 or 4 C-atoms, substituted (C1-C4-alkoxygroup,

4. alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3;

5. phenyl, 1-naphthyl or 2-naphthyl;

6. one of the residues defined in claim 5, which is substituted by 1, 2 or 3 identical or different residues from the series F, Cl, Br, CF3, NR(19)R(20), -CN;

R(22) R(23) independently from each other hydrogen or CO-OR(24);

R(24) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or-CnH2n-nnis phenyl and n is 1, 2 or 3;

q independently of one another are zero, 1 or 2;

and their physiologically acceptable salts.

Especially preferred are the compounds of formula (I)

R(1) 1. alkyl with 1, 2, 3, 4 or 5 C-atoms;

2. alkenyl with 2, 3 or 4 C-atoms;

3. -CnH2n-nn-Y

Y 1. phenyl;

2. one of the residues defined in claim 1, which is substituted by 1, 2, 3, 4 or 5 identical or different residues from the series is alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, cyano, CF3the hydroxy-group, NO2, SO2R(18), OR(16), SCF3, NR(19)R(20), CO-R(9);

3. OR(14) or

4. SO2-R(14);

5. 1-naphthyl or 2-naphthyl;

6. one of the residues defined in claim 5, which is replaced by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(18), OR(16), NR(19)R(20) or CO-R(9);

7. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, preferably thienyl, benzothiophene, indolyl or furyl;

8. one of the defined in section 3 of residues, which is replaced by the residue of the number of F, Cl, CF3CH3, a methoxy group, or N(CH3)2;

9. cycloalkyl with 3, 4, 5, 6 or 7 atoms;

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is zero or 1 if nn is equal to 2;

4. -CnH2n-nn-Y

Y 1. phenyl;

2. OR(14) or

3. heteroaryl, preferably thienyl;

nn is zero or 2, and

n is 1, 2 or 3, and n is not equal to 1 if nn is equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the rest of the series

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl or phenylacetyl;

2. amino group;

3. NR(22)R(23) or

4. alkyl with 1, 2, 3 or 4 C-atoms;

R(2)

1. hydrogen;

2. alkyl with 1, 2, 3, 4 or 5 C-atoms;

3. alkyl with 1, 2, 3, 4 or 5 C-atoms, in which one to all hydrogen atoms replaced by fluorine;

4. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms;

5. quinil 2, 3, 4 or 5 C-atoms;

6. -CnH2n-nn-Z

Z 1. phenyl;

2. one of the residues defined in claim 1, which is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, phenyl, F, CL, Br, CF3, SO2R(18), OR(16), nitro, cyano, NR(19)R(20), CO-R(9) or two together form the residue methylendioxy;

3. 1-naphthyl or 2-naphthyl;

4. one of the residues defined in claim 3, which is replaced by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(18), OR(16), nitro-, ceanography, NR(19)R(20) or CO-R(9);

5. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, preferably benzimidazolyl, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidin-1-carbonyl-4,5-dihydroisoxazole, benzofuranyl, for example, 1,3-dihydro-1-oxo-benzo[C]furanyl, hintline; for example 3,4-dihydroquinazolines;

6. one of the defined in claim 5 residues, which is replaced by the residue of the number of F, Cl, CF3CH3, methoxy-, hydroxy-group or N(CH3)2;

7. cycloalkyl with 3, 4, 5, 6, 7, 8, 9 - or 10 C-atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl;

8. one of the defined in paragraph 7 of the residue, which is substituted by phenyl; preferably vinylcyclopentane;

nn is zero or 2, and

n is zero, 1, 2 or 3; and n is not equal to the logistics or

1 if nn is equal to 2;

7. -CnH2n-nn-Z

Z 1. phenyl;

2. one of the residues defined in claim 1, which is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, phenyl, F, Cl, CF3, SO2R(18), -OR(16), nitro-, ceanography, NR(19)R(20) or CO-R(9);

nn is zero or 2, and

n is 1, 2 or 3; and n is 1 if nn is equal to 2;

with 1, 2 or 3 hydrogen atoms in the bivalent

the residue-CnH2n-nn- independently of each other replaced

for the rest of the series

1. (C1-C4-alkoxycarbonyl;

2. COOR(16) or

3. alkyl with 1, 2, 3 or 4 C-atoms;

8. -CnH2n-OR(17);

n is zero, 1, 2 or 3;

R(3) and R(4)

hydrogen or methyl;

R(5), R(6) R(7) independently of one another

hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3,

CN, SO2-R(18), CO-R(21) or-R(10);

R(8) alkyl with 1, 2, 3 or 4 C-atoms, N(CH3)2or phenyl, which is unsubstituted or substituted by a residue from a number of F, Cl, CF3, methyl, methoxy-, hydroxy-group or N(CH3)2;

R(9) and R(21) independently of one another hydrogen, methyl or(13);

R(10) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, if appropriate substituted (C1-C4-alkoxygroup; or phenyl, which is unsubstituted or substituted by a residue from a number of F, Cl, CF3, methyl, methoxy group, or N(CH3)2;

R(11) R(12) independently of one another hydrogen, alkyl with 1, 2, 3 is to 4 C-atoms, or (C 1-C4-alkanoyl, preferably acetyl;

R(13) is hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

X is carbonyl, -CO-CO-NH-CO - or sulfonyl;

R(14) 1. hydrogen;

2. alkyl with 1, 2, 3 or 4 C-atoms;

3. alkenyl 2, 3, 4, 5 or 6 C-atoms;

4. -CnH2n-nn-phenyl,

nn is zero or 2, and

n is zero, 1, 2, 3, or 4; and n is not zero

or 1 if nn is equal to 2;

5. one of the residues defined in claim 4, and the phenyl part is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3, SOqR(15), OR(16), NR(11)R(12), -CN, or CO-R(9);

R(15) is alkyl with 1, 2, 3 or 4 C-atoms or-N(CH3)2;

R(16) 1. hydrogen

2. alkyl with 1, 2, 3 or 4 C-atoms

3. alkyl with 1, 2, 3 or 4 C-atoms, substituted (C1-C4-alkoxygroup,

4. alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3;

5. phenyl, 1-naphthyl or 2-naphthyl;

6. one of the residues defined in claim 5, which is substituted by 1, 2 or 3 identical or different residues from the series F, Cl, Br, CF3, NR(19)R(20), -CN;

R(17) 1. hydrogen;

2. alkyl with 1, 2, 3 or 4 C-atoms;

3. alkenyl with 2, 3 or 4 C-atoms;

4. -CnH2n-nn-phenyl,

nn is zero or 2, and

n is zero, 1, 2, 3, or 4; and n is zero or 1 if nn is equal to 2;

5. one of the residues defined in claim 4, and the phenyl part is substituted mod is the first of a number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, CF3, SOqR(15), OR(16), NR(11)R(12), -CN, or CO-R(9) or

R(18) alkyl with 1, 2, 3 or 4 C-atoms, alkyl with 1, 2, 3 or 4 C-atoms in which one to all hydrogen atoms replaced by fluorine, preferably CF3or NR(11)R(12);

R(19) R(20) independently of one another hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, or (C1-C4-alkanoyl, preferably acetyl;

R(22) R(23) independently from each other hydrogen or CO-OR(24);

R(24) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or-CnH2nnis phenyl and n is 1 or 2;

q independently of one another are zero, 1 or 2;

and their physiologically acceptable salts.

Most especially preferred compounds of formula (I)

R(1) 1. alkyl with 1, 2, 3, 4 or 5 C-atoms;

2. alkenyl with 2, 3 or 4 C-atoms;

3. -CnH2n-nn-Y

Y 1. phenyl;

2. one of the residues defined in claim 1, which is substituted by 1, 2, 3, 4 or 5 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, cyano, CF3the hydroxy-group, NO2, SO2R(18), co3, OCF3SCF3N(CH3)2, NH-CO-CH3, CO-R(9), fenoxaprop or fenoxaprop, singly or multiply substituted with halogen, preferably Cl or F:

3. OR(14) or

4. SO2-R(14);

nn is zero or 2, and

n is zero, 1, 2, 3 or 4; and n is not zero

or 1 if nn is equal to 2;

4. -CnH2n-nn-Y

p> Y 1. phenyl;

2. OR(14) or

3. heteroaryl, preferably thienyl;

nn is zero or 2, and

n is 1, 2 or 3, and n is not equal to 1 if nn is equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the rest of the series

1. aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14

C-atoms, preferably phenyl, 1-naphthyl or 2-naphthyl or phenylacetyl;

2. amino group;

3. NR(22)R(23) or

4. alkyl with 1, 2, 3 or 4 C-atoms;

5. -CnH2n-Y

Y 1. 1-naphthyl or 2-naphthyl;

2. one of the residues defined in claim 1, which is replaced by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(18), co3N(CH3)2or CO-R(9);

3. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, preferably thienyl, benzothiophene, indolyl or furyl;

4. one of the residues defined in claim 3, which is substituted by a residue from the group of F, Cl, CF3CH3, a methoxy group, or N(CH3)2;

5. cycloalkyl with 3, 4, 5, 6 or 7 atoms;

n is zero, 1, 2, 3 or 4;

6. -CnH2n-OR(14);

n is zero, 1 or 2;

R(2) 1. alkyl with 1, 2, 3, 4 or 5 C-atoms;

2. alkyl with 1, 2, 3, 4 or 5 C-atoms, in which one to all hydrogen atoms replaced by fluorine;

3. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms;

4. quinil 2, 3, 4 or 5 C-atoms;

5. -CnH2n-nn-Z

Z 1. phenyl;

2. one of the residues defined in the .1, which is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, phenyl, F, CL, Br, CF3, SO2R(18), -co3, -O(C2H4)Och3ethoxy-, hydroxy-, nitro-, cyano, N(CH3)2, -NH-CO-CH3, CO-R(9), fenoxaprop or fenoxaprop, one or more times substituted by halogen, preferably CL or F, or where two together form the residue methylendioxy;

nn is zero or 2, and

n is zero, 1, 2 or 3; and n is zero or 1 if nn is equal to 2;

6. -CnH2n-nn-Z

Z 1. phenyl;

2. one of the residues defined in claim 1, which is substituted by 1, 2 or 3 identical or different residues from the series alkyl with 1, 2, 3 or 4 C-atoms, phenyl, F, CL, CF3, SO2R(18), -co3, -O(C2H4)Och3ethoxy-, hydroxy-, nitro-, ceanography, N(CH3)2or CO-R(9);

nn is zero or 2, and

n is 1, 2 or 3; and n is 1 if nn is equal to 2;

with 1, 2 or 3 hydrogen atoms in the divalent residue-CnH2n-nn- independently of each other replaced by the rest of the series

1. (C1-C4-alkoxycarbonyl;

2. COOR(16) or

3. alkyl with 1, 2, 3 or 4 C-atoms;

7. -CnH2n-Z;

Z 1. 1-naphthyl or 2-naphthyl;

2. one of the residues defined in claim 1, which is replaced by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(18), co32H4)Och3ethoxy-, hydroxy-, nitro-, ceanography, N(CH3)2-N3or CO-R(9);

3. heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, preferably benzimidazolyl, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidin-1-carbonyl-4,5-dihydroisoxazole, benzofuranyl, for example, 1,3-dihydro-1-oxo-benzo[C]furanyl, hintline; for example, 3,4-dihydroquinazolines;

4. one of the residues defined in claim 3, which is replaced by the residue of the number of F, Cl,

CF3CH3, methoxy-, hydroxy-group or N(CH3)2;

5. cycloalkyl with 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms; preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl;

6. one of the residues defined in claim 5, which is substituted by phenyl; preferably vinylcyclopentane;

n is zero, 1, 2 or 3;

8. -CnH2n-OR(17);

n is 2 or 3;

R(3) and R(4)

hydrogen;

R(5), R(6) R(7) independently of one another

hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2-R(8), CO-R(21) or O-R(10);

R(8) methyl or N(CH3)2;

R(9) and R(21) independently of one another hydrogen, methyl or(13);

R(10) is hydrogen, methyl or ethyl, if necessary substituted by a methoxy group; or phenyl, which is unsubstituted or substituted by a residue from a number of F, Cl, CF3, methyl, methoxy group, or N(CH3)2;

R(13) hydrogen and alkyl with 1, 2, 3 or 4 C-atoms;

X is carbonyl, -CO-CO-, -NH-CO - or sulfonyl;

R(14) 1. hydrogen;

2. methyl or ethyl;

3. alkenyl 2, 3, 4, 5 or 6 C-atoms, preferably allyl;

4. -CnH2nis phenyl and n is zero or 1;

5. one of the residues defined in claim 4, and the phenyl part is substituted by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(15), co3N(CH3)2or CO-R(9) or

6. alkenyl 2, 3, or 4 C-atoms;

R(15) methyl or N(CH3)2;

R(16) hydrogen or alkyl with 1, 2, 3 or 4 C-atoms, preferably methyl or tert-butyl;

R(17) 1. hydrogen;

2. methyl;

3. -CnH2nis phenyl and n is zero or 1;

4. one of the residues defined in claim 3, and the phenyl part is substituted by the residue of the number of alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, CF3, SO2R(15), co3N(CH3)2or CO-R(9) or

5. alkenyl with 2, 3 or 4 C-atoms;

R(18) methyl, CF3the amino group or N(CH3)2;

R(22) R(23) independently from each other hydrogen or CO-OR(24);

R(24) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or-CnH2nis phenyl and n is 1 or 2;

and their physiologically acceptable salts.

Preferred are also the compounds of formula Ia,

where the remains of X and R(1) no R(7) have the abovementioned meanings, and their physiologically acceptable salts

Further preferred are the compounds of formula I and/or Ia, where the remains of X, R(1), R(2), R(3), R(4), R(5), R(6) R(7) have the values listed in the Examples 1-568.

If groups or substituents may be present in compounds of formula I, many times, all they can take independent from each other values and may be the same or different.

As alkyl, alkenyl and quinil can independently from each other be linear or branched. This also applies to cases when they are contained in other groups, for example, in alkoxygroup, alkoxycarbonyl groups or amino groups, or when they are replaced.

Examples of alkyl residues with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert-butyl, tert-pentyl.

Examples alkenyl residues are vinyl, 1-propenyl, 2-propenyl (allyl), butenyl, 3-methyl-2-butenyl, 2-butenyl, 2-methyl-2-propenyl. Alkeneamine residues may also contain two or more double bonds, such as, for example, butadienyl or (CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-.

Examples etkinlik residues are ethinyl, 2-PROPYNYL (propargyl) or 3-butynyl. Alkyline residues may also contain two or more triple links

Cycloalkyl covers saturated and partially unsaturated cycloalkyl residues, which can be mono-, bi - or tricyclic. Examples of such cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1,2,3,4-tetrahydronaphthalen and indanyl, which can also be substituted, for example, by one or more identical or different (C1-C4)-alkyl residues, in particular, stands. Examples of such substituted cycloalkyl residues are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclobutyl.

Aryl groups 6, 7, 8, 9, 10, 11, 12, 13 or 14 C-atoms are, for example, phenyl, naphthyl, biphenyl, antrel or fluorenyl, and 1-naphthyl, 2-naphthyl and especially phenyl are preferred.

Heteroaryl residues and heterocyclic residues preferably are derived from heterocycles which contain one, two, three or four identical or different heteroatoms in the cycle; particularly preferably heterocycles, which contain one or two or three, in particular one or two identical or different heteroatoms. If not indicated otherwise, the compounds may be monocyclic or polycyclic, for example, monocyclic, bicyclic or tricyclic. Preferably they are monocyclic Il is bicyclic. The loops are preferably 5-membered, 6-membered or 7-membered. Examples of monocyclic and bicyclic heterocyclic systems, the remains of which may be suitable for compounds of formula I, are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole, 1,2-oxazole, 1,3-thiazole, 1,2-thiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazin, Piran, thiopyran, 1,4-dioxin, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1, 2,4,5-tetrazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine, 1,3-diazepine, indole, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, hinzelin, cinoxacin, phthalazine, thienothiophene, 1,8-naphthiridine and other naphthirydines, pteridine, or phenothiazines, all in a saturated form (perhydro-form), or a partially unsaturated form (for example the dihydro form or tetrahydro form) or in most unsaturated form, if this form is known and stable. To suitable heterocycles include, for example, saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine. Unsaturated heterocycles may, for example, contain one, two or three double bonds in the cycle. 5-Membered and 6-membered cycles in monocyclic and polycyclic-heterocyclic compounds of mo is ut, in particular, to be aromatic.

The remains of these heterocycles can be whenever connected through each suitable carbon atom. Nitrogenous heterocycles, which contain the cyclic nitrogen atom a hydrogen atom or Deputy, for example, pyrrole, imidazole, pyrrolidine, morpholine, piperazine, etc. may also be linked through a ring nitrogen atom, in particular if the corresponding nitrogen in the heterocycle is linked to a carbon atom. Examples can be thienyl as 2-thienyl residue or 3-thienyl residue, the remainder of the furan 2-fulllogo residue or 3-fulllogo residue, the residue pyridyl 2-pyridyl, 3-pyridyl or 4-pyridyl, the rest of the piperidine in the form of 1-piperidino residue, 2-piperidino residue, 3-piperidino residue or 4-piperidine balance, thiomorpholine balance in the form of 2-thiomorpholine residue, 3-thiomorpholine residue or 4-thiomorpholine balance (= Tiotropium residue). Linked through a carbon atom of the residue of 1,3-thiazole or imidazole can be linked in the 2-position, 4-position or 5-position.

If not stated otherwise, the heterocyclic groups can be unsubstituted or contain one or more, e.g. one, two, three or four identical or different substituents. The substituents in the heterocyclic compounds can be in any positions, for example, the 2-thienyl residue or 2-furilla residue at the 3-position and/or 4-position and/or 5-position, 3-thienyl residue or 3-furilla residue in the 2-position and/or 4-position and/or 5-position, 2-pyridinium residue at the 3-position and/or 4-position and/or 5-position and/or 6-position, 3-pyridinium residue in the 2-position and/or 4-position and/or 5-position and/or 6-position, 4-pyridinium residue in the 2-position and/or 3-position and/or 5-position and/or 6-position. Unless otherwise specified, as the substituents can be, for example, the substituents listed in the definition of aryl groups, in the case saturated or partially unsaturated heterocycles as an additional deputies in the carbonyl group and tocography. Vice-heterocycles, as well as deputies of carbocycles, can also form a ring, can also be condensed in the cyclic system of additional cycle, so that, for example, can be formed of cyclopent-condensed, cyclohexa-condensed or benzododecinium cycles. As deputies we can replace the nitrogen atom in the heterocycle we are talking about, for example, unsubstituted (C1-C5)-alkyl residues and aryl-substituted alkyl residues, aryl residues, acyl residues, as CO-(C1-C5)-alkyl or sulfanilic residues, as SO2-(C1-C5)-alkyl. Suitable nitrogen-containing heterocycles mo the ut can be represented as N-oxides or Quaternary salts with the anion of one of the physiologically acceptable acid, as counterion. Peredelnyj residue may be, for example, presented in the form of pyridine-N-oxide.

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

Heteroaryl residues may also be fully or partially gidrirovanie. For example, should be called pyrrolidin-1-carbonyl-4,5-dihydroisoxazole, 1,3-dihydro-1-oxo-benzo[C]furanyl or 3,4-dihydroquinazolines.

Phenyl, raftiline and heterocyclic residues, for example, heteroaryl residues may, unless otherwise stated, be unsubstituted or contain one or more, e.g. one, two, three or four identical or different substituents, which may be in any position. Unless otherwise noted, these residues as substituents can be, for example, the substituents listed in the definition of aryl groups. For example, aryl, such as phenyl and/or heterocyclic residues as substituents may be phenyl residues, fenoxaprop, benzyl residues or benzyloxy, and the benzene ring may also be asamese the governmental or may be substituted by one or more for example, two, three or four identical or different residues from the series (C1-C4)-alkyl, halogen, hydroxy, (C1-C4)-alkoxy groups, trifluoromethyl, cyan, hydroxycarbonyl, ((C1-C4)-alkoxy)carbonyl, aminocarbonyl, nitro-, amino-, (C1-C4)-alkylamino-, di-((C1-C4)alkyl) amino and ((C1-C4)-alkyl) carbonyl amino group.

In monosubstituted phenyl residues, the substituents can be in the 2-position, 3-position or 4-position, in disubstituted phenyl residues, the substituents can be in the 2,3-positions, 2,4-positions, 2,5-positions, 2,6-positions, 3,4-positions or 3,5-positions. In trisemester phenyl residues, the substituents can be in the 2,3,4-positions, 2,3,5-provisions, 2,3,6-provisions, 2,4,5-provisions, 2,4,6-positions or 3,4,5-positions. Tolyl (= were) is a 2-tolila, 3-tailam or 4-tailam. Naphthyl may be 1-naphthyl or 2-naphthyl. In monosubstituted 1-naftalina residues, the substituents can be in the 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position, monosubstituted 2-naftalina residues in the 1-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position.

Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

This invention coverage which covers all stereoisomeric forms of the compounds of formula I. Contained in the compounds of formula I of the asymmetric centers independently of each other can have the S-configuration or R-configuration. The invention includes all possible enantiomers and diastereoisomers, and also mixtures of two or more stereoisomeric forms, for example, mixtures of enantiomers and/or diastereomers, in all ratios. Enantiomers in an enantiomeric pure forms, as in the form levogyrate, and programada the antipodes, in the form of racemates and in the form of mixtures of both enantiomers in all ratios are also subject of the invention. In the presence of CIS/transitorie the subject invention are CIS-form and TRANS form and mixtures of these forms in all ratios. Getting the individual stereoisomers may, if necessary, be produced by the separation of mixtures by conventional means, for example by chromatography or crystallization, by using a uniform stereochemical starting substances in the synthesis or by stereoselective synthesis. If necessary, before separation of the stereoisomers can be downcast. Separation of a mixture of stereoisomers can be carried out at the stage of the compounds of the formula I or at the stage of an intermediate product in the synthesis. In the presence of mobile hydrogen atoms, the invention also includes all tautomeric f is RMI compounds of formula I.

If the compounds of formula I contain one or more acidic or basic groups, the subject matter of the invention are the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically applicable salt. Thus the compounds of formula I which contain acidic groups can be represented and, if necessary, used in the form of salts of alkali metals, salts of alkaline earth metals or ammonium salts. Examples of such salts are salts of sodium, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of formula I which contain one or more basic, so-called protonium groups can be represented and, if necessary, used in the form of their additive salts with physiologically acceptable inorganic or organic acids, such as salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulphonate, para-toluensulfonate, naphthalenedisulfonate, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pavlinovoi acid, diatroxal the second acid, malonic acid, succinic acid, pipelinewall acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of formula I contain in the molecule at the same time acidic and basic groups, the invention described along with the salt forms are also inner salts or betaines (zwitterions). Salts can be obtained from compounds of the formula I is of the usual well-known specialists of ways, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anyoneeven or casinoonline from other salts. The invention embraces all salts of the compounds of formula I, which, thanks to their low physiological tolerance is not directly applicable for use in medicines, but is applicable, for example, as intermediates for chemical reactions or to obtain physiologically acceptable salts. Under physiologically acceptable salts of the compounds of formula (I) see, for example, organic and inorganic salts, as described in Remington''s Pharmaceutical Sciences (17. edition, str (1985)). Due to the physical and chemical stability and solubility of the acid groups are preferred among other salts of sodium, potassium, calcium and ammonium; for the main group is preferred among the salts of hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and para-toluenesulfonic acid.

The invention additionally encompasses all the solvate of the compounds of the formula I, for example hydrates or adducts with alcohols, and also derivatives of the compounds of formula I, such as, for example, esters, and proletarienne forms and active metabolites.

The invention relates also to provide new compounds of the formula (I)and their physiologically acceptable salts.

Thus the compounds of formula I can be obtained, for example, by solid-phase synthesis.

The synthesis is carried out by a suitable binding benzolsulfonate structure of General formula (II) through chemical glue (linker) with the polymer matrix known in the art, the method of synthesis sulfonamida of the sulfonic acid chloride and amine. As the polymer matrix is applicable, for example, polystyrene, polytetrafluoroethylene, polyacrylamide, etc. that, if necessary, to improve the swelling can be extended polyoxyethylene chain (spacer). As a structural linker link por the good patterns, which release of the synthesized compound under the action of acid, base, reductant, oxidant, light or fluorine; and linker structural unit remains in the polymer matrix (overview of the linker groups and polymers in solid phase synthesis, seeG. Jung, Angew. Chemie Int. Ed. 1996, 35, 17-42).

Thus obtained, the main compound of General formula (III)associated with the polymer through sulfonamidnuyu group, can be subjected to interaction with the derived airborne acid of General formula (IV) to obtain biphenylol derivative of the formula (V). Been used for this purpose are known from the literature, the conditions of the reaction catalyzed by palladium, as described, for example, in Organometallics 1984, 3, 1261 or Synth. Commun. 11 (7), 513 (1981).

Synthesis basavaraj acid of General formula (IV) is conducted, for example, analogously to the synthesis of 4-formyl-basavaraj acid, as described in Liebigs Ann. 1995, 1253.

Reductive amination with NaBH3CN (review of NaBH3CN in Synthesis 1975, 135) gives a structural element (VI), which under the action of the carboxylic acid R1-X-Cl can be converted into a structural element of the General formula (VII). Synthesis in the solid phase has the advantage that R is the assets and reagents can be used in a large excess, the solvent can vary widely, and cleaning is carried out by simply washing the solid particles.

When the residues R(3), R(4) are not hydrogen atoms, you must enter the appropriate residues. This happens either as a result of the synthesis of the imine of General formula (X) by reductive amination in the absence of reductant from the aldehyde (V) and the appropriate amine and interaction with the ORGANOMETALLIC compound containing the remainder R(3) or R(4), for example, with a Grignard reagent or alkyllithium connection known to the specialist way. Or aldehyde function compounds of General formula (V) are oxidized to the nitrile of General formula (XI), as described in Synthesis 1982, 190, and then one by one enter the residues R(3) and R(4) using lithium or magyarkanizsa compounds known to the expert way. In the latter case, additionally, you have to spend another well-known specialist way aminoaniline or aminoalkylsilane remainder R(2).

After gradual implementation stages of the synthesis carried out the separation of the newly synthesized compounds using special reagents corresponding to the choice of linker (for the description of solid-phase synthesis, see:G.Jung, Angew. Chemie Int. Ed. 1996, 35, 17-42). Cleavage from the resin is carried out in accordance with the used linker known to the specialist way. The preferred polymer is suitable, for example, aminomethylpropanol company Fluka (1.1 mmole amine/g of resin; 2% crosslinked with divinylbenzene (DVB)). As the preferred linker is suitable, for example, known from the literature compound (VIII)

(G. Breipohl, J. Knolle, W. Stber, Int. J. Peptide Protein Res. 34, 1989, 262f). In this case, cleavage from the resin is carried out in acidic conditions. Compounds of General formula (VII) to do this process in an inert solvent, preferably CH2Cl2that acid with PKand<5, preferably acid with PKand<2, particularly preferably triperoxonane acid and get the sulfonamide of General formula (IX). Usually the reaction time is from 5 minutes to 10 hours at a temperature between -30°and the boiling point of the solvent, preferably the reaction time is from 20 minutes to one hour at room temperature.

The last stage of the synthesis differs in that the compounds of formula (IX),

where the residues have the above meanings, is subjected to the interaction with bromine cyan with the formation of the target compounds of General formula (I). The reaction of lead in a dipolar aprotic solvent, stable is relative to the bromine cyan, for example, acetonitrile, dimethylacetamide, N,N,N’,N’-tetramethylrhodamine or N-organic with a strong supporting base, which is weakly nucleophilic, as, For example, a2CO3or Cs2CO3. As the reaction temperature is suitable temperature between 0°and the boiling point of the solvent used, preferably it is about the temperature between 40°and 100°C.

The compounds of formula I may also be synthesized by classical synthesis, i.e. in solution, by the well-known specialist methods.

The proposed compounds of formula I are suitable as inhibitors retrieveimage bicarbonate/chloride exchange (NCBE) or sodium/bicarbonate of importrow.

In the application EP-A 855392 described imidazole derivatives with biphenylenediisocyanate side chain as NCBE inhibitors.

In European patent application 98117529.2 as NCBE inhibitors proposed biphenylenediisocyanate, which differ from the compounds of formula I the substituents in biphenylenes cyclic system.

Additionally, the invention relates to compounds of formula I, suitable for the production of pharmaceuticals for the treatment or prevention of diseases caused by ischemic state;

as well as compounds of the formula I used to get drugs on the I treatment or prevention of myocardial infarction;

as well as compounds of the formula I used for getting medicines for the treatment or prophylaxis of angina;

as well as compounds of the formula I used for getting medicines for the treatment or prophylaxis of ischemic conditions of the heart;

as well as compounds of the formula I, suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of the peripheral and Central nervous system and acute;

as well as compounds of the formula I, suitable for the production of pharmaceuticals for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

as well as compounds of the formula I, suitable for the production of pharmaceuticals for the treatment or prevention of shock;

as well as compounds of the formula I, suitable for medicinal products for introduction in surgical operations and organ transplants;

as well as compounds of the formula I used for getting medicines for preservation and storage of transplants for surgical events;

as well as compounds of the formula I used for getting medicines for the treatment of diseases in which the primary or secondary reason is the proliferation of the cells; and thus the way to get antiatherosclerotic means, remedies against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidney, prostate hyperplasia;

as well as compounds of the formula I used for getting medicines for the treatment of difficult breathing;

as well as medicines, different effective content of the compounds of formula I.

The proposed compounds of formula I show a very good antiarrhythmic properties, for example, that it is important for the treatment of diseases caused by oxygen deficiency.

The compounds of formula I because of their pharmacological properties as antiarrhythmic drugs are widely applicable with cardiotoxicity components for the prevention of heart attack and treatment of heart attack, as well as for the treatment of angina, and they also preventively inhibit or greatly slow down the pathophysiological processes in the occurrence of ischemia-induced disorders, in particular, when the expression of inducible ischemia cardiac arrhythmia.

Due to their protective effects against pathological hypoxic and ischemic conditions of the proposed compounds of formula I by inhibiting cellular PA+-dependent mechanism of CL-/FNL

-
3
-exchange or sodium/bicarbonate of importrow can be used as a drug for the treatment of all acute or chronic ischemia caused by violations or induced their primary or secondary disease. They protect the organs suffering from acute or chronic oxygen deficiency by reducing or difficulty ischemia-induced disorders and, thus, is applicable as a drug, for example, thrombosis, vascular spasms and atherosclerosis or during surgery (for example, when organ transplantation kidney or liver, and the connections of the applicable both to protect the organ from the donor before or during the taking, for the protection of separated body, for example, processing or storage in a saline solution, and when moving in the body of the recipient), or chronic or acute renal failure.

The compounds of formula I are equally valuable protective active drugs when conducting angioplasticheskih surgical interventions, for example, at heart, as well as the peripheral vessels. In accordance with their protective activity against ischemia induced violations of these compounds is applicable also in the quality of medicines is the R means for the treatment of ischemia of the nervous system, in particular, the Central nervous system, and they are applicable, for example, for the treatment of acute attacks or swelling of the brain. Due to this, the offered compounds of formula I are equally applicable to the treatment of various forms of shocks, as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Moreover the proposed compounds of formula I exhibit a strong inhibitory activity against the proliferation of cells, for example, the proliferation of fibroblast cells and proliferation of smooth muscle cells. So we are talking about the compounds of formula I as valuable therapeutic tools for diseases in which the growth of cells is a primary or secondary cause, and therefore they can be used as antiatherosclerotic funds funds against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or kidney fibrosis, hypertrophy and hyperplasia of the authorities, in particular in prostate hyperplasia or hypertrophy of the prostate.

Discovered that inhibitors of Na+-dependent CL-/FNL

-
3
-exchange or sodium/bicarbonate of importrow can stimulate breathing by raising sensitive the STI to chemicals of respiratory chemoreceptors. These chemoreceptors are responsible largely for the maintenance of orderly respiratory activity. They are activated by hypoxia, decreased pH and increased CO2(hypercapnia) and lead to adaptation of the minute volume of respiration. In a dream breathing especially vulnerable and largely depends on the activity of chemoreceptors.

Improvement of respiratory impulses by stimulation of chemoreceptors substances that slow down Na+dependent CL-/FNL

-
3
-currency leads to improved breathing with the following clinical conditions and diseases: poor Central respiratory pulse (for example, the Central temporary stoppage of breathing during sleep, sudden death of the fetus, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term mechanical ventilation, respiratory disorders during adaptation in the high mountains, obstructive and mixed forms of temporary stopping of breathing during sleep, acute and chronic lung disease with hypoxia and hypercapnia.

The proposed compounds of formula I and their physiologically acceptable salts can be used for animals, preferably to mammals, and in particular, for people in ka is este drugs individually, as mixtures with one another or in the form of finished pharmaceutical preparative forms. The subject of this invention are also the compounds of formula I and their physiologically acceptable salts for use as pharmaceuticals, their use in the treatment and prevention of these diseases and the preparation of medicinal drugs. Additionally the subject of this invention are pharmaceutical finished formulation, which as active constituent parts contain active dose of at least one of the compounds of formula I and/or physiologically acceptable salts along with the usual pharmaceutical, does not meet objections, carriers and excipients. Pharmaceutical compositions usually contain from 0.1 to 99 weight percent, preferably from 0.5 to 95 weight percent of compounds of formula I and/or their physiologically acceptable salts. Preparation of pharmaceutical compositions can be effected in a known manner. For this purpose the compounds of formula I and/or their physiologically acceptable salts with one or more solid or liquid galenovye carriers and/or excipients and, if desired, in combination with other active medicinal ingredients, bring to a suitable form or dosage forms for which it can be used as drugs in medicine or veterinary medicine.

Drugs, which contain the compound of formula (I) and/or its physiologically acceptable salt, may be administered orally, parenterally, intravenously, rectally or by inhalation, preferably the introduction depends on each manifestations of the disease. The compounds of formula I may be applied individually or together with galenovye excipients, both in veterinary and in human medicine.

What excipients are applicable for desirable forms of medicines known specialist on the basis of his special knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, excipients for tablets and other carriers of active substances can be used, for example, antioxidants, dispersing agents, emulsifying agents, blowing agents, taste correctors, preservatives, soljubilizatory or dyes.

For oral forms of application of active compound is mixed with appropriate additives, such as carriers, stabilizers or inert diluents, and conventional methods transferred to suitable forms of applications, such as tablets, coated tablets, capsules, aqueous, alcoholic or oily solutions. As inert carriers may be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, mo is full of sugar, glucose or starch, in particular corn starch. And ready preparative forms can be produced both as dry and as wet granules. As an oil carrier, or in a suitable solvent, such as vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active connection is transferred into a solution, suspension or emulsion, if desired with the usual substances, such as co-solvents, emulsifiers or other auxiliaries. As a solvent it is, for example, water, physiological salt solution, or alcohol, for example ethanol, propanol, glycerol, and solutions of sugars such as glucose or mannitol, or mixtures of these different solvents.

As finished pharmaceutical preparative forms for use in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of the active substances of the formula I in a pharmaceutically acceptable solvent, in particular, ethanol or water, or in mixtures of such solvents.

Ready preparationa form as required may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, t is the same as the working gas. Such a composition contains the active substance is usually in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3 wt.%.

The dosage of the applied active substances of the formula I and the frequency of introduction depends on the activity and duration of action of the compounds used; additionally also on the type and extent of the disease, as well as gender, age, weight and individual needs of the treated mammal.

The average daily dose of the compounds of formula I for a patient weighing about 75 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg to at most 10 mg/kg, preferably 1 mg/kg of body weight. In acute cases, it is possible directly after myocardial infarction may also be necessary even higher and especially more frequent dosing, for example up to 4 individual doses per day. In particular, when administered intravenously to patients with infarction in the intensive care unit, it may be necessary to 200 mg per day.

The compounds of formula I can be used as individual substances or in combination with other pharmacologically active compounds.

The compounds of formula I and/or their physiologically acceptable salts to achieve beneficial therapeutic effect can also be administered together with other pharmacologically active the compounds for the treatment or prophylaxis of the abovementioned diseases, in particular, for the treatment of cardiovascular diseases. Preferred is the combination with the inhibitors of the sodium/hydrogen exchange (NHE) and/or with other classes of substances active against cardio-vascular system.

The invention relates further to the combinations a) NCBE inhibitors of the formula I and/or their physiologically acceptable salts with NHE inhibitors and/or their physiologically acceptable salts; b) NCBE inhibitors of the formula I and/or their physiologically acceptable salts with other active classes in relation to the cardiovascular system of substances and/or their physiologically acceptable salts, as well as in NCBE inhibitors of the formula I and/or their physiologically acceptable salts NHE inhibitors and/or their physiologically acceptable salts and active substances from other classes active in cardiovascular system agents and/or their physiologically acceptable salts.

Among the known and identified NHE inhibitors talking about derivatives of guanidine, preferably about acyl-guanidino, among others, as described Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine", J. WILEY & Sons (1983), 303-341 or listed in the application OR NHE-inhibitors.

Suitable NHE inhibitors are, for example, also benzoylpyridine, as they are described in the patents and applications US 5292755, US 5373024, US 5364868, US 5591754, US 5516805, US 5559153, US 5571842, US 5641792, US 531293, EP-577024, EP-A 602522, EP-A 602523, EP-A 603650, EP-A 604852, EP-A 612723, EP-A 627413, EP-A 628543, EP-A 640593, EP-A 640588, EP-A 702001, EP-A 713864, EP-A 723956, EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171, EP-A 814077, EP-A 869116; ortho-substituted benzoylpyridine, as they are described in the applications EP-A 556673, EP-A 791577, EP-A 794172; ortho-aminosilane benzoylpyridine, as they are described in the application EP-A 690048; isoquinolines, as they are described in the application EP-A 590455; benzododecinium 5-membered heterocycles, as they are described in the application EP-A 639573; decylamine guanidine, as they are described in the application EP-A 640587; acylhalides, as they are described in the patent US 5547953; guanidine derivatives containing performanceline group phenylsilane alkyl - or alkenylboronic acids, as they described in the patent US 5567734 and the application EP-A 688766; heteroorganic, as they are described in the application EP-A 676395; bicyclic heteroaromatic, as they are described in the application EP-682017; andinorganic, as they are described in the application EP-A 738712; benzyloxycarbonylglycine, as they are described in the application EP-A 748795; guanidine derivatives containing forfinally group phenylsilane alkenylboronic acids, as they are described in the application EP-A 744397; guanidine derivatives of substituted cinnamic acids, as they are described in the application EP-A 755919; sulfanilamide, as they as described in the application EP-A 771788; biguanidine derivatives benzylcarbamoyl acid, as is described in applications EP-A 774458, EP-A 774457; biguanidine derivatives djarikatsebi acids, as they are described in the application EP-A 787717; guanidine derivatives substituted thiophenyl-alkenylboronic acids, as they are described in the application EP-A 790245; bis-ortho-substituted benzoylpyridine, as they are described in the application EP-A 810207; substituted 1 - or 2-naphtylamine, as they are described in the applications EP-A 810205 and EP-A 810206; indonesianization, as they are described in the application EP-A 837055; guanidine derivatives phenylsilane alkenylboronic acids, as they are described in the application EP-A 825178; aminopiperidin-benzoylpyridine, as they are described in the application EP-A 667341; heterocyclic-benzoylpyridine, as they are described in the application EP-A 694537; ortho-substituted benzoylpyridine, as they are described in the patent ER; ortho-substituted alkyl-benzoylpyridine, as they are described in the application EP-A 699660; ortho-substituted heterocyclyl-benzoylpyridine, as they are described in the application EP-A 699666; ortho-substituted 5-methylsulphonyl-benzoylpyridine, as they are described in the application EP-A 708088; ortho-substituted 5-alkylsulfonyl-benzoylpyridine with 4-amino-substituents, as they are described in the application EP-A 723963; ortho-substituted 5-alkylsulfonyl-benzoylpyridine with 4-mercapto-substituents as described in the application EP-A 743301; 4-sulfonyl - or 4-sulfinil-benzylguanine, as they are described in the application EP-A 758644; alkenylbenzenes, as they are described in C the turnout ER-AND 760365; benzoylpyridine with condensed cyclic sulfones, as they are described in the patent DE 19548708; benzoyl-, the polycyclic aroyl and heteroorganic, as they are described in the application WO 9426709; 3-aryl-heteroaryl-benzoylpyridine, as they are described in the application WO 9604241; 3-phenyl-benzoylpyridine with the main aminogroups in the 5-position as described in the application WO 9725310; 3-dehalogenase - or 3-dehalogenans-benzoylpyridine with a basic substituent in the 5-position as described in the application WO 9727183; 3-methylsulfonylmethane with defined aminosalicylate in the 4-position as described in the application WO 9512584; derivatives of amiloride, as they are described in the application WO 9512592; 3-methylsulphonyl-benzoylpyridine with defined aminosalicylate in the 4-position as described in the application WO 9726253; indolalkylamine, as they are described in the applications EP-A 622356 and EP-A 708091; indolealkylamine with additional condensed cyclic system, as they are described in the patent EP 787728; derivatives methylguanine, as they are described in WO 9504052; 1,4-benzoquinoneimine, as they are described in the application EP-A 719766; 5-bromo-2-naphtol-guanidine, as they are described in the patent JP 8225513; quinoline-4-carbonylcyanide with the phenyl residue in the 2-position as described in the application EP-A 726254; cinnamoylcocaine, as they are described in the patent JP 09059245; propanolamine with naphthalene Deputy, as is neither described in the patent JP 9067332; propanolamine with indole substituents as described in the patent JP 9067340; or heteroaromatic acryloylmorpholine, as they are described in the application WO 9711055, as well as their physiologically acceptable salts.

Suitable NHE inhibitors are compounds noted in these publications as preferred.

Especially preferred are compounds cariporide (NOE), NOAH 694, EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, as well as their physiologically acceptable salts. Most preferred is cariporide or another physiologically acceptable salt of N-(4-isopropyl-3-methanesulfonyl-benzoyl)-guanidine.

Examples of classes of active in the cardiovascular system of substances that are therapeutically appropriate to combine with NCBE inhibitors or additional combinations NCBE inhibitors and NHE inhibitors, blockers are beta-receptors, calcium antagonists, angiotensin converting enzyme inhibitors, receptor blockers angiotensin, tubular diuretics, thiazidelike, potassium-sparing diuretics, aldosterone antagonists, which, for example, is administered to reduce blood pressure, and cardiac glycosides or other increasing force reducing means in the treatment of heart failure and congestive heart failure, as well as antiaritmicheskie means classes I-IV, nitrates, KATP-openers, ToATP-blockers, inhibitors verallgemeinerung sodium channels, etc. Examples are: beta-blockers propanolol, atenolol, metoprolol; calcium antagonists diltiazem hydrochloride, verapamil hydrochloride, nifedipine; ACE inhibitors captopril, enalapril, ramipril; trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; antagonists of the receptor of angiotensin II losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; tubular diuretics furosemide, piretanide, torasemide; thiazide diuretics hydrochlorothiazide, metolazone, indapamide; potassium-sparing diuretics amiloride, triamterene, spironolactone; cardiac glycosides digoxin, digitoxin, strophanthin; antiarrhythmic substances amiodarone, sotalol, brutily, flecainide; nitrate glycerinated; K+(APR)-the discoverers of cromakalim, imaclim, nicorandil, pinacidil, Minoxidil; inhibitors verallgemeinerung Na+channels.

An example of such especially preferred combined with NCBE inhibitors of formula I of a substance is the blocker mainactivity sodium channels (verallgemeinerung sodium channels). The combination of an NCBE inhibitor with a blocker of mainactivity sodium channel (verallgemeinerung sodium channel) note the NIMA for the prevention of myocardial infarction and recurrent infarction and for the treatment of heart attack, as well as for the treatment of angina and inhibition induced by ischemia, cardiac arrhythmias, tachycardia, and the occurrence and duration of ventricular fibrillation; and combinations NCBE inhibitor with a blocker of mainactivity sodium channel also preventively inhibit or greatly reduce the pathophysiological harbingers in the occurrence of ischemia-induced disorders. Thanks to the enhanced protective effect against pathological hypoxic and ischemic situations, the proposed combination of inhibitor NCBE inhibitor of the formula I with a blocker mainactivity sodium channel due to increased inhibition of the input stream PA+the cell can be used as medicines for the treatment of all acute or chronic, caused by ischemia disorders or primary or secondary induced their diseases. This applies to their use as medicines during surgery, for example, in organ transplantation; and combinations NCBE inhibitor of the formula I with a blocker mainactivity sodium channels can be used to protect the organ from the donor before or in the process of separation, for the protection of separated body, for example, when it is stored in a physiological fluid, and introducing into the body of the recipient. Combine the AI NCBE inhibitor of the formula I with a blocker mainactivity sodium channels are equally valuable protective current medicines when conducting angioplasticheskih surgical interventions, for example, on the heart and peripheral vessels. In accordance with their protective effect against induced ischemia violations combination NCBE inhibitor of the formula I with a blocker mainactivity sodium channels also suitable as pharmaceuticals for the treatment of ischemia of the nervous system, particularly the Central nervous system, and they are applicable for the treatment of acute seizures and swelling of the brain. Moreover, the proposed combination NCBE inhibitor of the formula I with a blocker mainactivity sodium channels applicable for the treatment of various forms of shocks, as, for example, of allergic, cardiogenic, hypovolemic and bacterial shock.

Along with the application as fixed combinations the invention relates to the simultaneous, separate or sequential use NCBE inhibitors of formula I are inhibitors of sodium-hydrogen exchange and/or additional active substance from another class is active against cardiovascular substances for the treatment of the abovementioned diseases.

The invention relates to pharmaceutical compositions containing (a) NCBE inhibitor of the formula I and the inhibitor of sodium-hydrogen exchange and/or its physiologically acceptable salt;

or b) an NCBE inhibitor of the formula I and additionally active substance from another class of AK is positive in relation to the cardiovascular system of substances and/or their physiologically acceptable salts; or NCBE inhibitor of the formula I', the inhibitor of the sodium-hydrogen exchange and additionally active substance from another class is active against cardiovascular substances and/or their physiologically acceptable salts.

Through the combination of the effect of one combined component may increase other relevant component, that is, the action and/or the duration of the proposed combination or composition stronger or longer than the activity and/or duration of each individual component (synergistic effect). This leads combined applications to reduce the dose of each component of the combination compared with the individual usage. The proposed combination and ready preparative forms have the advantage that the used quantity of active substances is greatly reduced, and undesirable side effects can be eliminated or greatly reduced.

Further, the invention relates to packaging for sale, comprising as pharmaceutically active substances

a) NCBE inhibitor of the formula I and the inhibitor of sodium-hydrogen exchange and/or their physiologically acceptable salts; or

b) an NCBE inhibitor of the formula I and additionally active substance from another class is active against cardiovascular prophetic the TV and/or their physiologically acceptable salts; or NCBE inhibitor of the formula I, an inhibitor of Na+/H+-exchange and additionally active substance from another class is active against cardiovascular substances and/or their physiologically acceptable salts, together with instructions for the use of these active substances in combination for simultaneous, separate or sequential use in the treatment or prevention of the above diseases, in particular, in the treatment of cardiovascular diseases.

The pharmaceutical compositions according to the invention can, for example, be obtained either by intensive mixing of the individual component in the form of powders, or by dissolving a separate component in a suitable solvent, as, for example, lower alcohol, and subsequent removal of solvent.

The weight ratio NCBE inhibitor the inhibitor PA+/H+-exchange or active in relation to the cardiovascular system substance combinations according to the invention and compositions is suitable from 1:0.01 to 1:100, preferably from 1:0.1 to 1:10.

The proposed combinations and compositions are in General preferably from 0.5 to 99.5 wt.%, particularly preferably 4-99 wt.% such active substances.

When applied according to the invention to mammals, preferably humans, doses of various components of the active substances number is blude, for example, in the range from 0.001 to 100 mg/kg / day.

List of abbreviations:
BCAFC2’,7’-bis(2-carboxyethyl)-5,6-carboxyfluorescein
Bnbenzil
CH2CL2dichloromethane
THEdesorption-chemical ionization
The deepsimple diisopropyl ether
DMAdimethylacetamide
DMEdimethoxyethan
DMFN,N-dimethylformamide
EAthe ethyl acetate (EtOAc)
EUe-shock
EQ.equivalent to

ERelectrospray ionization
Arotrelectrospray negative ionization
Etethyl
EtOHethanol
The Belarusian library Associationmail bombing fast atom
Fmoc9-fluorenylmethoxycarbonyl
SEheptane
HOAcacetic acid
HOOBt3-is hydroxy-1,2,3-benzotriazin-4(3H)-he
KOtButert-butyl potassium
Memethyl
MeOHmethanol
TPLmelting point
MTBsimple tert-butyl methyl ether
NCBEdependent sodium chloride/bicarbonate exchange
NHEsodium/hydrogen exchange (PA+/N+-exchange)
NN-organic
PSpolystyrene
THFtetrahydrofuran
TMMN,N,N’,N’-tetramethylrhodamine
Toltoluene
CNSCentral nervous system

Examples:

General methods of solid-phase synthesis:

The syntheses of compounds of formula I in solid phase provide a suitable connection sulfonamidnuyu structures through chemical glue (linker) to the polymer matrix is well-known specialist of ways. Attached via sulfonamidnuyu group to the polymer base material is further subjected to conventional in organic chemistry organic reactions.

In particular, included the following stages (for example, described for the compounds of formula Ia,

where R(1) about the mean 2-chlorophenyl, R(2) benzyl, X is carbonyl and R(3) R(7) denote hydrogen.

A. Synthesis of structural link linker/polymer

As a commercially available polymer was used aminomethylation company Fluca (1.1 mmol amine/g of resin; 2% crosslinked with divinylbenzene). As the linker used is known from the literature connection 1 (G, Breipohl, J. Knolle,Int. J. Peptide Protein Res. 43, 1989, 262f).

For linking of the polymer and the linker were mixed to 14.4 g aminomethylpropanol 2, 28,2 1 g, 3.2 g HOOBt, 11.5g of diisopropylcarbodiimide in 105 ml of DMF and 45 ml of methylene chloride and shaken for 48 hours Then acidified and thoroughly washed with DMF and MTB.

B. Synthesis associated with resin sulfonamida

5 g 3 was treated with a mixture of piperidine/DMF (1:3) at room temperature, the solution was acidified and thoroughly washed with DMF. To moist DMF to the resin was added 3.1 g are known from literature connections 4 (Gilman, Marker, JACS 74, 1952, 5317) in 20 ml of DMF. After addition of 0.7 ml of pyridine was left to react for 18 h at room temperature. Acidified and washed with DMF and MTB.

C. Synthesis associated with the resin bullsonparade 7

Spent the swelling of 1 g 5 in 15 ml of DMF was added 1.5 g of boric acid 6,50 mg PD(h3)4and 3.5 ml of 2 M solution of PA2CO3. Left to react for 24 h at 100°C in argon atmosphere. Acidified and thoroughly washed with water, DMF and MTB.

He Reductive amination in the solid phase, for example, benzylamine

200 mg associated with the resin of the basic substance 7 was treated with 1 mmol amine, dissolved in 1 ml of a mixture of dimethoxyethane/methanol (3:1) was added 0.2 ml of 1 M solution of acetic acid in dimethoxyethane, and 0.5 ml of 1 M solution of NaBH3CN in dimethoxyethane. Left to react for 4 h at room temperature. Acidified and thoroughly washed with DMF and MTB.

After removal of the samples (10 mg) from the resin by treatment with 1 ml of a mixture of methylene chloride/triperoxonane acid (3:1) free amine 8 was characterized by high-performance liquid chromatography and mass spectrometry.

D. N-Acylation in the solid phase, for example, 2-CL-benzoyl chloride

To 190 mg 8 was added 2 ml of 1 M solution of N-ethylmorpholine in methylene chloride. Was cooled to 0°and added with stirring 0.5 mmole of carboxylic acid, dissolved in 0.5 ml of methylene chloride. Left to react for 1 h at 0°C. Acidified and washed with DMF and MTB. The reaction course was monitored by sampling 9 (see G) methods of high performance liquid chromatography and mass spectrometry.

That is, Cleavage from the resin/p>

180 mg 9 were treated 30 min at room temperature, 3 ml of methylene chloride/triperoxonane acid (3:1).

After separation of the solution from the polymer was treated in a rotary evaporator under vacuum. As the remainder received 30 mg of the free amide 10, which is directly sent to the stage of cinelibre (W).

J. Synthesis of sulfanilamide

30 mg 10 was dissolved in 3 ml of acetonitrile and was added 0.3 mmole of triethylamine and 0.12 mmole Enrichment, dissolved in acetonitrile. Left to react for 18 h at room temperature, was then added 3 ml of MTB and 2 ml of aqueous buffer solution (rn). After a good mixing of the separated upper phase and deposited on the silica gel. First washed with 5 ml of MTB, and then washed the product with 5 ml of a mixture of EA/SPLA (5:1). After concentrating the solution in vacuo received 12 mg of sulfanilamide 60-90%purity (for example, 11, 90%). Thus obtained product may be subjected to further purification by preparative high-performance liquid chromatography with reversed phase. The product is characterized by high-performance liquid chromatography and mass spectrometry, as well as selectively by NMR spectroscopy.

Similarly, there were obtained the following compounds of formula Ia (R(3) R(7) represent hydrogen), see table 1.

Table 1 R(2)R(1)-XMass spectrum (ER-):M-1)-Residual activity, % NCBE at 10 µm1-beneilCH3-CH2-CH2-CO-446 2-CH2-CH2-HECH3-CH2-CH2-CO-40078,134-methoxybenzyl-CH3-CH2-CH2-CO-47680,944-chlorbenzyl-CH3-CH2-CH2-CO-480 5-phenylCH3-CH2-CH2-CO-431to 89.56-cyclohexylCH3-CH2-CH2-CO-43884,57-benzilcyclohexyl-CH2-CH2/sub> -CO-51433,08-CH2-CH2-OHcyclohexyl-CH2-CH2-CO-46886,794-methoxybenzyl-cyclohexyl-CH2-CH2-CO-54486,6104-chlorbenzyl-cyclohexyl-CH2-CH2-CO-54884,911-phenylcyclohexyl-CH2-CH2-CO-49968,112-cyclohexylcyclohexyl-CH2-CH2-CO-50692,913-benzilcyclohexyl-CO-48674,714-CH2-CH2-HEcyclohexyl-CO-44088,7154-methoxybenzyl-cyclohexyl-CO-516 67,6164-chlorbenzyl-cyclohexyl-CO-520of 56.417-phenylcyclohexyl-CO-471 18-cyclohexylcyclohexyl-CO-478 19-benzil3-methoxyphenyl-CH2-CO-52425,920-CH2-CH2-HE3-methoxyphenyl-CH2-CO-47837,1214-methoxybenzyl-3-methoxyphenyl-CH2-CO-55452,3224-chlorbenzyl-3-methoxyphenyl-CH2-CO-558 23-phenyl3-methoxyphenyl-CH2-CO-509 25,924-cyclohexyl3-methoxyphenyl-CH2-CO-516to 92.125-benzil2-thienyl-CH2-CO-50016,626-CH2-CH2-HE2-thienyl-CH2-CO-45447,6274-methoxybenzyl-2-thienyl-CH2-CO-53035,5284-chlorbenzyl-2-thienyl-CH2-CO-534for 95.229-phenyl2-thienyl-CH2-CO-48555,730-cyclohexyl2-thienyl-CH2-CO-492for 95.231-benzil4-tert-butylphenyl-CO-536 52,232-CH2-CH2-HE4-tert-butylphenyl-CO-49068,0334-methoxybenzyl-4-tert-butylphenyl-CO-56667,2344-chlorbenzyl-4-tert-butylphenyl-CO-570 35-phenyl4-tert-butylphenyl-CO-52153,436-cyclohexyl4-tert-butylphenyl-CO-528 37-benzil2-forfinal-CO-49852,038-CH2-CH2-HE2-forfinal-CO-45266,7394-methoxybenzyl-2-forfinal-CO-528 51,3404-chlorbenzyl-2-forfinal-CO-532 41-phenyl2-forfinal-CO-48394,942-cyclohexyl2-forfinal-CO-490 43-benzilallyl-O-CO-46041,644-CH2-CH2-HEallyl-O-CO-41482,6454-methoxybenzyl-allyl-O-CO-49080,1464-chlorbenzyl-allyl-O-CO-49452,247-phenylallyl-O-CO-445at 88.148-cyclohexyl allyl-O-CO-452 49-benzil3,4,5-trimethoxyphenyl-57075,8  WITH-  50-CH2-CH2-HE3,4,5-trimethoxyphenyl-524   WITH-  514-methoxybenzyl-3,4,5-trimethoxyphenyl-600   WITH-  524-chlorbenzyl-3,4,5-trimethoxyphenyl-60459,9  WITH-   53-phenyl3,4,5-trimethoxyphenyl-555   WITH-  54-cyclohexyl3,4,5-trimethoxyphenyl-562   WITH-  55-benzil2-chlorophenyl-CO-51429,356-CH2-CH2-HE2-chlorophenyl-CO-46869,0574-methoxybenzyl-2-chlorophenyl-CO-54482,1584-chlorbenzyl-2-chlorophenyl-CO-548to 59.459 -phenyl2-chlorophenyl-CO-499 60-cyclohexyl2-chlorophenyl-CO-506      No.R(2)R(1)-XMass spectrum (ER-):(M-1)-The residual activity % NCBE at 10 µm61benzyl-phenyl-CO48056,6624-chlorbenzyl-CH3-CO-45294,563phenyl-CH3-CO-404 644-methoxybenzyl-E-SN3-CH=CH-CO-47488,0654-chlorbenzyl-CH3-(CH2)3-CO- 49480,0664-chlorbenzyl-phenyl-CH2-CH2-CO-54283,1674-chlorbenzyl-E-SN3-CH=CH-CO-478 682-hydroxyethyl-4-were-WITH-44894,4694-methoxybenzyl-CH3-CO-44895,4704-methoxybenzyl-4-were-WITH-52494,7712 chlorbenzyl-benzo[b]thiophene-2-yl-CO-57035,272isobutyl-benzo[b]thiophene-2-yl-CO-50286,3731(S)-phenylethyl-benzo[b]thiophene-2-yl-CO-55061,0742-methoxybenzyl-is Enzo[b]thiophene-2-yl-CO- 56654,7754-methylbenzyl-benzo[b]thiophene-2-yl-CO-55080,3763-methoxybenzyl-benzo[b]thiophene-2-yl-CO-566of 87.3773,4-methylenedioxybenzyl-benzo[b]thiophene-2-yl-CO-58081,8781(R)-phenylethyl-benzo[b]thiophene-2-yl-CO-55088,5794-trifloromethyl-benzo[b]thiophene-2-yl-CO-60461,7802-(4-methoxyphenyl)-ethyl-benzo[b]thiophene-2-yl-CO-58066,7812 chlorbenzyl-thienyl-2-yl-CO-52036,082isobutyl-thienyl-2-yl-CO-45299,8831S)-phenylethyl- thienyl-2-yl-CO-50097,5842-methoxybenzyl-thienyl-2-yl-CO-51654,7854-methylbenzyl-thienyl-2-yl-CO-50051,1863-methoxybenzyl-thienyl-2-yl-CO-51657,0873,4-methylenedioxy-benzyl-thienyl-2-yl-CO-530of 54.8881(R)-phenylethyl-thienyl-2-yl-CO-500 894-trifloromethyl-thienyl-2-yl-CO-55467,6902-(4-methoxyphenyl)-ethyl-thienyl-2-yl-CO-53084,2912 chlorbenzyl-2-forfinal-CO-53262,792 isobutyl-2-forfinal-CO-464 931(S)-phenylethyl2-forfinal-CO-51292,9942-methoxybenzyl-2-forfinal-CO-52887,7954-methylbenzyl-2-forfinal-CO-51274,7963-methoxybenzyl-2-forfinal-CO-528 973,4-methylenedioxy-benzyl-2-forfinal-CO-542 981(R)-phenylethyl-2-forfinal-CO-51298,0994-trifloromethyl-2-forfinal-CO-56689,61002-(4-methoxyphenyl)-ethyl-2-forfinal-CO-54294,1 1012 chlorbenzyl-2-chlorophenyl-CO-54862,6102isobutyl-2-chlorophenyl-CO-480 1031(S)-phenylethyl-2-chlorophenyl-CO-528 1042-methoxybenzyl-2-chlorophenyl-CO-544 1054-methylbenzyl-2-chlorophenyl-CO-528 1063-methoxybenzyl-2-chlorophenyl-CO-544the 98.91073,4-methylenedioxy-benzyl-2-chlorophenyl-CO-55896,41081(R)-phenylethyl-2-chlorophenyl-CO-52887,71094-trifloromethyl-2-chlorophenyl-CO-582 75,41102-(4-methoxyphenyl)-ethyl-2-chlorophenyl-CO-558 1112 chlorbenzyl-(phenyl)2CH-CO-60480,5112isobutyl-(phenyl)2CH-CO-53690,41131(S)-phenylethyl-(phenyl)2CH-CO-58494,61142-methoxybenzyl-(phenyl)2CH-CO-60081,71154-methylbenzyl-(phenyl)2CH-CO-58484,01163-methoxybenzyl-(phenyl)2CH-CO-600 1173,4-methylenedioxy-benzyl-(phenyl)2CH-CO-614 1181(R)-phenylethyl- (phenyl)2CH-CO-584for 95.31194-trifloromethyl-(phenyl)2CH-CO-63875,71202-(4-methoxyphenyl)-ethyl-(phenyl)2CH-CO-61481,31212-chlorophenyl-phenyl-CH2-CO-52872,1122isobutyl-phenyl-CH2-CO-46090,61231(S)-phenylethyl-phenyl-CH2-CO-50872,21242-methoxybenzyl-phenyl-CH2-CO-52446,51254-methylbenzyl-phenyl-CH2-CO-50863,61263-methoxybenzyl-phenyl-CH2-CO-52453,7127 3,4-methylenedioxy-benzyl-phenyl-CH2-CO-53861,71281(R)-phenylethyl-phenyl-CH2-CO-50861,41294-trifloromethyl-phenyl-CH2-CO-56247,41302-(4-methoxyphenyl)-ethyl-phenyl-CH2-CO-53877,81312 chlorbenzyl-phenyl-CH2-CO-CH(phenyl)-CO-64697,61321(S)-phenylethyl-(2-thienyl)CH2-CO-51463,81331(R)-phenylethyl-(2-thienyl)CH2-CO-514of 40.9134isobutyl-phenyl-CH2-CO-CH(phenyl)-CO-578 1354-methylbenzyl-phenyl-CH2 -CO-CH(phenyl)-CO-62697,41361(S)-phenylethyl-phenyl-CH2-CO-CH(phenyl)-CO-62693,61371(S)-(4-were)-ethyl-(2-thienyl)-CH2-CO-528 1381(R)-(4-were)-ethyl-(2-thienyl)-CH2-CO-528 1392-furylmethyl-(2-thienyl)-CH2-CO-49048,51404-(dimethylamino)-benzyl-(2-thienyl)-CH2-CO-54354,21412-(2-thienyl)-ethyl-(2-thienyl)-CH2-CO-52071,11422-phenoxyethyl-(2-thienyl)-CH2-CO-53027,11432 chlorbenzyl-(2-thienyl)-CH2-CO- 35,7144cyclopropylmethyl-(2-thienyl)-CH2-CO-46460,31453,4,5-trimethoxybenzyl-(2-thienyl)-CH2-CO-59039,6146(4-pyridyl)-methyl-(2-thienyl)-CH2-CO-50169,81474-terbisil-(2-thienyl)-CH2-CO-51853,21482-furylmethyl-(4-chlorophenyl)-CH2-CO-51845,61494-(dimethylamino)-benzyl-(4-chlorophenyl)-CH2-CO-57177,41502-(2-thienyl)-ethyl-(4-chlorophenyl)-CH2-CO-54844,71512-phenoxyethyl-(4-chlorophenyl)-CH2-CO-55829,0152 2 chlorbenzyl-(4-chlorophenyl)-CH2-CO-56229,5153cyclopropylmethyl-(4-chlorophenyl)-CH2-CO-49246,11542,4-dimethoxybenzyl-(4-chlorophenyl)-CH2-CO-58836,21553,4,5-trimethoxybenzyl-(4-chlorophenyl)-CH2-CO-61834,2156(4-pyridyl)-methyl-(4-chlorophenyl)-CH2-CO-52986,01574-terbisil-(4-chlorophenyl)-CH2-CO-54624,91582-furylmethyl-(CH3)3C-CH2-CO-46457,91592-(2-thienyl)-ethyl-(CH3)3C-CH2-CO-49461,21602-phenoxyethyl- (CH3)3C-CH2-CO-50471,6161cyclopropylmethyl-(CH3)3C-CH2-CO-43881,61623,4,5-trimethoxybenzyl-(CH3)3C-CH2-CO-56430,21634-terbisil-(CH3)3C-CH2-CO-492for 93.41642-furylmethyl-phenyl-O-CH2-CO-50076,41652-(2-thienyl)-ethyl-phenyl-O-CH2-CO-53056,81662-phenoxyethyl-phenyl-O-CH2-CO-54057,91672 chlorbenzyl-phenyl-O-CH2-CO-54447,5168cyclopropylmethyl-phenyl-O-CH2-CO- 47496,41693,4,5-trimethoxybenzyl-phenyl-O-CH2-CO-600 1704-terbisil-phenyl-O-CH2-CO-528 1712-phenylmethyl-(4-methoxyphenyl)-CH2-CO-514 1722-(2-thienyl)-ethyl-(4-methoxyphenyl)-CH2-CO-54489,71732-phenoxyethyl-(4-methoxyphenyl)-CH2-CO-55476,41742 chlorbenzyl-(4-methoxyphenyl)-CH2-CO-55850,2175cyclopropylmethyl-(4-methoxyphenyl)-CH2-CO-48893,21763,4,5-trimethoxybenzyl-(4-methoxyphenyl)-CH2-CO-61483,9 1774-terbisil-(4-methoxyphenyl)-CH2-CO-54264,41782-furylmethyl-CH3-CO-40870,61792-(2-thienyl)-ethyl-CH3-CO-438to 78.31802-phenoxyethyl-CH3-CO-44870,91812 chlorbenzyl-CH3-CO-45280,8182cyclopropylmethyl-CH3-CO-38274,91832,4-dimethoxybenzyl-CH3-CO-478 1843,4,5-trimethoxybenzyl-CH3-CO-508 1854-terbisil-CH3-CO- 43685,01863-phenylpropyl-(2-thienyl)-CH2-CH2-CH2-CO-556the 9.71872-methoxyethyl-(2-thienyl)-CH2-CH2-CH2-CO-49662,4188(2-pyridyl)-methyl-(2-thienyl)-CH2-CH2-CH2-CO-52952,3189cyclopropyl-(2-thienyl)-CH2-CH2-CH2-CO-47872,5190methyl-(2-thienyl)-CH2-CH2-CH2-CO-45243,4191ethyl-(2-thienyl)-CH2-CH2-CH2-CO-46639,3192(2-benzimidazolyl)-methyl-(2-thienyl)-CH2-CH2-CH2-CO-56849,11931-methoxycarbonyl-2-peneliti is- (2-thienyl)-CH2-CH2-CH2-CO-60062,81943-phenylpropyl-(2-thienyl)-CO-CO-54261,11952-methoxyethyl-(2-thienyl)-CO-CO-48258,3196(2-pyridyl)-methyl-(2-thienyl)-CO-CO-51562,8197cyclopropyl-(2-thienyl)-CO-CO-46479,9198methyl-(2-thienyl)-CO-CO-43851,1199ethyl-(2-thienyl)-CO-CO-45254,7200(2-benzimidazolyl)-methyl-(2-thienyl)-CO-CO-55455,22011-methoxycarbonyl-2-phenylethyl-(2-thienyl)-CO-CO-58669,6 2023-phenylpropyl-(indol-3-yl)-CH2-CO-561a 38.52032-methoxyethyl-(indol-3-yl)-CH2-CO-50130,3204(2-pyridyl)-methyl-(indol-3-yl)-CH2-CO-53452,4205cyclopropyl-(indol-3-yl)-CH2-CO-48341,7206methyl-(indol-3-yl)-CH2-CO-45723,8207ethyl-(indol-3-yl)-CH2-CO-47131,0208(2-benzimidazolyl)-methyl-(indol-3-yl)-CH2-CO-57350,72091-methoxycarbonyl-2-phenylethyl-(indol-3-yl)-CH2-CO-60556,22103-phenylpropyl-(be the zo[b]thiophene-3-yl)-CH 2-CO-57866,22112-methoxyethyl-(benzo[b]thiophene-3-yl)-CH2-CO-51850,6212(2-pyridyl)-methyl-(benzo[b]thiophene-3-yl)-CH2-CO-55160,2213cyclopropyl-(benzo[b]thiophene-3-yl)-CH2-CO-50045,0214methyl-(benzo[b]thiophene-3-yl)-CH2-CO-47444,3215ethyl-(benzo[b]thiophene-3-yl)-CH2-CO-48865,7216(2-benzimidazolyl)-methyl-(benzo[b]thiophene-3-yl)-CH2-CO-59062,22171-methoxycarbonyl-2-phenylethyl-(benzo[b]thiophene-3-yl)-CH2-CO-62246,02183-phenylpropyl-(2 Thillay who yl)-(CH 2)4-CO-57087,12192-methoxyethyl-(2-thienyl)-(CH2)4-CO-51082,5220(2-pyridyl)-methyl-(2-thienyl)-(CH2)4-CO-54373,2221cyclopropyl-(2-thienyl)-(CH2)4-CO-49272,3222methyl-(2-thienyl)-(CH2)4-CO-46676,7223ethyl-(2-thienyl)-(CH2)4-CO-48053,8224(2-benzimidazolyl)-methyl-(2-thienyl)-(CH2)4-CO-58279,82251-methoxycarbonyl-2-phenylethyl-(2-thienyl)-(CH2)4-CO-614at 88.12263-phenylpropyl-(3-thienyl)-CH 2-CO-52834,82272-methoxyethyl-(3-thienyl)-CH2-CO-46850,6228(2-pyridyl)-methyl-(3-thienyl)-CH2-CO-50194,8229cyclopropyl-(3-thienyl)-CH2-CO-45086,7230methyl-(3-thienyl)-CH2-CO-42468,6231ethyl-(3-thienyl)-CH2-CO-43857,8232(2-benzimidazolyl)-methyl-(3-thienyl)-CH2-CO-54062,62331-methoxycarbonyl-2-phenylethyl-(3-thienyl)-CH2-CO-57268,12342-phenylethyl-(2-thienyl)-CH2-CO-514 4-trifloromethyl-(2-thienyl)-CH2-CO-56867,12363-phenylpropyl-(2-thienyl)-CH2-CO-52835,12372-methoxyethyl-(2-thienyl)-CH2-CO-46850,3238(3,4-dihydroquinazolin-2-yl)-methyl-(2-thienyl)-CH2-CO-55454,7239methyl-(2-thienyl)-CH2-CO-42456,3240ethyl-(2-thienyl)-CH2-CO-43858,0241benzyl-phenyl-CH(NH2)- - 50966,0242benzyl-phenyl-CH(NHCO-O-benzyl)-CO-64372,4243benzyl-(2-nitrophenyl)-CH2-CO- 53999,9244benzyl-phenyl-(CH2)4-CO-53660,4245benzyl-(2-furyl)-CO-CO-49873,0246propargyl-phenyl-CH(NHCO-O-benzyl)-CO-59165,0247propargyl-phenyl-(CH2)4-CO-48474,6248propargyl-(2-furyl)-CO-CO-44666,6249propargyl-sikorksy-CH2-CH2-CO-46276,1250(2-thienyl)-methyl-(2-thienyl)-CH2-CO-50641,1251(2-thienyl)-methyl-phenyl-CH(NHCO-O-benzyl)-CO-64983,9252(2-thienyl)-methyl- (2-nitrophenyl)-CH2-CO-54544,5253(2-thienyl)-methyl-phenyl-(CH2)4-CO-54235,3254(2-thienyl)-methyl-(2-furyl)-CO-CO-50464,5255(2-thienyl)-methyl-cyclohexyl-CH2-CH2-CO-52061,0256cyclohexylmethyl-(2-thienyl)-CH2-CO-50636,4257cyclohexylmethyl-(2-nitrophenyl)-CH2-CO-54554,6258cyclohexylmethyl-(2-furyl)-CO-CO-50495,82593,4-dichlorobenzyl-(2-thienyl)-CH2-CO-56840,12603,4-dichlorobenzyl-phenyl-CH(NHCO-O-benzyl)-CO-69,82613,4-dichlorobenzyl-(2-nitrophenyl)-CH2-CO-60767,72623,4-dichlorobenzyl-phenyl(CH2)4-CO-60445,32633,4-dichlorobenzyl-(2-furyl)-CO-CO-56654,02643,4-dichlorobenzyl-cyclohexyl-CH2-CH2-CO-58274,3265cyclohexylmethyl-phenyl-CH(NHCO-O-benzyl)-CO-64968,9266cyclohexylmethyl-phenyl-(CH2)4-CO-54279,7267cyclohexylmethyl-cyclohexyl-CH2-CH2-CO-52057,9268phenyl-CH(SOON3)-(2-thienyl)-CH2-CO-558793 269phenyl-CH(SOOS(CH3)3)-(2-thienyl)-CH2-CO-60094,42702,4-dichlorobenzyl-(2-thienyl)-CH2-CO-56833,9271(1-naphthyl)-methyl-(2-thienyl)-CH2-CO-55015,92722-(4-N2NSO2-phenyl)-ethyl-(2-thienyl)-CH2-CO-59365,02733 chlorbenzyl-(2-thienyl)-CH2-CO-53432,4274phenyl-CH(SOON3)-(2-bromophenyl)-CH3-CO-63073,6275phenyl-CH(SOOS(CH3)3)-(2-bromophenyl)-CH3-CO-67254,62762,4-dichlorobenzyl-(2-bromophenyl)-CH3-CO-64036,8 277(1-naphthyl)-methyl-(2-bromophenyl)-CH3-CO-62236,32783 chlorbenzyl-(2-bromophenyl)-CH3-CO-60631,22792,4-dichlorobenzyl-phenyl-SO2-CH2-CH2-CO-64090,5280(1-naphthyl)-methyl-phenyl-SO2-CH2-CH2-CO-62263,32813 chlorbenzyl-phenyl-SO2-CH2-CH2-CO-60668,6282phenyl-CH(COOH)-(2-thienyl)-CH2-CO-54489,02832,4-dichlorobenzyl-(4-hydroxyphenyl)-CH2-CO-57880,0284(1-naphthyl)-methyl-(4-hydroxyphenyl)-CH2-CO-56052,9285 3 chlorbenzyl-(4-hydroxyphenyl)-CH2-CO-54458,8286phenyl-CH(SOON3)-(2-thienyl)-CH2-CH2-CO-57268,8287phenyl-CH(SOOS(CH3)3)-(2-thienyl)-CH2-CH2-CO-61451,12882,4-dichlorobenzyl-(2-thienyl)-CH2-CH2-CO-58263,1289(1-naphthyl)-methyl-(2-thienyl)-CH2-CH2-CO-56439,22903 chlorbenzyl-(2-thienyl)-CH2-CH2-CO-54845,82912 chlorbenzyl-(2-chlorophenyl)-CH2-CO-56223,72922,4-dichlorobenzyl-(2-chlorophenyl)-CH2-CO-596  293(1-naphthyl)-methyl-(2-chlorophenyl)-CH2-CO-57855,12942-(4-N2NSO2-phenyl)-ethyl-(2-chlorophenyl)-CH2-CO-62182,7295(2-thienyl)-methyl-phenyl-CH2-NH-CO-5158,0296(2-thienyl)-methyl-N-cyclohexyl-NH-CO-50731,7297benzyl-N-(2,6-differenl)-NH-CO-53180,4298benzyl-N-isopropyl-NH-CO-46174,7299benzyl-phenyl-CH2-NH-CO-50948,6300benzyl-N-cyclohexyl-NH-CO-50129,43013-methoxybenzyl-N-(2,6-deltorphin the l)-NH-CO- 56187,93023-methoxybenzyl-N-isopropyl-NH-CO-49180,43033-methoxybenzyl-phenyl-CH2-NH-CO-53965,83043-methoxybenzyl-N-cyclohexyl-NH-CO-53156,03053 chlorbenzyl-N-(2,6-differenl)-NH-CO-56584,93063 chlorbenzyl-N-isopropyl-NH-CO-49590,23073 chlorbenzyl-phenyl-CH2-NH-CO-54355,83083 chlorbenzyl-N-cyclohexyl-NH-CO-53532,13092,3-dichlorobenzyl-(2-thienyl)-CH2-CO-56888,9310(2-naphthyl)-ethyl- (2-thienyl)-CH2-CO-55047,73113-methylbenzyl-(2-thienyl)-CH2-CO-51410,43122-methylbenzyl-(2-thienyl)-CH2-CO-51412,5313(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-(2-thienyl)-CH2-CO-54617,23141 indanyl-(2-thienyl)-CH2-CO-52614.4V3151,2,3,4-tetrahydro-1-naphthyl(2-thienyl)-CH2-CO-54023,53162-terbisil-(2-thienyl)-CH2-CO-51814.4V3173-phenylbenzyl-(2-thienyl)-CH2-CO-57614,5318(1,2,3,4-tetrahydro-2-furyl)-methyl- (2-thienyl)-CH2-CO-49416,43192,3-dichlorobenzyl-methoxy-CH2-CH2-CO-53038,0320(2-naphthyl)-methyl-methoxy-CH2-CH2-CO-51238,83213-methylbenzyl-methoxy-CH2-CH2-CO-476 3222-methylbenzyl-methoxy-CH2-CH2-CO-476to 66.3323(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-methoxy-CH2-CH2-CO-50823,63241 indanyl-methoxy-CH2-CH2-CO-488of 60.53251,2,3,4-tetrahydro-1-naphthyl-methoxy-CH2-CH2-CO-502to 33.8326 2-terbisil-methoxy-CH2-CH2-CO-48025,63273-phenylbenzyl-methoxy-CH2-CH2-CO-53817,4328(1,2,3,4-tetrahydro-2-furyl)-methyl-methoxy-CH2-CH2-CO-456of 87.03292,3-dichlorobenzyl-2-methoxyphenyl-CO-57825,7330(2-naphthyl)-methyl-2-methoxyphenyl-CO-56014.4V3313-methylbenzyl-2-methoxyphenyl-CO-52437,63322-methylbenzyl-2-methoxyphenyl-CO-52431,7333(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN3-2-methoxyphenyl-CO-55622,33341-ind is Neal 2-methoxyphenyl-CO-536 3351,2,3,4-tetrahydro-1-naphthyl-2-methoxyphenyl-CO-55079,63362-terbisil-2-methoxyphenyl-CO-528to 58.13373-phenylbenzyl-2-methoxyphenyl-CO-58651,2338(1,2,3,4-tetrahydro-2-furyl) -methyl-2-methoxyphenyl-CO-50450,73392,3-dichlorobenzyl-phenoxy-CH2-CH2-CO-59246,8340(2-naphthyl)-methyl-phenoxy-CH2-CH2-CO-57437,23413-methylbenzyl-phenoxy-CH2-CH2-CO-53844,63422-methylbenzyl-phenoxy-CH2-The n 2-CO-53885,3343(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-phenoxy-CH2-CH2-CO-57048,13441 indanyl-phenoxy-CH2-CH2-CO-55052,23451,2,3,4-tetrahydro-1-naphthyl-phenoxy-CH2-CH2-CO-56439,83462-terbisil-phenoxy-CH2-CH2-CO-54236,03473-phenylbenzyl-phenoxy-CH2-CH2-CO-60019,3348(1,2,3,4-tetrahydro-2-furyl)-methyl-phenoxy-CH2-CH2-CO-51846,33492,3-dichlorobenzyl-cyclohexyl-CH2-CO-56850,4350 (2-naphthyl)-methyl-cyclohexyl-CH2-CO-550 3513-methylbenzoyl-cyclohexyl-CH2-CO-51427,23522-methylbenzyl-cyclohexyl-CH2-CO-51435,2353(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-cyclohexyl-CH2-CO-54647,93541 indanyl-cyclohexyl-CH2-CO-52637,23551,2,3,4-tetrahydro-1-naphthyl-cyclohexyl-CH2-CO-54046,83562-terbisil-cyclohexyl-CH2-CO-51847,43573-phenylbenzyl-cyclohexyl-CH2-CO-57661,9358 (1,2,3,4-tetrahydro-2-furyl) -methyl-cyclohexyl-CH2-CO-49455,53592,3-dichlorobenzyl-cyclohexyl-CH2-CO-554of 37.9360(2-naphthyl)-methyl-cyclohexyl-CH2-CO-53636,93613-methylbenzyl-cyclohexyl-CH2-CO-50029,43622-methylbenzyl-cyclohexyl-CH2-CO-50044,1363(CH3)2C=CH-CH2-CH2- (CH3)=SN-SN2-cyclohexyl-CH2-CO-53248,33641 indanyl-cyclohexyl-CH2-CO-51252,63651,2,3,4-tetrahydro-1-naphthyl-cyclohexyl-CH2-CO-52645,12-terbisil-cyclohexyl-CH2-CO-50438,43673-phenylbenzyl-cyclohexyl-CH2-CO-56225,5368(1,2,3,4-tetrahydro-2-furyl) -methyl-cyclohexyl-CH2-CO-48051,03692,4-differenl-4-were-SO2-59033,73704-tert-butylphenyl-3,4-acid-SO2-65650,13714-tert-butylphenyl-2,5-acid-SO2-65638,63722,4-differenl-2,3,4,5,6-pentamethylbenzyl-SO2-64623,13732,6-dichlorophenyl-3-fluoro-2,4-dimetilfenil-SO2-65420,6374 3-chloro-4-forfinal-4-fluoro-3, 5dimethylphenyl-SO2-63870,33752-cyanophenyl-4-were-SO2-57980,63764-chloro-2,5-acid-4-were-SO2-64866,63774-chloro-2,5-acid-4-chlorophenyl-SO2-66836,83784-forfinal2,4,5-trichlorophenyl-SO2-66043,63794-(4-pertenece)-phenyl-4-were-SO2-664 3802-chlorophenyl-2,5-acid-SO2-63428,13812-cyanophenyl-2,5-acid-SO2-62560,83822,3-dichlorophenyl- 3,4-dichlorophenyl-SO2-67647,13834-(4-chlorophenoxy)-phenyl-4-were-SO2-68042,23843-triptoreline-4-were-SO2-62257,23852-cyanophenyl-4-tert-butylphenyl-SO2-62164,83862-acetylphenyl-2,4-dichlorophenyl-SO2-65033,53872-acetylphenyl-2,3-dichlorophenyl-SO2-65029,8388benzyl-(3-thienyl)-CH-(CH3)- - 51463,7389benzyl-(2-furyl)-CH2-CO-48451,5390(1-naphthyl)-methyl-(2-thienyl)-CH-(CH3)- - 564 89,8391(1-naphthyl)-methyl-(2-furyl)-CH2-CO-53455,4392(1-phenylcyclohexyl)-methyl-(2-thienyl)-CH2-CO-56855,6393(1-phenylcyclohexyl)-methyl-(2-thienyl)-CH-(CH3)- - 58216,7394(1-phenylcyclohexyl)-methyl-(2-furyl)-CH2-CO-55272,53952-ethyl-2-(4-methoxyphenyl)-butyl-(2-thienyl)-CH2-CO-60050,9396[3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-5-yl]-methyl-(2-thienyl)-CH2-CO-59053,2397[3-(pyrrolidin-1-carbonyl)-4,5-dihydroisoxazole-5-yl]-methyl-(2-thienyl)-CH-(CH3)- - 60444,0398phenyl-phenyl-O 2-540 3994-acetylamino-2-were-4-chlorophenyl-SO2-645 4005-acetylamino-2-were-2,5-dichlorophenyl-SO2-679 4014-acetylamino-2,6-dimetilfenil-4-were-SO2-639 402phenyl-4-were-SO2-554 4032-acetylphenyl-2,4,5-trichlorophenyl-SO2-684 4042-acetylphenyl-4-triptoreline-SO2-650 4054-chlorophenyl-4-chlorophenyl-SO2-608 4064-chlorophenyl-phenyl-SO2- 574 4073-acetylphenyl-4-were-SO2-612 4083-acetylphenyl-2-chlorophenyl-SO2-616 4093-acetylphenyl-2-chloro-6-were-SO2-630 4103-acetylphenyl-4-tert-butylphenyl-SO2-638 4113-acetylphenyl-4-forfinal-SO2-600 4123-acetylphenyl-3,4-dichlorophenyl-SO2-650 4133-acetylphenyl-2,4-differenl-SO2-618 4143-acetylphenyl-3-triptoreline-SO2-650 415/td> 4-triptoreline-4-Acetylaminophenol-SO2-665 4162.5-differenl-4-Acetylaminophenol-SO2-633 4174-tert-butylphenyl-4-Acetylaminophenol-SO2-653 4184-isopropylphenyl-2-chloro-4-cyanophenyl-SO2-641 4194-methoxyphenyl-4-acetylaminophenol-SO2-627 4204-ethoxyphenyl-4-chlorophenyl-SO2-618 4215-chloro-2-methoxyphenyl-4-chlorophenyl-SO2-638 4225-chloro-2-methoxyphenyl-2,4,5-trichlorophenyl-SO2-706 42 2-forfinal-4-acetylaminophenol-SO2-615 4241-naphthyl-4-acetylaminophenol-SO2-647 4252-triptoreline-4-acetylaminophenol-SO2-665 4262-ethylphenyl-4-chlorophenyl-SO2-602 4272,4-dimetilfenil-phenyl-SO2-568 4282,4,5-trimetilfenil-4-chlorophenyl-SO2-616 4292,5-dimetilfenil-2,4,5-trichlorophenyl-SO2-670 4305-chloro-2-were-4-chlorophenyl-SO2-622 4314-forfinal- phenyl-SO2-558 4323-chloro-2-were-phenyl-SO2-588 4334-chloro-2-were-phenyl-SO2-588 4342,3-dichlorophenyl-4-chlorophenyl-SO2-642 4353-triptoreline-2,4,5-trichlorophenyl-SO2-710 4365-chloro-2-were-2,4,5-trichlorophenyl-SO2-690 4372-forfinal-2,4,5-trichlorophenyl-SO2-660 4382,6-dimetilfenil-phenyl-SO2-568 4392,3-dimetilfenil-phenyl-SO2- 568 4401-naphthyl-3,4-dichlorophenyl-SO2-658 4414-ethoxyphenyl-3,4-dichlorophenyl-SO2-652 4421-naphthyl-4-chlorophenyl-SO2-624 4433,5-dichlorophenyl-3,4-dichlorophenyl-SO2-676 4442,4,5-trimetilfenil-4-acetylaminophenol-SO2-639 4453,4-dichlorophenyl-3,4-dichlorophenyl-SO2-676 4463,4-acid-4-were-SO2-614 4474-forfinal-4-were-SO2-572 448 4-bromophenyl-2-naphthyl-SO2-668 4492-chlorophenyl-2-naphthyl-SO2-624 4502-were-2-naphthyl-SO2-604 4512-methoxyphenyl-2-naphthyl-SO2-620 452phenyl-2-naphthyl-SO2-590 4532,6-diethylphenyl-phenyl-SO2-596 4542,6-diisopropylphenyl-phenyl-SO2-624 4552-biphenylyl-4-were-SO2-630 4562-naphthyl-2-naphthyl-SO2-640  4574-were-2-naphthyl-SO2-604 4582,4-acid-4-were-SO2-614 4592,5-dimetilfenil-4-acetylaminophenol-SO2-625 4602-chloro-4-methoxyphenyl-4-chlorophenyl-SO2-638 4612-methoxy-5-were-phenyl-SO2-584 4623-methoxy-4-were-phenyl-SO2-584 4632-methoxyphenyl-4-chlorophenyl-SO2-604 4643-hydroxyphenyl-4-chlorophenyl-SO2-590 4653,4-is chlorphenyl- 4-chlorophenyl-SO2-642 4663-acetylphenyl-4-chlorophenyl-SO2-616 4672,6-diethylphenyl-4-were-SO2-610 4685-chloro-2-methoxyphenyl-4-acetylaminophenol-SO2-661 4695-chloro-2-were-phenyl-SO2-588 4702-chloro-5-triptoreline-4-chlorophenyl-SO2-676 4712-acetylphenyl-2,4-differenl-SO2-618 4721-acetylamino-2-naphthyl-4-were-SO2-661 4734-ethylphenyl-4-chloro who enyl-SO 2-602 4742,5-dichlorophenyl-4-methoxyphenyl-SO2-638 4752,4-differenl-4-fluoro-3, 5dimethylphenyl-SO2-622 4764 triptoreline-phenyl-2,5-acid-SO2-684 4772-chlorophenyl-3,4-acid-SO2-634 4782-methyl-1-naphthyl-phenyl-SO2-604 4792,6-dimetilfenil-4-acetylaminophenol-SO2-625 4801,3-dihydro-1-oxo-benzo[C]furan-6-yl-4-chlorophenyl-SO2-630 481benzyl-(5-methyl-2-thienyl)-CH-(CH3 )- - 52862,64823-nitrobenzyl-(2-thienyl)-CH2-CO-545 483neopentyl-(2-thienyl)-CH2-CO-480 484isopropyl-(2-thienyl)-CH2-CO-452 4852-ethoxybenzyl-(2-thienyl)-CH2-CO-544 4863-nitrobenzyl-(3-thienyl)-CH2-CO-545 487neopentyl(3-thienyl)-CH2-CO-480 488isopropyl-(3-thienyl)-CH2-CO-452 4892-ethoxybenzyl-(3-thienyl)-CH2-CO-544  4902,2,2-triptorelin-(3-thienyl)-CH2-CO-492 4912-(3-trifluoromethyl-phenyl)-ethyl(3-thienyl)-CH2-CO-582 4923-nitrobenzyl-(2-forfinal)-CH2-CO-557 493neopentyl-(2-forfinal)-CH2-CO-492 494isopropyl-(2-forfinal)-CH2-CO-464 4952-ethoxybenzyl-(2-forfinal)-CH2-CO-556 4962-(3-trifluoromethyl-phenyl)-ethyl(2-forfinal)-CH2-CO-594 4971 indanyl-phenyl-CH2-CO-520 4983-neath benzyl- phenyl-CH2-CO-539 499neopentyl-phenyl-CH2-CO-474 500isopropyl-phenyl-CH2-CO-446 5012,2,2-triptorelin-phenyl-CH2-CO-486 5022-(3-trifluoromethyl-phenyl)-ethylphenyl-CH2-CO-576 5031 indanyl-(4-chlorophenyl)-CH2-CO-554 5043-nitrobenzyl-(4-chlorophenyl)-CH2-CO-573 505neopentyl-(4-chlorophenyl)-CH2-CO-508 506isopropyl-(4-chlorophenyl)-CH2-CO- 480 5072-ethoxybenzyl-(4-chlorophenyl)-CH2-CO-572 5082-(3-trifluoromethyl-phenyl)-ethyl(4-chlorophenyl)-CH2-CO-610 5093-nitrobenzyl-4-chlorophenyl-CO-559 510isopropyl-4-chlorophenyl-CO-466 5112-ethoxybenzyl-4-chlorophenyl-CO-558 5122-(3-trifluoromethyl-phenyl)-ethyl4-chlorophenyl-CO-596 

Table 2
No.R2R1-XR7Mass spectrum (ER-):M-1)-The residual activity % NCBE at 10 µm
513benzyl-(2-thienyl)-CH2-CO-4-methyl- 51488,6
514(1-naphthyl)-methyl-(2-thienyl)-CH2-CO-4-methyl-56474,9
515(2-naphthyl)-methyl-(2-thienyl)-CH2-CO-4-methyl-56468,9
5162 chlorbenzyl-(2-thienyl)-CH2-CO-4-methyl-54898,7
517(2-thienyl)-methyl-(2-thienyl)-CH2-CO-4-methyl-52086,2
5182-phenylethyl-(2-thienyl)-CH2-CO-4-methyl-52893,5
5192-terbisil-(2-thienyl)-CH2-CO-4-methyl-53295,6
5202,3-dichlorobenzyl-(2-thienyl)-CH2-CO-4-methyl-58285,9
521benzyl-(2-thienyl)-CH(CH3)- - 4-methyl-52888,2
522(1-naphthyl)-methyl-(2-thienyl)-CH(CH3)- - 4-methyl-57885,6
523(2-naphthyl)-methyl-(2-thienyl)-CH(CH3/sub> )- - 4-methyl-57892,3
5242 chlorbenzyl-(2-thienyl)-CH(CH3)- - 4-methyl-562 
525(2-thienyl)-methyl-(2-thienyl)-CH(CH3)- - 4-methyl-53474,0
5262-phenylethyl-(2-thienyl)-CH(CH3)- - 4-methyl-54264,9
5272-terbisil-(2-thienyl)-CH(CH3)- - 4-methyl-54667,5
5282,3-dichlorobenzyl-(2-thienyl)-CH(CH3)- - 4-methyl-59672,0
529benzyl-(4-chlorophenyl)-CH2-CO-4-methyl-54289,4
530(1-naphthyl)-methyl-(4-chlorophenyl)-CH2-CO-4-methyl-59289,8
531(2-naphthyl)-methyl-(4-chlorophenyl)-CH2-CO-4-methyl-59275,6
5322 chlorbenzyl-(4-chlorophenyl)-CH2-CO-4-methyl-57671,0
533(-thienyl)-methyl- (4-chlorophenyl)-CH2-CO-4-methyl-54875,5
5342-phenylethyl-(4-chlorophenyl)-CH2-CO-4-methyl-55680,0
5352-terbisil-(4-chlorophenyl)-CH2-CO-4-methyl-56084,0
5362,3-dichlorobenzyl-(4-chlorophenyl)-CH2-CO-4-methyl-61076,3
537benzil(3-thienyl)-CH2-CO-4-methyl-51454,4
538(1-naphthyl)-methyl-(3-thienyl)-CH2-CO-4-methyl-56480,3
539(2-naphthyl)-methyl-(3-thienyl)-CH2-CO-4-methyl-56465,2
5402 chlorbenzyl-(3-thienyl)-CH2-CO-4-methyl-54864,6
541(2-thienyl)-methyl-(3-thienyl)-CH2-CO-4-methyl-52052,8
5422-phenylethyl-(3-thienyl)-CH2-CO-4-methyl-52867,4
543 2-terbisil-(3-thienyl)-CH2-CO-4-methyl-53258,3
5442,3-dichlorobenzyl-(3-thienyl)-CH2-CO-4-methyl-58282,2
545benzyl-cyclohexyl-CH2-CO-4-methyl-51470,1
546(1-naphthyl)-methyl-cyclohexyl-CH2-CO-4-methyl-56463,6
547(2-naphthyl)-methyl-cyclohexyl-CH2-CO-4-methyl-56476,5
5482 chlorbenzyl-cyclohexyl-CH2-CO-4-methyl-54865,2
549(2-thienyl)-methyl-cyclohexyl-CH2-CO-4-methyl-52067,3
5502-phenylethyl-cyclohexyl-CH2-CO-4-methyl-52863,3
5512-terbisil-cyclohexyl-CH2-CO-4-methyl-53282,6
5522,3-dichlorobenzyl-cyclohexyl-CH2-CO-4-methyl-5821,5
553benzyl-(2-thienyl)-CH2-CO-5-chloro-53485,7

Example 554

4’-{[Benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-chloro-biphenyl-2-sulfanilamide

a) 4-Bromo-1-methyl bromide-2-chlorobenzene

of 7.1 ml of 4-bromo-2-chlorotoluene was dissolved in 20 ml of chlorobenzene and at 130°With portions was added a mixture of 9.4 g of N-bromo-succinimide and 200 mg dibenzoylperoxide. Boiled for 30 minutes under reflux, after cooling, diluted with 100 ml of CH2Cl2and washed 1 time with 50 ml of a saturated aqueous solution of Na2SO3and 100 ml saturated aqueous solution Panso3. Dried over Na2SO4and the solvents were removed in vacuum.

Received of 11.0 g of pale yellow oil.

Rf(EA/GP 1:8)=0,49. Mass spectrum (DHI): 283(M+H)+.

b) Benzyl-(4-bromo-2-Chlorobenzyl)Amin

765 μl of benzylamine was dissolved in 10 ml of THF (anhydrous), and at 0°C was added 1.0 g of 4-bromo-1-methyl bromide-2-chlorobenzene and stirred 4 h at room temperature. After this was added 100 ml Polynesians aqueous solution PA2CO3and three times was extracted with 100 ml of EA. Dried over gSO4and chromatographically on silica gel with DIP. Got 590 mg of a colorless oil.

Rf(DIP)=0,30. Mass spectrum (DHI): 310 (M+N)+.

in) of Gasoline is-(4-bromo-2-Chlorobenzyl)amide 2-thiophene-2-yl-acetic acid

580 mg of benzyl-(4-bromo-2-Chlorobenzyl)amine was dissolved in 10 ml of CH2Cl2(anhydrous) was added first 300 μl of pyridine, and then 330 mg of the acid chloride of 2-thiophene-2-yl-acetic acid. Was stirred 4 h at room temperature, then diluted with 100 ml of CH2Cl2and washed with 50 ml saturated aqueous solution of Na2CO3. Dried over MgSO4and the solvents were removed in vacuum. Was chromatographically on silica gel with deep and got 490 mg of a colorless oil.

Rf(DIP)=0,56. Mass spectrum (ER): 434 (M+N)+.

g) Tert-butylamide 4’-{[benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-chlorobiphenyl-2-sulfonic acid

480 mg of benzyl-(4-bromo-2-Chlorobenzyl)amide 2-thiophene-2-yl-acetic acid, 426 mg of N-tert-butyl-2-dihydroxybis-2-yl-benzosulfimide (J. Med. Chem. 1997, 40, 547), to 26.2 mg of triphenylphosphine, and 11.2 mg acetate Pd(II) and 133 mg of Na2CO3suspended in 1 ml of water, 0.5 ml of EtOH and 5 ml of toluene and within 2 hours was boiled under reflux. Was cooled, after which the volatile components were removed in vacuum.

The residue was made in 2 ml of CH2Cl2and chromatographically on silica gel with DIP. Received 520 mg of a colorless amorphous solid.

Rf(DIP)=0,20. Mass spectrum (ER): 567 (M+N)+.

e) 4’-{[Benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-chlorobiphenyl-2-sulfonamide

510 mg of tert-butylamide 4'-{[benzyl-(2-type the-2-yl-acetyl) - amino]-methyl)-3’-chlorobiphenyl-2-sulfonic acid and 110 μl of anisole in 3 ml triperoxonane acid was left to stand for 18 h at room temperature. Then volatile components were removed in vacuum, were made in 5 ml of toluene and again volatile components were removed in vacuum. Received 586 mg of colorless oil, which was further used without purification. Rf(DIP)=0,12. Mass spectrum (ER): 511 (M+N)+.

e) 4’-{[Benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-chlorobiphenyl-2-sulfanilamide

586 mg of 4’-{[benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-chlorobiphenyl-2-sulfonamida, 372 mg2CO3and 180 μl of a 5 molar solution of Enrichment in acetonitrile was heated for 1.5 hours under reflux. After cooling, the entire reaction mixture was chromatographically on silica gel with EA/Meon (10:1). Received 181 mg of a colorless amorphous solid.

Rf(EA/Meon 10:1)=0,22. IR-spectrum (CN): 2172,5 cm-1.

Mass spectrum (ER): 536 (M+H)+. The residual activity NCBE at 10 μm: 15%.

The target connection Example 555 was synthesized analogously to Example 554.

Example 555

4’-{[Benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-methylsulfonylmethane-2-sulfanilamide

a) 2-Bromo-5-methyl-benzosulphochloride

40 g of 4-bromthymol while mixing, slowly made at -10°With 250 ml of chlorosulfonic acid. Was stirred for 30 minutes at this temperature, it was allowed to warm to 0°and was poured into an excess of ice. The product was aspirated and washed small to what iCustom water. Dried in vacuum over P4O10and got 63 g of colorless solid, which was immediately used further.

b) 2-Bromo-5-methylbenzenesulfonic acid

of 37.6 g of sodium sulfite was dissolved in 500 ml of water and heated to 70°C. At this temperature portions was added 62 g of 2-bromo-5-methylbenzenesulfonamide. At the same time was added dropwise 10 N. water solution of NaOH so that the pH value of the solution was maintained between pH=9 and pH=10. Was stirred 1.5 h at 70°C, the solution was filtered and then in an ice bath, saturated Hcl solution was brought to pH=0. Was stirred for 30 minutes, then the product was filtered off, washed with a small amount of water and dried. Received of 49.6 g of white crystals, TPL 120-122°C. Mass spectrum (ER): 236 (M+N)+.

a) 2-Bromo-5-methylbenzenesulfonate sodium

of 49.6 g of 2-bromo-5-methylbenzenesulfonic acid was dissolved in 400 ml of methanol was added an equimolar amount of NaOH in 50 ml water. Was stirred 3 hours at room temperature, the solution was filtered and then the solvent was removed in vacuum. At the end of the residual water azeotrope was removed with 50 ml of toluene. The solid residue was dried over P4About10in vacuum and received 54,0 g of the product, TPL 288-290°C (decomposition).

g) 1-Bromo-2-methanesulfonyl-4-methylbenzoyl

of 54.0 g of 2-bromo-5-methylbenzenesulfonate sodium suspended in 300 ml of espagnole DMF, and added 45,7 ml methyliodide. The temperature of the solution rose to 50°C. was Stirred for 3 hours at 50°S, and DMF was removed under vacuum. The residue was stirred with 500 ml of water, stirred for another 1 hour at 0°and was filtered. The product was washed with water, dried and recrystallized from 400 ml of SE/250 ml EA with active charcoal. Got to 27.0 g of colorless crystals, TPL 110-114°C.

Rf(EA/SE 1:4)=0,09. Mass spectrum (DHI): 250 (M+H)+.

d) 1-Bromo-4-methyl bromide-2-methansulfonate

to 9.9 g of 1-bromo-2-methanesulfonyl-4-methylbenzene was made in 100 ml of chlorobenzene, was added 77 mg of benzoyl peroxide, as well as of 7.1 g bromosuccinimide and boiled for 1 hour under reflux. After that, the solvent was removed in vacuo, the residue was made in 100 ml of CH2CL2and washed 2 times with saturated aqueous PA2CO3and 1 time with 50 ml water. Dried over Na2SO4and the solvent was removed in vacuum. The residue was recrystallized from 80 ml SE/30 ml EA and got to 6.9 g of pale yellow solid, TPL 120-124°C.

Rf(EA/GP 1:2)=0,38. Mass spectrum (DHI): 329 (M+N)+.

(e) Benzyl-(4-bromo-2-methylsulfonylbenzoyl)Amin

652 μl of benzylamine was dissolved in 10 ml of THF (anhydrous) and at 0°slowly added 1.0 g of 1-bromo-4-methyl bromide-2-methylsulfonylbenzoyl. Was stirred 4 h at room temperature, then was added 100 ml of n is Semenovo aqueous solution of Na 2CO3and 2 times was extracted with 100 ml of EA. Dried over gSO4and the solvent was removed in vacuum. Chromatography on silica gel with MTB/DIP 1:1 received 510 mg of a colorless oil.

Rf(DIP)=0,10. Mass spectrum (ER): 354 (M+N)+.

W) 4’-{[Benzyl-(2-thiophene-2-yl-acetyl) - amino]-methyl}-3’-methylsulfonylmethane-2-sulfanilamide

Rf(EA/Meon 10:1)=0,21. IR-spectrum (CN): 2175.3 cm-1.

Mass spectrum (ER): 580 (M+N)+.

The residual reactivity NCBE at 10 μm: 31%.

Example 556

4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-chloro-biphenyl-2-sulfanilamide

a) Benzyl-(4-bromo-2-Chlorobenzyl)amide thiophene-2-sulfonic acid

2.0 g benzyl-(4-bromo-2-Chlorobenzyl)amine (Example HB) and 1.0 g of pyridine were dissolved in 20 ml of CH2Cl2and at room temperature was slowly added 1.4 g of the acid chloride thiophene-2-sulfonic acid. Was stirred 4 h at room temperature, then diluted with 200 ml of EA and washed 2 times with 100 ml of 5%aqueous solution of sodium hydrosulphate and also 2 times with 50 ml saturated aqueous solution of sodium carbonate. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with DIP obtained 1.5 g of a colorless oil.

Rf(DIP)=0,21. Mass spectrum (of the Belarusian library Association): 456 (M+N)+.

Further transformation with the formation of the target with the unity carried out analogously to Examples 554 d) (e).

b) 4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-chlorobiphenyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,17. IR-spectrum (CN): 2178,5 cm-1. Mass spectrum (of the Belarusian library Association): 580 (M+Na)+. The residual reactivity NCBE at 10 μm: 0%.

The target connection Example 557 synthesized analogously to Example 556 of the target compound of Example b).

Example 557

4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-methylsulfonylmethane-2-sulfanilamide

Rf(EA/Meon 10:1)=0,28. IR-spectrum (CN): 2175,0 cm-1. Mass spectrum (ER): 602 (M+N)+.

The residual reactivity NCBE at 10 μm: 14%.

Example 558

4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfanilamide

a) 4-Methyl-3-(2-methoxy)ethoxyaniline

22,0 g of 3-hydroxy-4-methylaniline, 24,9 g simple 2-pomatoleios ether and 233 g Cs2CO3was dissolved in 570 ml of DMF and stirred 8 h at 40°C. was Added 3 l of 10%aqueous solution of sodium bicarbonate, 6 times was extracted with 750 ml of EA and washed 2 times in 1 l of 10%aqueous solution of sodium bicarbonate. Was dried over sodium sulfate, and the solvent was removed in vacuum. Got to 32.9 g of a yellow oil, which was used in the next.

Rf(EA/GP 1:1)=0,33.

b) 4-Methyl-3-(2-methoxy)ethoxypropanol

32,8 g of 4-methyl-3-(2-methods the si)ethoxyaniline suspended in 660 ml Polynesians aqueous solution NVG and at 0°C was slowly added dropwise 12.5 g NaNO 3in 25 ml of water.

Was stirred for 30 minutes at 0°and then the resulting solution was slowly added to the heated to 50°With the solution by 51.9 g of CuBr in 490 ml of a saturated aqueous solution NVG. The reaction mixture was then slowly, over 6 hours, heated from 50°C to 70°C. After subsequent cooling was extracted 4 times with 500 ml of diethyl ether, washed with 500 ml of an aqueous solution of NaCl and dried over sodium sulfate. Chromatography on silica gel with EA/GP 1:8 obtained by 15.4 g of a colorless oil.

rf(EA/GP 1:1)=0,41. Mass spectrum (DHI): 245 (M+H)+.

C) 4-methyl bromide-3-(2-methoxy)ethoxypropanol

of 15.3 g of 4-methyl-3-(2-methoxy)ethoxypropanol was dissolved in 300 ml of chlorobenzene was added in portions with stirring, a mixture of 11.1 g of N-bromosuccinimide and 125 mg of benzoyl peroxide. Boiled water for 24 h under reflux, the solvent was removed in vacuum and then combined with 500 ml of CH2Cl2. Washed first with 200 ml of a saturated aqueous solution of Na2SO4and then 100 ml of a saturated aqueous solution of sodium carbonate. Was dried over sodium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with EA/SE 1:15 obtained 12.8 g of pale yellow oil.

Rf(EA/SE 1:4)=0,42. Mass spectrum (DHI): 323 (M+N)+.

g) Benzyl-[4-bromo-2-(2-methoxy)ethoxybenzyl)Amin

2.4 ml of benzylamine was dissolved in 20 ml of THF (anhydrous) and at 0°With antenna was added 3.2 g of 4-methyl bromide-3-(2-methoxy)ethoxypropanol. Was stirred 19 hours at room temperature, then diluted with 200 ml of EA and washed with 100 ml saturated aqueous solution of sodium carbonate. Was dried over magnesium sulfate and removed under vacuum of the solvent. Chromatography on silica gel with MTB obtained 1.3 g of colorless oil.

Rf(MTB)=0,20. Mass spectrum (DHI): 350 (M+N)+.

d) Benzyl-[4-bromo-2-(2-methoxy)ethoxybenzyl]amide thiophene-2-sulfonic acid

1.2 g benzyl-[4-bromo-2-(2-methoxy)ethoxybenzyl)amine, 713 mg of the acid chloride thiophene-2-sulfonic acid and 430 μl of pyridine were dissolved in 50 ml of CH2CL2and stirred 17 h at room temperature. Then was diluted with 100 ml of CH2Cl2and washed first with 2 times 50 ml of 5%aqueous sodium hydrogen carbonate solution and then with 50 ml of a saturated aqueous solution of sodium carbonate. Dried magnesium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with deep received 900 mg of a colorless oil.

Rf(DIP)=0,2. Mass spectrum (ER): 496 (M+N)+.

e) Dihydroxybis-2-yl-benzosulfimide

50 g of N-tert-butyl-2-dihydroxybis-2-yl-benzosulfimide (J. Med. Chem. 1997, 40, 547) and 23.3 g of anisole was dissolved in 500 ml triperoxonane acid and was stirred for 2 days at room temperature. Volatile components were removed in vacuo, poured into 100 ml of water and then volatile components were removed in vacuum. Finally, it was made in 10 ml of toluene and again volatile components were removed in vacuum. Got 56 g of colorless oil which was used without further purification.

Rf(MTB)≈0,4.

g) Dimethylaminomethylene dihydroxybis-2-yl-benzosulfimide acid

20 g dihydroxybis-2-yl-benzosulfimide and 66 ml of dimethylacetal of dimethylformamide was dissolved in 200 ml of DMF (anhydrous) and was kept for 18 h at room temperature. The reaction mixture was poured into 1.5 liters of water and 4 times was extracted with 500 ml of EA. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Crystallization from 100 ml of EA obtained with 5.2 g of colorless crystals, TPL 175°C (with decomposition).

Rf(EA)=0,25.

C) Dimethylaminomethylene {[benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(methoxy)ethoxymethyl-2-sulfonic acid

900 mg of benzyl-[4-bromo-2-(2-methoxy)ethoxybenzyl]amide thiophene-2-sulfonic acid, 1.4 g of dimethylaminomethylene dihydroxybis-2-yl-benzosulfimide acid, 47 mg of triphenylphosphine, 20 mg acetate Pd(II) and 575 mg of Na2CO3suspended in 30 ml of toluene, 5 ml of water and 5 ml of EtOH.

Boiled for 6 hours under reflux, then cooled and diluted with 100 ml of EA. Washed 2 times with 50 ml saturated aqueous NaCl. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with MTB received 560 mg of a colorless viscous oil.

Rf(MTB)=0,13. Mass spectrum (ER):628 (M+N) +.

and) {[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfonamide

550 mg of dimethylaminomethylene {[benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy) ethoxymethyl-2-sulfonic acid in 5 ml of EtOH and 5 ml of a saturated aqueous solution of Hcl was heated 1 h under reflux. Added 100 ml of 10%aqueous sodium hydrogen carbonate solution and 3 times was extracted with 100 ml of EA. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with MTB/DIP 1:1 received 188 mg of a colorless oil.

Rf(MTB/DIP 1:1)=0,33. Mass spectrum (ER): 573 (M+N)+.

K) 4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfanilamide

180 mg of {[benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfonamida, 63 μl of a 5 molar solution of Enrichment in acetonitrile, and 131 mg2CO3suspended in 3 ml of acetonitrile (anhydrous) and boiled for 2 hours under reflux. Leave to cool and was chromatographically the entire reaction mixture on silica gel with EA/Meon 10:1 and received 149 mg of an amorphous solid.

Rf(EA/Meon 10:1)=0,13. IR-spectrum (CN): 2175,3 cm-1.

Mass spectrum (of the Belarusian library Association): 598 (M+N)+.

The residual activity NCBE at 10 μm: 30%.

Example 559

4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxylate the Il-2-sulfanilamide

a) 4-Fluoro-1-(2-methoxyethoxy)-2-methylbenzo

10 g of 4-fluoro-2-METHYLPHENOL, 7.5 ml of 1-bromo-2-methoxyethane, and 22 g2CO3suspended in 200 ml of DMF (anhydrous) and stirred for 12 h at 120°C. Leave to cool and the solvent was removed in vacuum. Was mixed with 400 ml of MTB and washed 3 times with 200 ml of 10%aqueous NaOH solution, and 1 time with 100 ml saturated aqueous NaCl. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Received 10.4 g of pale yellow oil.

Rf(EA/SE)=0,39. Mass spectrum (DHI): 185 (M+N)+.

b) 2-methyl bromide-4-fluoro-1-(2-methoxyethoxy)-benzene

10.4 g of 4-fluoro-1-(2-methoxyethoxy)-2-methylbenzene was dissolved in 100 ml of chlorobenzene and the boiling temperature of the portions was added to a mixture of 10.1 g of N-bromosuccinimide and 200 mg of benzoyl peroxide. Boiled for 30 minutes under reflux. Cooled and diluted with 300 ml of EA. Then washed first with 1 in every 100 ml of a saturated aqueous solution of PA2CO3then 2 times 100 ml of a saturated aqueous solution of sodium carbonate. Was dried over magnesium sulfate, and the solvent was removed in vacuum. Chromatography on silica gel with EA/SE 1:4 received of 5.2 g of a colorless oil.

Rf(EA/SE 1:4)=0,20. Mass spectrum (DHI): 262 (M+H)+.

b) 1-Bromo-4-methyl bromide-2-methansulfonate

to 9.9 g of 1-bromo-2-methanesulfonyl-4-methylbenzoyl NR is a force for stability in 100 ml of chlorobenzene, added 77 mg of benzoyl peroxide, as well as of 7.1 g of N-bromosuccinimide and boiled for 1 hour under reflux. Then the solvent was removed in vacuo, the residue was made in 100 ml of CH2CL2and washed 2 times with 50 ml of a saturated aqueous solution of Na2CO3and 1 time with 50 ml water. Dried over Na2SO4, and the solvent was removed in vacuum. The residue was recrystallized from 80 ml SE/30 ml EA and got to 6.9 g of pale yellow solid, TPL 120-124°C.

Rf(EA/GP 1:2)=0,38. Mass spectrum (DHI): 329 (M+N)+.

a) 2-(4-Bromo-2-methanesulfonylaminoethyl)-isoindole-1,3-dione

3.0 g of 4-bromo-1-methyl bromide-2-methysulfonylmethane and 2.0 g of phthalimide potassium was stirred in 30 ml of anhydrous DMF for 1 h at 100°C. was Cooled, diluted with 200 ml of water and stirred suspension for 30 minutes at room temperature. The product was filtered and obtained 1.8 g of colorless solid, TPL 188-190°C. Mass spectrum (ER): 393 (M+N)+.

d) 4-Bromo-2-methanesulfonanilide

1.8 g of 2-(4-bromo-2-methanesulfonylaminoethyl)-isoindole-1,3-dione and 1.5 ml of hydrazine hydrate is added in 30 ml of EtOH was first stirred at 60°1 h and then boiled for 4 h under reflux. Was cooled, the precipitate was filtered, and volatile components of the filtrate was removed in vacuum. The residue was placed in 100 ml of CH2CL2and again filtered, the solid components. The solvent delete the Lee of the filtrate in vacuo and obtained 1.3 g of pale yellow oil.

rf(EA/Meon 10:1)=0,10. Mass spectrum (DHI): 264 (M+N)+.

d) (4-Bromo-2-methanesulfonylaminoethyl)-[5-fluoro-2-(2-methoxyethoxy)-benzyl]-amine

1.3 g of 4-bromo-2-methanesulfonanilide and 1.4 ml of triethylamine were dissolved in 20 ml of THF (anhydrous) and at 0°C was added dropwise a solution of 1.3 g of 2-methyl bromide-4-fluoro-1-(2-methoxyethoxy)-benzene in 5 ml of THF (anhydrous). Was stirred for 60 h at room temperature, then diluted with 200 ml of EA and 2 times washed with 100 ml saturated aqueous solution of PA2CO3. Dried over gSO4and the solvent was removed in vacuum. Chromatography on silica gel with EA received 910 mg of a colorless oil.

Rf(EA)=0,43. Mass spectrum (ER): 446 (M+N)+.

Further transformations were produced analogously to Examples 558 e)-K)

e) 4’-{[Benzyl-(thiophene-2-sulfonyl)amino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,33. IR-spectrum (CN): 2174,3 cm-1.

Mass spectrum (ER): 694 (M+N)+.

The residual activity NCBE at 10 μm: 12%.

The target connection Example 560 synthesized analogously to Example 558.

Example 560

4’-{[Benzyl-2-(thiophene-2-yl)acetylamino]-methyl}-3’-(2-methoxy)ethoxymethyl-2-sulfanilamide

Rf(EA/Meon 5:1)=0,36. IR-spectrum (CN): 2175,0 cm-1.

Mass spectrum (ER): 579 (M+N)+.

TPL 95°C (decomposition). Residual is I activity NCBE at 10 μm: 8,0%.

Example 561

4’-{[Benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfanilamide

a) (dimethylamino)MachineName 4’-(benzylamino)-biphenyl-2-sulfonic acid

4,4 ml of benzylamine was dissolved in 90 ml of THF (anhydrous) and at 0°portions were added 7.6 g of 4’-(methyl bromide)-N-[(dimethylamino)methylene]-(1,1'-biphenyl)-2-sulfonamida (J. Med. Chem. 1995, 38, 2357). Was stirred 24 h at room temperature, then diluted with 500 ml of EA and 2 times washed with 200 ml saturated aqueous solution of Na2CO3. Dried over Na2SO4, and the solvent was removed in vacuum. Chromatography on silica gel with EA/Meon 10:1 is obtained 3.8 g of colorless oil.

Rf(EA/Meon 10:1)=0.25 in. Mass spectrum (of the Belarusian library Association): 408 (M+N)+.

b) o-Tolylacetylene

4.8 g of o-tolyl-acetic acid was dissolved in 36 ml of SOCl2and boiled for 12 hours under reflux. Volatile components were then removed in vacuo, and the residue after this 3 times was made in 50 ml of toluene and volatile components were removed in vacuum. Obtained 6.6 g of pale yellow liquid, which was used without further purification.

in) (dimethylamino)MachineName 4’-{[benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfonic acid

408 mg (dimethylamino)methylamide 4’-(benzylamino)-biphenyl-2-sulfonic acid was dissolved in 9 ml of CH2Cl2(bezvodno is) and at room temperature was added first 162 μl of pyridine, then 220 mg on-tolylacetylene. Was stirred 24 h at room temperature, diluted with 100 ml of CH2Cl2and 3 times washed with 50 ml saturated aqueous solution of PA2CO3. Dried over Na2SO4, and the solvent was removed in vacuum. Chromatography on silica gel with EA/GP 2:1 obtained 330 mg of a colorless oil.

Rf(EA/GP 2:1)=0,52. Mass spectrum (of the Belarusian library Association): 540 (M+N)+.

g) 4’-{[Benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfonamide

320 mg (dimethylamino)methylamide 4’-{[benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfonic acid was dissolved in 6 ml Meon and at room temperature was added 3 ml of a saturated aqueous solution of Hcl. Boiled for 8 hours under reflux and, after cooling, was established with the help of 6 N. aqueous NaOH solution of pH=5-6. Was diluted with 70 ml of water and 3 times were extracted with 70 ml EA. Dried over Na2SO4, and the solvent was removed in vacuum. Received 300 mg of colorless oil.

Rf(EA)=0,68. Mass spectrum (ER): 485 (M+N)+.

e) 4’-{[Benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfanilamide

280 mg of 4’-{[benzyl-2-(2-were)acetylamino]-methyl}-biphenyl-2-sulfonamida and 245 mg2CO3was dissolved in 6 ml of acetonitrile (anhydrous) and at room temperature was injected by syringe 116 μl of 5 n Enrichment solution in acetonitrile. Boil 2 h with inverse x is Hladilnika and after cooling, the entire reaction mixture was chromatographically on silica gel with EA/Meon 10:1. Received 130 mg of colorless solid, TPL 108°C (decomposition).

Rf(EA/Meon 10:1)=0,27. IR-spectrum (CN): 2177,0 cm-1.

Mass spectrum (of the Belarusian library Association): 532 (M+Na)+.

The residual activity NCBE at 10 μm: 16%.

The target compounds of Examples from 562 in 568 synthesized analogously to Example 561.

Example 562

4’-{[Benzyl-2-(2-triptoreline)acetylamino]-methyl}-biphenyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,30. IR-spectrum (CN): 2178,0 cm-1.

Mass spectrum (of the Belarusian library Association): 586 (M+PA)+.

TPL 90°C (decomposition). The residual activity NCBE at 10 μm: 33%.

Example 563

4’-{[Benzyl-2-(2-trifloromethyl)acetylamino]-methyl}-biphenyl-2-sulfanilamide

rf(EA/Meon 10:1)=0,26. IR-spectrum (CN): 2177,0 cm-1.

Mass spectrum (ER): 580 (M+N)+.

TPL 125°C (decomposition). The residual activity NCBE at 10 μm: 46%.

Example 564

4’-{[Benzyl-2-(2-trifloromethyl)acetylamino]methyl}-biphenyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,27. IR-spectrum (CN): 2176,0 cm-1.

Mass spectrum (ER): 596 (M+N)+.

TPL 122°C (decomposition). The residual activity NCBE at 10 μm: 23%.

Example 565

4’-{[Benzyl-2-methylbenzylamino]-methyl}-biphenyl-2-sulfanilamide

<> Rf(EA/Meon 10:1)=0,22. IR-spectrum (CN): 2174,0 cm-1

Mass spectrum (ER): 496 (M+N)+.

TPL 173°C (decomposition). The residual activity NCBE at 10 μm: 42%.

Example 566

4’-{[Benzyl-2-triphtalocyaninine]-methyl}-biphenyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,20. IR-spectrum (CN): 2176,0 cm-1.

Mass spectrum (ER): 550 (M+N)+.

TPL 165°C (decomposition). The residual activity NCBE at 10 μm: 72%.

Example 567

4’-{[Benzyl-2-triphtalocyaninine]-methyl}-biphenyl-2-sulfanilamide

rf(EA/Meon 10:1)=0,22. IR-spectrum (CN): 2176,0 cm-1.

Mass spectrum (ER): 566 (M+H)+.

TPL 160°C (decomposition). The residual activity NCBE at

10 micron: 69%.

Example 568

4’-{[Benzyl-(5-methylthiophene-2-yl)carbylamine]-methyl}-biphenyl-2-sulfanilamide

Rf(EA/Meon 10:1)=0,16. IR-spectrum (CN): 2175,0 cm-1.

Mass spectrum (of the Belarusian library Association): 524 (M+Na)+.

TPL 166°C (decomposition). The residual activity NCBE at 10 μm: 70%.

Pharmacological data

Inhibition of PA+-dependent CL-/FNL

-
2
-exchange (NCBE) in the endothelial cells of the person

Endothelially the human cells (ECV-304) from the culture vessel was dissolved with buffer trypsin/ethylenediaminetetraacetic acid (to 0.05/0.02% in phosphate buffer) and after centrifugation (100 g, 5 min) were placed in buffered saline solution (mmol/l): 115 NaCl, 20 NH4Cl, 5 KCl, 1 CaCl2, 1 MgSO4, 20 N- (2-hydroxyethyl) piperazine-N'-2-econsultancy acid (HEPES), 5 glucose and 1 g/l of albumin in the blood serum of cattle; pH 7.4). This cell suspension was incubated with 5 μm acetoxymethyl ether BCAFC 20 min at 37°C. the cells are Then washed and resuspendable in a buffer solution containing no sodium bicarbonate (mmol/l: 5 HEPES, 133,8 of choline chloride, a 4.7 KCl, 1.25 Or MgCl2, 0,97 K2HPO4, 0,23 KH2PO4, 5 glucose; pH 7.4).

For subsequent measurement of fluorescence in FLIPR (Fluorescent Imaging Plate Reader) into each well of 96-well microplate was placed in a pipette 100 ál of this cell suspension with 20,000 cells in each portion and centrifuged the microplate (100 g, 5 min). In FLIPR was collected from the next, the prepared microplate, 100 μl of buffer solution and was introduced by pipette into each of the 96 wells. For 100%control, the recovery of intracellular pH (pHi) beyond the NCBE, used buffer solution containing bicarbonate and sodium (mmol/l: 5 HEPES, 93,8 NaCl, 40 Panso3that 4.7 KCl, 1.25 Or CaCl2, 1,25 MgCl2, 0,97 Na2HPO4, 0,23 NaH2PO4, 5 glucose; pH 7.4), which contained 50 μm NOAH 642. For 0%of the control, i.e. the lack of recovery of pHi was added to the buffer solution without the soda is containing bicarbonate and sodium-containing (mmol/l: 5 HEPES, 133,8 NaCl, A 4.7 KCl, 1.25 Or CaCl2, 1,25 MgCl2, 0,97 Na2HPO4, 0,23 NaH2PO4, 5 glucose; pH 7.4), to which was added 50 μm NOAH 642. Proposed according to the invention compounds were added in various concentrations to a solution containing sodium and bicarbonate. After addition of buffer solutions in the microplate painted acidified the cells was determined by the increase in fluorescence intensity, which corresponded to the increase in pHi in each microplate. Measurements were made every 2 minutes at 35°C.

The increase in fluorescence intensity for different concentrations of the compounds according to the invention was correlated with both control experiments, and thus established inhibitory activity of the substances.

1. Biphenylenediisocyanate formula I

where the substituents have the following meanings:

R(1)

1. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

4. -CnH2n-nn-Y

nn is zero or 2, and

n is zero, 1, 2, 3, or 4; and n is not zero

or 1 if nn is equal to 2;

5. CnH2n-nn-Y

nn is zero or 2, and

n - 1, 2, 3, or 4; and n is 1 if nn

equal to 2;

and 1 hydrogen atom in the divalent residue CnH2n-nnsubstituted amino group, or NR(22)R(23),

R(2)

2. alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms;

4. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12

C-atoms;

5. quinil with 2, 3, 4, 5, 6, 7 or 8 C-atoms;

6. -CnH2n-nn-Z

nn is zero or 2, and

n is zero, 1, 2, 3, or 4; and n is not zero

or 1 if nn is equal to 2;

7. -CnH2n-nn-Z

nn is zero or 2, and

n - 1, 2, 3, or 4; and n is 1 if nn

equal to 2;

and 1 hydrogen atom in the divalent residue CnH2n-nnreplaced remaining from a number of

1. phenyl,

3. NR(22)R(23),

5. COOR(16);

R(3) and R(4) hydrogen

R(5) denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, SO2is alkyl with 1, 2, 3 or 4 C-atoms, F, Cl, Br, J, OR(10),

R(6) R(7) independently of one another denote hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, J, OR(10), where

R(10) is hydrogen, alkyl with 1, 2, 3 or 4 C-atoms

optionally substituted by methoxy or ethoxypropane,

R(9) mean OR(13),

R(13) is hydrogen or alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms,

X is carbonyl, -CO-CO - or sulfonyl,

Y and Z independently of each other means

1. phenyl, 1-naphthyl, 2-naphthyl,

2. one of the residues defined in claim 1, substituted 1, 2, 3, 4, 5 identical or different residues from the series of phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9); or two residue form methylenedioxy is the UPP,

3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophene, dihydroquinazolines,

5. cycloalkyl with 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, indanyl,

6. one of the residues defined in claim 5, substituted by phenyl;

R(16) means 1. hydrogen

2. alkyl with 1, 2, 3, 4 C-atoms;

3. alkyl with 1, 2, 3, 4 C-atoms, substituted (C1-C4-alkoxygroup,

R(19) R(20) independently mean

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

R(22) R(23) denote independently from each other

hydrogen or CO-OR(24);

R(24) means-CnH2nis phenyl with n equal to 1, 2, 3, 4,

q means 2,

and their physiologically acceptable salts.

2. The compounds of formula I according to claim 1, which are compounds of formula Ia

where the remains of X and R(1) R(7) have specified in claim 1 values, as well as their physiologically acceptable salts.

3. The compounds of formula I according to claim 1 or 2, where the substituents mean

R(1)

CH3-CH2-CH2-, cyclohexyl-CH2-CH2-, cyclohexyl-, 3-methoxy-phenyl-CH2-2-were-CH2-, 2-were 2-thienyl-CH2-, 4-trebuil-phenyl, 2-fluoro-phenyl, 3,4,5-trimethoxyphenyl-, 2-chlorophenyl, phenyl, CH3-, CH3-(CH2)3-, phenyl-CH2-CH2-, 4-IU the Il-phenyl-, benzo[b]thiophene-2-yl, Tien-2-yl - (phenyl)-CH2-, (4-chlorophenyl)-CH2-, (CH3)3C-CH2-, (4-methoxy-phenyl)-CH2-2-thienyl-CH2-CH2-CH2-, (2-thienyl) - (indol-3-yl)-CH2-, (3-thienyl)-CH2-, phenyl-CH(NH2)-, (2-nitrophenyl)-CH2-, phenyl-(CH2)4-, (2-furyl)-, cyclohexyl-CH2-CH2-, (2-bromophenyl)-CH2-, (4-hydroxyphenyl)-CH2-, 2-methoxy-phenyl-, cyclohexyl-CH2-, 4-forfinal-, phenyl-CH2-cyclopentyl-CH2-, 4-were-, 3,4-acid-, 2,5-dimethoxy-phenyl-, 2,3,4,5,6-pentamethylbenzyl-, 3-fluoro-2,4-dimethyl-phenyl-, 4-fluoro-3, 5dimethylphenyl-, 2,4,5-trichlorophenyl-, 4-Trebujeni-, 2,3-dichlorophenyl-, (3-thienyl)-CH-(CH3)-, (2-thienyl)-CH-(CH3)-, 4-chlorophenyl-, 4-trifluoromethyl-phenyl-, 4-methoxyphenyl, 2-chlorophenyl-, 2-forfinal-, (2-thienyl)-(CH2)4-, phenyl-(CH2)4-, (2-thienyl)-CH2-CH2-, (2-chlorophenyl)-CH2-, 3,4-dichlorophenyl-, 2,4-dichlorophenyl-, 2,5-dichlorophenyl-, 2,4-differenl-, (2-forfinal)-CH2-, (2-furyl)-CH2-, 2-chlorophenyl-, 2-chloro-6-were-, (2-thienyl)-CH2-, (3-thienyl)-CH2-3-triptoreline-, 2-triptoreline-, 5-methyl-2-thienyl-, 2-triptoreline-CH22-naphthyl-, 4-fluoro-3, 5dimethylphenyl-, (5-methyl-2-thienyl)-CH-(CH3)-;

R(2)

benzyl, 4-methoxy-benzyl, 4-chloro-benzyl, phenyl, cyclohexyl, 2-methoxy-benzyl, 2-chloro-benzyl, isobut is l, 1(S)-phenylethyl, 4-methyl-benzyl, 3-methoxy-benzyl, 3,4-methylenedioxy-benzyl, 1(R)-phenyl-ethyl, 4-trifluoromethyl-benzyl, 2-(4-methoxy-phenyl)-ethyl, 1(S)-(4-were)-ethyl, 2-furylmethyl, 1(R)-(4-were)-ethyl, 4-(dimethylamino)-benzyl, 2-(2-thienyl)-ethyl, 2,3-dichlorobenzyl, cyclopropylmethyl, 3,4,5-trimetoksi-benzyl, (4-pyridyl)-methyl, 4-fluoro-benzyl, 2,4-dimethoxy-benzyl, 3-phenyl-propyl, 2-methoxy-ethyl, methyl, ethyl, (2-pyridyl)-methyl, cyclopropyl, (2-benzimidazolyl)-methyl, 1-methoxy-carbonyl-2-phenyl-ethyl, propargyl, (2-thienyl)-methyl, cyclohexyl-methyl, 3, 4-dichloro-benzyl, phenyl-CH(COO-CH3), 2,4-dichloro-benzyl, (1-naphthyl)-methyl, 3-Chlorobenzyl, 2,3-dichlorobenzyl, 3-methylbenzyl, 2-methylbenzyl, (CH3)2C=CH-CH2-CH2-C(CH3)=CH-CH2, 1 indanyl, 2-fluoro-benzyl, 3-tormentil, 2,4-differenl, 4-trebutien, 2,6-dichlorophenyl, 3-chloro-4-forfinal, 4-chloro-2,5-acid, 2-cyano-phenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 4-forfinal, 2,3-dichlorophenyl, 3-triptoreline, 2-chloro-4-cyano-phenyl, (1-phenyl-cyclopentyl)-methyl, 4-chlorophenyl, 4-triptoreline, 2.5-differenl, 4-isopropylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 5-chloro-2-methoxy-phenyl, 2-forfinal, 1-naphthyl, 2-triptoreline, 2-ethylphenyl, 2,4-dimetilfenil, 2,4,5-trimetilfenil, 2,5-dimetilfenil, 3-chloro-2-were, 4-chloro-2-were 3-triptoreline, 2,6-dimetilfenil, 2,3-dimetilfenil, 4-ethoxyphenyl, 3,5-dichlorophenyl, 3,4-dichlo is phenyl, 3,4-dimethoxy-phenyl, 4-bromophenyl, 2-chlorophenyl, 2-were, 2-methoxyphenyl, 2,6-diethylphenyl, 2,6-aminobutiramida-phenyl, 2-biphenylyl, 2-naphthyl, 4-were, 2,4-dimethoxy-phenyl, 2,5-dimetilfenil, 2-chloro-4-methoxy-phenyl, 2-methoxy-5-were, 3-methoxy-4-were, 2-methoxy-phenyl, 3-hydroxyphenyl, 2-chloro-5-trifluoromethyl-phenyl, 4-ethylphenyl, 2,5-dichlorophenyl, 2-chlorophenyl, 2-methyl-1-naphthyl-, isopropyl, 3-nitrobenzyl, 2-ethoxy-benzyl, 2,2,2-triptorelin, 2-(3-triptoreline )ethyl, 1-indanyl, 2-phenyl-ethyl, (2-naphthyl)-methyl, 2-phenylethyl, phenyl-CH(COOH)-, 3-phenyl-benzyl, 5-chloro-2-were-, 2-forfinal, 1-naphthyl,

R(3) hydrogen

R(4) hydrogen

R(5) hydrogen, chlorine, -SO2CH3, (2-methoxy)ethoxy-;

R(6) hydrogen

R(7) is hydrogen, methyl, chlorine;

X-CO-, -CO-CO-, -SO2-;

and their physiologically acceptable salts.

4. Compounds according to any one of claims 1 to 3, inhibiting the sodium-dependent chloride/bicarbonate exchange ″NCBE″.



 

Same patents:

The invention relates to new N-sulfonylpiperidinylmethylene derivative of the formula I

< / BR>
where n = 1; R1means1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, C1-C6haloalkyl or a group NR11R12where R11and R12each independently from one another mean H, C1-C6alkyl; R2means N; R3means1-C6alkyl; R4, R5, R6and R7have the same or different values and each independently from one another mean H, C1-C4alkyl; R8means C1-C6alkyl; a represents C1-C6alkylen; means phenyl, optionally substituted by 1-3 substituents, which may be the same or different and selected from the group comprising C1-C8alkyl, C1-C8haloalkyl,1-C8alkoxy, C1-C8haloalkoxy, C2-C8alkanoyl, halogen, C1-C8alkoxycarbonyl, nitro; or naphthyl or thienyl

The invention relates to carboxylic acid derivative with condensed rings of the General formula (A), and its pharmaceutically acceptable salts, intending to obtain drugs that are effective agonists of the retinoic acid receptors

The invention relates to substituted guanidines thiophenemethylamine acid of the formula I

< / BR>
where mean:

at least one of the substituents R(1), R(2) and R(3)

- Op-(CH2)s-CqF2q+1, R(40)CO - or R(31)SOk-;

p is zero or 1;

s is zero, 1, 2, 3 or 4;

q 1,2, 3,4, 5, 6, 7 or 8;

k is zero, 1 or 2;

R(40) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms,

cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy;

R(31) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

or

R(31) NR(41)R(42);

R(41)and R(42)

independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

perfluoroalkyl with 1, 2, 3 or 4 C-atoms,

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

and sootwetstwii-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3, 4, 5, 6, 7 or 8;

ga zero or 1;

ha zero, 1, 2, 3 or 4;

R(10) cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy;

R(4) and R(5)

independently from each other hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6,

7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);

R(14)R(15)

independently from each other H, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms

and their pharmaceutically tolerable salts

The invention relates to new derivatives of tamilcanadian with the General formula (I) wherein R' represents 2-thienyl or 3-thienyl radical, R represents ceanorhaditis or a radical of the formula-C(O) - and R2 is optional saturated or unsaturated cyclic hydrocarbon radical or aryl radical

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

The invention relates to novel ortho-substituted arylbenzothiazoles formula (I), where R1denotes A, CF3, Gal; R2and R3each independently of one another denote H, Gal A, SOn-R6, -SO2NR4R5, Ph; R4denotes H, A, CF3, Ph; R5denotes H or A; R6means; And means alkyl with 1-6 C-atoms; Ph denotes unsubstituted or one-, two - or three-fold substituted with A, F, Cl, Br, J or CF3phenyl; n is 1 or 2; Gal denotes fluorine, chlorine, bromine or iodine, and their physiologically acceptable salts, which have a good cardiostim action and is therefore particularly suitable for the treatment of myocardial infarction, prophylaxis heart attack and to treat angina

The invention relates to benzosulfimide compounds of General formula I, where R1represents a hydrogen atom, halogen, such as chlorine or fluorine, or a linear or branched C1-4alkyl or C1-4CNS group, R2, R3and R4represent, independently from each other, hydrogen atoms or a linear, branched or cyclic C1-4alkyl group, and R5represents a hydrogen atom or a C1-2the alkyl group in the form of enantiomers or diastereoisomers or mixtures of these various forms, including racemic mixtures, as well as their salts obtained by joining pharmaceutically acceptable acid

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: invention proposes applying false flax plant oil as a hypoglycemic agent and agent that exerts the normalizing effect on lipid fraction of alpha-lipoproteins (high density lipoproteins; HDLP) and used in treatment of cardiovascular and endocrine diseases, and a method for it applying. This agent is known early as an antioxidant and a hypolipidemic preparation. Detection of new properties allows expanding application of this agent in clinics for treatment of patients with heart ischemic disease, stenocardia, hypertension and diabetes mellitus. The preparation reduces risk for development of atherosclerosis and allows significant reducing doses of basic drugs.

EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; R2 and R3 mean independently of one another F, Cl, Br, J, CO-R(6) or O-R(7); R(6) means hydrogen atom; R(7) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R4 means S(O)p-R(16); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also. Also, invention relates to pharmaceutical composition used for inhibition of cellular Na+-dependent bicarbonate/chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; or R2 and R3 mean independently of one another CO-R(6), O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17) wherein R(17) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(6) means hydrogen atom; R4 and R5 mean independently of one another hydrogen atom, F, Cl, Br, J, S(O)p-R(16) or O-(alkylene with 2, 3 or 4 carbon atoms)-OR(33); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(33) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also under condition that at least one of residues R2 or R3 means O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17). Also, invention relates to pharmaceutical composition used for inhibition of Na+-dependent bicarbonate-chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 ex

FIELD: medicine, pharmacology, pharmacy, medicinal biochemistry.

SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.

EFFECT: valuable medicinal properties of composition.

71 cl, 2 tbl, 3 ex

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