CZ20002808A3 - Biphenylsulfonylcyanamides and pharmaceutical preparation in which they are comprised - Google Patents

Abstract

Biphenylsulfonylcyanamides of the formula I in which they are present individual general symbols meanings defined in the description, a physiologically acceptable salts thereof. These compounds exhibit “Excellent antiarrhythmic properties with cardioprotective component. . These compounds can prevent or strongly inhibit to reduce pathophysiological processes in ischemic formation induced disorders, especially at ischemic origin induced cardiac arrhythmias. In addition, they show strong inhibitory effect on cell proliferation. A pharmaceutical is disclosed compositions comprising the same.

Description

Biphenylsulfonylcyanamides and pharmaceutical compositions containing them

Technical field

The invention relates to biphenylsulfonyl cyanamides, _(to processes for their preparation, to pharmaceutical compositions containing them, and to their use as medicaments.

BACKGROUND OF THE INVENTION, u

EP-A 855392 discloses imidazole derivatives with a biphenylsulfonyl cyanamide side chain as Na ⁺ -dependent inhibitors ^; bicarbonate / chloride exchange system (NCBE).

. 3> 3Y

In European patent application {9811752, biphenylsulfonylcyanamides are proposed as NCBE inhibitors which differ from the compounds of formula I according to the invention described below by substitution on the biphenyl cyclic system.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula I wherein:

R ¹ represents

1. alkyl carbon;

2. alkyl

group with 1, 2, 3, 4, 5, 6, group with 1, 2, 3, 4,. 5, 6, (I) or 8 atoms or 8 / atoms

carbon in which one to all hydrogen atoms are replaced by fluorine atoms,

3. an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, or 12 carbon atoms,

4 ,. -C _n H _2n _ _nn -Y ,. where nn is 0 or 2, and.

N is 0, 1, 2, -3 or. 4, wherein n is not 0 or 1 if nn is 2, or

5. a group wherein nn is 0. or 2, and.

n has a value. 1, 2, 3 or 4, where n is not of value if. nn. has a value of 2 in which 1, 2 or 3 hydrogen atoms are bivalent.

the rest. _H2n _ _nn - independently replaced by a moiety selected from the group consisting of ¹

1. aryl groups having 6, 7, 8, 9, 10, 11, 12, 13. . or 1,4-carbon atoms, preferably phenyl, 1-naphthyl. or a 2-naphthyl group;

2. amino,

Group 3 NR ²² R ²³ , - <·

4. - alkoxycarbonyl groups,

5. COOR ¹⁶ ,. • · · -, 6. alkyl groups having 1, 2, 3 or 4 atoms i. and (7) arylalkylcarbonyl having 6 to 14 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl portion, preferably a phenylacetyl group,

R ² . .. means - <^;

1. a hydrogen atom;

2 1 2 3 4 5 6, 7 or, 8 atpmy carbon, 3 1 2 3 4 5 6, '7 or 8- atoms of the carbon in which they are one to all- atoms hydrogen replaced by fluorine atoms, 4. an alkenyl group se 2, 3, 4, 5 6, 7, 8, 9, 10,

- .3 or 12 carbon atoms,

5. alkynyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

6. The group ~ C _n H _2n _ _nn -Z, where nn is 0 or 2, and _n is. 0, 1, 2, 3, or 4, wherein n is not 0 or: 1 if nn is 2, or 7 is -CK ₂ . ",, - Z, where. . ηή is 0 or '2', and · '. n has a value of 1, 2, 3 or 4, where n has no value if nn has a value of 2,. wherein they are 1, 2 or 3. hydrogen atoms in the bivalent radical ^- C _n H _2n _ _rin -. independently replaced by a residue selected from the group consisting of

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

2. amino,

3. groups NR ²² R ²³ ,

4. alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkoxy moiety; · ^{; ;} 5. · 'groups. COOR ^1S , and: 6. alkyl groups having 1, 2, 3 or 4 carbon atoms, R ³ and R ⁴ independently represent, in each case, a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 6, 7 nebo.8 carbon atoms, R ^5. R ⁶ and R ⁷ independently of one another represent a hydrogen atom or an alkyl group having 1, 2, 3, 4, 4, 4, 4, and 4, respectively. 5, 6, 7 or 8 carbon atoms, fluorine, chlorine, bromine or iodine, trifluoromethyl, cyano, nitro; ^_SO:.-R, CO-R ²¹ or OR ^10, ...

R ⁸ represents an alkyl group having 1, 2, 3, 14,. 5, 6, 7 or 8 carbon atoms; NR ⁿ R ¹² or phenyl which is unsubstituted or substituted by 1, 2 nebo.3

identical or different radicals selected from the group consisting of fluorine, chlorine, - bromine, iodine, trifiuorméthylovou, methyl, methoxy, hydroxyl and NR ⁿ R ^12, R ⁹ and R ²¹ independently represent hydrogen, an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR ¹³ ,

R ¹⁰ represents a hydrogen atom, an alkyl group having 1, -2, 3, 4, 5, 6, 7 or 8 carbon atoms, which is optionally substituted by an alkoxy group having 1 to 4 carbon atoms or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 identical or different, radicals selected from the group consisting of fluorine, chlorine, bromine and iodine, trifIuorméthylovou, methyl, methoxy, hydroxyl and NR ^{l R:;:} symbol "R ⁿ , R ¹² , Ø ¹ · ⁹ 'and "R ^{20" are each} independently hydrogen; an alkyl group having 1, 2, 3 or 4 carbon atoms or an alkanoyl group having 1 to 4 carbon atoms, preferably an acetyl group,

R ¹³ is hydrogen or alkyl having 1,. 2 ·, 3,

4,5, 6,7 or 8-carbon atoms,

X. represents a carbonyl group, -CO-NH-,. . . -CO-CO-, or a sulfonyl group,.

the symbols Y and Z are each independently

1. aryl. se group. 6, 7, 8, 9, 10, 11, 12, 13 or carbon atoms, preferably phenyl, 1-naphthyl or

2-naphthyl,

2. a residue as defined under 1 which is substituted with 1; 2, 3, 4 or 5 with the same or different radicals selected from the group consisting of alkyl groups having 1,

2, 3, 4, 5, 6, 7 or 8 carbon atoms, aryl groups having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl,. 1-naphthyl or 2-naftylovo.u group -atomy ,, fluorine, chlorine, bromine and iodine, .trifluor18 methylovou- groups, SOR, NR ¹⁹ R ^20, • kyanoOR> 9 group, nitro group and the group CO-R or wherein the two residues together form an fused heterocyclyl residue, preferably methylenedioxy; a heteroaryl group having 1, 2, 3, 4, 5, or 5. 6, 7, 8 or carbon atoms,

4. a radical as defined in 3 which is substituted by 1, 2 or 3 of the same or different radicals selected from the group consisting of fluorine, chlorine, bromine and iodine, trifluoromethyl, methyl, methoxy, hydroxyl and NR ¹¹ R ^12, ·, 5th cycloalkyl having 3, 4, 5, c, 7, 8, 9 or carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl. 1,2,3,4-tetrahydronaphthyl or indanyl,

6 '·.' . rest-. defined under · 'point.-? Substituted with an aryl group having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, -1-naphthyl. or a 2-naphthyl group _: 7. an O-R 'group ^; ,

8. The Group C - R ', ·. · - i., -SO ..- R ^1', ·.

arylalkylcarbonyl; methyl, carbonyl, or. '' '

11th heterocyclyl group, R ¹⁴ and R ¹⁷ independently of 'self-suffi- to imagine.

1. a hydrogen atom;

2. an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; /

3. an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, or 12 carbon atoms;

4. the group -C.H ... ....- phenyl, where. _.

^? ý nn has the value 0 or 2, and n has. a value of 0, .1, 2, 3 or - 4, with> n not having, 9. 10 preferably phenyl 7 '

or 0 if nn is 2, or

5. ' the residue as defined in item 4, wherein the phenyl moiety is present. substituted with 1, 2 or 3 with the same or different radicals selected from the group consisting of alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, fluorine, chlorine, bromine and iodine atoms, trifluoromethyl group, SO _q R ^15, oR ^16, NR ⁿ R ^12, cyano, nitro and groups CO-R ⁹ 'R ¹⁵ and R ^1S, independently of one another are alkyl having 1, 2, 3 or 4. carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are present. substituted by fluorine atoms, preferably trifluoromethyl, or

NR ¹¹ R ¹² , means

1. a hydrogen atom;

2. an alkyl group having 1, 2, 3 or 4 carbon atoms;

3. an alkyl group having 1, 2, 3 or 4 carbon atoms substituted by an alkoxy group. C 1 -C 4;

4. an alkyl group having 1, 2, 3 or 4 'carbon atoms in which one to all of the hydrogen atoms are replaced by fluorine atoms, preferably a trifluoromethyl group; aryl having 6, 7, 8, 9, 10, 11, 12, 13 or carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl, or.

6. the residue as defined in item 5, which is substi-U · -, * T -> νΛ I

L. UU in part J by the same or different residues selected from the group consisting of fluorine, chlorine,

bromo and iodo, a "trifluoromethyl" group

NR ^19, R ²⁰ , cyano and nitro, R ²² and R ^{23 are each} independently hydrogen or. CO-OR ²⁴ ; , '

R ²⁴ represents a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 5,

6, 7 or 8, carbon atoms, or a group -C _n H _2n -.fenyl wherein n is 1, 2, 3 nebo.4 and '

q is independently 0, 1 or 2, as well as physiologically acceptable salts thereof.

Preferred are compounds of formula I wherein R ¹ is'. · ·

1. alkyl having 1, 2, 3, 4 or 5 carbon atoms,

2. alkyl having 1, 2, 3, 4 or 5 carbon atoms to, in which one to all atomy'vodíku • replaced by fluorine atoms, _ · ^a

3. alkenyl. a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; -4. -C _n H _2n -Y _ _nn where ". , ·.

nn. is 0 or 2, and n has. value. 0, 1, 2, 3 or 4, wherein n is not 0 or 1 if nn is 2, or

5. The Group -G _H2n _ _nn -Y where.

nn - .... is 0 or 2, and. . n has a value of 1, 2, 3 or 4, with n not having a value if · nn has a value. 2,. in which 1, 2 or 3 hydrogen atoms in the divalent radical -C -H- _n .... are independently replaced by a radical selected from the group consisting of

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

The second amino group, · 'third NR ²³ R ^2z · ·

4. alkoxycarbonyl groups,

CGO? X groups

alkyl groups having 1, 2, 3 or 4 carbon atoms; · ..

7. arylalkylcarbonyl groups having 6 to 14 carbon atoms in the aryl part and 1 to 4 carbon atoms in the

An alkyl moiety, preferably a phenylacetyl group,

R ² is .1. . 1. a hydrogen atom;

2. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms, 3. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms, ve which are one to all atoms hydrogen replaced atoms of fluorine, 4. an alkenyl group having 2, 3 4 5 6 7 8 9 10 11 or 12 carbon atoms, 5. an alkynyl group having 2, 3 ,. 4 or 5 carbon atoms, 6. -C..H. ₂ ..Z, where nn has a value of 0 or 2, and. n is 0, 1, 2, 3 or 4, without it 0 or 1 if nn is 2, or 7. -C _n H _2n _ _NN -Z wherein · nn is 0 or 2; and n 1, 2, 3 or 4, with n not having a value. 1 if nn has a value 2, ve which are. 1, 2 or. 3 hydrogen atoms in divalent

- - · residue ·· -C _n H _2n _ _nn -. -'- independently. be replaced by a residue selected from the group consisting of.

1. aralkyl groups having 6, 7, 8, 9, 10, 11, 12 /, 13 or 14 carbon atoms, preferably a phenyl, n-naphthyl or 2-naphthyl group,

2. amino,

Group 3 NR ²² R ²³ ,, ·

4. C 1 -C 4 alkoxycarbonyl groups. alkoxy moieties.

COOR ¹ Group 5, a

(6) alkyl groups having 1, 2, 3 or 4 carbon atoms, R ³ and the like; R ^4, independently of one another, are each a hydrogen atom or an alkyl group having 1, 2, 3. or·. 4. the carbon atoms, R ⁵ , R ^b and R ^{7 are each} independently hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine or bromine, trifluoromethyl, cyano, a group SO _q -R ⁸ , CO-R ²³ or

'OR ¹⁰ ,

^R is alkyl having 1, 2, 3 or 4 carbon atoms, NR ¹² R or ^U or a phenyl group which is unsubstituted or substituted by 1 or 2 identical or different .zbytky .zahrnujícího selected from fluorine, chlorine and bromine Trifluoromethyl. , methyl, methoxyskupihu, hydroxyl and NR ⁿ R ^12, -. , R ⁹ and R ^{21 are each} independently of each other. hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms; or. OR ¹³ group, · ''

R ¹⁰ 'represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, which is optionally substituted. C1-4alkoxy; Or a phenyl group which is unsubstituted or substituted. 1 or 2 with the same or different residues selected from the group. including fluorine, chlorine and bromine atoms, trifluoromethyl, methyl. , methoxy, hydroxyl and NR ⁿ R ^12, R ^11, R ^12, R ¹⁹ and R ²⁰ independently represent hydrogen, alkyl having 1, 2, 3 or 4 carbon

·. _; 'Atoms or an alkanoyl group having 1 to 4 carbon atoms ,, preferably acetyl, ·' · R ¹³ represents. a hydrogen atom or an alkyl group having 1, 2 ', 3 or 4 carbon atoms; represents a carbonyl group,. . -CO-NH-, -CO-CO-. or a sulfonyl group, Y and Z independently. always mean to each other

1. phenyl, 1-naphthyl or 2-naphthyl group, ^'1 2. a radical as defined under point 1., which is substituted with 1, 2, 3, 4 or 5 identical or different radicals selected' from the group consisting of alkyl groups si, ¹

2, '3. or 4 carbon, atoms, phenyl, 1-naphthyl and 2-naphthyl group, fluorine, chlorine, bromine, trifluoromethyl, SO _q ri ^8, OR ^16, NR ¹⁹ R ^20, R

A cyano group and a CO-R ^{9 group} , or wherein the two residues together form an analkyheterocyclyl residue, preferably methylenedioxy,

3. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or carbon atoms;

4. the radical as defined in item 3, which is substituted by 1 or 2 of the same or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl, methyl, methoxy, hydroxy and hydroxy. and NR ^R12,

5. cycloalkyl: with 3, 4, 5, 6, 7, 8, 9 or.

carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl; under point 5, substituted. phenyl, 1-naphthyl or 2-naphthyl;

7th group OR ¹⁴ ,. ·

.. OR ¹⁷ group,

9th group -SO, -R ^:: ,

10.. an arylalkylcarbonyl group, preferably a phenylmethylcarbonyl group, or a heterocyclyl group, R ¹⁴ . and R ¹⁷ , independently of each other, are each

1 .. atom. hydrogen · · 2. an alkyl group having 1, 2, 3 or 4 carbon atoms, 3. an alkenyl group having 2; 3, 4, 5 or 6 atoms ,, 1 .___ UiillKli, 4. -C _n H _2n _ _NN -phenyl, wherein. 1 nn is 0 or 2; and n. . is 0, 1, 2, 3 or 4, wherein n does not

a value of 0 or 1 if nn has a value of 2, or> 5. a residue as defined in point 4, in which the phenyl moiety is substituted with 1, 2 or 3 by the same; - different radicals selected from the group consisting of alkyl groups having 1; 2, 3 or 4 carbon atoms, atoms

-11 fluorine, chlorine and bromine atoms, · a trifluoromethyl, a group of R ^15, OR ^16, 'NR ⁿ R ^12, cyano or a CO-R ^9; R ( ¹⁵⁾ and R ( ¹⁸⁾ independently of one another represent alkyl having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon atoms in which they are. one to all hydrogen atoms, replaced by fluorine atoms, 'preferably trifluoromethyl, or NR'^; R ² ,

R ¹⁶ denotes

1. a hydrogen atom;

2. an alkyl group having 1, 2, 3 or 4 carbon atoms;

(3) an alkyl group having 1, 2, 3 or 4 'carbon atoms substituted by an alkoxy group having 1 to 4 carbon atoms;

4. alkyl. a group having 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, preferably a trifluoromethyl group,

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

6. a residue as defined under 5 which is substi. tuován Ί ·, 2, or 3 'of identical or different, radicals selected from the group consisting of fluorine atoms, and .chloru. bromine, trifluoromethyl,' NR ^{19 R 0} and cyano, and R ²² 'R ²³ are independently imagine it. in each case a hydrogen atom or a CO-OR ²⁴ group. /.

R ²⁴ is hydrogen, .alkylovou. ·. a group having 1, 2, 3 or 4.

carbon atoms, or a group. _H2n -f.enyl wherein in · has. a value of 1, 2 or 3, and.

q 'is independently 0, 1 or 2; .

as well as their physiologically acceptable salts. . ' ^s · • ·, · y. . . . '/ ·.

Particularly preferred are compounds of formula (I) wherein. R 'represents ·

1. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms;

2. an alkenyl group. with 2, 3 or 4 carbon atoms.

• · · · · ·

-12 3 ·.

γ the group -C _n H _2n . _nn -Y, where represents

1. a phenyl group; ·

2. a residue as defined under point substituted by 1, 2, 3, 4 or 5 residues selected from the group consisting of alkyl atoms of carbon, atoms of the group 1, 2, fluoro, chloro cyano, trifluoromethyl

The first, which is the same or file 3 or 4 bromine groups, hydro xys buy well, nitro groups / SO ₂ R ^18, OR ^16,

SCF

3 '

NR ¹⁹ R ²⁰ and CO-R ⁵ ,

3. the group 0-R ¹⁴ ,

4. the group 3O-R '^; , ''''.

5. 1-naphthyl or 2-naphthyl;

6. a radical as defined in item 5, which is substituted by a radical selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine atoms, and a-1. chlorine, trifluoromethyl group- and group S0 ₂ R ^18, OR ^16, NR ¹⁹ R ^20, and CO-R ^9,

7. a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, or. 9 carbon atoms,. preferably a thienyl, benzothiophenyl, indolyl or furyl group ^;

8 is as defined under 7, which is substituted. a residue selected from. the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methoxy group and a group; methyl nn n

.

Ethy dimethylamino, or

9. a cycloalkyl group having 3, 4, 5, 6 or 7 carbon atoms; .

• is 0 or 2, and '0, 1, 2, 3 or. 4. A value of 0 or 1 when nn is 2 or a -C, H group. _{: r} . _nr -Y, where, represents +.

while not having any * · '·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-13 nn n

ve

1: a phenyl group,

2. OR ¹⁴ ; or

3. a heteroaryl group, preferably a thienyl group, having a value of 0 or 2, and having a value of 1, 2 or 3, with n not having a value of 1 if nn has a value of 2 which are 1, 2 or 3 hydrogen atoms in divalent radical; C _n H _2n - _nn - independent ^; are replaced by a residue selected from the group consisting of

1. aryl groups of 6, 7, 8, 9, .10, 11, 12, 13 _; Or 14 carbon atoms, preferably phenyl. 1-naphthyl or 2-naphthyl, or phenylacetyl,

2. amino group, '

3. Groups NR ²² R ²³ , and

4. alkyl 'groups having 1, 2, 3 or 4' carbon atoms, R ² represents ^;

(1) a hydrogen atom, or 5 carbon atoms; or. 5. Carbon atoms, hydrogen atoms replaced

4, 5, 6, 7, 8, 9 or 5 carbon atoms,

2. an alkyl group having 1, 2, 3,

(3) an alkyl group having 1, 2, 3, or 3; . which are one to all fluorine atoms,

4. an alkenyl group having 2, 3, carbon atoms

5. an alkyl group having 2, 3,

Sixth -C _{r H: .....:.-Z,} wherein Z represent E

1 ,. phenyl group,

2. the radical defined by p substituted by 1, 2 or 3 point 1. which is different or different radicals selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, phenyl, fluorine, chlorine and bromine atoms , trifluor-

- 13 - ·. · A methyl group, the group ¹ SOjR ®, ^OR16, 'nitro, cyano ·. and the groups NR ¹⁹ R ²⁰ 'and CO-R ⁹ , or in which the two residues together form a methylenedioxy group,. 1-naphthyl or 2-naphthyl,

4. a residue as defined in item 3 which is substituted. a radical selected from the group consisting of alkyl having 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl group / SO ₂ R ¹⁸ , OR ¹⁶ , nitro, cyano and NR ¹⁹ groups R ²⁰ and CO-R ⁹ ,

5. a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, or 9 carbon atoms, preferably benzimidazolyl, pyridyl. thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, benzo-furanyl, for example, dihydro-1-oxobenzo [c] turanyl, and quinazolinyl, for example 3,4-dihydroquinazinyl,

6. a radical as defined in point -5 which is substituted by a radical selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl, methyl, methoxy, hydroxy and dimethylamino;

7. a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably cyclopropyl;

·. ·. _: cyclopentyl ,. cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl, or

8. the radical as defined in point 7, which is substituted by a phenyl group, preferably a phenylcyclopentyl group.

nn is 0 or 2, and n · is 0, 1, 2, or 3, where n is not 0 or 1 if nn is 2,

7. The group -C _n H ...- .. Z, wherein - ^R • · ·· "··.

. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·.

OF . represents ,

1. a phenyl group; or

2. a residue as defined under 1 which is substituted by 1, 2 or 3 with the same or different residues selected from the group consisting of. alkyl groups having 1, 2, 3 or 4 'carbon atoms, phenyl, fluorine and chlorine atoms / trifluoromethyl, SO ₂ R ¹⁸ , OR ^1b , nitro,. cyano and NR ¹⁹ R ²⁰ · - CO-R '' - 'NN has the value 0 or 2, n · has a value of 1, 2 or 3, n. hodnotu.1 allowed if nn is 2,.

in which 1, 2 or 3 hydrogen atoms in the divalent radicals -C _n H _2n _ _NN independently replaced / radical atoms and

1, 2, 3 or 4. atoms selected from the group consisting of

the alkoxycarbonyl groups of the carbon in the alkoxy moiety;

2. COCR & apos ^{; R} groups; and

3. an alkyl group with carbon; or '

8. the group -C..H .... -3R ^: where n has the value, 0, 1, 2 or 3, the symbols R ³ and R ⁴ are each a hydrogen atom or a methyl group, the symbols R ⁵ , ^and R and R ⁷ independently. each represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, a fluorine atom or a chlorine atom. trifluoromethyl group, cyano group, SO ₂ -R, CO-R or O-R 'is alkyl having 1, 2,' 3 'or 4' carbon atoms, dimethylamino or phenyl groups which are unsubstituted or substituted by a radical selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl; methyl, methoxy; hydroxy. and dimethylamino,

or an alkanoyl group having 1 to preferably an acetyl group,

R ¹³ represents a hydrogen atom or an alkyl or 4 carbon atom,

X. ícarbonylovou represents a group -NH-CO-or. verifies-sulfonyl group, a fluoro, a group -CO-R ^9,

R ¹⁵ is R ⁹ and R ^{21 are each} independently hydrogen; methyl or a group OR ¹³ '

R ¹⁰ 'is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms which is optionally substituted by C 1-4 alkyl .atomy, .or phenyl group which is unsubstituted .or substituted radical selected -from the group consisting of fluorine and chlorine atoms, trifluoromethyl, methyl, methoxy and dimethylamino, symbols. R ( ¹¹⁾ and R ( ¹²⁾ independently of one another represent a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms and 4 carbon atoms, a group having 1, 2, 3 or a -CO-CO- group,

Ø ¹⁴ represents ·;

1. a hydrogen atom;

2. alkyl having 1, 2, 3 or 4 carbon atoms,

3. alkenyl having 2, 3, 4, 5 or 6 carbon atoms,

The fourth group _H2n -phenyl _ _NN where, .nn is 0 or 2, n. has a value of 0, 1, 2, 3, or 4, wherein n is not 0 or 1 if nn is 2, or 5. a radical as defined in (4) above wherein the phenyl moiety is substituted with 1; 2. or. 3 with the same or. different radicals selected from the group consisting of alkyl groups of 1, 2, 3 or 3; 4 and carbon, "chloro and bromo, trifluoromethyl, SO _q R ^{15. OR16} / NR ⁿ R ^12, CN and s'kupiny alkyl having 1, -2, -3 or 4 carbon atoms or dimethylamino, ·· ·· ♦ • · · · «·· · · · · · · · • · · · · · · · · · ·

- 17 R ¹⁶ means

1. a hydrogen atom;

(2) an alkyl group having 1, 2, 3 or 4 carbon atoms; (3) an alkyl group having 1, 2, 3 or 4 carbon atoms substituted by an alkoxy group having 1 to 4 carbon atoms;

4. an alkyl group having 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, preferably a trifluoromethyl group. _a phenyl, 1-naphthyl or 2-naphthyl group; or

6. a residue as defined in point 5 which is substituted by 1, 2 or 3 identical or different radicals selected from the group consisting of fluorine atoms, chlorine atoms

- and bromo, trifluoromethyl Iuorméthylovou, NR ¹⁹ R ^20. Cyano,

R represents

1. a hydrogen atom;

- '· - 2. alkyl having 1, 2/3 or 4 carbon atoms; an alkenyl group having 2, 3 or 4 carbon atoms; -carbonyl _H2n _ _nn-phenyl, -wherein.

nn, is 0 or '2-, -a

- n is 0, 1, 2, 3 or 4, where n is not 0 - 1 if nn is 2, or

5. the remainder defined in. bodert 4, wherein the phenyl moiety is substituted with a residue selected from the group

including alkyl groups with 1,. 2, 3 or 4 atoms carbon, fluorine, chlorine and bromine t trifluoromethyl- group. SQ _q R ¹⁵ OR ¹ ' ^s , NR ¹³ • r1? , cyano a. CO-R ⁹ group > - represents an alkyl group with- . -1, 2,. · 3, or. 4 atoms carbon; 1, 2, 3 or 4 atoms

The carbon in which they are one. to. all) of the hydrogen atoms are replaced by - fluorine, preferably trifluoromethyl Iuorméthylovou ,,. · radical, or -NR ⁿ R ^12, R ¹⁹ 'and R ² -' independently represent a hydrogen .sobě 0 0 • '• 0 ··

0 0 • 0 0 * ·· 0 · 0 0 0 0 0 0 0 0

18 hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or alkanoyl having 1 to 4 carbon atoms, preferably acetyl, R ( ²²⁾ and R ( ²³⁾ independently of one another are hydrogen or CO- oR ^24; R ²⁴ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms or -C _n H _2n -phenyl where n is 1 or 2 and,

q. independently has a value of 0, 1 or 2, and physiologically acceptable salts thereof.

Particularly preferred are compounds of formula I wherein

R ¹ represent the E

1. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms;

2. alkenyl having 2, 3 or 4 carbon atoms,

3. -C „H _{2n- nn} -Y, where,

Y represents - ·. . i. a phenyl group,

2. a residue as defined under 1-, which is substituted with 1, 2, 3, 4 or 5. with the same or different radicals selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, cyano, trifluoromethyl, trifluoromethyl, hydroxy. nitro skupiny- SO ₂ R ^13, OCH _3, OCF _3, SCF ₃ · N (CH _{3) 2, -NH-CO-CH3,} CO-R ^9, phenoxy proline. and phenoxy groups. one or more times substituted by halogen, preferably chlorine or fluorine,

3. OR ¹⁴ , or.

4. SO ₂ -R ¹⁴ , nn is 0 or 2, and n is 0, 1, 2, 3 or 4, where η is not 0 or 1 if nn is 2, or

4. the group -C, _H2r , -Y, where

Y 'represents,. , • 9 ·· <·

• 9 • 9 • 9

1. phenyl group ',

2. OR ¹⁴ ; or

3. a heteroaryl group, preferably a thienyl group, nn - having a value of 0 or 2, and n having a value of 1, 2 or 3, with n not having a value of 1 if nn has a value of 2,. · In which 1, 2 or-3 hydrogen atoms in the divalent radicals -C _n H _2n _ _nn - independently replaced by a moiety selected from the group consisting of.

1. aryl groups having 6, 7-, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl. or a phenylacetyl group. .

2. amino,

The third groups 'NR ²² R ^23, and the fourth alkyl group having' 1 ·, 2, 3 or 4 alkyl,

5th group where. . <.

Y represents. ... '

1.: 1-naphthyl or 2-naphthyl,

2. a radical as defined in (1) which is substituted by a radical selected from the group consisting of alkyl, s, 2, 3 or 3; 4 carbon atoms, the atoms of fluorine. · And chlorine, trifluoromethyl.. "And the groups SC ^ ^-R13, OCH _3, N (CH _{3) 2,} and CO-R ^9,

3 ,. heteroaryl having 1,2,3,3,5,5. 6, 7, ¹ 8 or 9 carbon atoms, preferably "thienyl, benzothiophenyl, indolyl or furyl. '. group

4. the rest defined. under point 3.,. which is substituted; a residue selected from. file containing fluorine atoms and chlo.ru,. trifluoromethyl, methyl, methoxy and dimethylamino, or.

• · · · · · · · · · · · · · · ·

5. a cycloalkyl group having carbon atoms; and 3, 4 ,. 5, 6 or n is 0, 1, ^{1 2 * * * 6 * *} 2, 3, or A ', or 6. -C _n H _2n -OR ¹⁴ wherein n is 0.1 or 2,

R ² . .means

1. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms, 2. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms; ve which are one to all atoms hydrogen replaced fluorine atoms, 3. an alkenyl group with 2 3 4 5 .6, 7, 8, 9 or .10 carbon atoms, 4. alkynyl group 2, 3, 4 or 5 carbon atoms, 5. -C _n .H _{2n. nn} -Z, where OF represents

1. a phenyl group; ,

2. the rest. defined by - under point 1.,. which is substituted by 1, 2 or 3 same or different radicals selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, phenyl, fluorine, chlorine and bromine atoms, trifluoromethyl group. SO ₂ R ¹⁸ , -OCH ₃ ,. -O (C ₂ H ₄ ) OCH ₃ , ethoxy, hydroxy,

-nitro, cyano, N (CH _{3) 2,}

-NH-CO-CH ₃ , CO-R ⁹ , phenoxy and phenoxy substituted one or more times with halogen, preferably chlorine or fluorine, or on which two n residues together form methylenedioxy, nn. has a value of 0 or 2, and an ·., has a value of Ό, 1, 2 or .3. where n has no value or 1 if nn has a value of 2,.

Group 6 ^- C _n ri ... where

OF .' represents '

1. a phenyl group; or. ,

2. a radical as defined in (1) which is substituted with 1, 2 or 3 of the same or different radicals selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, phenyl, fluorine and chlorine atoms; trifluoromethyl, SO ₂ R ¹⁸ ,. -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy,. hydroxy, nitro,. CN · N _{(CH3) 2,} and CO-R ^9, nn is 0 or 2, and.

n is 1, 2 or 3, wherein n has a value of 1 if .nn is 2, in which 1, 2 or 3 hydrogen atoms in the divalent radicals -C _n H _2n _ _nn - independently replaced by a radical from the group comprising 1. C 1 -C 4 alkoxycarbonyl groups in the alkoxy moiety;

2. COOR Group ^1fa , a

3. alkyl groups having 1, 2, 3 or 4 'carbon atoms,

7. a group _-CH2n -Z, wherein

Z represents

T. 1-naphthyl or 2-naphthyl;

2. a radical as defined in 1., which is substituted with a radical selected from the group consisting of alkyl groups having 1, 2, 3 or 4 atoms. carbon, fluorine and chlorine atoms, trifluoromethyl, SO ₂ R ¹⁸ , OCH ₃ , -O (G ₂ H ₄ ) OCH ₃ groups. ethoxy, hydroxy, nitro, cyano, N (CH ₃ ) ₂ , -N.HCOCH _{3 and} CQ-Ø ⁹ ,

3. a heteroaryl group s.1; 2, 3, 4, 5, 6, 7, or 9 carbon atoms, preferably benzimidazoles.

acid, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, benzofuranil, for example dihydro-1-oxobenzo [c] furanyl, and quinazolinyl. such as 3,4,4-dihydroquinazolinyl,

(4) the residue as defined in (3) which is substituted by a residue selected from the group consisting of. fluorine and chlorine atoms, trifluoromethyl, methyl, methoxy, hydroxy and dimethylamino.

5. a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydro-naphthyl or indanyl, or.

6. The radical as defined in 3, which is substituted by a phenyl group, preferably a phenylcyclopentyl group, and. / n is 0, 1, 2 or 3, or

8. The group _H2n -OR ^17, wherein. .

n is 2 or 3,. .

R ³ and R ⁴ are each hydrogen, R ⁵ , R ⁶ . and R ⁷ independently represent an atom. hydrogen, alkyl having 1, 2, 3 or 4 atoms.

carbon, atom, fluorine. or chlorine, trifluoromethyl, SO ₂ -R ⁸ , CO-R ^{21 or} O-R ¹⁰ ;

^R8 is methyl or dimethylamino, R ⁹ 'and R ^2' independently of ^one. in each case represent an atom ^: hydrogen, methyl or / OR ¹³ ,

R ¹⁰ is hydrogen, methyl or ethyl;

which is optionally substituted by methoxy, or phenyl, which is unsubstituted or

substituted by a radical selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl, methyl. methoxy and dimethylamino. group

R ¹³ represents a hydrogen atom or an alkyl group having 1, 2, 3, or 3. or 4 carbon atoms,

X is carbonyl. group, -C.O-CO-, · · · · · · · ·

-NH-CO- or. a sulfonyl group,

R ¹⁴ represents

1. a hydrogen atom;

2. a methyl or ethyl group,

3. an alkenyl group having 2, 3, 4, carbon, preferably an allyl group,

The fourth group _H2n -phenyl where n is 0 or 1,

5. the remainder defined in. point 4.,. wherein the phenyl moiety is substituted with a radical selected from the group consisting of alkyl having 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl group, SO ₂ R ¹⁵ , OCH ₃ , N (CH ₃ ) groups. , and CO-R ⁹ , or

6. alkenyl having 2, 3 'or 4 carbon atoms, ¹⁵ is methyl or dimethylamino, or 6' atoms

RR ¹

R ¹⁷

R @ ² represents a hydrogen atom or an alkyl group having 1, 2, -3 or 4 carbon atoms, preferably a methyl or tert-butyl group; 'represents j

1. hydrogen, .. ','

2. a methyl group;

The third group _H2n. Phenyl wherein n. Is 0. or 1;

4. a radical as defined in 3. wherein the phenyl moiety is substituted with a radical selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl, SO groups ₂ R ¹⁵ ', OCH ₃ ,' N (CH ₃ ) ₂ and CO-R ⁹ , or '51 alkenyl with 2, 3' or 4 carbon atoms, 'means methyl, trifluoromethyl, amino or dimethylamino, 11 independently of. sob.ě: are hydrogen or CO-OR ²

R 'represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, or. -C _n H _2n -phenyl where n is 1 or 2, ^·; as well as their physiologically acceptable salts. • ·

Also preferred are compounds of formula Ta

in which they have residues X and as well as their physiologically

R ¹ to. ^R7 acceptable salts of the above-mentioned 'meanings. Further preferred are compounds of general' vzorce.1 / or Ja 'in which X, R ^1, R ^2', R ^3, R ^4, R @ ^3, R @ and R 'as defined in Examples 1 to 568. ..

When &quot; groups of the formula I &quot; they may have substituents. all independently defined above and may be the same or different. , '' '. ’

Alkyl, alkenyl and alkynyl groups can be independently of each other. either directly or. 1 branched. It is true' . even when. j sou. contained in other groups, for example alkoxy groups, alkoxycarbonyl groups, or. or when substituted. ^;

As examples of alkyl groups having 1, 2, 3, 4, 5, 6, 7.

or. .8. . carbon atoms can be mentioned by methyl, ethyl, propylene. butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl. sec.butyl, target. butyl and t -pentyl.

Examples of alkenyl groups include vinyl,

- prenyl-sheep,. 2-propenyl-, ‘(allyl), butenyl, 3'-methyl-2-butenyl, 2-butenyl and 2-methyl-2-propenyl. Alkenyl groups may also contain two groups.

25 or more double bonds, such as a butadienyl group or a (CH ₃ ) ₂ C = CH-CH ₂ -CH ₂ -C (CH ₃ ) = CH-CH ₂ - group.

Examples of alkynyl groups include ethynyl, 2-propynyl (propargyl) or 3-butynyl. Alkynyl groups may also contain two or more triple bonds.

Among cycloalkyls, ^one group includes saturated and partially unsaturated cycloalkyl radicals which matches may be mono-, binebo also tricyclic. Examples takovýchcykloalkylových groups include, cyclopropyl, cyclobutyl, cyclo pentyl, ^{1, r} cyclohexyl; ' cycloheptyl,. 1,2,3,4-tetrahydronaphthalene and indanyl, all of which may also be substituted, for example by one or more of the same. or with different alkyl groups having 1 to 3 carbon atoms. 4 atoms. carbon ,. especially methyl. Examples of such substituted, cycloalkyl groups are 4-methylcyclohexyl, 4-tert-butylcyclohexyl. or

2,3-dimethylcyclopentyl.

- Aryl groups of 6, 7, 8, 9, 10, 11, 12 ,. 13 or carbon atoms are, for example. phenyl, naphthyl, biphenyl, anthryl or fluorenyl, with, being preferred. 1-naphthyl, 2-naphthyl, and in particular phenyl,

Heteroaryl. groups and '. heterocyclyl groups are preferably "derived from heterocycles" which contain in the ring η O Η ni ni A τ τ ts ts ts ts 7 7 7 7 7 7 7 + + + rn σ pI 1 1 n A j cu.Cn _t v <_a _r <_ x -l. More preferably, heterocycles contain one or more heteroatoms or one, or more particularly one or two, identical or different heteroatoms. Unless otherwise indicated, the heterocycles may be monocyclic or polycyclic. for example monocyclic, bicyclic or tricyclic. Preferably, these heterocycles are monocyclic or bicyclic. The rings are preferably five-membered, six-membered, or seven-membered. Examples of monocyclic and bicyclic heterocyclic systems from which the rings are derived. they can.

To derive residues occurring in the compounds of formula I include, 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, pyrazine, pyran, thiopyran, 1,4-dioxin,

1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine,

1,4-thiazine, 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-thiazepine, indole, benzo thiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, thienothiophene, 1, -8- naphthyridine and other naphthyridines, pteridine,. or pheno-thiazine, which are each in a saturated form (perhydro form). or in a partially unsaturated form (e.g., dihydroform or tetrahydroform). or. in the most unsaturated form, provided that the forms are known and stable. K heterocyklům ,. the saturated heterocycles pyrrolidine, piperidine, piperazine, morpholine and thiomprfoline are also contemplated. The unsaturated heterocycles may contain, for example, one, two or more in the ring system. three double bonds. Five-membered six-membered rings in monocyclic and polycyclic heterocycles - may in particular also be aromatic. The residues derived from these heterocycles may be. attached through any suitable carbon atom. Nitrogen heterocycles which on the ring nitrogen atom contain a hydrogen atom or a substituent, for example pyrrole, imidazole, pyrrolidine, morpholine, piperazine, etc., can also be bonded via a ring nitrogen atom _; particularly when the nitrogen heterocycle is attached to a carbon atom. -For example, thienyl. the rest can. be present as. A 2-thienyl or a 3-thienyl group, a furanyl residue such as a 2-furyl or a 2-thienyl group; 3-furyl, a pyridyl moiety such as 2-pyridyl. 3-pyridyl or 4-pyridyl, piperidine moieties such as 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl

- 27 group, a thiomorpholine residue such as 2-thiomorpholinyl,

3-thiomorpholinyl or 4-thiomorpholinyl (= thiomorpholino) group. The carbon-bonded moiety derived from 1,3-thiazole or imidazole may be attached at Appendix 2, position 4 or position. 5.

Unless otherwise indicated, heterocyclic groups may be unsubstituted, or may carry one or more, for example, one, two, three or four, identical or different substituents. The substituents may be present on the heterocycles in any position, e.g. 2-thienyl or

A 2-furyl group at the 3-position and / or at the 4-position and / or the 5-position at the 3-thienyl or 3-furyl group at the 2-position and / or the 4-position and / or the 5-position at the 2-pyridyl group at position 3, and / or at position 4 and / or at position 5 and / or at position 6, at

A 3-pyridyl group at position 2 and / or at position 4 and / or at position 5 and / or at position 6 and at the 4-pyridyl group at position 2 and / or at position 3 or at position 5 and / or at position 6. Unless otherwise stated, for example, substituents in the definition of an aryl group may be present as saturated substituents, in the case of saturated or partially unsaturated heterocycles, other substituents may also be oxo and thioxo substituents on heterocycles, as well. The carbon ring substituents may also form a ring, and other rings may also be fused on the ring system so that they may be formed, for example, cyclopentene-fused, cyclohexane-fused or benzo-fused. rings, such as substituents on the nitrogen atom in the heterocycles on which substitution may occur, include, in particular, unsubstituted alkyl groups having from 1 to 5 carbon atoms, aryl substituted alkyl groups, aryl groups, and .cýlové groups such as -CO-alkyl having 1-5 carbon atoms in the alkyl part, or a sulfonyl 'group such as _-SO2-alkyl having 1 to 5 carbon atoms- in .alkylové portion. Suitable nitrogen heterocycles may also be present as N-oxides or as quaternary acid. salts with an anion derived from a physiologically acceptable acid as the counterion. For example, pyridyl residues may be present as pyridine-N-oxides. ^;

Heteroaryl groups include, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl. thiazolyl ,. isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl groups.

pyrazinyl, indazolyl,

The heteroaryl groups may also be wholly or partially hydrogenated. Examples can be:. mention pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, 1,3-dihydro-1-oxobenol, furanyl. or 3,4-dihydroquinazolinyl. group.

Phenyl groups, naphthyl groups ... groups, for example heteroaryl. Unless otherwise indicated, unsubstituted or may carry. one or more, for example one, two, three or four, identical or different substituents which may be in any positions. the substituents mentioned in the definition of an aryl group, for example in aryl groups such as phenyl groups and / or heteroyclic radicals, may be present as substituents in these groups; the phenyl groups, phenoxy, benzyl or benzyloxy groups present therein may be 'benzene ring' itself again unsubstituted or substituted by one or more, for example, and heterocyclic may be if

For example, when one, two, substituents, three, or four, the same or different, for example, are selected. C1 -C4 alkyl, halogen, hydroxy, C1 -C4 alkoxy, trifluoromethyl, cyano, hydroxycarbonyl, alkoxycarbonyl; C 1 -C 4 alkoxy, aminocarbonyl, nitro, amino, alkylamino. 1 to 4 atoms · ·

C1 -C4 alkyl, C1-4 alkynyl, and C1 -C4 alkylcarbonylamino.

In monosubstituted phenyl groups, the substituent may be in position 2, position 3 or position 4, and in disubstituted phenyl groups the substituents may be in position 2-and 3, positions 2 and 4, positions 2 and 5, positions 2 and 6, positions 3 and 4 or positions 3 and 5. In trisubstituted phenyl groups, the substituents may be in positions 2, 3 and 4, positions 2, 3 and 5, positions 2, and 6, positions 2, 4, and 5, positions 2, 4 and 6 or the 3, 3 and 5 positions. The tolyl group (= methylphenyl) is. 2-tolyl, 3-tolyl or 4-tolyl. The naphthyl group may be a 1-naphthyl or 2-naphthyl monosubstituted 1-naphthyl group substituent. in position 2, position 3, position 4, position 5, position 6, position 7 or position 8, in monosubstituted 2-naphthyl groups in position 1, position 3, position 4, position 5, position 6, position 7: or position 8 .

group. V can

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. \ i

The invention encompasses all steroisomeric forms of the compounds of formula (I). The centers of asymmetry present in the compounds of formula (I) may each be independently

S-configuration or R-configuration. The invention. this includes all possible enantiomers. and diastereomers, as well as mixtures of two or more stereoisomeric forms, for example mixtures, of enantiomers, and / or diastereomers, in all ratios. Accordingly, the present invention provides enantiomers in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of both. enantiomers in. If the compounds of the present invention can exhibit cis / trans isomerism, the present invention provides both the cis form and the trans form and mixtures of these forms in all proportions. Production of individual

The stereoisomers may be carried out, if desired, by resolution of their mixture by conventional means, for example by chromatography. or crystallization, using stereochemically uniform starting materials in the synthesis or by stereoselective synthesis. Optionally, the compounds may be derivatized prior to resolution of the stereoisomers. The cleavage, with a mixture of stereoisomers, can be carried out on. at the level of the compounds of formula (I) or at the level of intermediates in the course of the synthesis. In the case of the presence of mobile atoms, hydrogen, the invention also includes all tautomeric forms of the compounds of formula I.

When the compounds of the formula I contain one or more acidic or basic groups, the invention also relates to the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically usable salts. Thus, the compounds of the formula I which contain acidic groups and these groups can be in the form of alkali metal, alkaline earth or earth ammonium salts and as such can be used according to the invention. Examples of such salts include sodium salts, potassium salts, calcium salts. salts, magnesium, salts or salts with ammonia or organic amines such as. for example, ethylamine,. ethanolamine, triethanolamine or amino acids. Compounds of formula I which contain one or more basic, i.e., protonatable, groups may be in the form of their addition salts with physiologically acceptable inorganic or organic acids, and as such are used in accordance with the invention. For example, salts with hydrochloric acid may be mentioned. hydrobromic, phosphoric, sulfuric, nitric, methanesulfonic, p-toluenesulfonic, naphthalenedisulfonic, oxalic, acetic, tartaric, lactic; 'benzo,' formic, propyne, pival, diethyloacetate, malon, amber, pimel, fumar, maleic, cider, sulfamic, phenylpropionic, glucuronic ,. ascorbic, isonicotinic, citric, adiocic, etc. If the compounds of formula I contain both acidic and basic groups in the molecule, the invention includes:

in addition to the above salt forms, internal salts or betaines. (bipolar ions) of the formula I can be obtained by processes, for example by reaction

Salts may be from the compounds of the general customary known to those skilled in the art with an organic or inorganic acid or base in a solvent or dispersant, or alternatively by anion exchange or cation exchange from other salts. The invention also encompasses all salts of the compounds of formula (I) which, due to poor physiological acceptability, are not suitable for use directly in pharmaceuticals, but are suitable, for example, as intermediates, for chemical reactions or for the preparation of physiologically acceptable salts. Physiologically acceptable salts of the compounds of formula (I) are, for example, their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences (17th edition, p. 1418 (1985)). As a result of their physical and chemical stability and. solubilities are preferred for acidic groups, among others sodium, potassium, calcium and ammonium salts, for basic groups, for example, salts with hydrochloric, sulfuric or phosphoric acids, or salts with carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid. maine, fumar, tartar and β-toluenesulfone.

The invention further encompasses all solvates of the compounds of formula I, for example hydrates or adducts with alcohols, as well as derivatives of the compounds of formula I. such as esters, and prodrugs and active metabolites. ,

The invention also relates to a process for the preparation of the novel compounds of the formula I as well as to their compounds. physiologically. at the liver. SOlí. . ;

The compounds of formula I can be prepared, for example, by solid phase synthesis.

The synthesis is generally carried out in such a way that the benzenesulfonyl structure of the general formula II is suitably bonded. via a chemical linker on the polymer matrix. by methods known to those skilled in the art for the synthesis of sulfonamides from sulfonic acid chloride and amine. Suitable polymer matrices are, for example, polystyrene, polytetrafluoroethylene, polyacrylamide, etc., which may optionally be extended with polyoxyethylene to improve the swelling capacity. j ednotkami. Suitable linker units are structures which, under the action of an acid or a base, are suitable. by reduction, oxidation, by the action of light or fludridions, specifically release the synthesized compound, wherein the linker unit remains 'on the polymer'

(review of linker groups and polymers for solid phase synthesis, see J. Fruchtel, J. Jung., Angew. Chemie Int. Ed. 1996, 35, 17-42). . '.

R7

R7. , ... • Fa _x Linksi \. 1 'Polymer f H'. 0 — S — N Poiymer. o. \ -. ,, - ^{/ Z} F Linker. w  í. Cl — s = o II  - o + H, N  (10 flll) '·. ^{From the} group basic linked bodies in this way over-sulfonamide to polymer, general. III

using the aryl boronic acid derivatives (aryldihydroxyboranes) of formula (IV) to prepare the bi-phenylderates of formula (V). They will. while the reaction 'conditions for the palladium catalyzed · reactions known from the literature, as described for example .jsou _..: .... 0 rganomet in all ICS' 1984, ¹ 3, 1261 or Synth.

Commun. 11 (7), 513 (1981).

00 »* 0« »· 0 0 • 0 00» · 0 and »· 4

cm):. fiv? (in)

The benzeneboronic acid of formula (IV) is synthesized - for example, analogously to the synthesis of 4-formylbenzeneboronic acid as described in Liebigs Ann. 1995, 1253.

IN

(v) X fvi); Reductive amination with sodium cyanoborohydride (review of sodium borohydride is: v. Synthesis 1975, 1-35) gives a compound of formula VI, which can be reacted; with an acid chloride R ^&lt; -X-Cl přeměnit- · ha compound of 'Formula · -VIL. Solid phase synthesis. it has the advantage that the reagents and the reactants can be used in large excess. a wide range of solvents can be used and the purification is accomplished by simply washing the resin particles.

* 99 99 • 9.

99

9 9 9

9 99 9 9 9 9 β · β 9 9 9 9 9 9

9 9 9 9 9 9

99 99 99

Polymer (knows). (νιι)

If the radicals R ³ and R ^{4 do} not represent hydrogen atoms, the corresponding radicals must be introduced. This is accomplished by synthesizing, without a reducing agent, an imine of the formula (X) via a reductive amination from the aldehyde of the formula (V); jícího- and corresponding ^amine: and this imino-n · is - subjected to a 'reaction. with an organometallic compound carrying the radical R or R ^4. , such as a Grignard reagent or an alkyllithium compound,. in a way that is. expert. Alternatively, the aldehyde function of the compound of the general formula is inhibited. V is oxidized to the nitrile of the general formula XI as described, for example, in Synthesis 1982, 190, and is then treated with organolithium or organotreated. they introduce the compounds to a specialist ^; known manner, the radicals R ³ and R ⁴ .- · In the last-mentioned case, 'except toho'musí ještě'zavést radical, R ² skilled' známým.- third way and? y Σ 3Cl nsbo - Σ y ηΣ third gi 3ininu.

• · · '·· O • 9 ··. • · ·· «· • t * · • · • · • • « ··. • · • · • · • • · • · • · • * ·· ··· ·· ♦ · · ·· ··

(x). / -. (XI)

After the gradual '.'provedení jednotlivých''stupňů synthesis, the newly synthesized compounds are cleaved .'pomocí specific reagents - which are selected according to the nature of the linker (for description of synthesis' refer to the solid phase. J .. ¹ Frúchfei G. Jung "Angew. Chemie Int. Ed." (19.96, 35, 17-42). The cleavage from the resin is carried out according to the linker used in a manner known to the person skilled in the art. A preferred polymer is, for example, aminomethylpolystyrene from Fluka (1.1 mmol-amine) per gram resins; 2% crosslinked DVBj. A preferred linker is, for example, a compound of formula VIII known from the literature (G. Breipohl, J. Knolle, W. Stuber, Int ... J. Peptide Protein 'Res. 34, 1989, 262f):' ¹

(VIII); fm.c = 9-fluorenylmethoxycarbonyl)

In this case, the cleavage from the resin is carried out under acidic conditions. The compounds of the general formula (VII) are:

-. 36 an inert solvent, preferably dichloromethane; reacting with an acid having a pK ý 5, preferably with an acid having a pK < _and 2 2, particularly preferably trifluoroacetic acid, to give the sulfonamide of formula IX. A typical reaction time is 5 minutes to 10 hours at a temperature between -30 ° C and the boiling point of the solvent, preferably a reaction time. 20 minutes to 1 hour at room temperature. . ·.

Last level; Synthesis is characterized in that the compounds of the general formula IX

in which they have individual. _; the general symbols defined above, meanings, react with. with cyanogen bromide to give a compound of formula I. The reaction is carried out in a dipolar aprotic. a solvent which is stable to cyanogen bromide, for example acetonitrile, dimethylacetamide (DMA); tetramethylurea (TMU) or N-methylpyrrolidin-2-one (NMP), with a strong auxiliary base which is low in nucleophilia such as potassium carbonate. or cesium carbonate. As the reaction temperature comes; a temperature between 0 ° C and the boiling point of the solvent used is considered, preferably between 40 ° C and 100 ° C.

The compounds of formula (I) may also be 'synthesized' by classical synthesis, that is. in 'solution,' using. of methods known to those skilled in the art. The compounds of the formula I according to the invention are suitable as inhibitors of the Na ^- dependent hydrogen carbonate / chloride exchange system (NCBE) or the sodium / hydrogen carbonate symporter. .

The invention further relates to the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions, as well as the use. a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of a heart attack, and the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of angina pectoris; prophylaxis of ischemic heart conditions, as well as the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions. peripheral and central nervous system conditions and apoplegia (stroke),. As well as the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

as well as the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of the treatment of shock conditions.

as well as the use of a compound of formula I for the manufacture of a medicament for use in surgical operations and organ transplants, as well as the use of a compound of formula I for the manufacture of medicaments for preservation and surgery for transplant storage. for as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of diseases caused by cell proliferation as a primary or secondary cause,. and hence its use, for the manufacture of an antiatherosclerotic,. .the.,. late diabetic complications, against cancer diseases, against fibrotic diseases such as lung fibrosis, liver fibrosis

• ·

38 or renal fibrosis, and against prostate hyperplasia, as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of impaired respiratory stimulation.

as well as a medicament which comprises an effective amount of a compound of formula I.

The compounds of the formula I according to the invention show very good antiarrhythmic properties. how. they are important, for example, in the treatment of oxygen-deprived diseases.

Due to their pharmacological properties, the compounds of the formula I are very suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis of infarction and the treatment of infarction as well as for the treatment of angina pectoris, while also preventing or severely inhibiting pathophysiological processes in ischemic emergence. Induced disorders, in particular in the development of ischemically induced cardiac arrhythmias. Because of their protective effects against pathological hypoxic and ischemic conditions, the compounds of the formula I may be:. according to 'the invention as a consequence of inhibiting the cellular .At ⁺ -dependentního .výměnného mechanism Cl- / HGO symporter ₃ ,, or of the sodium / bicarbonate .As used pharmaceuticals for treating all acute or chronic damage caused by ischemia or primary or. secondary induced diseases. These compounds protect organs acutely or chronically inadequately supplied with oxygen by reducing or preventing ischemically induced disorders and are therefore useful as medicaments, for example in thrombosis, vascular spasms, atherosclerosis, or surgical procedures (e.g., organ kidney transplantation and the compounds may be used to protect the organs from the donor before and during their removal, to protect the organs taken, for example, from handling or storing them in physiological baths, as well as during transfer to the recipient organism. or

chronic or acute renal failure.

The compounds of formula (I) are also valuable protective medicaments for performing angioplastic surgeries, for example on the heart as well as on peripheral vessels. Because of their protective action against ischemically induced disorders, these compounds are also suitable as medicaments for. treating ischemia of the nervous system, especially of the central nervous system, for example being suitable for the treatment of apoplexy (stroke) or cerebral edema. In addition, the compounds of formula I according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolaemic and bacterial shock.

In addition, the compounds of the formula I according to the invention are characterized by a potent inhibitory action on the proliferation of cells, for example cellular. · Proliferation of ribroblasts. and ... proliferation of vascular smooth muscle cells. Accordingly, the compounds of formula (I) are useful as therapeutics for diseases in which cell proliferation is the primary or secondary cause and can therefore be used as antiatherosclerotics, anti-late agents. diabetic complications, - cancerous diseases, fibrotic diseases such as fibrosis of the lungs, fibrosis of the liver or fibrosis. renal, and anti-hypertrophy and hyperplasia of organs, particularly prostate hyperplasia or prostate hypertrophy.

Inhibitors have been found to be - N? -Dependent. The Cl '/ HCO ₃ ' exchange system, or the sodium / bicarbonate symporter, may stimulate respiration by increasing the chemosensi- on. bility. respiratory chemoreceptors. . These. chemoreceptors are into. largely responsible for maintaining proper respiratory activity. They are. hypcxií activated in the body, reducing the 'pH and increasing the concentration of C0 ₂ (hypercapnia) and adapted minute volume .. In sleep -dýchání particularly' sensitive., disorders and

highly dependent on chemoreceptor activity.

Improved respiratory stimulation by stimulating chemoreceptors with agents that inhibit Na ⁺ -dependent α / HCO 3 exchange leads to respiratory distress in the following clinical conditions and diseases: impaired central respiratory stimulation (eg, central sleep apnea, sudden death of children, postoperative hypoxia), muscle conditional respiratory disorders, respiratory disorders, after long-term artificial respiration, respiratory disorders in adaptation to alpine environments, obstructive and mixed forms of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia. ··

The compounds of the formula I according to the invention and their physiologically acceptable salts can be used in animals, in particular in mammals, and in particular in humans, as medicaments, alone, in mixtures with one another or in the form of pharmaceutical compositions. hence it also refers to compounds. . of formula I and. their physiologically acceptable salts for use, such as. medicaments, their use in the treatment and prophylaxis of said diseases, and conditions, and the preparation of medicaments therefrom for said uses. The invention further provides pharmaceutical compositions. which, in addition to the usual pharmaceutically acceptable carriers and excipients, contain at least one compound of the general formula as an active ingredient. Or a physiologically acceptable salt thereof. These pharmaceutical compositions usually contain 0.1 to 99% by weight, preferably 0.5 to 95% by weight. and / or physiologically acceptable salts thereof. The pharmaceutical compositions can be prepared in a manner known per se. Doing so. the compounds of formula (I) and / or their physiologically acceptable salts are formulated together with one or more solid or liquid galenic carriers or excipients and, if desired, in combination with other therapeutically active compounds, into a suitable dosage form or dosage form, which can then be used as a medicament in human medicine or veterinary

medicine. '

The medicaments comprising a compound of the formula I and / or a physiologically acceptable salt thereof can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred mode of administration being dependent on the present manifestations of the disease. Compounds of general formula. It can also be used alone or together with galenic excipients, both in veterinary and in human medicine. , /

The skilled artisan will appreciate, based on his expert knowledge, which excipients are. suitable for the desired drug formulation. In addition to solvents, gelling agents, capping bases, tablet excipients and other active ingredients, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, solubilizers, or colorants can be used.

For oral use, the active compounds are admixed with excipients suitable for this purpose, such as carriers, stabilizers or inert diluents, and are formulated into suitable dosage forms, such as tablets, dragees, injectable capsules, by conventional means. aqueous, alcoholic or oily solutions. As inert carriers, for example, Arabic. gum, magnesia,. magnesium carbonate, potassium phosphate ,; milk sugar, glucose or glucose. starches, especially corn starch. The preparation can be carried out in the form of both dry and wet granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds, if desired, together with substances customary for this purpose, such as adjuvants, emulsifiers or &quot;

other excipients will be formulated as a solution, suspension or emulsion. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol, and also sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents.

If desired, the formulation may also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a composition usually contains the active ingredient in a concentration of about 0.1 to 10, in particular of about 0.3. to,. 3% by weight .... . .

The dosage of the active compound of the formula I to be administered is administered. the frequency of administration depends on the potency and duration of action of the compounds as well as the nature and severity of the disease being treated, as well as the sex, age, weight and individual responses of the mammal being treated.

On average, the daily dose of the compound of Formula I is in a patient; of a weight of about 75 kg to at least 0.001 mg / kg body weight, in particular 0.01 mg / kg body weight, up to a maximum of 10 mg / kg body weight, in particular 1 mg / kg body weight

In acute, outbreaks of disease, for example.

immediately after a cardiac infarction-may be, must be even higher and especially more frequent doses, for example up to ^one. . 4 sub-doses per day. Especially for intravenous use, for example in patients with a heart attack in an intensive care unit, doses of up to 200 mg per day may be necessary.

The compounds of formula (I) may be used as the only active ingredient or in combination with other pharmacologically

active compounds. '

The compounds of the formula I and / or their physiologically acceptable salts can be used for the treatment or prophylaxis of the aforementioned diseases and conditions, in particular for the treatment of heart and blood diseases, in order to obtain an advantageous therapeutic effect. circulation, also together with other pharmacologically active compounds. Combination of inhibitors of the sodium / hydrogen exchange system (NHE) and / or with active substances from other classes of substances acting on the heart and blood circulation is preferred.

The invention thus also relates to a combination of a) NCBE inhibitors of the formula I or / and 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 active substances from other classes, substances acting on the heart and blood circulation or / and their physiologically acceptable substances. salts; . as well as ... (c) NCBE inhibitors. and / or their physiologically acceptable salts with NHE inhibitors and / or their physiologically acceptable salts and active substances from other classes of substances acting on the heart and bloodstream and / or their physiologically acceptable salts.

Known active substances known to act as NHE inhibitors are guanidine derivatives, in particular acylguanidines, inter alia as described by Edward. J. Cragoe., Jr., - DIURETICS, Chemistry, Pharmacology and Medicine,. , J. WILEY & Sons (1983), 303-341, or inhibitors. NHE listed in ΈΡ98115754.8. ’

Suitable NHE inhibitors are, for example, also benzoylguanidines as described in US 5292755, US 5373024, US 5364868, US 5591754, US 5516805, US 5559153, US 5571842, US 5641792, US 5631293, EP-A. 577024, EP-A-602522, EP-A-602523, EP-A-603650, EP-A-604852, EP-A. 612723, EP-A'.627413, EP-A 628543, EP-A 6405.93, EP-A 640588, AP-A 702001, EP-A

- 713864 ,. EP-A 723956, ΈΡ-A 754680, EP-A 765868, EP-A 774,459, EP-A 794,171, EP-A 814077 and EP-A 869116; ortho-substituted genzoylguanidines as described in EP-A 556673, EP-A 791577 and EP-A 794172; ortho-amino substituted genzoylguanidines as described in EP-A · 690048; isoquinolines as described in EP-A 590455; benzofused five-membered heterocycles as described in EP-A 639573; di-substituted guanidines as described in ... EP-A 640587; acylguanidines as described in US 5547953; perfluoroalkyl groups bearing phenyl-substituted guanidines of alkyl or alkenyl carboxylic acids as described in US '5567734 and EP-A 688766'; heteroaroylguanidines,. as described in EP-A 676395; bicyclic. heteroarylguanidines as described in EP-A 682071; indenoyl guanidines as 'described' in EP-A 738712; benzyloxycarbonylguanidines as described in EP-A 748795; fluorophenyl groups bearing phenyl-substituted guanidines of alkenylcarboxylic acids as described in "EP-A.744397;" substituted cinnamic acid guanidines as described in EP-A 755919; sulfoniridamides as described in EP-A 771788; benzendicarboxylic acid diguanidines as described in EP-A 7744.58 and EP-A ^: 77 4457; diguanidines of diarylcarboxylic acids as described in EP-A 787717; substituted thiophenylalkenylcarboxylic acid guanidines as described in EP-A. '790245; bis-ortho-substituted benzoylguanidines as described in EP-A 810207; substituted 1 or 2-naphthylguanidines as described in EP-A, 810205 and EP-A 810206; indanylidinylacetylguanidines as described in EP-A 837055; phenyl-substituted guanidines of alkenylcarboxylic acids as described in EP-A 825178; aminopiperidylbenzoylguanidines as described in EP-A-667341; freterocyclyloxybenzylguanidines as described in EP-A 694537; ortho-substituted benzoyl guanidines as described in EP-A 704431 ortho-substituted alkylbenzylguanidines as described in EP-A. 699660; ortho-substituted heterocyclylbenzoylguanidines as described in EP-A 699666; ortho-sub45

substituted 5-methylsulfonylbenzoylguanidines as described in EP-A 708088; ortho-substituted 5-alkylsulfonylbenzoylguanidines with 4-amino substituents as are. described in EP-A 723963; ortho-substituted 5-alkylsulfonylbenzoylguanidines with 4-mercapto substituents as described in EP-A 743301 .;

4-sulfonyl- or 4-sulfinylbenzylguanidines as described. in EP-A 758644; alkenylbenzoylguanidines such as. are described in EP-A 760365; benzoylguanidines with -anelined, cyclic sulfones as described in DEW 19548708; benzoyl-, polycyclic aroyl- and heteroaroylguanidines as described in WO 9426709; 3-aryl / heteroarylbenzoylguanidines as disclosed in WO 9604241; 3-phenylbenzoylguanidines with a basic amide at the 5-position as described in WO 9725310; 3-dihalogenethenyl- or 3-dihalophenylbenzoylguanidines having a basic substituent at the 5-position as described in WO 9727183; 3-methylsulfonylbenzoylguanidines with certain amino substituents at position -4 as described in WO 9512584; amiloride derivatives as described in WO 9512592; 3-methylsulfonylbenzoylguanidines with certain amino substituents at the 4-position as described in WO 9726253; indoloylguanidines as described in EP-A 6222356 and EP-A 708091;

indoloylguanidines with a further one. a ring system as described in EP-A 787728; methyl guanidine derivatives as described in WO 9504052; 1,4-benzoxazinoylguanidines as described in EP-A 71976.6; 5-bromo-2-naphthoylguanidines as described in JP-8252513; quinoline-4-carbonylguanidines with a phenyl residue at the 2-position as described in EP-A 726254; cinnamoylguanidines, - as described in JP. 09059245; naphthalene-substituted propenoylguanidines as described in JP 9067332; propenoylguanidines, with an indole substituent, as described in JP 9067340; or heteroaroyl-substituted acryloylguanidinyl as described in WO 9711055, as well as physiologically acceptable salts thereof.

Preferred NHE inhibitors are the compounds mentioned above. of said publications as preferred. They are particularly preferred

- 46 • ··

compounds selected from the group consisting of cariporide (42642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, and physiologically acceptable salts thereof. Most preferred is cariporide or other physiologically acceptable salt of N - (4-isopropyl-3-methanesulfonylbenzoyl) guanidine.

As examples of classes of active substances acting on the heart and blood circulation which can be combined therapeutically advantageously with or with NCBE inhibitors. can also be combined with combinations of NCBE inhibitors ·. and NH.E inhibitors, such as beta-receptor blockers, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin blockers, loop diuretics. thiazide potassium sparing diuretics, aldosterone antagonists, as used, for example, in. blood pressure lowering as well as cardiac glycosides or other strength enhancers in the treatment of cardiac insufficiency and congestive heart failure, as well as class I-IV antiarrhythmics, nitrates, diuretic receptor openers,

Blockers

ATP ^γ inhibitors veratridine activatable quinapril, sodium channel antagonists etc ... So. propanolol beta-blockers are suitable, for example. atenolol, metoprolol; calcium antagonists diltiazem hydrochloride, verapamil hydride chloride, nefecipine; angiotensin converting enzyme captopril, enalapril, ramipril, trandolapril, spirapril, preferably ramipril or trandolapril; Angiotensin II receptor los.artan, valsartan, telmisartan.

epro.sartan, tasosartan, eandesartan, irbesartan; loop, diuretics furosemide, piretanide, -torasemide; thiazide diuretics, hydrochlorothiazide, metoiazone, -indapamide; Potassium sparing. diuretics. amiloride, triamterene,. spironplakton ;. cardiac glycosides digoxin, digitoxin, strofanthin, antiarrhythmics amiodarone, sotalol, brelium, flecainide; nitrate glyceryl tinitrate; K ⁺ (ATP) openers cromakalim, lemakalim, nocorandil, pinacidil, minoxidil; and veratridine-activatable sodium channel inhibitors. , -. ,

One example of a particularly preferred combination partner for NCBE inhibitors of Formula I are blockers of the non-inactivating sodium channel (veratridine activatable sodium channel). The combination of an NCBE inhibitor · with a non-inactivating sodium channel blocker (veratridine activatable sodium channel) is useful for the prophylaxis of infarction- and infarct recurrence, and for the treatment of infarction, as well as for the treatment of angina and angina. ischemically inducible. cardiac arrhythmias, tachycardia and the formation and maintenance of ventricular fibrillation, wherein the combination of an NCBE inhibitor with a non-inactivating sodium channel blocker is also preventive. inhibit or strongly reduce pathophysiological processes in the development of ischemically induced disorders. Due to their enhanced protective effects against 'pathological hypoxic and ischemic' conditions, combinations of an NCBE inhibitor of formula (1) with a non-inactivating blocker may be used. The sodium channel according to the invention is used as a medicament for the treatment of all acute or chronic disorders caused by ischemia or such primary or secondary induced diseases as a result of an enhanced inhibition of Na ^T cell entry. It. includes their use as medicines in surgical procedures,. for example, organ transplantation, a combination of NCBE inhibitors of the general formula. I. with a non-inactivating, sodium channel used both to protect organs in the donor before and during their harvesting, to protect the organs harvested, for example, during their storage in the transfer to the body when blocking as well as physiological recipients.

Inhibitor combination - NCBE. of the formula (I) with a non-inactivating sodium channel blocker are also valuable protective-acting drugs when performing angioplastic surgeries, for example on the heart as well as on the cardiovascular system. peripheral blood vessels. Due to . their protective action against ischemically induced disorders are these combinations of an NCBE inhibitor. - the general formula. Even with the blocker

• 9Φ ·· φ · 9 9 · φ φ · · 9 9

- '48 non-inactivating. They are also suitable for the treatment of ischemia of the nervous system, in particular of the central nervous system, and are suitable for the treatment of apoplexy (stroke) or cerebral edema. In addition, combinations of a NCBE inhibitor of formula I with a non-inactivating sodium channel blocker according to the invention are also suitable for the treatment of various forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

In addition to the use of the above ingredients as a solid combination, the invention also relates to the present invention. separate or graded use of NCBE inhibitors of the general formula.

I 's inhibitors. NHE and / or other active substances from another class of substances acting on. heart and blood circulation to 'treat,' 'λ' the above diseases and conditions. ,

The invention therefore also relates to a pharmaceutical composition which comprises a) an NCBE inhibitor of the formula I and an inhibitor, NHE and / or physiologically acceptable salts thereof, or b) an NCBE inhibitor of the formula I and furthermore an active compound of the invention. other groups of substances acting on the heart and blood circulation and / or their physiologically acceptable salts; or c) an NCBE inhibitor of the formula I, NHE inhibitors and another active substance from another. groups of substances acting on. heart and blood circulation, or physiologically acceptable salts thereof.

. . In the combined use, it can be the effect that it is one that the components of the combination; cross-linked with the other component, i.e., the effect and / or duration. the combination or composition of the invention is higher or more permanent than the effect. and / or - the time of adaptation of the components separately (synergistic effect). This results ⁱⁿ a reduced dose of the individual components of the combination when combined. compared to their separate, use. The combinations and compositions according to the invention thus exhibit the advantage that the amount of active substances to be applied can be substantially reduced. and

9.9 9 99 99 99 99 • 9 9 9 · 9 · 9 9

9 · 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9999

Eliminate or severely reduce unwanted side effects.

The invention further relates to a commercial package comprising as pharmaceutically active. a) an inhibitor. NCBE of formula. T and an NHE inhibitor and / or physiologically acceptable salts thereof; or b) an NCBE inhibitor of the formula. And an active substance from another group of substances acting on the heart and blood circulation and / or their physiologically acceptable salts; or c) an NCBE inhibitor of the formula. I, an NHE inhibitor, and an active agent, from another group of agents acting on the heart and bloodstream and / or their physiologically acceptable salts, together with instructions for use of these active agents in combination with simultaneous, separate or staggered application in therapy or prophylaxis above. said diseases and conditions, in particular for the treatment of heart disease and blood circulation.

The pharmaceutical compositions of the invention may be prepared, for example, either intensively. mixing the individual components in powder form, or dissolving the individual components in a suitable solvent such as a lower alcohol, and then removing the solvent.

Weight ratio of NCBE inhibitor to NHE inhibitor or other ha. the heart and blood circulation in the combinations and compositions according to the invention are suitably 1: 0.01 to 1: 10, preferably 1: 0.1 to 1: 10.

Combinations and compositions of the invention generally contain from 0.5% to 99.5% by weight, in particular from 4% to 99% by weight. these effective. substances. . -.

When used according to the invention in mammals, preferably humans, dosages of the various active ingredients are, for example, in the range of 0.001 to 100 mg / kg per day. '. ·

The following examples illustrate the invention but are not intended to limit the scope of the invention in any way. 'Φ · • · • · • φ ·· φφφ • Φ φ · • φ • .φ φ φ φφ • · φφ • φ φ φ ¹ φ • Φ φφ φφ «φ« φ φ φ · φ φ φ »φ φ φ φ φ φφ φφ

Examples of embodiments of the invention

The following abbreviations may be used in the examples and elsewhere herein:. . ' _z

BCECF =. 2,7'-bis- (2-carboxyethyl) -5,6-carboxyfluorescein,

Bn = benzyl,

DCI = desorption chemical ionization,.

El = electron impact ionization.

ES = electrospray ionization, '' ·

ESneg = electrospray negative ionization,

Et = ethyl, FAB = fast neutral particle ionization, fmoc = 9-fluorenylmethoxycarbonyl,

HOOBt = 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one,

HPLC = high performance liquid chromatography,

MS · mass spectrometry,

NCBE = ^T- dependent bicarbonate (chloride) exchange system.

NHE = sodium / hydrogen exchange system,. -. -

NMR = nuclear magnetic resonance, 'Ph = phenyl,' '

PS - polystyrene

General synthesis procedure for solid-phase synthesis:

Solid phase synthesis of the compounds of Formula I is accomplished by suitably coupling the sulfonamide structure via a chemical linker to a polymer matrix by methods known to those skilled in the art. 'Basic. the structure thus bonded through the sulfonamide group to the polymer can be readily subjected to further conventional organic reactions of organic chemistry.

In more detail. that is to say, the following steps are described, for example, for the compound of formula (Ia).

• ·

NH-CN

(Ia) wherein R ¹ is 2-chlorophenyl, R ² 'is benzyl, X is carbonyl and R ³ to R ⁷ are each hydrogen. '-.

A. Linker / Polymer Synthesis

As a commercially available polymer, aminomethylpolystyrene from Tluka (1.1 mmol of amine per gram resin; 2% crosslinked-DVB) was used. The compound is used as the linker. 1 known from literature (G. Breipohl, J. Knolle, W. Stuber,

Peptide Protein Res. 34, 1989, 262f).

Others

J.

+

(2) (3) 'PS

14.4 g-Aminomethylpolystyrene-2, 28.2 g are mixed to combine the polymer and the linker. of compound 1, 3.2 g of 3-hydroxy-1,2,3-benzotriazin-4- (3H) -one and 11.5 g of diisopropylcarbodiimide in 105. ml of,, Ν, Ν-dimethylformamide and 45 ml of methylene chloride and the mixture was shaken. for 48 hours. The mixture was then filtered off with suction and washed thoroughly with N, N-dimethylformamide and methyl tert-butyl ether. '

4,

B.

Synthesis of sulfonamide

bonded to the resin

Per 5 g of compound 3 is added. A mixture of piperidine and N, N-dimethylformamide v. 1: 3, the solution is filtered off with suction and the resin is washed thoroughly with N, N-dimethylformamide. To the resin. damp from Ν, Ν-dimethylformamide, add 3.1 g ... of compound 4 known from the literature (Gilman, Marker, JACS 74, 1952, 531-7) in 20 ml

Ν, Ν-dimethylformamide. After the addition of 0.7 ml of pyridine, the mixture is allowed to react for a period of time. .18. hours at room temperature. The mixture is then filtered off with suction and washed. with N, N-dimethylformamide and methyl tert-butyl ether. · '.

.C.-

Synthesis of biarylsulfonamide 7 linked

resin

g of compound 5 is swelled with ml of N, N-dimethylformamide and 1.5 g of boronic acid 6, 50 mg of Pd (PPh ₃ ) ₄ and 3.5 ml of 2M sodium carbonate solution are added; The mixture was allowed to react for 2.4 hours at 10 ° C under an argon atmosphere. Then, the mixture is aspirated and washed thoroughly and aa aa aaaaa aaaaa aaaa

Water, N, N-dimethylformamide and methyl t-butyl ether.

D _r Reductive solid amination; as an example: benzylamine

To 200 mg of the resin-bound intermediate of formula 7 was added 1 mmol of the amine dissolved in. 1 ml of a 3: 1 mixture of dimethoxyethane and methanol, then 0.2 ml of a 1M solution of acetic acid in dimethoxyethane and 0.5 ml of a 1M solution of sodium cyanoborohydride in dimethoxyethane are added. The mixture is allowed to react for 4 hours at room temperature. . The mixture was then filtered off with suction and washed thoroughly with N, N-dimethylformamide and methyl ether. butyl ether. ¹ 'After removal of the sample (1.0 mg) from the resin by treatment with methylene chloride LML acid' trifluoroacetic poměru-, 3: 1 with a free amine such as triethylamine '8 .charakterizuje .pomocí HPLC (high performance liquid chromatography) and MS (mass spectrometry). - '/.

solid phase,. Examples are 2-chloro-benzoyl-N-acylation to the chloride

Ke 190; mg of 8 was added with 2 ml of a 1M solution of N-ethylmorpholine in methylene chloride. The mixture was cooled to 0 ° C and 0.5 with stirring. mmol of the acid chloride dissolved in 0.5 ml of methylene chloride. The mixture was allowed to react for 1 hour at 0 ° C. The mixture was then filtered off with suction and washed with N, N-dimethylformamide and methyl tert-butyl ether. Reality, . that the reaction was complete, it was checked after cleavage of sample 9 (see step D) by HPLC and MS. . ''. '

F., Cleavage from resin,

180 mg of compound 9 is added over a period of time. It is treated with 3 ml at room temperature for 30 minutes. 3: 1 methylene chloride / trifluoroacetic acid solution. After separation of the solution from the polymer, it is centrifuged in vacuo. The residue was 30 mg of free amide 10, which was directly subjected to cyanation G.

G. Synthesis of sulfonylcyanamide;

mg. of compound 10 is dissolved in 3 ml of acetonitrile and 0.3 mmoles of triethylamine and 0.12 mmol are added; cyanogen bromide dissolved in acetonitrile. The mixture is allowed to react for < 1.8 hours at room temperature and then 3 ml of methyl tert-butyl ether and 2 ml are added. % aqueous buffer solution. 6. After mixing well, remove the upper phase and apply to silica gel, first wash with 5 ml of methyl tert-butyl ether and then wash the product with 5 ml of a 5: 1 mixture of ethyl acetate and acetic acid. vacuum is obtained. 12. mg of sulfonoyl cyanamide in 60 to 90% purity (for example, compound 11 in 90% purity). The products thus obtained can be further purified by preparative HPLC on reversed phase materials. Characterization of the product by HPLC, MS and NMR of example ¹ by using spectroscopy. _*

The following compounds of formula (Ia) are prepared analogously (R @ ³ to R @ ^b are in each case hydrogen atoms and R @ ⁷ in the compounds from 1 to 512 is also hydrogen):

At- klad. ' No ·. R ² ./. R ^x -X MS * (ES-) (M-1) - Residual activity (%) NČBE at 10 μΜ 1 benzyl ch, -ch ₂ -ch ₂ -co- • 446 · - · -. 2 - '2' - --CH ₂ -CH ₂ -OH CH ..- CH ..- CK -CG- ' p 2 2 400 '' 78,1 ·. - '3- 4-methoxybenzyl ’ ch ₃ -ch ₂ -ch ₂ -co-. 476 .8.0,9 '4 4-chlorobenzyl ch ₃ -ch ₂ -ch ₂ -co-. 480 5 phenyl ch ₃ -ch ₂ -ch ₂ -cg- 431 89.5 6 cyclohexyl Cx4 ₃ -CH ₂ -CH ₂ -CO- 438 84.5. , , 7 benzyl cyclohexyl - _CH2 - _CH2 --CO - . 514 ' 33.0 •. 8 '-ch ₂ -ch ₂ -oh ·' cyclohexyl i-CH ₂ -CH ₂ -CO - 468 86.7 9. . 4-methoxybenzyl cyclohexyl-CH ₂ -CH ₂ -CO-.  544 '. 86.6 ¹⁰ 4-chlorobenzyl '. _: cyclohexyl-GH ₂ -CH ₂ -CO- , 548 84-, 9 11 · phenyl . cyclohexyl-CH ₂ -CH ₂ -CO- 499 . ' 68,1 · 12 cyclohexyl cyclohexyl-CH ₂ -CH ₂ -CO- 506. , 92, 9 ' '' 13 benzyl · ohexyl-CO- 486. 74.7. '.14. -ch ₂ -ch ₂ -oh Cyclohexyl-CO- 440  88 ', 7  15 Dec 4-methoxybenzyl cyclohexyl-CO-.  516u 67.6 16 4-chlorobenzyl cyclohexyl-CO- 520 56.4 17 . phenyl cyclohexyl-CO- ⁴⁷¹ .

At- klad No ·. R ² ·. r’-x . MS (ES-) (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 18 cyclohexyl cyclohexyl-CO- 478 . 1θ benzyl 3-methoxyphenyl-CH ₂ -CO- 524 25.9. 20 May .-ch ₂ -ch ₂ -oh 3-methoxyphenyl-CH ₂ -CO- 478 37.1 21 . 4-methoxybenzyl 3-methoxyphenyl-CH ₂ -CO- 554 . 52.3 22nd 4-chlorobenzyl 3-methoxyphenyl-OH ₂ -CO- 558 23 phenyl 3-methoxyphenyl-CH ₂ -CO- 509 25.9 24 cyclohexyl. 3-methyl-methoxyphenoxy _{phenyl-CH2-CO-} .516 92.1 '25, , benzyl 2-thienyl-CH ₂ -CO- .. 500 16.6 26 -ch ₂ -ch ₂ -oh 2-thienyl-CH ₂ -CO-  454 47.6 27 Mar: 4-methoxybenzyl 2-thienyl-CH ₂ -CO- 530 '35,5 . 28 4-chlorobenzyl 2-1-enyl-CH 2 -CO - 534. ., 95.2, 29 / phenyl 2-thienyl-CH ₂ -CO- 485 55,7 * 30 cyclohexyl 2-thienyl-CH ₂ -CO-, 492. 95.2 31. benzyl 4-tert-butylphenyl-CO- 536 52.2 32 -ch ₂ -ch ₂ -oh 4-tert-butylphenyl-CO- . '49.0' , 68.0. . 33 4-methoxybenzyl 4-tert-butylphenyl-CO- 566. 67.2 34 4-chlorobenzyl ^; 4-tert-butylphenyl-CO- . 570 35 ‘Phenyl .4-tert-butylphenyl-CO- . 521 -53.4 _: . 36 cyclohexyl 4-tert-butylphenyl-CO-  528 ' 37 benzyl 2-fluorophenyl-CO- 498 52.0 38 ; -ch ₂ -ch ₂ -oh .2-fluorophenyl-CO- .. 452 66.7 ‘39 · 4-methoxybenzyl 2-fluorophenyl-CO- 528 '51.3 ... .4 0 4-chlorobenzyl 2-fluorophenyl-CO- 532 41 - · phenyl. 2-Fluorophenyl-CO- 483 : 94.9. 42 cyclohexyl 2-fluorophenyl-CO- 490 ' Ί 43 • _: benzyl allyl-O-CO- .460. 41.6.

• · ·

At- klad no. R ² R ^T -X. '\ MS (ÉS-) (Μ-l) ’ Residual activity (%) NCBE at 10 μΜ 44 -ch ₂ -ch ₂ -oh allyl-O-CO- 414 . 82.6 45 4-methoxybenzyl allyl-C-CO- 490. 80.1 '46' 4-chlorobenzyl allyl-O-CO- 494 52.2 47 phenyl allyl-O-CO- 445 . 88.1 48 cyclohexyl allyl-O-CO- ..452 • 49 benzyl 3,4,5-trimethoxy- fenvl-CO- 570 75,8 ' . 50 - -ch ₂ -ch ₂ -oe 3,4,5-trimethoxy- phenyl-CO- 524 51 - 4-Methoxybenzyl 3,4,5-trimethoxyphenyl-CO- 600 7 . 52 4-chlorobenzyl 3,4,5-trimethoxyphenyl-CO- 604 . 59,9 ‘ 53 phenyl 3,4,5-trimethoxyphenyl-CO- . -555 54 ' cyclohexyl. .3,4,5-trimethoxyphenyl-CO- 562 55 benzyl-. ·. 2-chlorophenyl-CO-. 514 .29.3 56  -CiL-CH, -OH , ώ · 2 2-chlorophenyl-CO- , 468 69.0 57 4-methoxybenzyl 2-chlorophenyl-CO-. '544' .82,1 . 58 4-chlorobenzyl 2-chlorophenyl-CO- 548- 59.4. . 59 '  phenyl ’ 2-chlorophenyl-CO- 499. 60 cyclohexyl 2-chlorophenyl-CO- '506 61 .benzyl phenyl-CO- · ·. 480. 56.6 62 4-chlorobenzyl . CH, -CC ~ ' 452 94.5 ·.  63 phenyl CH, -CO- 404 64 4-methoxybenzyl e-ch ₃ -ch = ch-co- 47.4  88.0

At- klad C. R ² . R ^J -X MS (ES-) (M-1) ’ Residual activity (%) NCBE at 10 μΜ ⁶⁵ 4-chlorobenzyl CH ₃ - (CH ₂ ) ₃ -CO- 494 80.0 '66 . 4-chlorobenzyl .. phenyl-CH ₂ -CH ₂ -CO- 542 , 83.1 . 67 4-chlorobenzyl e-ch ₃ -ch = ch-co- ' 478 68  2-hydroxyethyl  4-methylphenyl-CO- 448 94.4 69 4-methoxybenzyl ch ₃ -.co- 448 95.4 • 70 4-methoxybenzyl 4-methylphenyl-CO- .524 94.7 '71' 2 - chlor o rben z y .1 benzof b] thiophen-2-yl-CO- 570; '35.2 . 72 isobutyl benzof b] thiophene- -2-yl-CC- 502 86.3. '73 1 (S) -phenylethyl benzof b] thiophen-2-yl-CO- 550 ' 61.0 .'74 2-methoxybenzyl benzof b] thiophene-2-yl-CO- 566 54.7. ,. 75 4-Methylbenzyl. benzof b] thiophene- -2-yl-CO- 550, 80.3 76 3-Methoxybenzyl ... benzof b] thiophen-2-yl-CO- .566 87.3 . 77 3,4-methylenedioxybenzyl Benzof bj thiophene; -2-yl-CO- 580 ., · 81.8 . 78 1 (R) —phenylethyl; benzof; b] thiophene.  -2-yl-CO- 550 88.5 79 4-trifluoromethylbenzyl benzof b] thiophene. -2-yl-CO- 604 61.7 · 80 2- (4-methoxyphenyl) ethyl benzof b] inhiben-2-yl-CO-. '580' 66.7 81 2-chlorobenzyl thien-2-yl-CO- 520 36.0 82 isobutyl thien-2-yl-CO- 452 99.8

At- klad C. R ² R'-X MS (ES—) (M-1) · Residual activity (%) NCBE at 10 μΜ .83 1 (S) -phenylethyl thien-2-yl-CO- 500 97.5 .84 ' . 2-methoxybenzyl thien-2-yl-CO- 516 54.7 85 4-methylbenzyl. thien-2-yl-CO- 500 51, l ' 86 3-Methoxybenzyl thien-2-yl-CO-. 516 57.0 87 3,4-methylenedioxy- benzyl thieri-2-yl-CO- 530. 54.8 . 88 ' 1 (R) -phenylethyl thien-2-yl-CO- 500 ⁸ .9 ' 4-trifluoromethyl- benzyl thien-2-yl-CO- 554 67.6 90 ' 2- (4-methoxyphenyl) ethyl thien-2-yl-CO-  530 84.2  91. : 2-chlorobenzyl 2-fluorophenyl-CO- 532 . 62.7 92 isobutyl 2-fluorophenyl-CO-. 464 93 1 (S) -phenylethyl 2-fluorophenyl-CO- 512: 92.9 94 2-methoxybenzyl , 2-fluorophenyl-CO-. 528. 87.7 .. ⁹⁵  4-methylbenzyl 2-fluoro-phenyl-CO- 512 74.7 96. 3-methoxybenzyl . 2-fluorophenyl-CO- 528 '97 3,4-methylenedioxy-, benzyl 2-fluorophenyl-CO- 5.42 -, ' ⁹⁸ 1 (R) -phenylethyl 2-fluorophenyl-CO-  512 98.0 99 4-Trifluoromethyl . benzyl o -CH _ΓΥΝ - iiuuxtciiyx u-v . 566 SQ 6 , v- 100 ALIGN! 2- (4-methoxyphenyl) ethyl. 2-fluorophenyl-CO- 542 '94.1 . 101 2-chlorobenzyl 2-chlorferiyl-CO-  548. 62.6 102 isobutyl 2-chlorophenyl-CO- 480 103 1 (S) -phenylethyl 2-chlorferiyl-CO-. 528-

At- klad C. r2 R ^x -X> MS (ES-) (Μ-l) ’ Residual activity (%) NCBE at 10 pM 104 2-methoxybenzyl . 2-chlorophenylzCO- 544 105 . 4-methylbenzyl 2-chlorophenyl-CO- 528 106 3-methoxybenzyl 2-chlorophenyl-CO- 544. 98.9 107 3,4-methylenedioxybenzyl 2-chlorophenyl-CO- 558 96.4 108 1 (R) -phenylethyl 2-chlorophenyl-CO- 528 87.7. 109 4-Trifluoromethyl - benzyl • 2-chlorophenyl-CO- ' 582 . 75.4  110 2- (4-Methoxyphenyl) - .ethyl 2-chlorophenyl-CO- 558 111 2-chlorobenzyl (phenyl) ₂ CH-CO- 604 80.5 . 112 isobutyl (phenyl) ₂ CH-CO- . 536 / 90,4 113 1 (S) -phenylethyl . (phenyl) ₂ CH-CO- '584, 94,6 ' ¹¹⁴ 2-methoxybenzyl (phenyl) ₂ CH-CO- 600  81.7 115 4-methylbenzyl (phenyl) ₂ CH-CO- 584 - .84,0 . 116 3-Methoxybenzyl (phenyl) ₂ CH-CO- 600 . 117 3,4-methylenedioxybenzyl. (phenyl) ₂ CH-CO-  614  , . 118 1,1 (R) -phenylethyl (phenyl) CH-CO-. '584'  95.3 119 4-three'fluoromethyl- , benzyl (phenyl) ₂ CH-CO- 638 ' 75.7 120 2- (4-Methoxyphenyl) -. ethyl (phenyl) CH-CO- 614 81.3 . 121; . 2-chlorobenzyl Phenyl-CH2- CC- '528 . 72.1 '' 122 isobutyl phenyl-CH ₂ -CO- 460 90.6 123 1 (S) -phenylethyl phenyl-CH ₂ -CO- ..508- 72.2 124 2-methoxybenzyl  phenyl-CH 2 -CO- 524 '46.5

At- klad C·. R ² R * -X MS (ES-) (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 125 4-methylbenzyl . phenyl-CH ₂ -CO- 508 63.6. 126 3-methoxybenzyl phenyl-CH ₂ -CO- 524. 53.7 127 1 3,4-methylenedioxy- benzyl phenyl-CH ₂ -CO- 538 61.7 128 1 (R) -phenylethyl phenyl-CH ₂ -CO- 508 61.4 129 i 4-trifluoromethyl- benzyl phenyl-CH ₂ -CO- 562 47,4 · 130 '2- (4-methoxyphenyl) ethyl' phenyl-CH ₂ -C0-  538 . 77.8 131 2-chlorobenzyl ¹ phenyl-CH ₂ -CO-CH (phenyl) -CO- 646 97.6 132 1 (S) -phenylethyl (2-thienyl) -CH ₂ -CO- '514' . 63.8 '133 1 (R) -phenylethyl (2-thienyl) - CH ₂ - CO - 514 40.9. 134 isobutyl phenyl-CH ₂ -CO-CH (phenyl) -CO- 578 135 4-methylbenzyl Phenyl-CH 2 - CO-CK (phenyl) -CO- 626 .. 97.4 136 1 (S) -phenylethyl 'Phenyl-CH ₂ -CO-CH (Fe'.. Phenyl) -CO- . 626, 93.6 137 1 (S) - (4-Methyl-phenyl) -ethyl (2-thienyl) -CH ₂ -CO- 528 138 1 (R) - (4-methylphenyl) ethyl (2-thienyl) -CH ₂ -CO- 528 .139 2-furylmethyl (2-thienyl) -CH 2 -CO- 490 48.5 140, ' 4- (dimethylamino) benzyl (2-thienyl) -CH ₂ -CO- 543 54.2 141 2- (2-thienyl) ethyl (2-thienyl) -CH ₂ -OO- 520 71.1 142 2-phenoxyethyl . (2-thienyl) -CH ₂ -CO- 530 27.1

··

- 62. ··

At- klad 'č. R ² r ⁴ -x MS. (ES—) (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 143 .2-chlorohenzyl (2-thienyl) -CH ₂ -CO- 534 35.7 144 cyclopropylmethyl (2-thienyl) -CH ₂ -CO- 464 60.3. 145 3,4,5-trimethoxybenzyl (2-thienyl) -CH ₂ -CO- 590 39.6 146 (4-pyridyl) methyl (2-thienyl) -CH ₂ -CO- 501 69,8 - 147 4-fluorobenzyl (2-thienyl) -CH ₂ -CO- 518 53.2 148 2-furylmethyl (4-chlorophenyl) -CH ₂ -CO- 518 45, 6 149 4- (dimethylamino) benzyl (4-chlorophenyl) -CH ₂ -CCH '.571 77.4. 150 2- (2-thienyl) ethyl (4-chlorophenyl) -CH ₂ -CO- 548 44.7. 151 2-phenoxyethyl (4-chlorophenyl) -CH ₂ -CO- 558 '  29.0 * 152 2-chlorobenzyl (4-chlorophenyl) -CH ₂ -CO- 562 29.5 153 cyclopropylmethyl (4-chlorophenyl) -CH ₂ -CO- 492 . 46.1 '154 2,4-dimethoxybenzyl (4-chlorophenyl) -CH ₂ -CO- 588 36.2 .155 3,4,5-trimethoxybenzyl (4-chlorophenyl) -CH ₂ -CO- 618 '34.2 '156 (4-pyridyl) methyl (4-chlorophenyl) -CH ₂ -CO- ⁵²⁹ 86.0 157 4-fluorobenzyl . (4-chlorophenyl) - CH ₂ -CO- . 546, 24.9 158 '. 2-furyimethyl (CH ₃ ) ₃ C-CH ₂ -CO- . 464 . 57.9 '559. . 2- (2-thienyl) ethyl (CH ₃ ) ₃ C-CH ₂ -CO- . 494 61,2 · - 160 2-phenoxyethyl <(CH ₃₎ C-CH ..- CC- 504 71.6 161 cyclopropylmethyl (CH ₃ ) ₃ c-ch ₂ -co- 438 ' 81.6 '· 162. 3,4,5-trimethoxybenzyl _^(CH,)? C-CH ... -CO- ' 564 30.2 163 4-fluorobenzyl (CH 2) ₃ C-CH ₂ -CO-. 492 '93, 4 ' , 164 2-furylmethyl . phenyl-O-CH-CO- 500 '76.4 165 2- (2-thienyl) ethyl phenyl-OCH ₂ -CCD 530 '56.8 166 '' 2-phenoxyethyl phenyl-CH ₂ -CO- 540 . 57.9 ¹⁶⁷ ' 2-chlorobenzyl phenyl-CH ₂ -CO- 5.44 '. 47.5

At- klad C. R ² R'-X MS ‘(ES -) (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 168 ' “cyclopropylmethyl” phenyl-CH ₂ -CO- 474 96, 4 169 3,4,5-trimethoxybenzyl . phenyl-O-CH ₂ -CO- ' 600 170 4-fluorobenzyl ¹ phenyl-CH ₂ -CO- 528 Í71 2-furylmethyl (4-methoxyphenyl) -ch ₂ -co- 514 172 2- (2-thienyl) ethyl (4-Methoxyphenyl) - - -CH.-CO- and. 544 89,7 ' 173 2-phenoxyethyl (4-methoxyphenyl) -ch ₂ -co- 554 • 76.4 '174 2-chlorobenzyl (4-methoxyphenyl) -ch ₂ -co- 558 50.2 _; 175 ' cyclopropylmethyl (4-Methoxyphenyl) - -CH.-C0- ' of. 488 93.2 176 ' 3,4,5-trimethoxybenzyl (4-methoxyphenyl) - '- ₂ -co- . 614 . 83, 9 177 4-fluorobenzyl (4-Methoxyphenyl) - -CH ..- CO- 542 64.4 178 2-furylmethyl ch ₃ -co- ' , 408 70.6 179 2- (2-thienyl) ethyl - ch ₃ -co- 438. 78.3 180 2-phenoxyethyl ch ₃ -co- . 448 ' 70.9 - -181 ' 2-chlorobenzyl ch, -co-. 452, 80.8 182 cyclopropylmethyl 'ch ₃ -co- 382 74.9 , .183 2,4-dimethoxybenzyl CH.-CO- 478 184 3,4 ,. 5-trimethoxybenzyl CH.-CA- O. • 508 , 185 4-fluorobenzyl 'CH.-CO- '436. 85.0 '186 3-phenylpropyl (2-thienyl) - _{(CH2) 3} -CO- 556 9.7: 187 2-methoxyethyl (2-thienyl) - _{(CH2) 3} -C0- 496 ' 62.4 • 188 ' (2-pyridyl) methyl (2-thienyl) - _{(CH2) 3} -C0- 529 52.3

At- - klad C. R ² . . R ^ X MS (ES-) (M-l) ’ Residual activity (%) NCBE at 10 μΜ 189 cyclopropyl (2-thienyl) - _{(CH2) 3} -CO- 478 72.5 190 methyl (2-thienyl) - _{(CH2) 3} -CO- 452. 43.4 191 ethyl (2-thienyl) - _{(CH2) 3} -CO- 466 39.3 192 (2-benzimidazolyl) methyl (2-thienyl) - _{(CH2) 3} -C0- 568 . 49.1  193 1-methoxycarbonyl-2-phenylethyl . (2-thienyl) - _{(CH2) 3} -OO- . 600. 62.8 194 .3-phenylpropyl (2-thienyl) -CO-CO-- 54-2 61.1 .195 2-methoxyethyl (2-thienyl) -CO-CO-- 482. 58.3. ., 196 ' (2-pyridyl) methyl (2-thienyl) -CO-CO-- 515. 62.8 197 ' cyclopropyl (2-thienyl) -CO-CO-- 464 . 79.9 198 methyl (2-thienyl) - CO-CO- 438. .51.1 ’’. · .199 ethyl . (2-thienyl) -CO-CO-- 4.52. 54.7 20 .0 (2-benzimidazolyl) <methyl ' . (2-thienyl) -CO-CO-- .554 . 55.2 and 2 01 1-methoxycarbonyl-2-phenylethyl (2-thienyl) -CO-CO-- 586, , 69.6 202 3-Phenylpropyl (indol-3-yl) -CEL-CO- ⁵⁶¹ 38.5 • 203. 2-methoxyethyl (indol-3-yl) -CH ₂ -CO- 501 ' 30.3 ’ 204 (2-pyridyl) methyl (indol-3-yl) -CH _{2 -} .CO'- 534 • 52.4 , 205 cyclopropyl,; i '' ·. (indol-3-yl) -CH ₂ -CO- ^r '483 -41.7. . 206 - methyl. (indol-3-yl.) -CH ₂ -CO- - 457 ' 23.8  207 ·· ethyl (Indol-3-yl) -CH ₂ -CO- ´ 471. 31.0 208 . (2-benzimidazolyl) methyl ¹ (indol-3-yl) -CH ₂ -CO- . 573 50.7 209 1-methoxycarbonyl-2-phenylethyl (indol-3-yl) -CH ₂ -CO- '60 5 56.2

9 9 9 9 9 9 9 9 9

9 9 9

99 '99 99

At- klad C. R ² . R ³ -X MS .. (ES-), (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 210 3-phenylpropyl (benzoph b] thiophen-3-yl) -CH ₂ -CO- 578 66.2 211 2-methoxyethyl . (benzoph b] thiophen-3-yl) -CH 2 -CO-  518 ’50.6 212. (2-pyridyl) methyl (benzof b) thiophene- (3-yl) -, CH, -CO- 551 60.2 213 . cyclopropyl (benzof b] thiophen-3-yl) -CH ₂ -CO- '500 • 45.0 214. methyl (benzoph b] thiophen-3-yl) -CH ₂ -CC- 474 44,3 - '215 ethyl . (benzoph b] thiophen-3-yl) -CH., -CO- '488 65.7 216 (2-benzimidazolyl) methyl (benzoph b] thiophen-3-yl) -CH ₂ -CO- . 590 62.2 217 1-methoxycarbonyl! -2-phenylethyl (benzoph b] thiophen-3-yl) -CH ₂ -CO- 622 46.0 '218 .3-phenylpropyl. (2-thienyl) - (CH ₂ ) ₄ -CO- 570 37.1 .219. 2-methoxyethyl. (2-thienyl) - (CH ₂ ) ₄ -C 0 - ⁵¹⁰ 82.5 220 ' (2-pyridyl) methyl (2-thienyl) - (OH ') ₄ -CO- 543 73,2 ' , 221 ' cyclopropy1 ' .. (2-thienyl) - _{(CH2) 4} -CC- 492 .. 72.3. 222. methyl (2-thienyl) - (CH ₂ ) ₄ -CO-  466 '76, 7 . 223 .. ethyl (2-thienyl) - (CH ₂ ). ₄ -CQ- . 480 53.8 224 (2-benzimidazolyl) methyl . (2-thienyl) - _(CH2).-CO- , 582 79.8 225 1-methoxycarbonyl. -2-phenylethyl (2-ťhi.enyl) - _(CH2) -CO- 614 , 88.1 '226 3-Phenylpropyl (3-thienyl) -CH ₂ -CO- 528 34.8 221 2-methoxyethyl (3-thienyl) -CH ₂ -CO- 468 50,6 '

99 99 · 99 99 99 99 99 99 99

- 66 · «© © 66 66 66 66 66 66 66 66

99 • 9 9 • 9

9 9 9

99

At- klad C. . . R ² R ^x -X. MS (ES-) (M-l) ’ Residual activity (%) NCBE at 10 μΜ 228 (2-pyridyl) methyl (3-thienyl) -CH ₂ -CO- 501 94.8 229, cyclopropyl. (3-thienyl) -CH ₂ -OO- 450 86.7 230 methyl (3-thienyl) -CH ₂ -CO- . 424 68.6 231 ethyl (3-thienyl) -CH ₂ -CO- 438 57.8 232 (2-benzimidazole) - methyl (3-thienyl) -GH ₂ -CO- 540 62.6 233 , 1-methoxycarbonyl - · -2-phenylethyl (3-thienyl) -CH ₂ -CO- 572. 68.1 ... 234 ' 2-phenylethyl (2-thienyl) -CH ₂ -CO- 514 235 4-trifluoromethylbenzyl (2-thienyl) -CH ₂ -CO- 568 67.1 236  3-phenylpropyl (2-thienyl) -CH ₂ -CO- 528 35.1 '237 2-thoxye thyl - (2-thienyl) -CH ₂ -CO- 468. 50.3 238 ί (3,4-dihydroquinazo- lin-2-yl) methyl (2-thienyl) -CH ₂ -CO- 554 '54, 7 239 methyl. (2-thienyl) -CH ₂ -CO- 424 , 56.3 '240' ethyl (2-thienyl) -CH ₂ -CO- . 438 58.0 241. benzyl phenyl-CH (NH ₂ ) -CO- 509 66.0 , 242. ' benzyl phenyl-CH (NHCO-O-benzyl) -CO- . 643 72.4 243 benzyl (2-nitrophenyl) -CH ₂ -CO- - · 539- 99.9 244 benzyl , Phenyl- (CH _{2) 4} -CO- 536 .60,4. 245 benzyl (2-furyl) -CO-CO- 498  73.0 '246 propargyl phenyl-CH (NHCO-O-benzyl) -CO- 591 65, .0 247. .propargyl phenyl- (CH _{2) 4} -CO- 484 , .74,6 248 ² propargyl (2-furyl) -CO-GO-. 446 66,6 ' 249 propargyl cyclohexyl-CH ₂ -CH ₂ -CO- 462 76.1

φ • * * * * * · • · · • • • φ φ φ φ φ φ. > φφ '· Φ Φ «11 ·

Φ Φ - φ Φ Φ

ΦΦΦ ΦΦ ΦΦ

ΦΦ ΦΦ • Φ Φ · • Φφφ

Φ Φ Φ Φ

Φ Φ Φ Φ

Φ «ΦΦ

 Example C. R ² Ø-X MS. (ES-) (M-1) ’ Residual activity (%) NCBE at 10 μΜ 250 (2-thienyl) methyl (2 = thienyl) -CH ₂ -CO- 506 41.1 - ²⁵¹ (2-thienyl) methyl phenyl-CH (NHCO-O-ben- zyl) -GO- 649 83.9 252 (2-thienyl) methyl (2-nitrophenyl) -CH ₂ -CO- 545 44.5 253 (2-thienyl) methyl. . phenyl- (CH _{2) 4} -CO- 542 35.3 - 254 (2-thienyl) methyl · (2-Furyl) -CO-CO- 504. 64.5 255 (2-thienyl) methyl cyclohexyl-CH ₂ -CO ₂ -.CH 520 61,0 · 256. cyclohexylmethyl (2-thienyl) -CH ₂ -CO- 506 .36,4 '257 ... cyclohexylmethyl • (2-nitrophenyl) -CH ₂ -CO- 545. 54,6 ' , 258. cyclohexylmethyl (2-Furyl) -CO-CO- -504 95,8 ^: . 259 3,4-dichlorobenzyl (2-thienyl) -CH ₂ -CO- '568  40.1 260 3,4-Dichlorobenzyl phenyl-CH (NHCO-O-benzyl) -CO- .711 69.8 '261' 3,4-dichlorobenzyl (2-nitrophenyl) -CH ₂ -CO- . 607 . ' 67.7 262 3,4-dichlorobenzyl phenyl- (CH3) ₄ -CO-; 604 45.3 ²⁶³ 3,4-dichlorobenzyl (2-furvi) -CO-CO- . 566 54.0 . 264 3,4-Dichlorobenzyl _{cyclohexyl-CH2 --CH2} --CO-- 582 ^; .74,3. .265 cyclohexylmethyl phenyl-CH (NHCO-O-benzyl) -CO- 649 68, 9 266  cyclohexylmethyl. · phenyl- (CR.), -CO-. 542 79.7 . 267 cyclohexylmethyl cyclohexyl-CH ₂ -CH ₂ -ČQ- 520 57, 9 268 phenyl-CH (COOCH3 -). (2-thienyl) -CH ₂ -CO- . 558 79,3 ' 269 phenyl-CH (COOC. (CH3) ₃₎ - '(2-thienyl) -CH ₂ -CO = _; 600 94.4 7 270 2,4-dichlorobenzyl (2-thienyl) -CH ₂ -CO- '568 33,9 ' '27.1 (1-naphthyl) methyl (2-thienyl) -CH ₂ -CO- 550 . 15.9 272 2- (4-H ₂ NSO ₂ -phenyl) ethyl (2-thienyl) -CH ₂ -CO- 593 ,. 65.0

• · · · · · · ·

At- klad C. -R ² R ^-1 -X MS (ES-) (Μ-l) ' Residual activity (%) NCBE at 10 μΜ 273 3-chlorobenzyl (2-thienyl) -CH ₂ -CO- 534 32.4 274 - phenyl-CH (COOCH ₃₎ - (2-bromophenyl) -GH ₂ -CO- 630 73.6 -275 phenyl-CH (COOC (CH3) ₃₎ - - (2-bromophenyl) -CH ₂ -CO- 672 54,6, 276 2,4-dichlorobenzyl (2-bromophenyl) -CH ₂ -CO- 640 36.8 277. (1-naphthyl) methyl (2-bromophenyl) -CH ₂ -CO- . 622 ' 36.3. 278 3-chlorobenzyl . (2-bromophenyl) -CH ₂ -CO- 606. 31.2. 279. - 2,4-dichlorobenzyl. phenyl-SO ₂ -CH ₂ -CH ₂ -CO- 640 90.5 280 (1-naphthyl) methyl phenyl-SO ₂ -CH ₂ -CH ₂ -CO- . 622 63, .3 .281 3-chlorobenzyl phenyl-SO ₂ -CH ₂ -CH ₂ -CO- 606 ' 68> 6 282 phenyl-CH (COOH) - (2-thienyl) -CH ₂ -CO- 544 89.0 283 2,4-dichlorobenzyl (4-hydroxyphenyl). -ch ₂ -co-. 578 80.0. '284 (i-naphthyl) methyl (4-hydroxyphenyl) · -ch ₂ -co- 560 52, 9 '285 3-chlorobenzyl (4-Hydroxyphenyl) -. -ch ₂ -co- 544 '. 5.8,8 286 phenyl-CH (COOCH ₃₎ - ^{(2-1-thia-phenyl)} -CH ₂ - -CH ..- CO- '572 68.8 287 phenyl-CH (COOC (CH3) ₃₎ - (2-thienyl) -CH ₂ -CH ₂ -co- 614 51,1 ' . 288 ' 2,4-dichlorobenzyl - (2-thienyl) -CH 2 - •. * of. -CH.-CO- ’ 582 63.1 289 (1-naphthyl) methyl (3-thienyl) -CH ₂ - -CH ₂ -co- 564 « 39.2 290 - 3-chlorobenzyl (2-thienyl) -CH ₂ -CH ₂ -co- 548 45.8 291- 2-chlorobenzyl (2-chlorophenyl) -CH ₂ -CO- '562 - 23.7. 292. 2,4-dichlorobenzyl (2-chlorophenyl) -CH ₂ -CO- 596 -

At- klad C. R ² T R ^! -X MS (ES.-) (Μ-1); Residual activity. (%) NCBE at 10 μΜ 293 (1-naphthyl) methyl (2-chlorophenyl) -CH ₂ -CO- '578 55.1 294 2- (4-H ₂ NSO ₂ -phenyl) -. ethyl (2-chlorophenyl) -CH ₂ -CO- '621 82.7 295 (2-thienyl) methyl phenyl-CH ₂ -NH-CO- 515 8.0 ... 296 (2-thienyl) methyl N-Cyclohexyl-NH-CO-. 507 31.7: 297 . benzyl N- (2,6-difluoro- . phenyl) -NH-CO- 531. 80,4 ' 298 benzyl N-isopropyl-NH-CO- 461 74.7 -299 benzyl phenyl-CH ₂ -NH-CO- ' 509 48.6 300 benzyl N-cyclohexyl-NH-CO- 501 29.4 301. 3-methoxybenzyl N- (2,6-difluoro ·· phenyl) -NH-CO-1 ' '561 87.9 3.02 3-methoxybenzyl. . N-isopropyl-NH-CO- 491 80.4 , 303 3-methoxybenzyl phenyl-CH2-NH-CO- 539 65.8 304 ' . 3-methoxybenzyl N-cyclohexyl-NH-CO- .531 .56,0 ·. . 305 3-chlorobenzyl N- (2,6-difluoro- phenyl) -NH-CO- 565 84.9 306 3-chlorobenzyl, N-isopropyl-NH-CO- . 495. 90.2 307. 3-chlorobenzyl, phenyl-CH ₂ -NH-CO- 543. . 55.8 . 308 3-chlorobenzyl N-Cyclohexyl-NH-CO- 535 ^; 32.1. . 309 2,3-dichlorobenzyl (2-thienyl-) -Cn ₂ -CO- .568 /  88.9 310 (2-naphthyl) methyl. (2-thienyl) -CH ₂ -CO- . 550 47.7  311 3-methylbenzyl (2-thienyl) -CH ₂ -CO- 514 .. 10.4 ' 312 2-methylbenzyl . (2-thienyl) -CH2- CO- . 514 ' 12.5 .313 (CH ₃ ) ₂ C = CH-CH ₂ -CH ₂ -. -C (CH ₃ ) = CH-CH ₂ - (2-thienyl) -CH 2 -CO-. 546 17.2 314 1-indanyl (2-thienyl) -CH ₂ -CO- .526. 14.4

At- klad C. R ² r ¹ --x MS (ES-) (M-1) - Residual activity (’%) NCBE at 10 μΜ. 315 1,2,3,4-tetrahydro- -1-naphthyl (2-thienyl) -CH ₂ -CO- 540 23.5 . 316 2-fluorobenzyl (2-thienyl) -CH ₂ -CO- 518 .. 14.4 317 3-phenylbenzyl (2-thienyl) -CH ₂ -CO- 576 _ 14.5 318 (1,2 ', 3,4-tetrahydro-2-furyl) methyl (2-thienyl) -CH ₂ -CO- 494 16.4 319 2,3-dichlorobenzyl _{methoxy-CH2 -CH2} -CO- 530 38.0 . 320 (2-naphthyl) methyl _{methoxy-CH2 -CH2} -CO- 512 38.8 , 321 . 3-methylbenzyl . methoxy-CH ₂ -CH ₂ -CO- 476 322 2-methylbenzyl. _{methoxy-CH2 -CH2} -CO- 476 66.3 323 (CH ₃ ) ₂ C = CH-CH ₂ -CH ₂ -c (CH ₃ ) = ch-ch ₂ -. _{methoxy-CH2 -CH2} -CO- 508 , 23.6 . . 324 1-indanyl _{methoxy-CH2 -CH2} -CO- .488 60.5 325 1,2,3,4-tetrahydro-1-naphthyl _{methoxy-CH2 -CH2} -CO- 502 .33.8 326 2-fluorobenzyl _{methoxy-CH2 -CH2} -CO- - 480 25.6 327 * 3-phenylbenzyl , Methoxy, -CH ₂ -CH ₂ -CO- / 538 17.4 328 (1,2,3,4-tetrahydro-2-furyl) methyl \ _{methoxy-CH2 -CH2} -CO- ' .456 87.0 329 2,3-dichlorobenzyl 2-methoxyphenyl-CO- ⁵⁷⁸ 25.7 75 on JJO (2-naphthyl) methyl 2-methoxyphenyl-CO ^- 560 .14,4 331 · 3-methylbenzyl 2-methoxyphenyl-CO- 524 .37.6 .332 2-methylbenzyl 2-methoxyphenyl-CO- 524 31.7 '333 (CH ₃ ) ₂ c = ch-ch ₂ -ch ₂ -C (CH ₃ ) = CH-CH ₂ - .2-methoxyphenyl-CO- . 556 '22.3 ·' 334 1-indanyl 2-methoxyphenyl-CO- 536 335, 1,2,3,4-tetrahydro-1-naphthyl 2-methoxyphenyl-CO- 550 79.5

At- klad - č. R ² 'R ^L -X. . MS (ES-) (Μ-l) ' Residual activity (%) NCBE at 10 pM 336 2-fluorobenzyl 2-methoxyphenyl-CQ-. 528 58, i. 337 3-phenylbenzyl 2-methoxyphenyl-CO- 586 • 51.2 338. (1,2,3,4-tetrahydro-2-furyl) methyl 2-methoxyphenyl-CO- 504  50.7 , 339 2,3-dichlorobenzyl phenoxy-CH ₂ -CH ₂ -CO- 592 46.8 340 (2-naphthyl) methyl phenoxy-CH ₂ - CH ₂ CO - 574 37.2. 341 3-methylbenzyl phenoxy-CH ₂ - CH ₂ - CO - 538. 44.6 342 2-methylbenzyl phenoxy-CH ₂ -CH ₂ -O-CO- 538 85.3. '' 343 , (CH ₃ ) ₂ C = CH-CH ₂ -CH ₂ -C (CH ₃ ) = ch-ch ₂ - phenoxy-CH ₂ -CH ₂ -CO- 570. 48.1 344 1-indanyl phenoxy-CH ₂ -CH ₂ -CO- 550 52.2 345 1,2,3,4-tetrahydro-1-naphthyl _{phenoxy-CH2 --CH2} --CO--. /. , 564 · 39,8 ·· i 346 2-fluorobenzyl. _{phenoxy-CH2 --CH2} --CO-- 542 - 36.0 347 - 3-phenylbenzyl phenoxy-CH ₂ -CH ₂ -CO- 600 ' 19.3 348 (1,2,3,4-tetrahydro-2-furyl) methyl phenoxy-CH ₂ -CH ₂ -CO-, ^-: /. \ / 51.8 46.3 349 ‘ 2,3-dichlorobenzyl ohexyl-CH ₂ -CO- , 568 50.4 350 (2-naphthyl) methyl, oykÍohexyl-CH ₂ -CO- 550, 351 . 3-methylbenzyl · cyclohexyl-CH, -CO- b ¹ J • 514 27.2 352 - 2-methylbenzyl 1 -cyclohexyl-CH ₂ -CO - 514 .. QQ 0 ' 353 (CH 2 O 2 CH 2 -C 1 CH ₂ ) - -C (CH ₃ ) = ch-, ch ₂ - ... Cycle ohexyl - CH ₂ - CO - 546 47.9 '354, . 1-indanyl cyclohexyl-CH ₂ -C0- 526 .-37.2 355 1,2,3,4-tetrahydro-1-naphthyl 'Cyclohexyl-CH ₂ -CO- . 540. ' / 46.8 356 ¹ 2-fluorobenzyl ohexyl-CH ₂ -CO-  518 47.4

'• Ύ-Τ ⁷ ' -:

At- klad C. R ² R ^x -X MS (ES-) (Μ-l) ’ Residual activity (%) NCBE at 10 μΜ 357 3-Phenylbenzyl cyklohexy1 - CH ₂ - CO - 576 61,9 ' 358 (1,2,3,4-tetrahydro-2-furyl) methyl Cycle ohexy 1 - CH ₂ - CO - 494, of' 55,5 - 359  2,3-dichlorobenzyl cyklbpentyl -CO-CH ₂ -. 554 37.9 360 (2-naphthyl) methyl open tyl cycle - CH ₂ - CO - 536. 36.9 361. 3-methylbenzyl _{cyclopentyl-CH2} -CO- ¹ 500 29.4 362 '. , 2-methylbenzyl open-cycle - CH - CO - 500 '44, 4 363. (CH 2 -CH 2 -CH 2 CH 2 -C (CH ₃ ) = ch-ch ₂ - opentyl-CH ₂ -CO- 532 48.3  '364 1-indanyl cyclopentyl-CH ₂ -CO- 512 52.6 . 365 1,2,3,4-tetrahydro-1,2-naphthyl cyclopentyl-CH ₂ -CO- 526 45,1 ' 366 2-fluorobenzyl cyclopentyl-CH ₂ -CO- 504 38.4 367 3-phenylbenzyl Cyclopentyl yl t - CH ₂ - CO - 562 25.5 '368 (1,2,3,4-tetrahydro-2-furyl) methyl cyclopentyl-CH ₂ -CO- 480 51.0. . 369 2,4-difluorophenyl 4-methy1feny1-SO ₂ - 590 . 33.7 370 4-tert-butylphenyl. 3,4-dimethoxyphenyl-SO ₂ - 656 50.1 '371 4-tert-butylphenyl 2,5-dimethoxy- · fenvl-SO ^ - . · Í. 656 ' . 38.6 372., 2,4-difluorophenyl 2,3,4,5,6-Penetramethylphenyl-SO ₂ - 646  23,1 ' 373 • '. 2,6-dichlorophenyl 3-fluoro-2,4-dimethylphenyl-SO ₂ -, 654 20.6. - 374 3-chloro-4-fluorophenyl 4-fluoro-3,5-dimethylphenyl-SO ₂ - 638 . 70.3. 375 '. ; 2-cyanophenyl. - 4-methylphenyl-SO ₂ -  579 80.6

At- klad C.' R ² R ^x -X MS (ES-) (M-1) - Residual activity (%) NCBE at 10 pM 376 4-chloro-2,5-di- methoxyphenyl 4-methylphenyl-SO ₂ - 648 66.6 .377 4-chloro-2,5-dimethoxyphenyl 4-chlorophenyl-S0 ₂ - 668 36.8. 378 ' 4-fluorophenyl 2,4,5-trichloro, nyl-SO ₂ - . 660: 43/6 - 379. 4- (4-fluorophenoxy) phenyl 4-methylphenyl-SO ₂ - . 664 380 2-chlorophenyl 2,5-dimethoxy- phenyl-SO ..- 634 28.1 381 2-cyanophenyl 2, .- 5-dimethoxyphenyl-SO ₂ - 625 60 ,, 8 382 2,3-dichlorophenyl 3,4-Dichlorophenyl- SO ₂ - 676 '. -47.1 . 383 ^; 4- (4-chlorophenoxy) phenyl 4-methylphenyl-SO ₂ ~ 680 42.2 384. 3-trifluoromethylphenyl 4-methylphenyl-SO ₂ - 622 57.2 ' ³⁸⁵ 2-cyanophenyl 4-tert-butylphenyl-SO ₂ - 621 · .- 64.8 ^: 386 2-acetylphenyl 2,4-dichlorophenyl-SO ₂ - 650 : 33,5 387. 2-Acetylphenyl 2, 3-dichlorophenyl-S0 ₂ - . 650. . 29.8 388 . benzyl - (3-thienyl) -CH-. 7- (CH3) -CO- 514 - 63.7 • 389. benzyl - (2-furyl) -CH 2 - CO- 484 • 51.5 . 390 ,. (1-naphthyl) methyl (2-thienyl) -CH- . - (CH) -CO- 564, 89.8; -391. (1-naphthyl) methyl. (2-furyl) -CH ₂ -CG- 534 55.4 392 (1-phenylcyclopentyl) methyl (2-thienyl) -CH ₂ -CO- 568. 55.6 393 (1-phenyl cyclopentyl) methyl (2-thienyl) -CH-. - (CH ₃₎ -CO- 582 16.7

At- klad no. R ² R ^ X MS (ES-) (M-l) ’  Residual activity (%) NCBE at 10 μΜ 394 (1-phenylcyclo- pentyl) methyl (2-furyl) -CH ₂ -CO- 552 72.5 395 2-ethyl-2- (4-methoxyphenyl) butyl (2-thienyl) -CH ₂ -CO- 600 '50 / .9 396 [3- (pyrrolidine-1-car- bonyl) -4,5-dihydroiso- xazol-5-yl] methyl (2-thienyl) -CH ₂ -CO- 590 53.2 397 ' [3- (pyrrolidine-1-carbonyl) -4,5-dihydroiso- xazol-5-yl] methyl (2-thienyl) -CH- - (CH ₃₎ -CO- 604 . 44, Ό 398 phenyl .phenyl-SO ₂ - 540- 399 4-Acetylamino-2-methyl-phenyl 4-chloro-phenyl-SO ₂ - - · 645 4.00 5-acetylamino-2-methylphenyl 2, 5-dichlorophenyl-S0 ₂ - 679 401 . 4-acetylamind-2,6- -dimethylphenyl 4-methylphenyl-SO ₂ - 639 402 phenyl 4-methylphenyl-S0 ₂ - .554 403 2-acetylphenyl. ' 2,4,5-trichlorophenyl-SO ₂ - 684. 404 2-acetylphenyl 4-trifluoromethyl, phenyl-SO ₂ - ' 650 405 4-chlorophenyl 4-chlorophenyl-S0 ₂ - 608 ' 406 4-chlorophenyl phenyl-SO ..- 574 407 3-acetylphenyl _; ·. · 4-methoxyfeny1-S0 ₂ - 612 408 3-Acetylphenyl _{2-chlorophenyl-2-SO} 616 409 ·. 3-acetylphenyl 2-chloro-6-methyl · - 'phenyl-SO ₂ - 630, 410 3-acetylphenyl 4-tert-butylphenyl-SO ₂ - ·. 638 -

At- klad C. R ² R * -X MS (ES-) (M-l) ’ Residual activity (%) NCBE at 10 pM 411 ' 3-acetylphenyl _{4-fluorophenyl-2'S0} - 600 ' 412 3-acetylphenyl 3,4-dichlorophenyl-SO ₂ - 650. 413 3-acetylphenyl 2,4-difluorophenyl-S0 ₂ - 618 414 . 3-acetylphenyl . 3-Trifluoromethylphenyl-SO ₂ - 650 415 4-trifluoromethylphenyl 4-acetylamino-phenyl-SO ₂ - 665 . 416 2,5-difluorophenyl. 4-acetylamino-phenyl-SO ₂ - 633 .417 ' 4-tert-butylphenyl '. 4-acetylamino- ... fenvi-SO.- 653 418 4-isopropylphenyl 2-chloro-4-cyano-phenyl-SO ₂ - 641 419 ' 4-methoxyphenyl 4-acetylamino-phenyl-SO ₂ - 627 420 4-ethoxyphenyl 4-chlorophenyl-S0 ₂ - '. 618  421 5-chloro-2-methoxyphenyl _{4-chlorophenyl-SO2} - 638 .422 5-chloro-2-methoxyphenyl 2,4,5-trichloro- phenyl-SC-. . 706. ' ⁴²³ . '. 2-fluorophenyl - 4-Acetylaminophenyl-SO ₂ - , 615 ' 424 1-Naphthyl '. '4-acetylamino.' feryl-SO., - 647. 425 2-trifluoromethylphenyl 4-acetylamino-. phenyl-SO ₂ - . 665 426 2-ethylphenyl - 4-chlorophenyl-S0 ₂ -. 602 . 427 2,4-dimethylphenyl phenyl-SO, - .568 ^: 428 2,4,5-trimethylphenyl _{4-chlorophenyl-SO2} - 616

At- klad C. R ² r ³ -x MS (ES-) (M-1) ' Residual activity (%) NCBE. at .10 μΜ 429 - 2,5-dimethylphenyl. 2,4,5-Trichlorophenyl-SO ₂ - 670 - ¹ 430 5-chloro-2-methylphenyl 4-chlorophenyl-S0 ₂ - 622. 431- 4-fluorophenyl phenyl-SO ₂ - 558 432 3-chloro-2-methylphenyl phenyl-SC ..- 588 433 4-chloro-2-methylphenyl, phenyl-SO ₂ - 588 434 2,3-dichlorophenyl - 4-chlorophenyl-S0 ₂ -. .642 '435 3-trifluoromethylphenyl 2,4,5-Trichloro-phenyl-SO ₂ - 710 436 ' 5-chloro-2-methylphenyl 2,4,5-trichlorophenyl-SO ₂ - 690 437. . 2-fiuorfenvl · 2,4,5-trichloro. phenyl-SO ₂ - 660 · 438 2,6-dimethylphenyl) phenyl-SC ·., - 568 . 439 2,3-dimethylphenyl phenyl-SO ₂ - 568 440 1-Naphthyl 3, 4-dichlorophenyl-S0 ₂ - 658 · ' 441 4-ethoxyphenyl 3,4-dichlorophenyl-S0 ₂ - .652 , 442 . 1-Naphthyl 4-chlorophenyl-S0 ₂ - 624. 443, 3,5-dichlorophenyl 3, 4-dichlorophenyl-S0 ₂ - 676 444 2,4,5-trimethylphenyl 4-acetylamino-phenyl-SQ ₂ - 639 445 3,4-dichlorophenyl · 3,4-Dichlorophenyl-SO _from - 676 446 ' 3,4-dimethoxyphenyl Is 4-methylphenyl-SO ₂ - • 614 447 · 4-fluorophenyl 4-methylphenyl-SO ₂ - 572 '448 ‘ 4-bromophenyl 2-naphthyl-SO ₂ - 668 449 2-chlorophenyl 2-naphthyl-SO ₂ - 624 450 2-Methylphenyl · 2-naphthyl-SO ₂ - '604

At- klad C. R ² R‘-X MS ' (ES-) (M-l) ’ Residual activity (%) NCBE at 10 μΜ '451 2-methoxyphenyl 2-naphthyl-SO ₂ - 620 452 phenyl,. 2-naphthyl-SO ₂ - 590. .. 453 2,6-diethylphenyl _phenyl-SO2 ~. 596 454 2,6-diisopropyl-phenyl phenyl-S0 ₂ - 624 455 ' 2-Biphenylyl 4-methylphenyl 1 - SO ₂ - 630 ’456 2-Naphthyl 2-naphthyl-SO ₂ - 640 457 4-methylphenyl 2-naphthyl-SO ₂ - 604 458 2,4-dimethoxyphenyl 4-methylphenyl-SO ₂ - . 614 .459 2,5-dimethylphenyl 4-acetylamino-phenyl-SO ₂ - 625 460 2-chloro-4-methoxyphenyl _{4-chlorophenyl-SO2} - 638 ' ^: 461 2-Methoxy-5-methyl- fényl _phenyl-SO2 - 584 462 3-Methoxy-4-methylphenyl phenyl-SO ..- 584 463 2-methoxyphenyl 4-chlorophenyl-SO ₂ - 604 464 _x . 3-hydroxyphenyl 4-chlorophenyl-S0 ₂ -. .590 465 · . 3,4-Dichloro-phenyl 4-chlorophenyl-SO ₂ - '642' 466. 3-acetylphenyl 4-chlorophenyl-S0 ₂ - 616 467 2,6-Diethylphenyl 4-Methylphenyls 1 - SO ₂ - 610 468 5-chloro-2-methoxyphenyl 4-acetylamino-phenyl-SO ₂ - 661 '469 5-chloro-2-methylphenyl phenyl-SO ,, - 588 470 2-chloro-5-trifluoro- methylphenyl _{4-chlorophenyl-SO2} - 67.6 .471 2-acetylphenyl 2, 4-.difluorfenyl-S0 ₂ - '618 '' 472 1-acetylamino-2-naphthyl 4-methylphenyl-SO ₂ - . 661

• Φ

I «φ · e ·

At- klad C. R ² . ' , R-X .MS (ES-) (M-1) Residual activity (%) NCBE at 10 pM . 473 4-ethylphenyl 4-chlorophenyl-S0 ₂ - 602 474 2,5-dichlorophenyl · 4-methoxy-phenyl-SO ₂ - - 638 475 2,4-difluorophenyl 4-fluoro-3,5-dimethylphenyl-SO ₂ - 622 476 4-trifluoromethoxyphenyl 2,5-dimethoxy-phenyl-SO ₂ - 684 477 2-chlorophenyl 3,4-dimethoxyphenyl-SO ₂ - 634 : 478 2-methyl-1-naphthyl phenyl-SO ₂ - • 604 479 2,6-dimethylphenyl 4-c, ethylamino-phenyl, and SO ₂ - 625 . 430. 1,3-dihydro-1-oxo-. benzofi] furan-6-yl 4-chlorophenyl-S0 ₂ -. 630 481 benzyl (5-Methyl-2-thienyl) -CH- (CH ₃ ) -CO- • 528 • 62.6 '482 3 - ni t hen z.y 1 (2-thienyl) -CH ₂ -CO- '545 483. neopentyl (2-thienyl) -CH ₂ -CO- 480 '484 isopropyi (2-thienyl) -CH ₂ -CO- .452 485 2-ethoxybenzyl (2-thienyl) -CH ₂ -CO- 544. 486 3-nitrobenzyl . (3-thienyl) -CH ₂ -CO- '545 , 487 ^: ·· neopentyl (3-thienyl) -CH ₂ -CO- 480 ' .488 isopropyi (3-thienyl) -CH ₂ -CO = . 452 '489 2-ethoxybenzyl (3-thienyl) -CH ₂ -CO- 544 . 490 2,2,2-trifluoroethyl (3-thienyl) -CH ₂ -CO-. . 492 -. '  491 · 2- (3-Trifluoro- methylphenyl) ethyl (3-thienyl) -CH ₂ -CO- 582 492 3-nitrobenzyl. (2-fluorophenyl) -CH ₂ -CO- 557 ' 493 ¹ . neopentyl. (2-Fluorophenyl) -CH ₂ -CO- 492

··

At- klad C. . R ² R ² -X . MS (ES-) (M-1) Residual activity (%) NCBE at 10 pM 494 isopropyl (2-fluorophenyl) -CH ₂ -CO- 464 495 .. 1,2-ethoxybenzyl . (2-fluorophenyl) -CH ₂ -CO- 556- 496 2- (3-Trifluoromethylphenyl) ethyl. (2-fluorophenyl) -CH ₂ -CO- 594 497 1-indanyl phenyl-CH ₂ -CO- 520 .498 3-Nitrobenzyl phenyl-CH ₂ -CO- ' 539 499 neopentyl phenyl-CH ₂ -CO- . 474, 500 , isopropyl  phenyl-CH-CO- 446. . 501 2,2,2-trifluoroethyl 'Phenyl-CH ₂ -CO- 486 502 2- (3-Trifluoromethylphenyl) ethyl . phenyl-CH ₂ -CO- 576 , 503, 1-indanyl · (4-chlorophenyl) -CH ₂ -CO- 554 • 504 ' 3-nitrobenzyl (4-chlorophenyl) -CH ₂ -CO- . 573 505. neopentyl (4-chlorophenyl) -CH ₂ -CO- 508 ' .506 ' isopropyl (4-chlorophenyl) -CH ₂ -CO- .480 , 507 2-ethoxybenzyl (4-chlorophenyl) -CH ₂ -CO- 572 508 2- (3-Trifluoro- methylphenyl) ethyl (4-chlorophenyl) -CH ₂ -CO-. , 610 509 3-nitrobenzyl 4-chlorophenyl-CO-. 559 510 isopropyl  4-chlorophenyl-CO- 466 511 2-ethoxybenzyl 4-chlorophenyl-CO-. '558 512 2- (3-trifluoromethylphenyl) ethyl. , 4-chlorophenyl-CO-, ⁵⁹⁶ '

··. of

4 4 4 44 44 4 44 4 4 4 *

4

4,444 44 4

4 4.4 4 4 4 .443 44 44

At- klad C. R ² R ^ X , R ⁷ MS (ES-) (M-1), 7 .Zbytková activity (%) NCBE at 10 μΜ 513 benzyl (2-thienyl) -CH ₂ -CO- 4-methyl 514 88.6 514. (1-naphthyl) methyl (2-thienyl) -CH ₂ -CO- 4-methyl 564 74.9 515 (2-naphthyl) methyl (2-thienyl) -CH ₂ -CO- 4-methyl 564 68, 9 .516 2-chlorobenzyl (2-thienyl) -CH ₂ -CO- 4-methyl 548 98.7 517 (2-thienyl) methyl (2-thienyl) -CH ₂ -CO- 4-methyl 520 86.2 518 2-phenylethyl (2-thienyl) -CH ₂ -CO- 4-methyl 528 93.5 519 · 2-fluorobenzyl (2-thienyl) -CH ₂ -CO- 4-methyl 532 95.6 520 2,3-dichlorobenzyl (2-thienyl) -CH ₂ -CO- 4-methyl 582 85.9 521 - benzyl (2-thienyl) -. -CH (CH ₃ ) -CO- 4-methyl , 528 88.2 522 (1-naphthyl) methyl (2-thienyl) -, -CH (CH ₃₎ -CO- 4-methyl 578 '85.6 523 (2-naphthyl) methyl . (2-thienyl) -CH _(CH3) -CO- 4-methyl, 578 92.3 524. 2-chlorobenzyl '(2-thienyl) -, -CH (CH ₃₎ -CO- 4-methyl 562 525 '. (2-thienyl) methyl (2-thienyl) -CH _(CH3) -CO-. 4-methyl 534 74.0 526 2-phenylethyl (2-thienyl) ^f -CH (CH 2) -CO- 4-methyl 542 - 64.9 527 2-fluorobenzyl. (2-thienyl) -CH _(CH3) -CO- 4-methyl 546. , 67.5 528 ' 2,3-dichlorobenzyl (2-thienyl.), -CH (OH ₃ ) -CO-. 4-methyl '596 72.0 '529 benzyl (4-chlorophenyl) -ch ₂ -co- 4-methyl 542 89,4, _: 530 (1-naphthyl) methyl (4-chlorophenyl) -ch ₂ -co- 4-methyl • 592. 89.8

············

I · · 4 β β <

At- klad C. , R ² r ³ -x R ⁷ MS (ES-) (Μ-l) ' Residual activity (%) NCBE at 10 pM 531 (2-naphthyl) methyl (4-chlorophenyl) -ch ₂ -co- 4-methyl 592 75,6 ‘ 532 2-chlorobenzyl (4-chlorophenyl) -ch ₂ -co- 4-methyl 576 71., 0 533 (2-thienyl) methyl (4-chlorophenyl) -CH ..- CO- 4-methyl. 548 75.5 534 2-phenylethyl (4-chlorophenyl) - • -CE ..- CO- 4-methyl 556 . 80.0 535 2-fluorobenzyl (4-Chlorophenyl) - .. _-CH2 -CO- 4-methyl 560 '84.0 536 2,3-dichlorobenzyl (4-chlorophenyl) - '-CH ..- CO- 4-methyl 610 7.6,3 . 537 benzyl (3-thienyl) -CH ₂ -CO- 4-methyl 514 ' 54.4 538. (1-naphthyl) methyl (3-thienyl) -CH ₂ -CO- 4-methyl . 564 .80,6 '539. (2-naphthyl) methyl. (3-thienyl) -CH ₂ -CO- 4-methyl 564 65.2 540 2-chlorobenzyl, (3-thienyl) -CH ₂ -CO- 4-methyl 548 64.6 541 ' (2-thienyl) methyl (3-thienyl) -CH ₂ -CO- 4-methyl 520 52.3 542 . 2-phenylethyl. (3-thienyl) -CH ₂ -CO- 4-methyl ⁵²⁸ 67.4 . 543 2-fluorobenzyl (3-thienyl) -CH ₂ -CO- 4-methyl 532 . 58,3 ' 544 2,3-dichlorobenzyl (3-thienyl) -CH ₂ -CO- 4-methyl 582 . ² , 2 545 benzyl cyclohexyl - CH ₂ - CO - 4-methyl '514 70.1 '546 (1-naphthyl) methyl · cyclohexyl-CH ₂ -CO-. 4-methyl 564 '.63,6' 547. (2-Haphthyl) methyl cyclohexyl-CH ₂ -CO- 4-methyl 564 ' 76.5. .548 2-chlorobenzyl cyclohexyl-CH ₂ -CO- 4-methyl 548 ’65.2 549 (2-thienyl) methyl cyclohexyl-CH ₂ -CO- 4-methyl 520 67.3 550 2-phenylethyl cyclohexyl-CH ₂ -CO- 4-methyl 528 63.3. ;. 551 2 - f l.uo rben z y 1 cyclohexyl-CH ₂ '-CO- 4-methyl 532. '82.6.

4 4 4 4 • 4 4 • 44 • 4 4 4

4 4 4 • · ·

4> »4

4 ·

At- klad C. R ² _s ' R ^J -X R ⁷ . MS. (ES-) (M-1) -  Residual activity- (%) NCBE at 10 μΜ 552 2,3-dichlorobenzyl cyclohexyl-CH ₂ -CO- 4-methyl 582 61.5 553 benzyl (2-thienyl) -CH ₂ -CO- 5-chloro 534 85.7

Example 554 ·, '- {[. benzyl- (2-thiophen-2-ylacetyl) amino] methyl} -3'-chlorobiphenyl-2-sulfonyl cyanamide.

(a) 4-bromo-1-bromomethyl-2-chlorobenzene;

7.1 ml of 4-bromo-2-chlorotoluene are dissolved in 20 ml of chlorberizene and a mixture of 9.4 g of N-bromosuccinimide and 200 mg of dibenzoylperoxide is added in portions at 130 ° C. The mixture is refluxed for 30 minutes, after cooling it is not diluted from 100 ml of dichloromethane and washed. 50 ml. a saturated aqueous solution of sodium sulfite and once 100 ml of a saturated aqueous sodium bicarbonate solution. se. It is dried over sodium sulphate and the solvent is removed in vacuo. 11.0 g of a pale yellow oil are obtained. ].

Rf ₍ 1: 8 ethyl acetate / n-heptane) = 0.49.

Mass spectrometry (DCI): 283- (M + H) &lt; + &gt;. ...

b) benzyl- (4-bromo-2-chlorobenzyl) amine;

. Dissolve 765 μΐ of benzylamine in 10 ml of anhydrous tetrahydrofuran at 0 ° C and add. 1.0 g

• 0 0 00 00 00 0 « 0 0 00 • 0 0 0 0 0 0 0 • 0 0 • 0 00 0 0 0 0 • · 0 0 0 0 0 · 0 0 0 0 00 000 00 00 0 · 00

83-4-bromo-1-bromomethyl-2-chlorobenzene, and the mixture was stirred for 4 hours at room temperature. 100 ml of half-saturated aqueous sodium carbonate solution were added and the mixture was extracted three times with 100 ml of ethyl acetate each time. The extract was dried over magnesium sulphate and chromatographed on silica gel using diisopropyl ether as eluent. 590 mg of a colorless oil are obtained.

R _f (DIP) - 0.30,

MS (DCI) 310 (M + H) &lt; + & gt ^;.

c) 2-Thiophen-2-ylacetic acid benzyl- (4-bromo-2-chlorobenzyl) amide

Dissolve 580 mg of benzyl- (4-bromo-2-chlorobenzyl) amine in 10 ml of anhydrous dichloromethane and then add 300 μΐ of pyridine first, followed by 330 mg of 2-thiophen-2-ylacetyl chloride. The mixture is stirred for 4 hours at room temperature, then diluted with 100 ml of dichloromethane and washed with 50 ml of saturated aqueous sodium carbonate solution. Mixture. is dried over. magnesium sulfate. and the solvent is removed. under vacuum. The rest is. Chromatography on silica gel using diisopropyl ether as eluent. 490 mg of i are obtained. ·. Colorless oil.

R _f '(diisopropyl ether) - 0.56. ''

MS (ES): 434 (M + H) &lt; + & gt ^;

d). 4 '- {[Benzyl- (4-thiophen-1-ylacetyl) amino] methyl} -3'-chlorobiphenyl-2-sulfonic acid tert-butylamide 480 mg benzyl- (4-bromo-2-chlorobenzyl) amide 2- thiophen-2-ylacetic acid, 426 mg N-tert-butyl-2-dihydroxyboran-2-ylbenzenesulfonamide (J. Med. Chem: 1997, 40, 547), 26.2 mg triphenylphosphine, 11.2 mg of palladium acetate. and 133. mg of sodium carbonate is suspended in ml1 ml. water, 0.5 ml ethanol and 5 ml toluene and the mixture was refluxed for 2 hours. The mixture is allowed to cool and then the volatile components are removed under vacuum. The residue is taken up in 2 ml of dichloromethane and chromatographed, which is worked up on silica gel using diisopropyl ether as eluent. 520 mg of a colorless amorphous solid are obtained. .

_Rf (DIP) = 0.20 ·

Mass spectrometry (ES): 567 (M + H) ⁺ .

e) 4 - {<[benzyl- (2-thiophen-2-ylacetyl) amino] methyl] -3'-chlorobiphenyl-2-sulfonamide

510 mg of 4 '- {[benzyl- (2-thiophen-2-ylacetyl) amino] methyl) -3'-chlorobiphenyl-2-sulfonic acid tert -butyl amide and 110 μΐ of anisole were allowed to stand in 3 ml of trifluoroacetic acid for 18 h. The volatiles were removed in vacuo, the residue was taken up in 5 ml of toluene and the volatiles were removed again in vacuo. 586 mg of a colorless oil are obtained, which product is used without further purification.

Rf (diisopropyl ether) = 0.12

Mass spectrometry. (ES): 511 (M + H) &lt; + & gt ^;.

f) 4 '- {[benzyl' (2-thiophen-2-ylacetyl) amino} methyl} -3'-chlorobiphenyl-2’sulfonyl cyanamide;

586 mg of 4 - {[benzyl- (2-thiophen-2-ylacetoethyl) amino] methyl} -3'-chlorobiphenyl-2-sulfonamide, 372 mg of potassium carbonate and ISO μϊ of a 5 M solution of cyanogen bromide in acetonitrile are boiled for 1 h , 5 hours, under reflux. After cooling, the entire reaction mixture was quenched. Chromatography on silica gel using 10: 1 ethyl acetate / methanol as eluent. 181 mg of a colorless amorphous solid are obtained. . .

Rf ₍ 10: 1 ethyl acetate / methanol) = 0.22

Infrared (CN) spectrum: 2172.5 cm ^-1

Mass spectrometry (ES): 536 (M + H) &lt; + & gt ^; .

Residual NCBE activity at 10 μΜ: 15%

The title compound of Example 555 was synthesized in analogy to Example 554. '

Example 555

4 - {[benzyl- (2-thiophen-2-ylacetyl) amino] methyl} -3'-methylsulfonylbiphenyl-2-sulfonylcyanamide

a) 1-bromo-S-methylbenzenesulfonyl chloride.

40 g of 4-bromotoluene were slowly added to 25 ml of chlorophsulfonic acid at -10 ° C with stirring. The mixture was then stirred at this temperature for a further 30 minutes, allowed to warm to 0 ° C and poured into excess ice. The product is filtered off with suction and washed with a small amount of water. It is then dried over P ₄ O ₁₀ in vacuum. 63 g of a colorless solid are obtained, which is directly subjected to a further reaction.

b) 2-bromo-5-methylbenzenesulfinic acid

37.6 g of sodium metabisulphite are dissolved in 500 ml of water and the solution is heated to 70 [deg.] C. At this temperature, 2-bromo-5-methylbenzenesulfonyl chloride is added portionwise. At the same time, a 10M aqueous sodium hydroxide solution is added dropwise, so that the pH of the spread is maintained between pH = 9 and pH = 1Ό. The mixture is then stirred for a further 15 hours at room temperature. 70 ° C, the solution is filtered and then adjusted to pH 0 with an aqueous saturated solution of hydrogen chloride in an ice bath. The mixture is stirred for a further 30 minutes, then the product is filtered off, washed with a small amount of water and dried. 49.6 g of white crystals are obtained, m.p. 120 DEG-122 DEG C .;

• · · ·

- 8.6 Hmotová'spektrometrie (EC) :. 236 (M + H) + ¹ '

c) Sodium 2-bromo-5-methylbenzenesulfinate

49.6 g of 2-bromo-5-methylbenzenesulfinic acid are dissolved in 400 ml of methanol and an equimolar amount of sodium hydroxide in 50 ml of water is added. The mixture was stirred for. 3 hours at room temperature, the solution is filtered and then the solvents are removed in vacuo. The residual water is then removed azeotropically with 50 ml of toluene. The solid residue is dried under vacuum over P ₄ O ₁₀ . Gets. with 54.0 g of product melting at 280 DEG-290 DEG C. on decomposition.

d) 1-bromo-2-methanesulfonyl-4-methylbenzene

54.0 g of sodium 2-bromo-5-methylbenzenesulfinate are suspended in 300 ml of anhydrous N, N-dimethylformamide and 45.7 ml of methyl iodide are added. The temperature of the solution is raised to 50 ° C. The mixture was stirred. After stirring for 3 hours at 50 ° C, the N, N-dimethylformamide was removed in vacuo. The residue is stirred with 500 ml of water, stirred for 1 hour at 0 ° C and filtered. The product was washed with water, dried and recrystallized. that. mix -400 mi. of n-heptane and 250 ml of ethyl acetate with activated carbon. 27.0 g of colorless crystals of melting point 110 DEG-114 DEG C. are obtained.

Rf ₍ 1: 4 ethyl acetate: n-heptane) = 0.09.

: Mass Spectrometry (DCI): 250 (M + H) ⁺

e) 1-bromo-4-bromomethyl-2-methanesulfonylbenzene. 9.9 g of 1-bromo-2-methanesulfonyl-4-methylbenzene are taken up in 100 ml of chlorobenzene, 77 mg of benzoyl peroxide and 7.1 g of N-bromosuccinimide are added and the mixture is boiled for 1 hour. hours under reflux. . The solvent is then removed in vacuo, the residue is taken up in 100 ml of dichloromethane and washed twice with 50 ml of saturated aqueous sodium carbonate solution and once with 50 ml of water. The mixture was dried, over sodium sulfate and the solvent removed in vacuo. The residue was recrystallized from a mixture of 80 ml

n-heptane and 30 mL of ethyl acetate to give 6.9 g of a pale yellow solid, m.p. 120-124 ° C.

_Rf (1: 2 ethyl acetate / n-heptane) = 0.38 Mass Spectrometry (DCI): 329 (M + H) &lt; + & gt ^;

f) Benzyl- (4-bromo-2-methylsulfonylbenzyl) amine

Dissolve 652 μΐ of benzylamine in 10 ml of anhydrous tetrahydrofuran and slowly add 1.0 g of 1-bromo-4-bromomethyl-2-methanesulfonylbenzene at 0 ° C. The mixture is stirred for 4 hours at room temperature, then 100 ml of saturated aqueous sodium carbonate solution are added and the mixture is extracted twice with ¹ ml of 100 ml of ethyl acetate each time. The extract was dried over magnesium sulphate and the solvent removed in vacuo. Chromatography on silica gel using 1: 1 methyl tert-butyl ether and diisopropyl ether as the eluent afforded 510 mg of a colorless oil.

Rf (diisopropyl ether) = 0.10. ·, ·. · .. ·

Mass spectrometry (ES): 354 (M + H) &lt; ⁺ &gt;

g): 4 [- {[benzyl- (2-thiophen-2-ylacetyl) amino] methyl} -3'-methylsulfonylbiphenyl-2-sulfonylcylamide

Rf ₍ 10: 1 ethyl acetate / methanol) = 0.21

Infrared spectrum. (CN): 2175.3 cm ^-1

MS (ES): 580 (M + H) &lt; + &gt;.' ^:

Residual NCBE activity at · 10 μΜ: 31%

Example 556 '. ¹ '' - {[benzyl (thiophene-2-sulfonyl) amino] methyl} -3'-chloro-biphenyl-2-sulfonylcyanamide '

N

(a) Thiophene-2-sulfonic acid benzyl- (4-bromo-2-chlorobenzyl) amide; _t ·· · '

2.0 g of benzyl- (4-bromo-2-chlorobenzyl) amine (Example 554b) and 1.0 g of pyridine are dissolved in 20 ml of dichloromethane and 1.4 g of thiophen-2 chloride are slowly added at room temperature. -sulfonic acids. The mixture was stirred for 4 hours. hours at room temperature, then diluted with 200 ml of ethyl acetate and washed twice with 100 ml of 5% aqueous sodium hydrogen sulphate solution each time and twice each time. 50 ml of saturated aqueous sodium carbonate solution. The mixture was dried over magnesium sulfate. and the solvent is removed in vacuo. Chromatography on silica gel using diisopropyl ether as eluent. 1.5 g of a colorless oil is obtained.

R _f (DIP). = 0.21, ....

MS (FAB): 456 (M + H) &lt; + & gt ^;.

Further reactions to give the title compound of Example 556 were carried out in analogy to Example 554 d) through

f) .. '

b). 4 '- {[benzyl (thiophene-2-sulfonyl) amino] methyl] -3'-chlorobiphenyl-2-sulfonyl cyanamide

R _f (EA methanolu'v.poměru 10: 1) = 0.17 IR (CN): 2178.5 cm ^"1.

Mass Spectrometry (FAB): 580 (M + Na) &lt; + &gt;

Residual NCBE activity at 10 μΜ: 0%.

The title compound of Example 557 was synthesized in analogy to Example 556 from the title compound of Example 555b).

Example 557 ··

4 '- {[benzyl (thiophene-2-sulphonyl) amino] methyl} -3'-methylsuifortylbiphenyl-2-sulfonylcyanamide

N

Rf ₍ 10: 1 ethyl acetate / methanol) ~ 0.28 Infrared (CN): 2175.0 cm @ ^-1 (MS) .: 602 (M + H) @ ⁺

Residual NCBE activity at 10 pM: 14 '% - Example 558 ´' 4 '· - {[benzyl (thiophene-2-sulfonyl) amino] methyl} -3' - (2-methoxy) ethoxybiphenyl-2-sulfonylcyanamide

N

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

22.0. 3-hydroxy-4,4'-methylaniline, 24.9 g of 2-bromomethyl methyl ether, and 233 g of cesium carbonate are dissolved in 570 ml of N, N-dimethylformamide and the mixture is stirred for 8 hours. 3 l of 1.0% aqueous sodium bicarbonate solution are added, and the mixture is extracted 6 times with 750 ml of ethyl acetate each time. Then, it is washed twice with 1 l of 10% aqueous sodium bicarbonate each time. The mixture was dried over sodium sulfate and the solvent was removed in vacuo. It is obtained. 32.9 g yellow. oil, which. se. without further purification, it is used in a subsequent reaction. - - '

Rf ₍ 1: 1 ethyl acetate: n-heptane) = 0.33 ··

- 90 • * · · · · · · · · · · · · · · · · · · · · · · · · ·

b) 4-methyl-3- (2-methoxy) ethoxybromobenzene

32.8 g of 4-methyl-3- (2-methoxy) ethoxyaniline are suspended in 660 ml of half-saturated aqueous hydrogen bromide solution at 0 °. A solution of 12.5 g of sodium nitrate in 25 ml of water was slowly added dropwise. The solution was stirred for 30 minutes at 0 ° C and then slowly added to a solution of 51.9 g of copper (I) bromide in 490 ml of saturated aqueous hydrogen bromide solution heated to 50 ° C. The reaction mixture was then added over 6 hours. Heat slowly from 50 ° C to. The mixture was cooled, extracted, washed with diethyl ether (4.times.500 ml), washed with saturated aqueous sodium chloride (500 ml) and dried over sodium sulfate. Chromatography on silica gel using ethyl acetate / n-heptane (1: 1). 8, 15.4 g of a colorless oil are obtained.

Rf ₍ 1: 1 ethyl acetate: n-heptane) = 0.41; Mass Spec (DCI): 245 (M + H) @ ⁺ .

. c) 4-bromomethyl-3- (2-methoxy) ethoxybromobenzene 15.3 g of 4-methyl-3- (2-methoxy) ethoxybromobenzene are dissolved in 300 ml of chlorobenzene and refluxed in portions. add a mixture of 1.1.1 g of N-bromosuccinimide and 125 mg of benzoyl peroxide · The mixture is refluxed for 24 hours, the solvent is removed in vacuo and then taken up in 500 ml of dichloromethane. The mixture was washed first with 200 ml of saturated aqueous sodium sulfate solution and then with 100 ml of saturated aqueous sodium carbonate solution. The mixture was dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using ¹ L of ethyl acetate: n-heptane (1: 15) as eluent.

The reagents gave 12.8 g of a pale yellow oil. \

Rf ₍ 1: 4 ethyl acetate: n-heptane) = 0.42 MS (DCI): 323 (M + H) @ ⁺

d) Benzyl- [4-bromo-2- (2-methoxy) ethoxybenzyl] amine

2, 4. ml of benzylamine is dissolved in - 20 ml of anhydrous tetrahydrofuran and 3.2 g is slowly added at 0 ° C

4-bromomethyl-3- (2-methoxy) ethoxybromobenzene. The mixture was stirred for 19 hours at room temperature then. Dilute with 200 ml of ethyl acetate and wash with 100 ml of saturated aqueous sodium carbonate solution. The mixture was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatographic.

Work-up on silica gel using methyl t-butyl ether as eluent gave 1.3 g of a colorless oil.

_Rf (MTB) = .0,20 ⁱⁿ MS (DCI): -350 (M + .H) ^{@ +} e). Thiophene-2-sulfonic acid benzyl- [4-bromo-2- (2-methoxy) -ethoxybenzyl] -amide

1.2 g of benzyl- [4-bromo-2- (2-methoxy) -ethoxybenzyl] -amine. 713 mg of thiophene-2-sulfonic acid chloride and 430 μΐ of pyridine are dissolved in 50 ml of dichloromethane and the mixture is stirred for 17 hours at room temperature. The mixture was then diluted with 100 mL. dichloromethane and then washed twice with 50 ml -5% each.

+ aqueous hydrogen sulphate solution. sodium then 50 ml.

saturated aqueous sodium carbonate solution. The mixture was dried over sulfate. The solvent was removed in vacuo and the solvent removed by chromatography on silica gel using diisopropyl ether as the eluent. obtains 900 '. mg colorless oil. .; , ''. . R _f (DIP) '' = 0.2.

MS (ES): 496 (M + H) &lt; + &^gt;·;

f) Dihydroxyboran-2-ylbenzenesulfonamide 50 g of N-tert-butyl-2-dihydroxyboran-2-ylbenzenesulfones. du (J, Med., Chem. 1997, 40, 547) and 23.3 g of anisole are dissolved in 500 ml of trifluoroacetic acid and the solution is allowed to stand at room temperature for 2 days. The volatiles were removed in vacuo, the mixture was taken up in 100 mL of water and the volatiles again

- 92 removed under vacuum. The residue is taken up in 100 ml of toluene and the volatiles are removed. once again removed in vacuo. 56 g of a colorless oil are obtained, which is reacted further without purification. _Rf. (Methyl-tert butyl) ~ 0.4

g) Dihydroxyboran-2-ylbenzenesulfonic acid dimethylaminomethylenamide g Dihydroxyboran-2-ylbenzenesulfonamide and 66 ml of dimethylformamide dimethylacetal were dissolved in 200 ml of anhydrous Ν, Ν-dimethylformamide and the solution was allowed to stand at room temperature for 18 hours. The reaction mixture was poured into 1.5 L of water and extracted four times with 500 ml of ethyl acetate each time. The extract was dried over magnesium sulfate and the solvent was removed in vacuo. Crystallization from 100 ml of ethyl acetate gave 5.2 g of colorless crystals which melted with decomposition at 175 ° C.

Rf (ethyl acetate) = 0.25%

h) {[Benzyl (thiophene-2-sulfonyl) amino] methyl} -3 '- (2-methoxy) ethoxybiphenyl-2-sulfonic acid dimethylaminomethylenamide

Thiophene-2-sulfonic acid benzyl- [4-bromo-2- (2-methoxy) ethoxybenzyl] amide, 1.4 g of dihydroxyboran-2-ylbenzenesulphonic acid dimethylaminomethylene amide, 47 mg of triphenylphosphine, 20 mg of palladium acetate and 575 mg of sodium carbonate are suspended in 30 ml of toluene, 5 ml of water and 5 ml of ethanol. The mixture was refluxed for 6 hours, then allowed to cool and diluted with 100 mL. ethyl acetate. The mixture was washed twice with 50 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using methyl tert-butyl ether gave 560 mg of a colorless viscous solid. oils. . '. 00 00 00 00

0 ··· 0 «0 0 · · · 0

0 0 0 ··· 0 0 0 0 • * 0 0 0 0 0 0 0 0 0 0 0 0

0 <0 0 0 0 000

000 00 00

_Rf (MTB) = 0.13 MS (ES): 628 (M ⁺ H)

i) {[Benzyl (thiophene-2-sulfonyl) amino] methyl} -, 3 '- (2-methoxy) ethoxybiphenyl-2-sulfonamide

550 mg of dimethylaminomethylenamide {[benzyl (thiophene-2-sulfonyl) amino] methyl] -3 '- (2-methoxy) ethoxybiphenyl-2-sulfonic acid is boiled in 5 ml of ethanol and 5 ml of a saturated aqueous solution of hydrogen chloride. for 1 hour under reflux. 100 ml of 10% aqueous sodium bicarbonate solution are added and the mixture is extracted three times with 100 ml of ethyl acetate each time. The extract was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using 1: 1 methyl tert-butyl ether and diisopropyl ether as eluent gave 188 mg of a colorless oil.

Rf ₍ 1: 1 mixture of methyl tert-butyl ether and diisopropyl ether) = 0,33

Mass spectrometry (ES): 573 (M + H) &lt; + &^gt;.

j) 4 '- {[Benzyl (thiophene-2-sulfonyl) amino] methyl] -3'- (2'-methoxy) ethoxybiphenyl-2-sulfonyl cyanamide ^;

180 mg of {[Benzyl (thiophene-2-sulfonyl) amino] methyl} -3 '- (2'-methoxy) ethoxybiphenyl-2-sulfonamide, .63 μΐ of a 5 M solution of cyanogen bromide in acetonitrile and 1.31 mg of potassium carbonate is suspended in 3 ml of anhydrous acetonitrile and the mixture is boiled for 1 h. for 2 hours under reflux. The mixture was. the reaction mixture is cooled. chromatographed on silica gel. for. using a 1.0: 1 mixture of ethyl acetate and methanol as eluent. 149 mg of amorphous solid are obtained. -,

R _; (10: 1 mixture of ethyl acetate and methanol) = 0.13 IR (CN): 2175.3 cm @ ^-1 . ¹ ,.

FAB-MS: 598 (M + H) &lt; + & gt ^;

Residual NCBE activity at 10, μΜ: 30%

Example 559 '. . - {[[benzyl (thiophene-2-sulfonyl) amino] methyl} -3 '- (2-methoxy) ethoxybiphenyl-2-sulfonylcyanamide "]. ,

(a) 4-fluoro-1- (2-methoxyethoxy) -2-methylbenzene.

g of 4-fluoro-2-methylphenol, 7.5 ml of 1-bromo-2-methoxy-, ethane and 22 g of potassium carbonate are suspended in 2-00 ml; of anhydrous N, N-dimethylformamide and the mixture was stirred for 12 hours at 120 ° C. The mixture was cooled and the solvent was removed in vacuo. The residue is taken up in 400 ml of methyl tert-butyl ether and washed three times with 200 ml of 10% aqueous sodium hydroxide solution each time and once with 100 ml of saturated aqueous sodium chloride solution. The mixture was dried over sodium sulfate and the solvent was removed in vacuo. 10.4 g of a pale yellow oil are obtained. . . ,

P. (mixture of ethyl acetate and n-heptane) = 0.39

MS (DCl): 185 (M + H) + ¹ ·. -.

b) 2-bromomethyl-4-fluoro-1- (2-methoxyethoxy) benzene

10.4 g of 4-fluoro-1- (2-methoxyethoxy) -2-methylbenzene are dissolved in 100 ml of chlorobenzene and refluxed for 2 hours. A mixture of 10.1 g of N-bromosuccinimide and 200 mg of benzoyl peroxide is added in portions. The mixture was allowed to cool and diluted with 300 mL of ethyl acetate. Subsequently, the mixture was washed first with 100 ml of a saturated aqueous sodium sulfite solution and then twice with 100 ml of a saturated aqueous solution.

0 0 0 0 0 0 0 0 0 ·· 00 0 · - e 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0

- 95 sodium carbonate. The mixture was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel. using ethyl acetate: n-heptane (1: 4) as the title compound. elution. of the reagent is obtained. 5.2 g of a colorless oil.

Rf ₍ 1: 4 ethyl acetate: n-heptane) = 0.20

Mass spectrometry (DCI): 262 (M + H) ⁺ b) 1-bromo-4-bromomethyl-2-methanesulfonylbenzene

9.9 g of 1-bromo-2-methanesulfonyl ^- 4-methylbenzene was taken up in 100 ml of chlorobenzene, 77 mg of benzoyl peroxide and 7.1 g of N-bromosuccinimide were added and the mixture was boiled under stirring. reflux condenser for 1 hour. The solvent is then removed in vacuo, the residue is taken up in 100 .ml of dichloromethane and washed twice with 50 ml of saturated aqueous sodium bicarbonate solution and once with 50 ml of water .. The mixture is dried over sodium sulfate and removed in ^{rozpouštědlo_:} vaccuum. - The rest. was recrystallized from a mixture of 80 ml of n-heptane and 30 ml of ethyl acetate to give 6.9 g of a pale yellow solid, m.p. 12.0-124 ° C.

Rf ₍ 1: 2 ethyl acetate: n-heptane) = 0.38 (DCI): 329 (M + H)

c) 2- (4-bromo-2-methanesulfonylbenzyl) isoindole-1,3-dione

3.0 g of 4-bromo-1-bromomethyl-2-methanesulfonylbenzene and 2.0 g of potassium phthalimide were stirred in 30 ml of anhydrous N / N-dimethylformamide for 1 hour at 100 ° C. Allow to cool, n-ared '200 ml of water and the suspension is stirred. times. 30' minutes at room temperature. Then is _filtered: the _product? to give 1.8 g of a colorless solid, mp 190 to i88 ° C.

(ES) 393 (M + H) ^&lt; ^{+ &gt};

d). 4-Bromo-2-methanesulfonyl-benzylamine

2- (4-Bromo-2-methanesulfonylbenzyl) isoindole-1,3-dimethylamine (1.8 g);

One and 1.5 ml of hydrazine hydrate in 30 ml of ethanol are first stirred for 1 hour at 60 [deg.] C. and then refluxed for 4 hours. The mixture is allowed to cool, the precipitate is filtered off and the volatile components of the filtrate are removed in vacuo. The residue is taken up in 100 ml of dichloromethane and the solid is collected. filter again. The solvent of the filtrate was removed in vacuo to give 1.3 g of a pale yellow oil.

Rf ₍ 10: 1 ethyl acetate / methanol) = 0.10. Mass spectrometry (DCI): 26.4. (M + H) &lt; + & gt ^;.

e) (4-Bromo-2-methanesulfonylbenzyl) - [5-fluoro-2- (2-methoxyethoxy) benzyl] amine

1.3 g of 4-bromo-2-methanesulfonylbenzylamine and 1.4 ml of triethylamine are dissolved in 20 ml of anhydrous tetrahydrofuran and a solution of 1.3 g of 2-bromomethyl-4-fluoro-1- (2-) is added dropwise at 0 ° C. methoxyethoxy) benzene in 5 ml of anhydrous tetrahydrofuran. The mixture is stirred for 60 hours at

The mixture was diluted with 200 ml of ethyl acetate and washed twice with 100 ml of saturated aqueous sodium carbonate solution each time. The mixture was dried over magnesium sulfate and the solvent was removed in vacuo. '.vakuu. Chromatography on silica gel using ethyl acetate. 910 mg of a colorless oil are obtained.

R. (ethyl acetate) - 0.43

MS (ES): 446 (M + H) ^&lt; ^{+ &gt};. Further reactions were carried out analogously to Example 558f) to 5.58j). '(f). 4 '- {[benzyl (thiophene-2-sulfonyl) amino] methyl} -3- (2-methoxy) ethoxybiphenyl-2-sulfonylcyanamide

Rf ₍ 10: 1 ethyl acetate: methanol) = 0.33 • Infrared (CN): 2174.3 cm @ ^-1

MS (ES) 694 (M + H) &lt; + & gt ^;.

- Residual NCBE activity at 10 μΜ: 12% · 9 · 9 · 9 9 9 9 9 9

9 9 9 9 9 9 9 · ·. 9 · 9 · · · · · · · ·

9 9. '· 9 9 9 9 9 9 9.9

9 99 99 99

The title compound of Example 560 was synthesized in analogy to Example 558.

Example 560

4 '- {[benzyl-2- (thiophen-2-yl) acetylamino] methyl} -3'- (2-methoxy) ethoxybiphenyl-2-sulfonylcyanamide

Rf ₍ 5: 1 ethyl acetate / methanol) = 0.36. Infrared (CN): 2175.0 cm @ ^-1 (ES): 597 (M + H) @ ⁺

The product melts with decomposition at 95 ° C Residual NCBE activity at 10 μΜ: 8.0%

Example 561

4 '- {[benzyl-2- (2-methylphenyl) acetylamino] methyl) biphenyl-2-sulphonylcyanamide

a) / (Dimethylamino) methylenamide 4 '- (benzylaminomethyl). biphenyl-2-sulfonic acids, 'i'

Dissolve 4.4 ml of benzylamine in 90 ml. of anhydrous tetrahydrofuran and is added portionwise at 0 ° C. 7.6 g of 4 '- (bromomethyl) -N - [(dimethylamino) methylene] - (1,1'-biphenyl) -2-sulfonamide (J. Med. Chem. 19.95, 38, 2357). po z

9 9 9 99 99 9 9 9 9 9

9 · 9 999 9 99 9 • 9 .9 9 «99 999 · 9 9

9 «999 999

999 99 99 99 99 for 24 hours at room temperature, then diluted with 500 ml of ethyl acetate and washed twice with 200 ml of saturated aqueous sodium carbonate solution each time. The mixture was dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using 10: 1 ethyl acetate / methanol afforded 3.8 g of a colorless oil.

R. (10: 1 ethyl acetate / methanol) = 0.25. FAB: 408 (M + H) &lt; + & gt ^; .

b) on-tolylacetylchlorid of 4.8 g of o-tolylacetic acid are dissolved in '3.6 ml SOC1 _2' F

The solution is refluxed for 12 hours. The volatiles were removed in vacuo, the residue was taken up in toluene (3 x 50 ml) and the volatiles removed in vacuo. 6.6 g of a pale yellow liquid are obtained, which is further used without purification. ,. ’

c) (Dimethylamino) methylenamide · 4 '- {[benzyl-2- (2-methylphenyl) acetylamino] methyl} biphenyl-2-sulfonic acid

408 mg of 4 '- (benzylaminomethyl) biphenyl-2-sulfonic acid (dimethylamino) methylenamide are dissolved in: 9 ml of anhydrous dichloromethane and, firstly, 162 μΐ of pyridine are added at room temperature, followed by 220 mg of o-tolyl acetyl chloride. The mixture was stirred for. 24 hours at room temperature, diluted with 100 ml of dichloromethane and washed three times with 50 ml each. ml? of saturated aqueous sodium carbonate solution. The solvent was removed in vacuo. Chromatography on silica gel using ethyl acetate / n-heptane (2: 1) as eluent gave 330 mg of a colorless oil. ,

Rf ₍ 2: 1 ethyl acetate / n-heptane) 0.52. FAB-MS: 540 (M + H) &lt; + & gt ^;

• 4 4 •

4 4 • 4 • 4 e

·· 44

44 • 4 4 »4 4 4

4 4 4 • 44

-I 9 9

d) 4 '- {[benzyl-2- (2-methylphenyl) acetylamino] methyl} biphenyl-2-sulfonamide.

320 mg of (dimethylamino) methylenamide -47 - {[benzyl-2- (2-methylphenyl) acetylamino] methyl} biphenyl-2-sulfonic acid are dissolved in 6 ml of methanol and 3 ml of saturated aqueous hydrogen chloride solution are added at room temperature. . The mixture was boiled for 8 hours under reflux and after cooling, the pH was adjusted to 5-6 with 6M aqueous sodium hydroxide solution. The mixture was diluted with 70 ml of water and extracted three times with 70 ml of ethyl acetate each time. The extract was dried over sodium sulfate and the solvent was removed in vacuo. 300 mg of a colorless oil are obtained. '' · '·

Rf (ethyl acetate) = 0.68

MS (ES): 485 (M + H) &lt; + &gt;

e) 4 '- {[benzyl-2- (2-methylphenyl) acetylamino] methyl} bife'. N-yl-2-sulfonylcarbamide.

280 mg of 4 '- {[benzyl-2- (2-methylphenyl) acetylamino] methyl} biphenyl-2-sulfonamide and 245 mg of potassium carbonate are dissolved in - 6 ml of anhydrous acetonitrile - and at room temperature. - Add 116 μΐ of a 5 M solution of cyanogen bromide in acetonitrile. The mixture 7 is boiled. 2. After cooling to reflux, the entire reaction mixture was chromatographed on silica gel with ethyl acetate. and methanol in a ratio of 10: 1 as eluent. It is obtained

130 mg of a colorless solid, melting, with decomposition, at 108 ° C.

Rf ₍ 10: 1 ethyl acetate / methanol) = 0.27. Infrared (CN): 2177.0 cm @ ^-1 FAB: 532 (M + Na) *

Residual NCBE activity at 10 μΜ: 16%.

The title compounds of Examples 562 to 568 · are synthesized ^analogously: Example 561st

- 100

Example 562 ·

4 '- {[benzyl-2- (2-trifluoromethylphenyl) acetylamino] methyl} biphenyl-2-sulfonylcyanamide

R _f (ethyl acetate · and MeOH = 10: 1) = 0.30 IR (CN): 2178.0 ^cm-1 MS (FAB): 586 (M + Na) ⁺ 'product melts. for. decomposition at 90 ° C Residual NCBE activity at 10 μΜ: 33% '

Example. 563.

'- {[benzyl-2- (2-trifluoromethoxyphenyl) acetylamino] methyl] biphenyl-2-sulfonylcyanamide -

R _f (EA methanolu.v = 10.: 1) = 0.26 IR (CN): 2177.0 cm ¹ - -. '

MS (ES): 580 (M + H) &lt; + &gt;. ...

The product melts. with decomposition at 125 ° C

Residual activity '. NCBE at 10 μΜ: 46%

Example 564 ·.

1- {1-Benzyl-2- (2-trifluoromethyl-thiophenyl) -acetylamino] -methyl) -biphenyl-2-sulfonyl-cyanamide. , ...

Rf (ethyl acetate / methanol 10: 1) = 0.27. Infrared (CN): 2176.0 cm @ ^-1. Mass spectrometry (ES): 596 (M + H) @ ⁺

Melts with decomposition at 122 ° C Residual NCBE activity at 10 μři: 23%

Example 565 '- ([Benzyl-2-methylbenzoyl amino] methyl] biphenyl 1-2 + sulfonyl cyanamide

Rf (ethyl acetate / methanol 10: 1) = 0.22 IR (CN): 2174.0 cm

Mass spectrometry (ES): 496 (M + H) &lt; + & gt ^;.

The product melts with decomposition at 173 ° C.

Residual NCBE activity, at '10. μΜ: 42%

Example 566

4 - {[benzyl-2-trifluoromethylberisoylamino] methyl) biphenyl-2-sulfonylcyanamide

• ·

- 102 -

Rf (10: 1 ethyl acetate: methanol) = 0.20 IR (CN) 2176.0 cm @ -1 ^;

Mass spectrometry (ES): 550 (M + H) 7 The product melts with decomposition at 165 ° C Residual NCBE activity at 10 μΜ: 72%

Example 567

4 '- {[benzyl-2-trifluoromethoxybenzoylamino] methyl} biphenyl-2-sulfonylcyanamide

Rf (10: 1 ethyl acetate / methanol) = 0.22. Infrared (CN): 2176.0 cm @ ^-1. MS (ES): 566 (M + H) @ ⁺ .

The product melts at 160 ° with decomposition. C Residual NCBE activity at 10 μΜ: 69%

Example 568 '- {[Benzyl- (5-methylthiophehl-2-yl) carbon-ylamino] methyl} bi-phenyl-2-sulfonyl cyanamide ·

Rf (10: 1 ethyl acetate / methanol). = 0.16. Infrared spectrum. (CN) ·: 2175.0 · cm ^-1 Mass spectrometry (FAB): 524 (M + Na) ⁺

Product melts at 166 ° C ’

- 103 Residual NCBE activity at 10 μΜ: 70%

Pharmacological data:

Inhibition of Na ⁺ ~ dependent bicarbonate / chloride exchange system (NCBE) in human endothelial cells

Human endothelial cells (ECV-304) were released from culture flasks using Trypsin / EDTA-buffer '(0.05% trypsinized 0.02% EDTA (ethylenediaminetetraacetic acid) in phospha ^J ments concerning buffer) and, after centrifugation at 100 g were added for 5 minutes. to a buffered saline solution (containing 115 mmol / l sodium chloride, 20 mmol / l ammonium chloride, mmol / l potassium chloride, 1 mmol / l calcium chloride,

- mmol / l magnesium sulphate, 20 mmol / l HEPES (N - (- 2-hydroxy-ethyl) piperazine-N'-2-ethanesulfonic acid), 5 mmol / l glucose and 1 g / Γ bovine serum albumin, pH 7.4). This cell suspension. Incubate ... ..s ,, ... 5μΜ. BCECF-acetoxymethyl ester (2 ', 7'-bis- (2-carboxyethyl) -5,6-carboxyfluorescein-acetoxymethyl ester) for 20 minutes at 37 ° C. The cells are then washed and resuspended in sodium-free buffer solution. and bicarbonate ions (containing 5 mmol / l HEPES, 133.8 mmol / l choline chloride, 4.7 mmol / l potassium chloride, 1.25 mmol / l, magnesium chloride, 0.97 mmol / l potassium hydrogen phosphate, 0, : 23 mmol / l potassium dihydrogen phosphate, 5 mmol / l glucose, pH 7.4).

For the following fluorescence measurements, in a FLIPR (Fluorescent Imaging Plate Reader), 100 µL of the above cell suspension is pipetted into each well of a 96-well microtiter plate and the microtiter plate is centrifuged at 100 g po. for 5 minutes. In the FLIPR, 100 μΐ of buffer solution is then removed from the next, prepared microtiter plate and pipetted into each of the 96 wells of the measuring plate. Doing so for. 100%. control, i.e., restoration of intracellular pH (pHJ by NCBE will use a buffer solution containing bicarbonate and sodium ions (containing

104

mmol / l HEPES, 93.8 mmol / l sodium chloride, 40 mmol / l sodium bicarbonate, 4.7 mmol / l potassium chloride, 1.25 mmol / l calcium chloride, 1.25 mmol / l magnesium chloride, 97 mmol / 1 sodium hydrogen phosphate; Q, 23 mmol / 1 sodium dihydrogen phosphate, 5 mmol / 1 glucose, pH 7.4) containing 50 μΜ HOE 642, for 0% control, ie no pH recovery buffer was used _£ ' sodium bicarbonate - free solution,. ions (containing 5 mmol / l HEPES, 133.8 mmol / l sodium chloride, 4.7 mmol / l, potassium chloride, 1.25 mmol / l calcium chloride, 1.25 mmol / l magnesium chloride, 0.97 mmol / l disodium phosphate / 0.23 mmol / l sodium dihydrogen phosphate, 5 mmol / l glucose, pH 7.4), also containing 50 μΜ HOE 642. The compounds of the invention are added at various concentrations to a sodium-containing solution; bicarbonate ions. After addition of the buffer solutions to the stained and acidified cells found, the increase in fluorescence intensity corresponding to the increase in pH _{i 2} in each well of the microtiter plate is measured in the measuring plate. The kinetics are monitored for 2 minutes at 35 °. G. - ''. <

The increase in fluorescence intensities for different concentrations of the compounds of the invention is related to both controls and the inhibitory action of these compounds is determined.

Claims (12)

1. Biphenylsulfonylcyanamides of formula I (i): in which R ¹ represents'. 1 ,. alkyl having 1, 2, 3, 4, 5, 6-, 7 or 8 carbon atoms; 2. an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in which one to all of the hydrogen atoms are replaced by fluorine atoms, -3. alkenyl, se. 2, 3 ,. 4 5 6 7 8 9 10 11 or 12 carbon atoms, ' 4. -C.H. -Y, where '; nn - is 0 or 2, and n is 0, 1, 2, 3, or 4, n is not. . 0 or 1 if nn 'has a value of 2, or _r . 5. the group -C, where nn 'is 0 or 2, and; . h is' ¹ ',' 2 ',' 3 'or' 4 ', with n not' even if nn is 2, .. '_; in which 1 is. 2 or .3. hydrogen atoms in a divalent _radical. -0 _η Η ₂ ".. _Γπ - independently replaced by a radical selected from the group consisting of 1. aryl groups having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms; Second amino groups NR ²² R ^23, alkoxycarbonyl groups, ² 4. - 106 '5. COOR ¹⁶ 6 1, 2,, 3 or 4 atoms carbon 7. arylalkylcarbonyl groups se . 6 to 14 atoms of carbon in the aryl part and 1 to 4 carbon atoms in alkyl moieties. is 1. hydrogen; ^; (2) an alkyl group having 1, 2; 3, 4 ,. 5, 6, - 7 or.8 atoms carbon, 3. an alkyl group having 1, 2, 3, 4, 5 6, 7 or 8 ' atoms carbon in which one to all hydrogen atoms are replaced by fluorine atoms, 4. an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 5. an alkynyl group having 2, 3, 4, 5, 6, 7 or 8 carbon atoms; The sixth group _H2n _ _nn-Z, where. ' nn is 0 or 2, and. ‘. n has a value of 0, 1, 2, 3 'or 4, wherein n-does not have a value of 0 or 1 if nn has a value of 2, or 7. group -Ο _π Η. _{; π} .. _ηη -Ζ, where. . nn · has a value of 0, or 2, and 'n ^: has a value of 1, 2, 3 or 4, with n not equal to 1 if nn has a value of 2,. wherein there are 1, 2 or 3 hydrogen atoms in the divalent radical; ^- C _n H _2r ^ _nn - independently replaced ./zbytkem ,, selected from the group Bifuctional 1. aryl groups having 6, 7, 8.9, 10, 11,. 12, 13 or 14 carbon atoms, 2. amino, Group 3 NR ²² R ²³ , -. . ''. 4. C 1 -C 4 alkoxycarbonyl groups in the alkoxy moiety; §. COOR ¹⁶ , a. . . . ₍ ' - 107 - 6. alkyl groups having 1, 2, 3 or 4 carbon atoms, R ³ and R ^{4 each} independently represent a hydrogen atom or an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 atoms atoms, 'R ^5, R ^Z and R ⁷ independently represent hydrogen, alkyl having 1, 2, 3, 4, 5,' 6, 7 or 8 carbon atoms, fluorine, chlorine ,, bromine or iodine, trifluoromethyl, cyano, nitro,. SO _q R ^8, -CO-R ^z or OR ^10, '·. R ⁸ is alkyl having 1, 2, 3, '4, 5, 6, 7 or 8 carbon atoms', NR ⁿ R ^12', or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different , residues selected from the group. Comprising ^; fluorine, chlorine, bromine and iodine, trifluoromethyl, methyl, .. ... methoxy, hydroxy and .. 'NR ⁿ R ^12, - R ⁹ and R ²¹ independently represent a hydrogen' · H, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or OR ¹³ , R ¹⁰ represents a hydrogen atom, an alkyl group having 1, 2, 3, 4, 4, or 3, 4, 3, 4, 5 or 6; 5, 6, 7 or -8 carbon atoms optionally substituted by C 1 -C 4 alkoxy; or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 with the same or different radicals selected from the group consisting of fluorine, chlorine, bromine and iodine atoms, a trifluoromethyl group. methyl, methoxy, hydroxy. and NR ^{'R 2'} <. symbols R, R ^12,. R ¹⁹ and R ^{20 are each} independently hydrogen, alkyl having 1, 2, 3 or 4 atoms. C1-C4 alkanoyl, R < ¹³ &gt; means hydrogen or alkyl 1,2,3 4, 5, 6, 7 or 8 carbon atoms, X- 'represents a carbonyl group, -CO-NH- group, - 108 - -CO-CO-, or a sulfonyl group, Y and Z are each independently 1. an aryl group having 6, 7, 8, 9, 10, 11,, 12, 13. or 14 carbon atoms, 2. a residue as defined in 1) which is substituted by 1, 2, 3, 4 or 5-identical or different radicals selected from the group consisting of alkyl groups having 1; 2, 3, 4, 5. 6, 7 or 8 carbon atoms, aralkyl groups having 6, 7, 8, 9, 10, 11, 12, 1.3 or 14 carbon atoms, fluorine, chlorine,. bromine and iodine, trifluoromethyl, SO _q R ^18, OR ^16. NR ¹⁹ R ²⁰ , cyano, nitro and CO-R ⁹ , or in which the two residues together form an anellated hexocyclyl residue, ,. 3. a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, 4. -the remainder defined in point 3 ·. substituted with 1, 2 or. The same or different radicals selected from the group consisting of fluorine, chlorine, bromine and iodine, trifluoromethyl, methyl; methoxy, hydroxyl group ..and · 'MR ^{:: R:} \ 5. cycloalkyl; with 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, - /, 6.: the residue defined under (5), substituted with an aryl group having 6, 7, -8, 9, 10, 11, 12; 13 or. 14 3. carbon atoms; 7th group O-Ř ¹⁴ , / - 8th group OR ¹⁷ ,, 9. the group -SO ₂ -R ¹⁴ , / 10. an arylalkylcarbonyl group; or 11th heterocyclyl group, · R ¹⁴ .and R ¹⁷ independently of one another are 1. a hydrogen atom; 2. an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 atoms - 109 • · carbon, 3. an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 'carbon atoms; The fourth group _H2n _ _NR) -phenyl, where nn is 0 or 2, and. n- is 0, 1 ,. 2, 3 or 4, wherein n is not 0 or 1 if nn is 2, or 5. the radical as defined in 4, wherein the phenyl moiety is substituted with 1, 2 or. 3. the same or different radicals selected from the group consisting of alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, fluorine, chlorine, bromine and iodine atoms, trifluoroethyl group, 'groups. SO _q R ^15, -OR ^{16, NR n} R ^12, cyano, nitro and groups CO-R ^9, R ¹⁵ a'R ¹⁸ independently of one another are alkyl having 1, 2, 3 or 4 carbon atoms , alkyl - ·. -s 1, 2, 3 or 4. the carbon atoms in which they are one to. all. hydrogen atoms replaced by fluorine atoms, or NR ¹¹ R ¹² , R ¹⁶ - represents 1. a hydrogen atom, 'j ¹ 2. an alkyl group having 1, 2, 3 or 4 carbon atoms; · 3. alkyl. C 1, 2, 3 or 4 carbon atoms substituted by C 1 -C 4 alkoxy; 4. an alkyl group having 1, 2, 3, or 4 carbon atoms in which they are. one, until all hydrogen atoms have been replaced. fluorine atoms. 5. an aryl group having 6, 7, 8, 9, 10, 11-, 12, 13 or 14. carbon atoms, or 6. the remainder defined in 5. which is. tuován Ί, ² or 3 identical or., .vybranými different radicals from the group comprising fluorine, .chloru, Br. and iodine, trif, fluoromethyl,. NR ^19, R ²⁰ , cyano and nitro, R ²² and R ²³ independently represent an atom 110 hydrogen or CO-OR ²⁴ , R ²⁴ signify hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 th or 8 carbon atoms or -C _n H _2n -phenyl where n is 1, 2, 3 or 4 aq is independently 0, 1 or 2, as well as physiologically acceptable salts thereof. A compound of formula I according to claim 1, wherein R ¹ represents 1. an alkyl group having 1, 2, 3, 4 or 5 carbon atoms; 2, 3, 4 or 5 carbon atoms in which they are one to. all hydrogen atoms replaced by fluorine atoms, 7 n / alkenyl having 2, 3, 4, 5, 6, 7, 8, 9, 10, or. 12 carbon atoms, -C _n H _2n _ _nn -Y, wherein has a value. 0 or .2, and is Ό, 71, 2, 3, or 4, with n not - a value of 0 or 1 if nn has a value of 2, or '-Y, where. - 7. is 0 or 2, and is 1, 2, 3, or 4, with n not being 1 if nn. has a value of 2, which is 1, 2 or 3 hydrogen atoms in the divalent form replaced by the radical ⁹ 9, 10, 11, 12, 13 3. 11 4. nn n 5. nn n in the remainder of -CH, independently of the screw - ² n .2n-nn .. τ * * * * * * * * * * * * r n n n n n n Cl ii ý z z. Oi-iiý 1. aryl -se 6, 7, _8,: or, 14 carbon atoms, " 2. amino, 3. NR ²² R ²³ groups, 1-4 alkoxycarbonyl groups, -5. COOR ¹⁶ , 6. 1, 2, 3 or 4 atoms 111 7. arylalkylcarbonyl groups having 6 to 14 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl portion; R ² . means. 1. a hydrogen atom; 2. alkyl having 1, 2, 3, 4 or 5 carbon atoms, 3. an alkyl group having 1, 2, 3, or 3; 4. or 5 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, 4. an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, 5. alkynyl having 2, 3, 4 or 5 carbon atoms, Group 6 ^- C _n H _{2n - nn -} Z, where nn is 0 or 2, and n. has a value of 0, 1, 2, 3 or 4, where n is not 0 or L when nn is 2, or. · Group 7 - C _n H 2 _n -. _in -Z, where nn ’ has a value 0 or 2, and n has .value 1, 2, 3 or 4, wherein n is not a value 1 if nn has a value of 2,. '. ve which are 1, 2 or 3 hydrogen atoms, bivalent residue _H2n j _nn - '.nezávisle wearing. replaced by a residue selected from the group consisting of <. '. '. 1. aryl groups having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, 2. amino,. ; Of the group NR ²² R ²³ '. / 4. C 1 -C 4 alkoxycarbonyl; in the alkoxy moiety, 5. COOR groups ', and'. ... 6. alkyl groups having 1, 2, 3 or 4 '. atoms .. · carbon> R ³ and R ⁴ independently of each other. each represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms; . < • 9 R @ ⁵ , R @ ⁶ and R @ ⁷ are each independently hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine or bromine, trifluoromethyl, cyano or SO2; R ⁸ , CO-R ²¹ or STEED R 'represents an alkyl group with. 1, 2, 3 or 4 carbon atoms, NR ⁿ R ¹² or a phenyl group which is nesubsti.tuovaná or substituted by 1 or 2 identical or different radicals. selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl. methyl, methoxy, hydroxy. and NR ¹² R ^U, R ⁹ and R ²¹ independently represent hydrogen, alkyl having 1,2, 3 or. 4 carbon atoms or OR ¹³ , ¹⁰ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms which is optionally substituted by an alkoxy group having 1 to 4 carbon atoms or a phenyl group which is unsubstituted or substituted with 1 or 2 same or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl, methyl,. · Methoxy, and hydroxy., NR ⁿ R ¹² · 'R ^u, R ^12, R ¹⁹ and R ²⁰ independently of one another. in each case represent a hydrogen atom, an alkyl group having 1, 2, 3, 4, 3 or 4; R @ ¹³ represents a hydrogen atom or an alkyl group having from 1, 2, 3 or 4 carbon atoms or an alkanoyl group having from 1 to 4 carbon atoms; 2, 3 or 4 carbon atoms,. X represents a carbonyl group (s). -CO-NH-, -CO-CO-, or a sulfonyl group. the symbols Y and Z are independently of one another. always. . '. 1. phenyl, 1-naphthyl or 2-naphthyl; the radical as defined under 1, which is substituted with 1,. 2, 3, 4 or 5 with the same or different radicals selected from the group consisting of alkyl having 1, - ·· - 113.2, 3 or 4 carbon atoms, phenyl, 1-naphthyl and 2-naphthyl group, fluorine, chlorine, bromine, trifluoromethyl, SO _q R ^18, OR ^16, NR ¹⁹ R ^20, cyano, and CO-R ^{5 * * 9 *} or on which two 'radicals together forms an fused heterocyclyl radical; heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or ^Λ 9 carbon atoms, 4. a radical as defined in 3 which is substituted by 1 or 2 of the same or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl; methyl, methoxy, hydroxyl and NR ¹² R ^U, / 5. cycloalkyl having 3, 4, 5, 6, 7, 8, or 9. 10 carbon atoms. · 6. residue / as defined under 5., substituted. •. phenyl, 1-naphthyl or 2-naphthyl, ... OR ⁷ , 8,. OR ¹⁷ ·, .. 9th -SO ..- R ¹⁴ '.10. an arylalkylcarbonyl group, or the 11th heterocyclyl group, R ^14, and R ^17, independently of one another, are each ^; 1. hydrogen atom, ' ^f ' 2. an alkyl group having 1, 2, 3 or 4 carbon atoms, 3. alkenyl. sě 2, 3,. 4, 5 or 6. atoms carbon - 4. 1/ 1/11 r> ΐ rm —V ¹ U _-F q η τ; 1 Lr Ω SKclP-uxiua ^ _n ^xx 2n-nn ΚναΘ  · nn is 0 or 2; and n has a value of 0, 1, 2, 3 or 4, wherein, n . does not 0 or 1 if nn is 2, ..or 5. The rest 'defined' under point 4 in / which phenyl is substituted with 1, 2 or 3 identical or r · ¹ different radicals selected from the group consisting of alkyl, groups with 1, 2, 3 or 4 carbon atoms, the atoms fluorine, chlorine, and bromine, trifluoromethyl; I 9 9 9 9 - 114 · 9 • SO _q R ^15, OR ^16, NR ⁿ R ^12, CN ', and CO-R ^9, R ¹⁵ and R ¹⁸ independently of one another are alkyl having 1, 2,. (3) or (4) carbon atoms, an alkyl group having 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, or NR ⁽ R) ² , R ¹⁶ means' 1. a hydrogen atom; 2. alkyl having 1, 2, 3 or 4 carbon atoms, 3. an alkyl group having 1, 2, 3, or 4 carbon atoms substituted by an alkoxy group having 1 to 4 carbon atoms, 4. an alkyl group having 1; 2, 3 or 4 carbon atoms in which one, until all hydrogen atoms are replaced by fluorine atoms; . 5. ferryl, l-naphthyl. or. A 2-naphthyl group; or. . . Λ ·. '-? .. 6. a residue as defined in point 5 which is substituted with 1, 2 or 3 of the same or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl, NR ¹⁹ R ²⁰ and cyano; R ²² and R ²³ independently represent, in each case. hydrogen or a ^CC-OR24, R ²⁴ represents a hydrogen atom, an alkyl group having 1, 2, 3, or 4 atoms. carbon, or '.. group _H2n-phenyl where. n is 1, 2 or 3, and q is independently 0, 1 or 2, and physiologically acceptable salts thereof. 3 ... Biphenylsulfonylcyanamides. of the general formula I according to claim 1 and / or 2, wherein. R ¹ represents _t 1. an alkyl group having 1; 2, 3, 4 or 5 carbon atoms; 2. an alkenyl group having 2, 3 or 4 carbon atoms; 44 ··> »4 < 3. Υ ηη η 4. Υ - 115 -C _n H _2n _ _nn -Y wherein represents 1. a phenyl group; 2. the remainder defined in 1. which is. substituted with 1, 2, 3, 4, or 5 with the same or different radicals selected. is selected from the group consisting of alkyl groups having 1, 2, carbon, fluorine, chlorine, cyano and trifluoromethyl groups. 3 or 4 ,, bromine, hydroxy, nitro, 'SO ₂ R ^18. OR ^1S , SCF ₃ , NR ¹⁹ R ²⁰ and CO-R ⁹ , 3rd group OR ¹⁴ , .. 4. SC, -R ' ⁴ , 5. 1-naphthyl or 2-naphthyl; 6. the remainder defined in point 5.,. which is substituted by a radical selected from the group consisting of -alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine atoms and chlorine atoms, trifluoromethyl groups and SO ₂ groups R ¹⁸ , OR ¹⁶ , NR ¹⁹ R ²⁰ and. CO-R ⁹ 7. a heteroaryl group having 1, 2, 3; 4 5 6 7 8 or 9 carbon atoms, 8. the rest .defined under. 7. which is substituted by a radical selected from the group consisting of fluorine atoms, and -, chlorine, trifluoromethyl. methyl, methyl, methoxy. and dimethylamino, or. . ·, ·. · -. '---------- atcm in carbon,' has a value of 0 or 2, and has a value of 0.1, 2, 3 or 4, a value of 0 or 1 if nn 'has a value. 2, or -C _n H _2n _ _nn -Y where represent the E 1. phenyl group, Q Γ’χζίτΐ γίλ 1 mrmi «Vnninii 6 or 7 pncemz n 2nd group OR, or 9 9 «9 9» 9 9 9.9 9 · · - 116 nn n 3. a heteroaryl group having a value of 0 or 2, and a having a value of 1, 2 or 3, wherein n is not 1 if nn has a value of 2 in which 1, 2 or 3 are hydrogen atoms in the divalent radical ~ C _n H _2n - _nn - independently replaced by a residue selected from the group consisting of 1., arylové.se 6, 7, 8, 9, 10, 1-1, 12, 13 or 14 carbon atoms, 2. amino, 3. groups NR ²² R ²³ , 4. alkyl groups. with 1 , 2,. : carbon, means 1. hydrogen, ' 2 ·· alkyl. group with 1, 2, ³ >. 4 or. 3. an alkyl group having 1, 2, 3, 4-. or ve, which are one to all atoms fluorine atoms, 4. an alkenyl group having 2, 3, 4, 5, 10 carbon atoms, '5. an alkynyl group having 2, 3, 4 or 6. -C _n H _2n _ _NN -Z wherein OF represents .. 1. a phenyl group; 3 or 4 atoms 9 or 2. a residue as defined under 1. which is Si η Ο + · · · Ηη / ^ ττόη 1 O r \ QO h Q ^- '? rm τ τ “\ Vs» 7 <1 ί 1 n Srm τ LXXJ l__LLUOV Cul Λ- O F O 2-> - J II% III _u iiCU.U i. U V-A-J-ii J / ULL radicals selected from alkyl -carbonyl having 1, _2, 3 or 4 atoms, carbon, phenyl, fluorine, chlorine and bromine atoms, trifluoromethyl, SO ₂ R ¹⁸ , OR ¹⁶ , nitro, cyano and NR ¹⁹ R ²⁰ and CO-R ⁹ , or on which two. residues together form methylenedioxy, 3 '. A 1-naphthyl or 2-naphthyl group; : / - 75-¾ · '? 0 * 9 00 00 • »··· 0 · 0 · 0 0 0 0 0 · «·· 0 0 0 0 0 0 0 · 0 0 0 0.0 0.000 ·· 00 00 00 0 · «0 9 0 0 6 0 0 0 0 0 0 0 0 0 0 - 117 4th residue defined under the third, which is substituted with a radical selected from the group consisting of alkyl having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, trifluoromethyl, 'SO ₂ R ^18, OR ¹⁶ , nitro, cyano and NR ¹⁹ R ²⁰ and CO-R ⁹ , 5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, ¹ ..- + 6 .. the residue defined under. Item 5, which is substituted by a radical selected from the group consisting of fluorine and chlorine atoms, -trifluoromethyl, methyl, methoxy, hydroxy and dimethylamino, 7. a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, or 8. -the rest, -defined under. point 7., which is -----. substituted by phenyl, nn is 0 or 2. a. n has a value of 0, 1, 2 or 3, n having no value 0 or 1 if nn is 2, 7th group -C "H ......" - Z, where Z represents. 1. a phenyl group; or 2 - rest. defined under. Item 1, which is substituted by 1, 2 or 3 same or different radicals selected from the group comprising alkyl I i Iri i »» 7 O O Λ b '. p. / 1 - “v 4“ τ τ i 1 “. Ί i 1 »· ·» -. £ 5 _ - ...... o. x _r . x, o-nexu-aukjiiiy iun.xjs.iij iSuyiuVOu group, chlorine fluorine, trifluoromethyl (, SO ₂ R ¹⁸ , OR ¹⁶ , nitro, cyano and NR ¹⁹ R ²⁰ and CO-R ⁹ groups. (nn '- · has a value of 0 or 2, a., n. / has a value of 1, 2 or .3, with n not having a value of 1 if nn has a value of 2 in which, are 1, 2 or 3 hydrogen atoms in bivalent , 1: - 118 residue _H2n _ _nn - independently replaced by radicals selected from the group consisting of 1. alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkoxy moiety; COOR Group ¹ The third carbon alkyl groups, or a '· --C _n H _2n -OR ¹⁷ where · = 0, 1, 2 or 3, 3 or 4 atoms 1, R ³ and R ⁴ are each atom. hydrogen or methyl, R ⁵ , R ⁶ and R ⁷ independently of one another. in each case a hydrogen atom is an alkyl group having 1, 2, 3 or 4 carbon atoms, a fluorine atom. . or chlorine, trifluoromethyl, cyano, SO ₂ -R ⁸ , CO-R ²¹ or OR ¹⁰ , R ⁸ represents an alkyl group having -1, 2, 3 or 4 carbon atoms, dimethylamino or a phenyl group which is unsubstituted or substituted by a radical selected from the group consisting of fluorine atoms and chlorine, . Trifluoromethyl, methyl. methoxy, hydroxy and dimethylamino, R ⁹ 'a. R ²¹ independently represent hydrogen, methyl or a group OR ¹³ .1 ¹⁰ is hydrogen, alkyl having 1, 2, 3 or 4 / · carbon atoms., ..Která. is optionally substituted by C 1 -C 4 alkoxy or phenyl which is unsubstituted or substituted Slrn RVI and / radicals selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, methoxy a'dimethylaminoskupinu, R ^and R ¹² represent the wearing nezávisle- 'are hydrogen, alkyl having 1, 2, 3 or C 4 or C 1 -C 4 alkanoyl; R ¹³ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms; 119 X - represents a carbonyl group, -CO-CO-, -NH-CO- or a sulfonyl group, R ¹⁴ represents 1. a hydrogen atom; 2. alkyl having 1, 2, 3 or 4 carbon atoms, 3. an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms, The fourth group -C _n II _ _2n -phenyl _nn, where nn is 0 or 2, n is 0, 1 ·, 2, 3 or 4, wherein n has a value of 0 or 1 if nn is 2, or 5. the rest. as defined in item 4, wherein - the phenyl moiety is substituted by 1, 2 or _: 3. by the same 'or' - different radicals selected from the group consisting of: 1 alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, trifluoromethyl group; . SO ¹⁵ , OR. ^fe , .NR ^U R ¹² ,. cyano and- groups CO-R ⁹ , R ¹⁵ 'is alkyl having 1, 2, 3 or 4 carbon atoms or dimethylamino, R ¹⁶ ; means i ... hydrogen atom, '', 2. an alkyl group having 1, 2, 3 or 4 carbon atoms; ^{5 * * * *} 3. alkyl. a group having 1, 2/3 'or 4 atoms. C 1 -C 4 -alkoxy substituted carbon, 6. a radical as defined in point 5 which is substituted by 1, 2 or 3 of the same or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, trifluoromethyl; of group NR ¹⁹ R ²⁰ . and cyano, -, -, and -. ·· · - 120 R ¹⁷ represents 1. a hydrogen atom; 2. alkyl having 1, 2, 3 or 4 carbon atoms; 3. alkenyl having 2, 3 or 4 carbon atoms, The fourth group _H2n -phenyl _ _nn, where nn is hodnotu.0 or 2, n is 0, 1.2, 3 or 4, wherein n does not have the value 0 or 1 if nn is the value of .2 or (5) a radical as defined in (4) in which the phenyl moiety is substituted by a radical selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, trifluoromethyl group, SO _q R ¹⁵ -, OR ^16, NR ¹² R ^U, 'and cyano groups' CO-R ^9. '· R ¹⁸ represents an alkyl group having 1, 2, 3 or 4 carbon atoms, an alkyl group having 1, 2, 3. or 4 atoms / carbon in which they are one to all hydrogen atoms. - I. replaced by fluorine atoms ,, or NR ¹² R ^U · 'R ¹ independently represent a hydrogen ....,. hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or alkanoyl having 1 to 4 carbon atoms, R @ ²² , R @ ²³ and R @ ²³ independently. wearing. each represent a hydrogen atom or a CQ-OR ²⁴ group, R ²⁴ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, or a -C ₁ H _n -phenyl group wherein n. . ; a value of 1 or 2; and. q has an independent value of 0, i or 2 as well as their physiologically acceptable salts. . ’. The biphenylsulfonylcyanamides of formula (I) according to one or more of claims 1 to 3, wherein R ¹¹ 'is 7. 1. alkyl having 1, 2, 3, 4 or 5 carbon atoms, 2. alkenyl having 2, 3 or 4 carbon atoms, 3. group ~ C _n H _2n _ _nn ~ Y, where [-, n - - -121 ϊ · ¢. Υ poses 1. phenyl group, 2. a residue as defined under 1 which is substituted with 1, 2, 3, 4 or 5 with the same or different residues selected from the group consisting of: C 1 -C 2 -alkyl groups having 1, 2, 3 or 4 'carbon atoms, fluorine, chlorine and bromine atoms, cyano, trifluoromethyl, hydroxy, nitro, SQ groups₂R¹⁸, .OCH₃, OCF₃SCF₃, N _{(CH3) 2, -NH-CO-CH3,} CO-R ^9, phenoxy fenoxys.kupiny mono- or polysubstituted ^»one halogen. 3- OR ¹⁴ , or 4. the group SO ₂ -R ¹⁴ , nn has a value of 0 or 2, and n · 'has a value of Ό, 1, 2, 3 or' 4, with n not having. .. 0 or. ; .l if, nn is 2, or < The fourth group _H2n _ _nn -Y wherein Y represents 1. phenyl group., 2. OR ¹⁴ ; or 3. heteroaryl, preferably thienyl, nn is 0 or 2, and. < has a value. 1, 2 or 3, where n is not 1 if nn is. value 2,. ’J '. in which it is related CL C CJILLy \ Ί Ί TT «Λ ΤΛ Z 'ΤΊΠ in aZiLiLt residue ^- C _n H _2n _ _nn - independently replaced by a residue selected from the group consisting of 1. aryl groups of 6; 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms or a phenylacetyl group 2. amino, Group 3 22R ²² R ²³ , 'a' 4. Alkyl groups having 1> 2, 3 or 4 carbon atoms · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. · · 122 The fifth group _H2n -Y where. Y represents, 1. A 1-naphthyl or 2-naphthyl group; 2. a radical as defined in 1 which is substituted by a radical selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl and SO ₂ R ¹⁸ groups, OCH ₃ , N (CH ₃ ) ₂ and CO-R ⁹ , 3. a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, C nebo nebo 9 9 9 9 nebo nebo,,. '. · 4. a radical as defined in item 3, which is substituted by a radical selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl, a group, a methyl group, a methoxy group and a. _____, dimethylamino ,. sky 5. cycloalkyl having 3, 4, 5, 6 or ¹ to 7 carbons, and ·. · n has the value 0, 1, 2, 3 or 4, or. . '; 6. -C _n H, _n -OR ^: where n is 0, 1 or 2; R ² means' · 1 ,. alkyl group having 1,. 2, 3, 4 or 5 carbon atoms, 2. ‘alkyl having 1, 2, 3, 4 or 5 atoms. The carbon atoms in which one to all of the hydrogen atoms are replaced by ahrurnr -Fl imm L-. 3. an alkenyl group having 2, 3,4,5,6,7 8, 9 or 10 carbon atoms, 4. an alkynyl group is 2; 3, 4 or 5 carbon atoms, 5. skupihu _{H2n. nn} -Z, where OF represents · *. 1. a phenyl group, 2. the rest defined. under point 1., ,which is ,, substituted with 1, 2 or 3 with the same or different • · 123 radicals selected from the group consisting of alkyl having 1, 2, 3 or 4 carbon atoms Ru, phenyl, fluorine, chlorine and bromine atoms, trifluoromethyl. SO ₂ R ¹⁸ , -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy, hydroxy, nitro, cyano, N (CH ₃ ) ₂ , -NH-CO-CH ₃ , CO -R ⁹ , phenoxy; and phenoxy groups substituted one or more times with halogen, or wherein the two radicals together form a methylenedioxy group, nn. is 0 or 2; and. . n is 0, 1, 2, or 3, and n is not 0 or 1 if nn is 2, .. 6. The group -C _n H _2n _ _NN -Z wherein. Z represents i. a phenyl group; or. .2 .. -. the rest: def ingenious. under. - point 1, which is substituted with 1, 2 or 3 of the same; different radicals selected from the group consisting of alkyl groups having 1, 2, 3 or 4 carbon atoms, phenyl groups, atoms. fluorine and chlorine, trifluoromethyl, groups. SO ₂ R ¹⁸ , -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy, hydroxy, nitro, cyano ,. groups Ň (.CH ₃ ) ₂ and CO- ^{9 9} , -. Π · rvs — i h / Λ z ~ J r i lUO likJ UliU ΛΧ -. if nn has V in which j are 1, nn has a value of 0 or 2, and TO r> z “\ z“ \ J »» »·, z ^ λ η X - 1«. zJ · »“. of·. X »* Π xr ncbu sj _r pxxtidLiZ ii iicma uuuuuuu x value 2,. 2 or 3 hydrogen atoms in the divalent radical, _π - independently replaced by a radical selected from the group consisting of; ' C 1 -C 4 alkoxycarbonyl in the alkoxy moiety, 2. groups, COOR ¹⁶ , and 3. alkyl groups with 1, 2, 3 or. 4 atoms - 124 - carbon, 7. The group _H2n -Z wherein Z represents 1. A 1-naphthyl or 2-naphthyl group; 2. a radical as defined in 1 which is substituted by a radical selected from the group consisting of alkyl groups 1, 2, 3 or 4. carbon atoms, fluorine and chlorine atoms, trifluoromethyl, SO ₂ R ¹⁸ , O'CH ₃ ,. -O (C ₂ H ₄ ) OCH ₃ , ethoxy, hydroxy, nitro, cyano, N (CH ₃ ) ₂ , -NHCO ₃ and CO-R ⁹ , 3. a heteroaryl group having 1, 2, 3, 4, 5, 6, 7, Or 8, or 9 carbon atoms, preferably benzimidazolyl, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, benzofuranyl. for example dihydro-1-oxobenzo [f] furanyl, and quinazolinyl, for example. 3,4-dihydroquinazolinyl, -. 4. the rest. as defined in Item 3, which is substituted by a radical ... selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl a methyl group, a methoxy group, a hydroxy group and a dimethylamino group; . (5) a cycloalkyl group having 3,4; 5, 6, 7,, 8, 9 or 10. carbon atoms, preferably cyclopropyl, (cyclohexyl), cyclohexyl, 1,2,3,4-tetrahydro-naphthyl or indanyl, or 6. a residue as defined in item 5 which is substituted by a phenyl group, preferably a phenylcyclopentyl group, and n is 0, 1, 2 or 3, or 8. The group _H2n -OR ^1.7, wherein, n is 2 or 3, R ³ and R ⁴ are hydrogen, - 125 - 9 '· symbols R ⁵ ,. R ⁶ and R ⁷ independently represent a hydrogen. hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms; a fluorine or chlorine atom, a trifluoromethyl group, a SO ₂ -R ⁸ , CO-R ²¹ or O-R ^{10 group} , R ⁸ is methyl or dimethylamino; R ⁹ and R ^{21 are} each independently hydrogen, methyl or OR ¹³ , R ¹⁰ . represents a hydrogen atom, a methyl or ethyl group which is optionally substituted by a methoxy group, or a phenyl group which is unsubstituted or substituted by a radical selected from the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group. and dimethylamino. group R ¹³ represents a hydrogen atom or an alkyl group having 1/2, 3. or 4 carbon atoms, X represents an α'carbonyl group. ‘-Group. —CO-CO--, -NH-CO-. or a sulfonyl group, R ¹⁴ represents 1st atom. hydrogen. ... (2) a methyl or ethyl group; The third ^one alkenyl having 2, 3, 4, ·. 5 or 6 atoms. A carbon, preferably an allyl group, The fourth group -C _{n H; n-phenyl,} n. A. 0 or 1 5. The residue as defined in Item 4. wherein the phenyl moiety is substituted with a residue selected from. -carbonyl alkyl group with carbon atoms, fluorine, chlorine,> 15 'from j neoo. + atoms trifluoromethyl, SO ₂ R ^15, OCH _3, N _{(CH3) 2,} and CO-R ^9, or 6. alkenyl having 2, 3 or 4 carbon atoms, R ¹⁰ represents a methyl group or a dimethylamino group, R ^{@ 1} is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R ¹⁷ represents ·. 1. a hydrogen atom; 126 2. methyl group, The third group _H2n -phenyl where n is 0 or 1, 'the fourth the radical as defined in item 3, wherein the phenyl moiety is substituted with a radical selected from the group consisting of alkyl having 1, 2, 3 or 4 carbon atoms; fluorine and chlorine atoms, -trifluoromethyl, SO ₂ R ¹⁵ , - OCH ₃ , N (CH ₃ ) ₂ and CO-R ⁹ , or (5) an alkenyl group having 2, 3 or 4 carbon atoms; R ^{@ 1} is methyl, trifluoromethyl, amino or dimethylamino; R @ ²² and R @ ^{23 are each} independently hydrogen or CO - OR @ ²⁴ ; R ²⁴ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 atoms. Carbon,. or a group -C _n II _2n -phenyl where n is 1 or 2, and their physiologically acceptable salts. The biphenylsulphonylcyanamides of the formula I according to one or more of claims 1 to 4, which correspond to the general formula Ia. V 'wherein the radicals X and R ^first to R ⁷ are as defined in claims 1 to 4 as well as their physiologically acceptable salts. -, '''-·' *,. 6. A compound of the formula I as claimed in one or more of claims 1 to 5 or / or their physiologically acceptable salts for use as a medicament. · · · · · · · · · · · · · · 127 7. A pharmaceutical composition comprising an effective amount of a biphenylsulfonyl cyanamide of the formula I as claimed in one or more of claims 1 to 5. and / or a physiologically acceptable salt thereof. 8. A pharmaceutical composition according to claim 7, further comprising an effective amount of an exchange system inhibitor. sodium and hydrogen and / or active substances from another class of substances acting on the heart and blood circulation and / or their physiologically acceptable salts. , 9. The biphenylsulphonylcyanamides of the formula I according to one or more of claims 1 to 5 and / or their physiologically acceptable salts for use as inhibitors of the Na ⁺ -dependent bicarbonate / chloride exchange system. '. A compound of formula (I) as claimed in one or more of the preceding claims. 1 to 5. and / or their physiologically acceptable salts for use in. therapy and / or. prophylaxis of heart attack,. angina pectori, diseases caused by ischemic conditions, impaired respiratory stimulation, ischemic conditions, heart, ischemic, peripheral and central nervous system conditions, and apoplexy, peripheral organ ischemic conditions, and limbs, diseases whose primary or secondary cause is cellular, prolifera.ee, or. for the treatment of shock conditions, or for use in surgical operations and organ transplants, or for the preservation and storage of transplants for surgical interventions. 11. Biphenylsulfonylcyanamides of general formula. I. podle. one or. more of claims 1 to 5 and / or physiologically acceptable. .alts for use, therapy or ./a. prophylaxis of cancer. A pharmaceutical composition according to claim 7 and / or 8 rg —- rt :. - 128 - ·· φφ · · • φφ • ·. φ φ φ φ · · · φ φ · · · · For use in the therapy and / or prophylaxis of heart attack, angina pectoris, diseases caused by ischemic conditions, impaired respiratory stimulation, ischemic conditions of the heart, ischemic conditions of the peripheral and central nervous system and apoplexy, peripheral organ and extremity ischemic conditions, whose primary or secondary cause is. cell proliferation, or. to heal. shock conditions / or for use in surgical operations and organ transplants, or for the preservation and storage of transplants for surgical procedures. A pharmaceutical composition according to claim 7 and / or 8 for use in the treatment, therapy and / or prophylaxis of cancer.