CZ20002808A3 - Biphenylsulfonylcyanamides and the pharmaceutical composition containing them - Google Patents

Abstract

Biphenylsulfonylcyanamides of the general formula I, in which the individual general symbols have the meanings defined in the description, and their physiologically acceptable salts. These compounds exhibit “V excellent antiarrhythmic properties with a cardioprotective component. . These compounds can preventively inhibit or strongly limit pathophysiological processes in the development of ischemically induced disorders, especially in the development of ischemically induced cardiac arrhythmias. In addition, they exhibit a strong inhibitory effect on cell proliferation. A pharmaceutical composition containing these compounds is described.

Description

Biphenylsulfonylcyanamides and pharmaceutical composition containing them

Technical field

The invention relates to biphenylsulfonylcyanamides, _processes for their production, pharmaceutical compositions containing them, and their use as medicaments.

The current state of the art,

EP-A 855392 describes imidazole derivatives with a biphenylsulfonylcyanamide side chain as inhibitors of the Na ⁺ -dependent ^bicarbonate /chloride exchange system (NCBE).

. 3>3Ý

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

The essence of the invention

The invention relates to compounds of general formula I in which

R ¹ represents

1. alkyl carbon,

2. alkyl

a group with 1, 2, 3, 4, 5, 6, a 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 with .2, 3, 4, 5, 6, 7, 8, 9, 10, or 12 carbon atoms,

4,. the group -C _n H _2n _ _nn -Y,. where nn has the value 0 or 2, and.

• n has the value 0,' 1, 2, -3 or . 4, where n does not have the value 0 or 1 if nn has the value 2, or'

5th group where nn has the value 0. or 2, and .

n has the value 1, 2, 3 or 4,- where n has no value if nn has the value 2, in which there are 1, 2 or 3 hydrogen atoms in the divalent .

residue . -C _n H _2n _ _nn - independently of each other replaced by a residue selected from the group consisting of ¹

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

2. amino group,

3rd group NR ²² R ²³ , - < ·

4. - alkoxycarbonyl groups, ,

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

R ² . ..means - <^;

1. hydrogen atom,

2. alkyl group with 1, 2, 3, 4, 5, 6, 7 or , 8 atpm carbon, 3. alkyl group with 1, 2, 3, 4, 5, 6, '7 or 8- atoms carbon, in which there are one to all- atoms hydrogen replaced by fluorine atoms, 4. alkenyl group with 2, 3, 4, 5, 6, 7, 8, 9, 10,

- .3 or 12 carbon atoms,

5. an alkynyl group with 2, 3, 4, 5, 6, 7 or 8 carbon atoms,

6. 'the group ~C _n H _2n _ _nn -Z, where nn .has the value Ό or 2, and n has the value . 0, 1, 2, 3 or' 4, with n not having the value 0 or:1 if nn has the value 2, or ' 7. the group -CK ₂ . „,,-Z, where . . ηή has the value 0 or ,2, and · ' . n has the value 1, 2, 3 or 4, with n not having the value if nn has the value 2, . in which 1, 2 or 3 . hydrogen atoms in the divalent residue ^- C _n H _2n _ _rin - . independently of each other ' are replaced by a residue selected from the group consisting of

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

2. amino group,

3. groups NR ²² R ²³ ,

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

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

identical or different radicals selected from the group consisting of fluorine, chlorine, bromine and iodine atoms, trifluoromethyl group, methyl group, methoxy group, hydroxy group and NR ⁿ R ¹² groups, the symbols R ⁹ and R ²¹ independently of each other each represent a hydrogen atom, an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or the group OR ¹³ ,

R ¹⁰ represents a hydrogen atom, an alkyl group with 1, -2, 3, 4, .5,6, 7 or 8 carbon atoms, which is -optionally substituted by an alkoxy group with 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 comprising fluorine, chlorine, bromine and iodine atoms, trifluoromethyl group, methyl group, methoxy group, hydroxy group and groups NR' ^l R ^:;: , the symbols 'R ⁿ , R ¹² , Ø ¹ · ⁹ ' and 'R ²⁰ independently of each other each represent ·· a hydrogen atom, an alkyl group with' 1, 2, 3. or 4 carbon atoms or an alkanoyl group with 1 to 4 carbon atoms, preferably an acetyl group, - '

R ¹³ represents a hydrogen atom or an alkyl group with 1,.· 2, 3,

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

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

the symbols Y and Z independently of each other always mean

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

2-naphthyl group, ,

2. a residue as defined under point 1., which is substituted by 1, 2, 3, 4 or 5 identical or different residues selected from the group consisting of alkyl groups with 1,

2, 3, 4, 5, 6, 7 or 8 carbon atoms, aryl groups with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or ² -naphthyl, fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, SOR groups, cyanoOR groups, nitro ^groups and CO-R groups, or two of which together form an fused heterocyclyl radical, preferably methylenedioxy, heteroaryl groups with 1, 2, 3, 4, 5, 6, 7, 8 or carbon atoms,

4. a radical as defined under point 3., which is substituted by 1, 2 or 3 identical or different radicals selected from the group consisting of fluorine, chlorine, bromine and iodine atoms, trifluoromethyl, methyl, methoxy, hydroxy and NR ¹¹ R ¹² groups, 5. a cycloalkyl group with 3, 4, 5, c, 7, 8, 9 or carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl or indanyl group,

6'·.' . residue- . defined under ·' point.-? - 5 ., - substituted by an aryl group with 6, 7, 8., 9, 10, 11, 12, .13 or 14 carbon atoms, preferably a phenyl, -1-naphthyl. or 2-naphthyl group, _: 7. group O-R'^; ,

8. group C--R', · .·- i ., group -SO..-R ¹ '', · .

an arylalkylcarbonyl group, a methylcarbonyl group, or

11. a heterocyclyl group, the symbols R ¹⁴ and R ¹⁷ independently represent.

1. hydrogen atom,

2. an alkyl group with 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, .

4th group -C.H... ....-bitches!, where . _.

^? y nn has the value 0 or 2, and n has the value 0, .1, 2, 3 or - 4, .wherein> n does not have ,9 . 10 preferably .phenylrharh 7' V

value 0.or 1 if nn has the value 2, or

5.' a radical as defined under point 4., in which the phenyl part is substituted by 1, 2 or 3 identical or different radicals selected from the group consisting of alkyl groups with 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 groups, cyano group, nitro group and CO-R ⁹ groups, ' symbols R ¹⁵ and R ¹⁵ independently of each other each represent an alkyl group with 1, 2, 3 or 4 carbon atoms, an alkyl group with 1, 2, 3 or 4 carbon atoms, in which '' one to all hydrogen atoms are replaced by fluorine atoms, preferably a trifluoromethyl group, or a group

NR ¹¹ R ¹² , sign

1. hydrogen atom,

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

3. an alkyl group of 1, 2, 3 or 4 carbon atoms substituted by an alkoxy group of 1 to 4 carbon atoms.

4. an alkyl group with 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, preferably a trifluoromethyl group, 5. an aryl group with 6, 7, 8, 9, 10, 11, 12, 13 or more carbon atoms, preferably a phenyl, 1-naphthyl or 2-naphthyl group, or .

6. the remainder defined under point 5., which is substi-U· -, * T —> νΛ I

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

- bromine and iodine trifluoromethyl group

NR ¹⁹ R ²⁰ , cyano group and nitro group, symbols, R ²² and R ²³ independently of each other always represent a hydrogen atom or. group CO-OR ²⁴ , . , '

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

6, 7 or 8 carbon atoms, or the group -C _n H _2n -.phenyl, where n has the value 1, 2, 3 or.4, and '

q independently has the value 0, 1 or 2, as well as physiologically acceptable salts thereof.

Preferred are compounds of general formula I, wherein R ¹ represents ' . · ·

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

2. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, _ · ^from

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

nn . has the value 0 or 2, and n has the value 0, 1, 2, 3 or 4, with n not having the value 0 or 1 if nn has the value 2, or

5. group -G _n H _2n _ _nn -Y, where.

nn - .... has the value 0 or 2, and . . n has the value 1, 2, 3 or 4, wherein n has no value if·.nn, has the 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 - comprising

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

2. amino group,· ' 3. groups NR ^2z R ²³ , ·, ·

4. alkoxycarbonyl groups,

5. groups CGO?X,

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

7. arylalkylcarbonyl groups with 6 to 14 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the

Λ ' 1 alkyl moiety, preferably a phenylacetyl group,

R ² represents .1 . . 1. hydrogen atom,.

2 . an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, 3 . an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, in which are one to all atoms hydrogen replaced fluorine atoms, 4 . an alkenyl group with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, 5 . an alkynyl group with 2, 3,. 4 or 5 carbon atoms, 6. group -C..H. ₂ ..Z, where nn has a value, 0 or 2, and. n has the value 0, 1, 2, 3 or 4, while it doesn't have value 0 or 1 if nn has the value 2, or 7 . the group -C _n H _2n _ _nn -Z, where · nn has a value of 0 or 2, and n has the value 1, 2, 3 or 4, where n does not have the value . 1 if nn has the value 2, in which are. 1, 2 or. 3 hydrogen atoms in a divalent

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

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

2. amino group,

3rd group NR ²² R ²³ , , ·

4. alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy moiety.

5. groups COOR ¹ ·, and

6. alkyl groups, sl, .2, 3 or 4 carbon atoms', , , the symbols R ³ and. . R ⁴ independently of., each represent a hydrogen atom or an alkyl group with 1, 2, .3. or·. 4.· carbon atoms, the symbols R ⁵ , R ^b and. R ⁷ independently of each other represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, a fluorine, chlorine or bromine atom, a trifluoromethyl' group, a cyano group, a group SO _q -R ⁸ , CO-R ²³ or

'OR ¹⁰ ,

R ^s represents an alkyl group with 1, 2, 3 or 4 carbon atoms, a group NR ^U R ¹² or a phenyl group which is unsubstituted or substituted by 1 or 2 identical or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group and groups NR ⁿ R ¹² ,- . , the symbols R ⁹ and R ²¹ independently of each other each represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms or a group OR ¹³ , · ''

R ¹⁰ ' means a hydrogen atom, an alkyl group with 1/ 2, 3 or 4 carbon atoms,, which ' is optionally substituted by an alkoxy group with 1 to. 4 carbon atoms, or a phenyl group, which, is unsubstituted or substituted by 1 or 2 identical or different radicals selected from the group . comprising fluorine, chlorine and · bromine atoms, a trifluoromethyl group, a methyl ' . group, a methoxy group, a hydroxy group and the groups NR ⁿ R ¹² , the symbols R ¹¹ , R ¹² , R ¹⁹ and R ²⁰ independently of each other each represent a hydrogen atom, an alkyl group with 1, , 2, 3 or 4 carbon atoms

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

1. a phenyl, 1-naphthyl or 2-naphthyl group, ' ¹ 2. a residue defined under point 1., which is substituted by 1, 2, 3, 4 or 5 identical or different residues selected from the group comprising alkyl groups' si, ¹

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

- 10 cyano group and CO-R ⁹ groups, or on which two radicals together form an anionic heterocyclyl radical, preferably a methylenedioxy group,

3. a heteroaryl group with 1, 2, 3, 4, 5, .6, 7, 8 or more carbon atoms,

4.. a residue as defined under point 3., which is substituted by 1 or 2 identical or different residues selected from the group consisting of fluorine, chlorine, and bromine atoms, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group, and NR^R ¹² groups,

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

carbon atoms, preferably a cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl' or' indanyl group, , 6. a radical as defined under point 5., substituted by a phenyl, 1-naphthyl or 2-naphthyl group,.

• ' 7th group OR ¹⁴ , . ·

.. group OR ¹⁷ ,

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

10. an arylalkylcarbonyl group, preferably a phenylmethylcarbonyl group, or •11. a heterocyclyl group, the symbols R ¹⁴ and R ¹⁷ independently of each other always represent

1.. atomic hydrogen, ·' 2. alkyl group with 1, 2, .3 or 4 carbon atoms, 3. an alkenyl group with 2,. 3, 4, 5 or 6 atoms , , 1.___ UiillKli, 4 . the group -C _n H _2n _ _nn -phenyl, where. 1 nn has a value of 0 or 2, and n . . has the value 0, 1, 2, 3 or 4, where n has no

value 0 or 1 if nn has the value 2, or > ' 5. a residue as defined under point 4., in which the phenyl' part is substituted by 1, 2 or 3 identical or . · different residues selected from the group comprising alkyl groups with 1,. 2, 3 or 4 carbon atoms, atoms

-11 fluorine, chlorine and bromine, trifluoromethyl group, SO R ¹⁵ , OR ¹⁶ , ' NR ⁿ R ¹² , cyano group and CO-R ⁹ groups; ' symbols R ¹⁵ and R ¹⁸ independently of each other each represent an alkyl group with 1, 2, 3 or 4 carbon atoms, ' alkyl.. group with 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, ' preferably a trifluoromethyl group, or a NR group'^; R ² ,

R ¹⁶ means

1. hydrogen atom,

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

3. an alkyl group with 1, 2, 3 or 4 carbon atoms substituted by an alkoxy group with 1 to 4 carbon atoms,.

4. an alkyl group with 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 radical .defined under point 5., which is substituted 1, 2 or 3' with the same or different radicals selected from the group comprising fluorine, chlorine and bromine atoms, a trifluoromethyl group, the groups NR ¹⁹ R ^?0 and a cyano group, the symbols R ²² and R ²³ independently of each other represent j í·'. each a hydrogen atom or a CO-OR ²⁴ group, '' . / .

R ²⁴ represents a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms.

..carbon atoms, or the group . -C _n H _2n -phenyl, where in·, has. ' the value 1,' 2 or 3, and.

q ' independently has the value 0, 1 or 2, . . .

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

Particularly preferred are compounds of the general formula, I, wherein R' represents

1. an alkyl group with 1,2, 3, 4 or 5' carbon atoms,

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

• · · • · ·« ··

-12 3·.

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

1. phenyl group,. ·

2. the residue defined under point substituted with 1, 2, 3, 4 or 5 residues selected from different alkyl atoms, carbon atoms, atoms from the group 's 1, 2, fluorine, chlorine, cyano group, trifluoromethyl

1. which is the same or a group of 3 or 4 and a bromine, group, hydroxy group, nitro group, groups/SO ₂ R ¹⁸ , OR ¹⁶ ,

SCF

3'

NR ¹⁹ R ²⁰ and CO-R ⁵ ,

3. group 0-R ¹⁴ ,

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

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

6. a residue defined under point 5., which is substituted by a residue selected from the group comprising alkyl groups having 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, a trifluoromethyl group and the groups S0 ₂ R ¹⁸ , OR ¹⁶ , NR ¹⁹ R ²⁰ and CO-R ⁹ ,

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

8 a residue defined, .under point 7. , which is' substituted . by a residue selected' from . the group- comprising fluorine and chlorine atoms, trifluoromethyl group, methoxy group and methyl group nn n

.

Ύ dimethylamino group, or

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

• has the value 0 or 2, and ' has the value 0, 1, 2, 3 or. 4., the value 0 or 1 if nn has the value 2, or the group -C,H. _:r . _nr -Y, where , represents +.

pricemz n .has *· ' ·· • · ♦ · • · ·· • · · « • · · · · · ♦· • ·

-13 n n n

in

1:, phenyl group,

2. group OR ¹⁴ , or

3. a heteroaryl group, preferably a thienyl group, has a value of 0 or 2, and has a value of 1, 2 or 3, wherein n does not have a value of 1 if nn has a value of 2, which are 1, 2 or 3 hydrogen atoms in the divalent residue -C _n H _2n _ _nn - independently of each ^other replaced by a residue selected from the group consisting of

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

2. amino group, , ’

3. groups NR ²² R ²³ , and

4. alkyl groups with 1, 2, 3 or 4 carbon atoms, R ² means ^;

1. hydrogen atom, , or 5 carbon atoms, or·. 5 carbon atoms, hydrogen atoms replaced

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

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

3. an alkyl group with 1, .2, .- 3, in which one to all fluorine atoms are present,

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

5. an alkyl group with 2, 3,

6. group -C _r H _: ..... _: .-Z, where Z represents

1. phenyl group,

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

- 14 - · . · a methyl group, the groups SOjR ¹ ®, OR ¹⁶ ,' a nitro group, · a cyano group. and the groups NR ¹⁹ R ²⁰ ' and CO-R ⁹ , or on which two residues together form a methylenedioxy group, . 1-naphthyl· or 2-naphthyl group,

4. a residue defined under point 3., which is substituted by a residue selected from the group consisting of alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, a trifluoromethyl group, / groups · SO ₂ R ¹⁸ , .OR ¹⁶ ,' a nitro group, a cyano group and' groups NR ¹⁹ R ²⁰ and CO-R ⁹ ,

5. a heteroaryl group with 1, 2, 3, 4, 5, 6, 7, or 9 carbon atoms, preferably a benzimidazolyl, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinyl-1-carbonyl-4,5-dihydroisoxazolyl, benzofuranyl, for example dihydro-1-oxobenzo[clturanyl, and quinazolinyl, for example 3,4-dihydroquinazolinyl, group,

6. a residue defined under point -5., which is substituted by a residue selected from the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group and a dimethylamino group, ..'·..:

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

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

8. , a residue as defined under point 7., which is substituted by a phenyl group, , preferably a phenylcyclopentyl group, , .

nn has the value 0 or 2, and n has the value 0, 1, 2 or 3, with n not having the value 0 or 1 if nn has the value 2,

7. group -C _n H.. ...-Z, where - ^ř • ·· · «·· .

. · · ·· ···♦ .*· ·· · · · · β β • ·· · · ·· · ·· ·· ·« ·· .

Z . represents ,

1. a phenyl group, or

2. a radical defined under point 1., which is - substituted by '1, 2 or 3 identical or different radicals selected from the group comprising. alkyl groups with 1, 2, 3 or 4'carbon atoms, phenyl group, fluorine and chlorine atoms/trifluoromethyl group, SO ₂ R ¹⁸ groups, 0R ^lb , nitro group, . cyano group and NR ¹⁹ R ²⁰ groups and ·- CO-R', - ' nn has the value 0 or 2, and an has the value 1, 2 or 3, with n. not having the value.1 if nn has the value 2, .

in which 1, 2 or 3 hydrogen atoms in the divalent radical -C _n H _2n _ _nn , are independently replaced by /residues and az atoms

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

í.· alkoxycarbonyl groups of the carbon in the alkoxy moiety,.

2. groups COCR' ^R , and

3. · alkyl groups 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 each represent a hydrogen atom or a .methyl group, the symbols R ⁵ , R ^a and R ⁷ independently. each represent, each a ·'· hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, a ·. fluorine or· chlorine atom·, . trifluoromethyl group, cyano group, SO ₂ ~R group, CO-R or O-R' group, means an alkyl group with 1, 2, '3' or 4.' carbon atoms, a dimethylamino group· or a phenyl group, which is unsubstituted or substituted by a residue' selected from the group comprising fluorine and. chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group,. hydroxy group. and a dimethylamino group,

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

R ¹³ represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms,

X represents a -carbonyl group, -NH-CO- or -Sulfonyl group, fluorine, CO-R ⁹ groups,

R ¹⁵ means the symbols R ⁹ and R ²¹ independently of each other each represent a hydrogen atom, a methyl group or a group OR ¹³ ,

R ¹⁰ ' means a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, which is optionally substituted by an alkoxy group with 1 to 4 carbon atoms, .or a phenyl group, which is unsubstituted .or substituted by a residue selected from the group comprising fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group and a dimethylamino group, the symbols . R ¹¹ and R ¹² independently, each represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms 4 carbon atoms, a group with 1, 2, 3 group -CHO.-CO-,

Ø ¹⁴ represents · ;

1. hydrogen atom,

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

3. an alkenyl group with 2, 3, 4, 5 or 6 carbon atoms,

4. the group -C _n H _2n _ _nn -phenyl, where , .nn has the value 0 or 2, and n . has the value 0, 1, 2, 3 or '4, whereby n does not have the value 0. or 1' if nn has the value 2, or ,5. the residue defined .under point 4., -in which the phenyl part is substituted 1,. 2. or. 3 with the same or . different residues selected from the group comprisingalkyl groups with 1, 2, 3 or. 4 carbon atoms, chlorine and bromine atoms, trifluoromethyl group, SO _q R ¹⁵ ,. OR ¹⁶ / NR ⁿ R ¹² , a cyano group and a group of alkyl groups with 1,-2,-3 or 4 carbon atoms or a dimethylamino group, ·· ·· ♦· • · · « · ·· · · · · · • ·

- 17 R ¹⁶ means,

1. hydrogen atom,

2. an alkyl group with 1, 2, 3 or 4 carbon atoms, ' 3. an alkyl group with 1, 2, 3 or 4 carbon atoms substituted with an alkoxy group with 1 to 4 carbon atoms,

4. an alkyl group with 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 defined under point 5., which is substituted by 1, 2 or 3 identical or different residues selected from the group consisting of fluorine, chlorine atoms

- and bromine, trifluoromethyl group, NR ¹⁹ R ²⁰ group and cyano group,

R represents

1. hydrogen atom,

- '· - 2. an alkyl group with 1, 2/ 3 or 4 carbon atoms, 3. an alkenyl group with 2, 3 or 4 carbon atoms, . . a -C _n H _2n _ _nn -phenyl group, -where .

nn , has the value 0 or' 2-, -a

- n has the value 0,1, 2, 3 or 4, with n not having the value '- ' of 0 or 1 if nn has the value 2, or

5. a residue as defined in claim 4, wherein the phenyl moiety is substituted with a residue selected from the group consisting of

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

• '' carbon, in which one. to. all) hydrogen atoms' are replaced - fluorine atoms, preferably trifluoromethyl.· group, or the group NR ⁿ R ¹² , the symbols R ¹⁹ 'and R ² -' independently of each other always represent an atom • 0 0' • 0 ··

0 0 • 0 0 *·· «· 0 0 0 «0 » 0 « > « 00 * 0 00 «Φ

- 18 hydrogen, an alkyl group with 1, 2, '3 or 4 carbon atoms or an alkanoyl group with 1 to 4 carbon atoms, preferably an acetyl group, ' the symbols R ²² and R ²³ independently of each other each represent a hydrogen atom or the group CO-OR ²⁴ , ' R ²⁴ represents a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, or the group -C _n H _2n -phenyl, where n has the value 1 or 2, and ,

q. independently has the value 0, 1 or 2, as well as their physiologically acceptable salts.

Particularly preferred are compounds of the general formula I, \ · · where

R ¹ represents

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

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

3. group -C„H _2n _ _nn -Y, where ,

Y represents - · . . i 1. a phenyl group,

2. a radical defined under 'point 1-, which is substituted by 1, 2, 3, 4 or 5 . identical or different radicals selected from the group comprising' alkyl groups with .1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, cyano group, trifluoromethyl group, hydroxy group,. nitro group, groups- SO ₂ R ¹³ , OCH ₃ , , OCF ₃ ,· SČF ₃ , N(CH ₃ ) ₂ , NH-CO-CH ₃ , CO-R ⁹ , phenoxy group. and phenoxy groups. one ;.or more times, substituted by halogen, preferably. chlorine or fluorine,

3. group OR ¹⁴ , or.

'4.· the group SO ₂ -R ¹⁴ , nn has the value 0 or 2, and ' n has the value 0, 1, 2, 3 or 4, whereby η does not have the value 0 or 1 if nn has the value 2, or

4. the group -C,H _2r „,,-Y, where

Y' represents , . , •9 ·· <·

• · 9 • · 9 • · · • · · ··' Γ·

1. phenyl group',

2. group OR ¹⁴ , or

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

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

2. amino group,

3. groups 'NR ²² R ²³ , and 4. alkyl groups with ' 1·, 2, 3 or 4' carbon atoms,

5. group where . . < .

Y represents . ...'

1. : 1-naphthyl or 2-naphthyl group,

2. a radical as defined in point 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, a trifluoromethyl group and the groups SC^-R ¹³ , OCH ₃ , N(CH ₃ ) ₂ and CO-R ⁹ ,

3. a heteroaryl group with 1, 2, 3, 4, 5, 6, 7, ¹ 8 or 9 carbon atoms, preferably a thienyl, benzothiophenyl, indolyl or furyl group,

4. a residue defined under point 3., which is substituted by a residue selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl, methyl, methoxy and dimethylamino, or • ·.

• · • · · · · · · · · ·

5. a cycloalkyl group with carbon atoms, and 3, 4,. 5, 6 or n has the value 0, 1, ^{1 2 * * * 6 * *} 2, 3 or A', or 6 . the group -C _n H _2n -OR ¹⁴ , where n has a value of 0,1 or 2,

R ² . .means

1. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, 2. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms,' in which are one to · all atoms hydrogen replaced fluorine atoms, 3 . an alkenyl group is 2, 3, 4, 5., .6, 7, 8, 9 or .10 carbon atoms, 4 . alkynyl group.se 2, 3, 4 or 5 carbon atoms, 5. group -C _n .H _2n . _nn -Z, where From represent

1. phenyl group, . ,

2. a residue . defined -under point 1.,. which is substituted by 1, 2.or 3 identical or different residues selected from the group comprising alkyl ' groups with 1, 2, 3 or 4 carbon atoms, phenyl group, fluorine, chlorine and bromine atoms, trifluoromethyl group, groups . SO ₂ R ¹⁸ , -OCH ₃ , . -O (C ₂ H ₄ )OCH ₃ , ethoxy group, hydroxy group, '

- nitro group, cyano group, groups' N(CH ₃ ) ₂ ,

-NH-CO-CH ₃ , CO-R ⁹ , a phenoxy group and ' phenoxy groups substituted one or more times by halogen, preferably chlorine or fluorine, or on which two n radicals together form a methylenedioxy group, nn. has the value 0 or 2, and n · .has, the value Ό, 1, 2 or .3,. where n has no value or 1 if nn has the value 2, .

6th group ^- C _n ri... where

Z .' represents '

1. a phenyl group, or. ,

2. a residue defined under ..point 1., 1 which is substituted by 1, 2 or 3 identical or different residues selected from the group comprising alkyl groups with 1, 2, 3 or 4 carbon atoms, phenyl group, fluorine and chlorine atoms, trifluoromethyl group, SO ₂ R ¹⁸ groups, . -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy group, . hydroxy group, nitro group, . cyano group, N(CH ₃ ) ₂ groups and CO-R ⁹ , nn has the value 0 or 2, and .

n has the value 1, 2 or 3, with n not having the value 1 if .nn has the value 2, in which 1, 2 or 3 hydrogen atoms in the divalent radical -C _n H _2n _ _nn - are independently replaced by a radical selected from the group consisting of 1. alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy part,

2. groups COOR ^lfa , and

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

7. the group -CH _2n -Z, where

Z represents

T. 1-naphthyl or 2-naphthyl group,.

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

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

yl, pyridyl, thienyl, furyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, benzofuranyl, for example dihydro-1-oxobenzo[c]furanyl, a. quinazolinyl, for example 3,,4-dihydroquinazolinyl, group,

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

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

6. a residue as defined under point 3., which is substituted by a phenyl group, preferably a phenylcyclopentyl group, and n has the value 0, 1, 2 or 3, or

8. group -C _n H _2n -OR ¹⁷ , where. .

n has the value 2 or 3, . .

the symbols R ³ and R ⁴ each represent a hydrogen atom, the symbols R ⁵ , R ⁶ and R ⁷ independently of each other each represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 atoms.

carbon, fluorine or chlorine atom, trifluoromethyl group, SO ₂ -R ⁸ , CO.-R ²¹ or O-R ¹⁰ , '

R ⁸ represents a methyl group or a dimethylamino group, the symbols R ⁹ and R ² ' ¹ independently of each other always represent a hydrogen ^atom , a methyl group or a group /OR ¹³ , ,

R ¹⁰ represents a hydrogen atom, a methyl or ethyl group;

which is optionally substituted with a methoxy group, or a phenyl group, which is unsubstituted or

- substituted with a residue selected from the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group and a dimethylamino group,

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

X represents a carbonyl group, a -C.O-CO- group, ·' · · · » · · ·

-NH-CO- or a sulfonyl group,

R ¹⁴ represents

1. hydrogen atom,

2..methyl or ethyl group,

3. an alkenyl group with 2, 3, 4, carbons, preferably an allyl group,

4. the group -C _n H _{2 n} -phenyl, where n has the value 0 or 1,

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

6. an alkenyl group with 2, 3' or 4 carbon atoms, ¹⁵ means a methyl group or a dimethylamino group, or 6' atoms

Year ¹

R ¹⁷

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

1. hydrogen atom, ..’·,'

2. methyl group, - .'

3. the group -C _n H _2n .-phenyl, where n has the value 0 or 1,

4. a radical as defined in point 3., in which the phenyl moiety is substituted by a radical selected from the group consisting of alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, a trifluoromethyl group, the groups SO ₂ R ¹⁵ , OCH ₃ , N(CH ₃ ) ₂ and CO-R ⁹ , or an alkenyl group with 2, 3 or 4 carbon atoms, ' means a methyl group, a trifluoromethyl group, an amino group or a dimethylamino group, 11 independently of each other: each represents a hydrogen atom or a CO-OR ² group

R' represents a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, or the group -C _n H _2n -phenyl-, where n has the value 1 or 2 ^, as well as physiologically acceptable salts thereof.

Compounds of the general formula Ta are also preferred.

which have -residues X and as well as, their;physiologically

R ¹ to R ⁷ have the meanings given above, , Further preferred are compounds of the general formula 1 or/and Ja, in which the symbols X, R ¹ , R ² , 'R ³ , R ⁴ , R ³ , R° and R' have the meanings given in Examples 1 to 568 . ..

If 'in compounds of general formula I 'there are identically designated groups or. substituents, ·they·can·have. all independently of each other the above-mentioned meanings' and can always be the same or different. , ' ' ' . ’

Alkyl, alkenyl and alkynyl groups can be independently straight or branched. This also applies if they are contained in other groups, for example in alkoxy groups, alkoxycarbonyl groups or amino groups, or if they are substituted ^.

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

or -. .8 . . carbon atoms - can ..mention methyl,, .ethyl, propyl,. butyl, · 'pentyl, hex-yl, heptyl, octyl,-i isopropyl, isobutyl, ' isopentyl, neopentyl, isohexyl, 3^methylpentyl, ·. sec.butyl, tert. .'.butyl and -tert. .pentyl groups.

Examples of alkenyl groups include vinyl,

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

- 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.

Cycloalkyl groups include ^saturated and partially unsaturated cycloalkyl radicals, which may be mono-, bi- or tricyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, ^cyclopentyl , ^cyclohexyl ; cycloheptyl, 1,2,3,4-tetrahydronaphthalene and indanyl, all of which may also be substituted, for example, by one or more identical or different alkyl groups having 1 to 4 carbon atoms, in particular methyl. Examples of such substituted cycloalkyl groups include 4-methylcyclohexyl, 4-tert-butylcyclohexyl or

2,,3-dimethylcyclopentyl group.

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

Heteroaryl groups and heterocyclyl groups are preferably derived from heterocycles which contain one or two or three, in particular one or two, identical or different, heteroatoms in the ring. Unless otherwise stated, 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-, six- or seven-membered. Examples of monocyclic and bicyclic heterocycle systems from which the heterocycles may be derived include:

• · derive residues occurring in compounds of general formula I, including 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, benzothiophene, benzofuran, benzothiazole, benzimidazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, thienothiophene, 1,-8-naphthyridine and other naphthyridines, pteridine, or phenothiazine, which are always in saturated form (perhydro. . form) . or in partially unsaturated form .(for example dihydroform or , tetrahydroform) . or in maximally unsaturated form, if the given forms are known and stable. The heterocycles. which come into consideration also include, for example, the saturated heterocycles pyrrolidine, piperidine, piperazin-, morpholine and thiomphorine. Unsaturated heterocycles can contain, for example, one, two or. three double bonds in the ring system. Five-membered and six-membered rings in monocyclic and polycyclic heterocycles - can in particular also be aromatic. The radicals derived from these heterocycles can be. bonded via any suitable carbon atom. Nitrogen-containing heterocycles, which contain a hydrogen atom or a substituent on the ring nitrogen atom, for example pyrrole, imidazole, pyrrolidine, morpholine, piperazine, etc., can also be bonded via the ring nitrogen atom, _; in particular if the given nitrogen-containing heterocycle is bonded to a carbon atom. -For example, a thienyl. radical can. be present as. 2-thienyl or · 3-thie-enyl group, a furan. radical as 2-furyl or . 3-furyl group, a pyridyl radical as 2-pyridyl,. 3-pyridyl or 4-pyridyl group, piperidine residue such as 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl

- 27 group, thiomorpholine residue as 2-thiomorpholinyl,

3-thiomorpholinyl or 4-thiomorpholinyl (= thiomorpholinic) group. The residue attached via a carbon atom derived from 1,3-thiazole or imidazole can be attached in position 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 located at any position on the heterocycles, for example on the '2-thi'enyl or

2-furyl group in position 3 or/and position 4 or/and position 5, on a 3-thienyl or 3-furyl group in position 2 or/and position 4 or/and position 5, on a 2-pyridyl group in position 3, or/and position 4 or/and position 5 or/and position 6, on

3-pyridyl group in position 2 or/and position 4 or/and position 5 or/and position 6 and.on the 4-pyridyl group in position 2 or/and position 3 or/and position 5 or/and position 6. Unless otherwise stated, the substituents present may be, for example, the substituents given in the definition of the aryl group, in the case of saturated or partially unsaturated heterocycles, further substituents may also be, oxo and thioxo. Substituents on the heterocycles, as well as. Substituents on the carbon ring, may also form a ring, and further rings may also be fused onto the ring system, so that, for example, cyclopenta-fused, cyclohexa-fused or benzo-fused rings may be formed. rings. Suitable substituents on the nitrogen atom in heterocycles on which substitution may occur are, in particular, for example, unsubstituted alkyl groups with 1 to 5 carbon atoms, aryl-substituted alkyl groups, aryl groups, acyl groups, such as -CO-alkyl groups with 1 to 5 carbon atoms in the alkyl moiety, or sulfonyl groups, such as -SO ₂ -alkyl groups with 1 to 5 carbon atoms in the alkyl moiety. Suitable nitrogen-containing heterocycles may also be present as N-oxides or as quaternary salts with an anion derived from a physiologically acceptable acid as 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,

Heteroaryl groups may also be fully or partially hydrogenated. Examples include pyrrolidine-1-carbonyl-4,5-dihydroisoxazolyl, 1,3-dihydro-1-oxobenzoyl, furanyl or 3,4-dihydroquinazolinyl.

Phenyl groups, naphthyl groups ... groups, for example heteroaryl groups, are not otherwise specified, unsubstituted, or may carry one or more, for example one, two, three or four, identical or different substituents, which may be in any position. Unless otherwise specified, the substituents mentioned in the definition of aryl groups may be present in these groups, for example in aryl groups, such as phenyl groups or/and heterocyclic radicals; phenyl groups, phenoxy groups, benzyl groups or benzyloxy groups, in which the benzene ring itself may be unsubstituted or substituted by one or more, for example and heterocyclic may be, if

-for example, if there are one, two, substituents, three or four, the same or different, for example, groups selected from the group consisting of alkyl groups with 1 to 4 carbon atoms, halogen atoms, hydroxy group, alkoxy groups with 1 to 4 carbon atoms, trifluoromethyl group, cyano group, hydroxycarbonyl group, alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxyl part, aminocarbonyl group, nitro group, amino group, alkylamino groups with 1 to 4 carbon atoms.

carbon atoms in the alkyl moiety, dialkylamino groups with 1 to 4 carbon atoms in each alkyl moiety, and alkylcarbonylamino groups with 1 to 4 carbon atoms in the alkyl moiety.

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

The invention includes all stereoisomeric forms of the compounds of general formula I. The centers of asymmetry present in the compounds of general formula I can all independently of each other always be in

S-configuration or R-configuration. The invention thus encompasses all possible enantiomers and diastereomers as well as mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers or/and diastereomers, in all ratios. The enantiomers are therefore subject to the invention 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 all ratios. If the compounds according to the invention can exhibit cis/trans isomerism, the invention encompasses both the cis form and also the trans form and mixtures of these forms in all ratios. The production of individual

The separation of stereoisomers can be carried out as required by resolving their mixture by conventional methods, for example chromatography or crystallization, using stereochemically uniform starting materials in the synthesis or by stereoselective synthesis. Before: separating the stereoisomers, the compounds can optionally be derivatized. The resolution of the mixture of stereoisomers can be carried out at the level of the compounds of the general formula I or at the level of intermediates during the synthesis. In the case of the presence of mobile hydrogen atoms, the invention also includes all tautomeric forms of the compounds of the general formula I.

If the compounds of the general formula I contain one or more acidic or basic groups, the invention also provides the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically usable salts. Thus, compounds of the general formula I which contain acidic groups and these groups can be in the form of alkali metal, alkaline earth metal or ammonium salts and used as such according to the invention. Examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the general formula I, which contain one or more basic, i.e. protonable, groups, can be in the form of their addition salts with physiologically acceptable inorganic or organic acids, and as such can be used according to the invention. Examples of salts include hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, methanesulfonic, p-toluenesulfonic, naphthalenedisulfonic, oxalic, acetic, tartaric, lactic, salicylic, benzoic, formic, propynic, pivalic, diethyloic, malonic, succinic, pimelic, fumaric, maleic, malic, sulfamic, phenylpropionic, -glucoric,. ascorbic, isonicotinic, citric, adipic, etc. If the compounds of general formula I contain simultaneously acidic and basic groups in the molecule, the invention includes

in addition to the above-mentioned salt forms, also internal salts or betaines (dipolar ions) of formula I can be obtained by methods such as the reaction

Salts can be prepared from the compounds of the general formula I which are not suitable for direct use in pharmaceuticals due to their poor physiological acceptability, 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 the general formula I are understood to mean, 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 For acidic groups, sodium, potassium, calcium and ammonium salts are preferred, among others, for basic groups, salts with hydrochloric, sulfuric or phosphoric acid, or salts with carboxylic or sulfonic acids, such as acetic, citric, benzoic, maleic, fumaric, tartaric and p-toluenesulfonic acids are preferred.

The invention further includes all - solvates of the compounds of general formula I, for example hydrates or adducts with alcohols, as well as - derivatives of the compounds of general 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 general formula I, as well as their physiologically acceptable salts.

Compounds of general formula I can be prepared, for example, by solid phase synthesis.

The synthesis generally proceeds in such a way that the benzenesulfonyl structure of the general formula II is suitably linked via a chemical linker to a polymer matrix using 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 units to improve the swelling ability. Suitable linker units are structures which, under the action of an acid or base, by reduction, oxidation, by the action of light or fludridions, specifically release the synthesized compound, whereby the linker unit remains on the polymer matrix.

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

R7

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

using derivatives of arylboronic acids (aryldihydroxyboranes) of the general formula IV to prepare biphenyl derivatives of the general formula V.. . The reaction conditions for palladium-catalyzed reactions known from the literature are used, as described, for example _, in Organometallics 1984, ¹³ , 1261 or in Synth.

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

00 » * 0 « » · 0 0 •0 00 » · 0 and » · · 4

cm) : . fiv? (in)

Benzeneboronic acid of the general 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. šyntheši-s ' 1975,. ' 1-.,35) gives the compound of general formula 'VI, which can be converted into a compound of general formula · -VIL by reaction with acid chloride R ^l -X-Cl. Solid phase synthesis. has the advantage that · reagents and reactants can be used in ' large, excess, . a wide range of solvents can be used and- purification is carried out by simple washing of the resin particles.

*· · • 9 99 • 9 · .

• · · • · · · · · ·· ·» ·· 99

9 9 · 9 9 9 9

9 99 9 9 9 9 β · β 9 9 9 9 9 9

9 9 9 9 9 9 9

99 99 99

Polymer (ví) . (νιι)

If the radicals R ³ and R ⁴ do not represent hydrogen atoms, it is necessary to introduce the corresponding radicals. This is done by synthesizing the imine of the general formula X, via which the reductive amination takes place, without a reducing agent from the aldehyde of the general formula V; and the corresponding amine ^, and this imine is subjected to a reaction with an organometallic compound carrying the radical R 1 or R ⁴ , such as a Grignard reagent or an alkyllithium compound, in a manner known to the person skilled in the art. Alternatively, the aldehyde function of the compound of the general formula V is oxidized to a nitrile of the general formula XI, as described, for example, in Synthesis 1982, 190, and then introduced using an organolithium or organomagnesium compound ^. in a known manner the residues R ³ and R ⁴ .- In the latter case, in addition, the residue R ² must be introduced in a manner known to the expert 3. i?y Σ 3ci nsbo - ηΣ Ry Σ 3. gi 3ininu .

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

(x) . /- . (XI)

After successively carrying ^out the individual synthesis steps, the newly synthesized compounds are cleaved using specific reagents, which are selected according to the nature of the linker (for a description of solid phase synthesis, see J. Früchfei, G. Jung, Angew. Chemie Int. Ed. 1996, 35, 17-42). 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 resin; 2% cross-linked DVB). A preferred linker is, for example, a compound of the general formula VIII known from the literature (G. Breipohl, J. Knolle, W. Stúber, Int. J. Peptide Protein Res. 34, 1989, ^262f ) :

(VIII) ;fmó.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 thereby

-. 36 in an inert solvent, preferably. dichloromethane, . is reacted with an acid with a pK <'5, preferably with an acid with a pK _a < 2, particularly preferably with trifluoroacetic acid, and the sulfonamide of the general formula IX is obtained. The typical reaction time is 5 .minutes to 10 hours at a temperature between -30° C. and the boiling point of the solvent, preferably the reaction time is. 20 minutes to 1 hour at room temperature . . · .

The last stage of the synthesis is characterized by the fact that the compounds of general formula IX

in which the individual . _; general symbols have the meanings defined above, are reacted with . cyanogen bromide to form a compound of the general formula I. The reaction is carried out in a dipolar aprotic . 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' little· nucleophilic, such as for example potassium carbonate . or cesium carbonate. As ' reaction temperature comes; in''consideration temperature between 0° C. and ' boiling temperature' of the solvent used,· a temperature between 40° C. and- 100° C. is preferred. .

The compounds of the general formula I can also be synthesized by classical synthesis, i.e. in solution, using methods known to the person skilled in the art. The compounds of the general formula I according to the invention are suitable as inhibitors of the Na ⁺ -dependent bicarbonate/chloride exchange system (NCBE) or of the sodium/bicarbonate symporter.

- 37 The invention further relates to the use of a compound of general formula I for the manufacture of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions, as well as the use of a compound of general formula I for the manufacture of a medicament for the treatment or prophylaxis of heart attack, as well as the use of a compound of general formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the heart, as well as the use of a compound of general formula I for the manufacture of a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and apoplexy (stroke), , . ' "as well as the use of a compound of general 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 general formula I for the manufacture of a medicament for the treatment or prophylaxis of shock states.

as well as the use of a compound of general formula I for the manufacture of a medicament for use in surgical operations' and. organ transplantations, as well as -use, a compound of general formula I for the manufacture, a medicament for preserving and surgical- procedures, storage of transplants .' for as well as - use of a compound of general formula I for the manufacture of a medicament for '.treatment - diseases whose primary or secondary cause is cell proliferation, . and thus 'its use, for the manufacture of an antiatherosclerotic, . .means., .against. late diabetic complications, against cancer diseases., against fibrotic diseases.such as lung fibrosis, liver fibrosis

• ·

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

as well as a medicament, which is characterized in that it contains an effective amount of a compound of general formula I.

The compounds of the general formula I according to the invention exhibit very good antiarrhythmic properties, which are important, for example, in the treatment of diseases which occur in the absence of oxygen.

The compounds of the general formula I are, due to their pharmacological properties, very suitable as antiarrhythmic drugs with a cardioprotective component for the prophylaxis and treatment of infarction, as well as for the treatment of angina pectoris, while also preventively inhibiting or strongly limiting the pathophysiological processes in the development of ischemically induced disorders, in particular in the development of ischemically induced cardiac arrhythmias ^. Due to their protective effects against pathological hypoxic and ischemic conditions, the compounds of the general formula: ₁ according to the invention can be used as drugs for the treatment of all acute or chronic disorders caused by ischemia or diseases induced primarily or secondarily in this way. These compounds protect organs that are acutely or chronically under-oxygenated by reducing or preventing ischemically induced disorders and are therefore suitable as drugs, for example in thrombosis, vasospasm, atherosclerosis or surgical procedures (for example in organ transplantations of kidneys and liver, where these compounds can be used both to protect the organs in the donor before and during their removal, to protect the removed organs, for example during handling or storage in physiological baths, as well as during transfer to the recipient organism), or

chronic or acute renal failure.

The compounds of the general formula I are also valuable protective drugs in the performance of angioplasty operations, for example on the heart, as well as on peripheral vessels. Due to their protective effect against ischemically induced disorders, these compounds are also suitable as drugs for the treatment of ischemia of the nervous system, in particular the central nervous system, for example, they are suitable for the treatment of apoplexy (stroke) or cerebral edema. In addition, the compounds of the general formula 1 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, the compounds of the general formula I according to the invention are characterized by a strong inhibitory effect on cell proliferation, for example on cell proliferation of fibroblasts and vascular smooth muscle cells. Therefore, the compounds of the general formula I are considered as effective therapeutics for diseases in which cell proliferation is the primary or secondary cause and can therefore be used as antiatherosclerotic agents, agents against late diabetic complications, against cancer, against fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against organ hypertrophies and hyperplasias, in particular prostate hyperplasia or prostatic hypertrophy.

It has been found that inhibitors of the Na^-dependent exchange system Cl'/HC0 ₃ ", or the sodium/bicarbonate symporter, can stimulate breathing by increasing the chemosensitivity of respiratory chemoreceptors. These chemoreceptors are largely responsible for maintaining proper respiratory function. They are activated in the body by hypoxia, a decrease in pH and an increase in the concentration of C0 ₂ (hypercapnia) and adjust the minute respiratory volume. During sleep, breathing is particularly sensitive to disturbances and is

highly dependent on chemoreceptor activity.

Improving the stimulation of respiration by stimulating chemoreceptors with substances that inhibit Na ⁺ -dependent exchange of ď/HCOý leads to the improvement of respiration in the following clinical conditions and diseases: impaired central stimulation of respiration (for example, central sleep apnea, sudden infant death syndrome, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term artificial respiration, respiratory disorders during adaptation to high-altitude environments, obstructive 'and mixed' forms of sleep apnea, acute and chronic lung diseases with hypoxia and hypercapnia. ··

The compounds of the general 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 each other or in the form of pharmaceutical compositions. The invention therefore also relates to compounds of the general formula I and their physiologically acceptable salts for use as medicaments, their use in the treatment and prophylaxis of the diseases and conditions mentioned and the preparation of medicaments from these compounds for the said uses. The invention also provides pharmaceutical compositions which, in addition to the usual pharmaceutically acceptable carriers and auxiliaries, contain at least one compound of the general formula I or/and its physiologically acceptable salt as the active ingredient. These pharmaceutical compositions usually contain 0.1 to 99% by weight, preferably 0.5 to 95% by weight. compounds of the general formula I or/and their physiologically acceptable salts. The pharmaceutical compositions can be prepared in a manner known per se. In this case, the compounds of the general formula I or/and their physiologically acceptable salts are processed together with one or more solid or liquid galenic carriers or/and excipients and, if desired, in combination with other medicinally active substances, into a suitable application form or dosage form which can then be used as a medicament in human or veterinary medicine.

medicine. '

Medicinal products containing a compound of the general formula I or/and a physiologically acceptable salt thereof can be administered orally, parenterally, intravenously, rectally or by inhalation, the preferred method of administration depending on the current manifestations of the disease. The compounds of the general formula I can be used alone or together with galenic excipients, both in veterinary and human medicine. , /

For the skilled person, it is clear from his professional knowledge which excipients are suitable for the desired formulation of the drug. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active substance carriers, for example antioxidants, dispersants, emulsifiers, defoamers, flavouring agents, preservatives, solubilising additives or colouring agents can be used.

For oral use, the active compounds are mixed with additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and are processed by conventional methods into suitable application forms, such as tablets, coated tablets, insertable capsules and aqueous, alcoholic or oily solutions. Inert carriers that can be used include, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starches, in particular corn starch. The preparation can be carried out in the form of both dry and moist granules. Suitable oily carriers or solvents include, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds are, if desired, combined with substances customary for this purpose, such as dispersing agents, emulsifiers or "

other excipients, prepared in the form of a solution, suspension or emulsion. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerol, and in addition also sugar solutions, such as glucose or mannitol solutions, or also 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 ingredient of the general formula I in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or in a mixture of such solvents,'

The formulation may, if necessary, contain further 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 from about 0.1 to 10, in particular from about 0.3 to 3% by weight. . . .

The dosage of the active ingredient of the general formula I to be administered, and the frequency of administration depend on the strength and duration of the effects of the compounds used, and in addition also on the type and severity of the disease to be treated, as well as on the sex, age, weight and individual reactions of the mammal to be treated.

On average, the daily dose of the compound of general formula I for a patient weighing approximately 75 kg is 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 an acute, disease outbreak, for example.

Immediately after a heart attack, even higher and, above all, more frequent doses may be necessary, for example up to 4 divided ^doses per day. Especially with intravenous use, for example in patients with a heart attack in the intensive care unit, doses of up to 200 mg per day may be necessary.

The compounds of general formula I can be used as sole active ingredients or in combination with other pharmacologically active

effective compounds. '

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

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

Known active ingredients known to act as NHE inhibitors are guanidine derivatives, especially acylguanidines, among others as described by Edward. J. Cragoe., Jr.,- DIURETICS, Chemistry, Pharmacology and Medicine, . ,J. WILEY & Sons (1983), 303 - 341, or the NHE inhibitors 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-Α 754680, EP-A 765868, EP-A 774.459, EP-A 794171, 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; diacyl-substituted guanidines as described in ...EP-A .640587; acylguanidines, as described in US Pat. No. 5,547,953; perfluoroalkyl groups bearing phenyl-substituted guanidines of alkyl or alkenylcarboxylic acids, as described in US Pat. No. 5,567,734 and EP-A 688,766; heteroaroylguanidines, as described in EP-A 676,395; bicyclic heteroarylguanidines, as described in EP-A 682,071; indenyl guanidines, as described in EP-A 738,712; benzyloxycarbonylguanidines, as described in EP-A 748,795; 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; sulfonamides as described in EP-A-771788; diguanidines of benzenedicarboxylic acids as described in EP-A-774458 and EP-A ^- 774457; 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-790245 ,810205 and' EP-A 810206; indanylidinesacetylguanidines, as described in EP-A 837055; phenylsubstituted guanidines·· 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 .are 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 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, as described in EP-A 760365; benzoylguanidines with -annelated, cyclic sulfones, -as described in DEW 19548708; benzoyl-, polycyclic aroyl- and .heteroaroylguanidines, as described in WO 9426709; 3-aryl/heteroarylbenzoylguanidines, as described in WO 9604241; 3-phenylbenzoylguanidines with a basic amide in position 5, as described in WO 9725310; 3-dihalothienyl- or 3-dihalophenylbenzoylguanidines with a basic substituent in the 5-position, as described in WO 9727183; 3-methylsulfonylbenzoylguanidines with certain amino substituents in the 4-position, as described in WO 9512584; amiloride derivatives, as described in WO 9512592; 3-methylsulfonylbenzoylguanidines with certain amino substituents in the 4-position, as described in WO 9726253; indoloylguanidines, as described in EP-A 622356 and EP-A 708091;

indoloylguanidines with an fused additional 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-A 8225513; quinoline-4-carbonylguanidines with a phenyl residue in position 2, as described in EP-A 726254; cinnamoylguanidines, as described in JP-A 09059245; propenoylguanidines with a naphthalene substituent, as described in JP 9067332; propenoylguanidines with an indole substituent, as described in JP 9067340; or heteroaroyl-substituted acryloylguanidines, as described in WO 9711055, as well as their physiologically acceptable salts.

Preferred NHE inhibitors are the compounds mentioned in the above-mentioned publications as being preferred. Particularly preferred are

- 46 • ··

compounds selected from the group consisting of cariporide (ΗΟΈ642)', HOE 694, EMD 96785, FR 168888, FR 183998', SM-20550., KBR-9032, as well as their physiologically acceptable salts. Most preferred is cariporide or another physiologically acceptable salt of N-(4-isopropyl-3-methanesulfonylbenzoyl)guanidine.

Examples of groups of active substances acting on the heart and blood circulation which can be therapeutically advantageously combined with NCBE inhibitors or can be further combined with combinations of NCBE inhibitors and NH.E inhibitors include beta-receptor blockers, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin blockers, loop diuretics, thiazide potassium-sparing diuretics, aldosterone antagonists, as used, for example, in lowering blood pressure, as well as cardiac glycosides or other substances increasing the force of contractions in the treatment of heart failure and congestive heart failure, as well as antiarrhythmics of classes I-IV, nitrates, receptor openers, diuretics,

K, K blockers

ATP ^and veratridine-activatable quinapril inhibitors, sodium channel antagonists, etc. Thus, for example, the following are suitable: beta-blockers propanolol, atenolol, metoprolol; calcium antagonists diltiazem hydrochloride, verapamil hydrochloride, nifedipine; angiotensin-converting enzyme inhibitors captopril, enalapril, ramipril, trandolapril, spirapril, preferably ramipril or trandolapril; angiotensin II receptor losartan, valsartan, telmisartan.

' epro.sartan, tasosartan, eandesartan, irbesartan; loop diuretics furosemide, piretanide, -torasemide; thiazide diuretics, hydro.chlorothiazide, metoiazone, -indapam.ide; potassium, sparing. diuretics. amiloride, triamterene, . spironolactone;. cardiac glycosides digoxin, digitoxin, strophanthin;· antiarrhythmics amiodarone, sotalol, bre.tylium, flecainide; nitrate glyceryl trinitrate; , openers- K ⁺ (ATP) cromakalim, lemakalim, nocorandil, pinacidil, minoxidil;, and inhibitors of veratridine-activated -sodium channel. , - . ,

4Ί One example of particularly advantageous combination partners for NCBE inhibitors of the general formula í are blockers of the non-inactivating sodium channel (veratridine-activatable sodium channel). The combination of an NCBE inhibitor with a blocker of the non-inactivating sodium channel (veratridine-activatable sodium channel) is suitable for the prophylaxis of infarction and recurrence of infarction and the treatment of infarction, as well as for the treatment of angina pectoris and the inhibition of ischemically induced cardiac arrhythmias, tachycardia and the development and maintenance of ventricular fibrillation, wherein the combination of an NCBE inhibitor with a blocker of the non-inactivating sodium channel also preventively inhibits or strongly limits the pathophysiological processes in the development of ischemically induced disorders. Due to their enhanced protective effects against pathological hypoxic and ischemic conditions, combinations of the NCBE inhibitor of the general formula .1 with a blocker of a non-inactivating ^sodium channel according to the invention can be used as drugs for the treatment of all acute or chronic disorders caused by ischemia or diseases induced primarily or secondarily in this way. This includes their use as drugs in surgical procedures, for example organ transplantations, combinations of the NCBE inhibitor of the general formula. I with a non-inactivating sodium channel can be used both to protect organs in the donor before and during their removal, to protect the removed organs, for example during their storage and during transfer to the organism when the blocker can be used as well as physiological recipients.

Combinations of an inhibitor - NCBE. of the general formula I with a blocker of a non-inactivating sodium channel are also valuable protective drugs when performing angioplastic surgical procedures, for example on the heart, as well as on peripheral vessels. Due to their protective effect against ischemic-induced disorders, these combinations of an inhibitor - NCBE. of the general formula I with a blocker

• 9Φ ·· φφ • 9 9 · φ φ φ · · 9 9

- '48 non-inactivating sodium channel blockers are also suitable as ' ' · drugs for the treatment of ischemia of the nervous system, especially the central nervous system, and are suitable for the treatment of apoplexy (stroke) or cerebral edema. In addition, combinations of an NCBE inhibitor of the general 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-mentioned components as a fixed combination, the invention also relates to the simultaneous, separate or time-staged use of NCBE inhibitors of the general formula.

I with’ inhibitors . NHE or/and- other active substances from another. group of substances acting on . heart and .blood circulation· for ' treatment , ' · ' λ ' above-mentioned diseases.and conditions. ,

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

. . When used in combination, the effect may occur that one of the components of the combination is enhanced by a given other component, i.e. the effect or/and duration of action of the combination or the composition according to the invention is higher or more permanent than the effect or/and duration of action of the given components separately (synergistic effect). This leads ^to a reduction in the dose of the individual components of the combination in comparison with their separate use. The combinations and compositions according to the invention thus have the advantage that the amount of active substances that must be applied can be substantially reduced. and

9.9 9 99 99 99 99 • 9 9 9 · 9 · · · 9 4 9

9 · · I 99 9 9 9 · • · · 9 9 9 9 9 9 · ·« 9 • '· 9 ·9 9 · 9999

999 99 99 99 99 eliminate or significantly reduce undesirable side effects.

The invention further relates to a market package containing as a pharmaceutically active substance a) an NCBE inhibitor of the general formula I and an NHE inhibitor or/and their physiologically acceptable salts; or b) an NCBE inhibitor of the general formula I and further an active substance from another group of substances acting on the heart and blood circulation or/and their physiologically acceptable salts; or c) an NCBE inhibitor of the general formula I, an NHE inhibitor and further an active substance from another group of substances acting on the heart and blood circulation or/and their physiologically acceptable salts, together with instructions for the use of these active substances in combination for simultaneous, separate or time-phased application in the treatment or prophylaxis of the above-mentioned diseases and conditions, in particular for the treatment of heart and blood circulation diseases.

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

The weight ratio of the NCBE inhibitor to the NHE inhibitor or other substance acting on the heart and blood circulation in the combinations and compositions according to the invention is suitably 1:0.01 to 1:100, preferably 1:0.1 to 1:10.

The combinations and compositions according to the invention generally preferably contain 0.5 to 99.5% by weight, preferably 4 to 99% by weight, of these active ingredients. . - .

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

The invention is illustrated by the following examples, which, however, do not limit the scope of the invention in any way. ' φ · • · • · • φ ·· φφφ • 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

- 50 Examples of embodiments of the invention

The following abbreviations may be used in the examples and elsewhere in this text: . . ' _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 = Na ^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:

The synthesis of compounds of the general formula I on the solid phase is carried out by suitably linking the sulfonamide structure via a chemical linker to the polymer matrix using methods known to the person skilled in the art. The basic structure thus linked via the sulfonamide group to the polymer can then be subjected to further conventional organic reactions of organic chemistry.

In more detail, the following steps are carried out, described exemplarily for the compound of general formula Ia.

• ·

NH - CN

(Ia) in which R ¹ represents a 2-chlorophenyl group, R ² represents a benzyl group, X represents a carbonyl group and the symbols R ³ to R ⁷ each represent hydrogen atoms.

A. Synthesis of the linker/polymer unit

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

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

Others

J.

+

(2) (3) 'P.S.

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

4,

B.

Sulfonamide synthesis

resin-bound

5 g of compound 3 is. allowed to act for 30 minutes at room temperature with a mixture of piperidine and N,N-dimethylformamide in a ratio of . 1 : 3, the solution is filtered off with suction and the resin is thoroughly washed with N,N-dimethylformamide. To the resin . wet from N,N-dimethylformamide is added 3.1 g...of compound 4 known from the literature (Gilman, Markér, JACS 74, 1952, 531-7) in 20 ml

N,N-dimethylformamide. After adding 0.7 ml of pyridine, the mixture is allowed to react for 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 allowed to swell 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 is allowed to react for 2.4 hours at a temperature of 10'0° C in an argon atmosphere. Then the mixture is suction filtered and thoroughly washed aa aa • · • · · aaaaa · · · · · aaa ·· ·· ·· ··

- 53 with water, N,N-dimethylformamide and methyl tert.butyl ether.

D _r Reductive amination on solid phase; example: benzylamine

To 200 mg of the resin-bound intermediate of general formula 7 is added 1 mmol of the amine dissolved in 1 ml of a 3:1 mixture of dimethoxyethane and methanol, and 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 is then filtered off with suction and washed thoroughly with N,N-dimethylformamide and methyl tert. butyl ether. ¹ ' After cleaving a sample (1.0 mg) from the resin by treating with 1 ml of a 3:1 mixture of methylene chloride and trifluoroacetic acid, the free amine '8 is characterized by HPLC (high performance liquid chromatography) and MS (mass spectrometry). - ' /.

solid phase, for example, 2-chlorobenzoyl-N-acylation to chloride

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

F., Splitting from resin,

180 mg of compound 9 are treated for 30 minutes at room temperature with 3 ml of a 3:1 solution of methylene chloride and trifluoroacetic acid. After separation of the solution from the polymer, it is centrifuged in vacuo. As a residue, 30 mg of free amide 10 is obtained, which is directly subjected to cyanation G.

G. Synthesis of sulfonylcyanamide;

mg of compound 10 is dissolved in 3 ml of acetonitrile and 0.3 mmol of triethylamine and 0.12 mmol of cyanogen bromide dissolved in acetonitrile are added. 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 of an aqueous buffer solution of pH 6 are added. After good mixing, the upper phase is removed and applied to silica gel. First, 5 ml of methyl tert-butyl ether is washed and then the product is washed with 5 ml of a mixture of ethyl acetate and acetic acid in a ratio of 5:1. After evaporation of the solvent in vacuo, 12 mg of sulfonyl cyanamide in 60 to 90% purity (for example, compound 11 in 90% purity) are obtained. The products thus obtained can be further purified by preparative HPLC on materials with reversed phases. Characterization of the products is carried out by HPLC and, MS, as well as, for example, by NMR- ¹ spectroscopy., _: *

The following compounds of the general formula Ia are prepared analogously (R ³ to R ^b each represent hydrogen atoms and R ⁷ in compounds 1 to 512 also each represents a hydrogen atom):

Example.' No. ·. R ² ./ . R ^x -X MS* (ES-) (M-l)- Residual activity (%) NCBE 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 -,CH ₂ - CH ₂ -CO - . 514 ' 33.0 • . 8 ' -ch ₂ -ch ₂ -oh ·' cyclohexyl-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- cycle 486 . ' 74.7 . '.14 . -ch ₂ -ch ₂ -oh Cyclohexyl-CO- 440 88', 7 15 . 4-methoxybenzyl cyclohexyl-CO- . 516u 67.6 16 4-chlorobenzyl cyclohexyl-CO- 520 56.4 17 . phenyl cyclohexyl-CO- ⁴⁷¹ .

Example 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 . .-ch ₂ -ch ₂ -oh 3-methoxyphenyl-CH ₂ -CO- 478 37.1 21 . 4-methoxybenzyl 3-methoxyphenyl-CH ₂ -CO- 554 . 52.3 22 4-chlorobenzyl 3-methoxyphenyl-OH ₂ -CO- 558 23 phenyl 3-methoxyphenyl-CH ₂ -CO- 509 25.9 24 cyclohexyl .' 3-methoxyphenyl-CH ₂ ~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 . 4-methoxybenzyl 2-thienyl-CH ₂ -CO- 530 ' 35.5 . 28 4-chlorobenzyl 2 -1 hi enyl -CH„~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 .

• · ·

Example 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- phenyl-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

Example No. R ² . R ^J -X MS (ES-) (M-1)’ Residual activity (%) NCBE at 10 μΜ ⁶⁵ 4-chloroben zy1 _CH3- ( _CH2 ) 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 - chlorobenzene .1 benzoph b]thiophen-2-yl-CO- 570; ' 35.2 . 72 isobutyl benzoph b]thiophen- -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 . benzoph b]thiophen- -2-yl-CO- 550, 80.3 76 3-methoxybenzyl ... benzoph b] thio.phen-2-yl-CO- .566 87.3 . 77 3,4-methylenedioxybenzyl ' •benzof bj thiophene-; -2-yl-CO-'' 580 .,· 81.8 . 78 1(R)—phenylethyl·' - benzoph;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] hibphen-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

Example No. R ² R'-X MS (ES—) (M-l) · 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 thier-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-CÓ- . 464 93 1 (S)-phenylethyl 2-fluorophenyl-CO- 512 : 92.9 94 2-methoxybenzyl ,2-fluorophenyl-CO-. 528 . 87.7 .. ⁹⁵ 4-methylbenzyl 2-fluorophenyl-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 — z. iiuuxtciiyx u-v . 566 SQ 6 , in- 100 2-(4-methoxyphenyl)• ethyl. 2-fluorophenyl-CO- , 542 ' 94.1 . 101 2-chlorobenzyl 2-chloroferriyl-CO- 548 . 62.6 102 isobutyl 2-chlorophenyl-CO- 480 103 1 (S)-phenylethyl 2-chloroferriyl-CO- .. 528-

Example No. 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-CH-O- 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(R)-phenylethyl (phenyl) “CH-CO- ·.. ' 584' 95.3 119 4-trifluoromethyl- , benzyl (phenyl) ₂ CH-CO- 638' 75.7 120 2-(4-methoxyphenyl)-. ethyl (phenyl) "CH-CO- / 614 81.3 . 121; . 2-chlorobenzyl .· phenyl-CH.-.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„-CO- 524 ' 46.5

Example No. 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 (phe, nyl)-CO- 578 135 4-methylbenzyl i f onyl-CH..-CO-CK (fe. nyl)-CO- 626 .. 97.4 136 1 (S)-phenylethyl ' phenyl-CH ₂ -CO-CH (phe' . . . nyl)-CO- . 626, 93.6 137 1(S)-(4-methyl-.phenyl)ethyl (2-thienyl)-CH2 _- CO- 528 138 1 (R)-.(4-methylphenylethyl (2-thienyl)-CH2 _- CO- 528 .139 2-furylmethyl (2-thienyl)-CH,-CO- 490 48.5 140, ' 4-(dimethylamino)benzyl (2-thienyl)-CH ₂ -CO- 543 54.2 141 2-(2-thienyl)ethyl (2-thiyl) -CH ₂ -OO- 520 71.1 142 2-phenoxyethyl .(2-thienyl)-CH2 _- CO- 530 27.1

··

- 62 . ··

Example ' No. R ² r ⁴ -x MS. (ES—) (Μ-l)' Residual activity (%) NCBE at 10 μΜ 143 .2-chlorobenzyl (2-thienyl)-CH ₂ -CO- 534 35.7 144 . cyclopropylmethyl (2-thienyl)-CH2 _- 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-dichlorophenyl)-CH ₂ -CO- 518 45, 6 149 4-(dimethylamino), benzyl (4-chlorophenyl)-CH2- _CCH ' .571 77.4. 150 2-(2-thienyi)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 -C0- ⁵²⁹ 86.0 157 . 4-fluorobenzyl . (4-chlorophenyl).-CH ₂ -CO- . 546 , 24.9 158'. 2-furylmethyl (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 ' (CHg) 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-O-CH ₂ -CO- 540 . 57.9 ¹⁶⁷ ' 2-chlorobenzyl phenyl-O-CH ₂ -CO- 5.44 ' . 47.5

Example No. R ² R'-X MS ‘ (ES-) (Μ-l)' Residual activity (%) NCBE at 10 μΜ 168 ' ,cyclopropylmethyl' phenyl-O-CH ₂ -CO- 474 96, 4 169 3,4,5-trimethoxybenzyl . phenyl-O-CH ₂ -CO-' 600 170 4-fluorobenzyl ¹ phenyl-O-CH ₂ -CO- 528 Í71 2-furylmethyl (4-methoxyphenyl)-ch ₂ -co- 514 172 2-(2-thienyl)ethyl (4-methoxyphenyl)- - -CH.-CO- í. 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- ' from. 488 93.2 176' 3,4,5-trimethoxybenzene (4-methoxyphenyl)-' -ch 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 -what- 438 . 78.3 180 2-phenoxyethyl ch ₃ -what- . 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.-CÚ- o. • 508 ,185 4-fluorobenzyl ' CH.-CO- '436 . 85.0 ' 186 3-phenylpropyl (2-thienyl)-(CH ₂ ) ₃ -CO- 556 9.7 : 187 2-methoxyethyl1 (2-thienyl)-(CH ₂ ) ₃ -C0- 496 ' 62.4 • 188' (2-pyridyl)methyl (2-thienyl)-(CH ₂ ) ₃ -C0- 529 52.3

Ex- - example no. 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-Methoxycarbons1-2-Phenylethyl . (2-thienyl)-(CH ₂ ) 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 í 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 -CÓ- - 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 (indo'l-3-yl)-CH ₂ -CO- ' 60 5 56.2

·· ·· ·· ·· • 9 9 · 9 « · · • · ·Φ · · · · • · · · · · * ·· 9

9 9 · 9 9 9 9

99 ' 99 99

Example No. R ² . R ³ -X MS.. (ES-), (Μ-l)' Residual activity (%) NCBE at 10 μΜ 210 3-phenylpropyl (benzob]thiophen-3-yl)-CH ₂ -CO-' 578 66.2 211 2-methoxyethyl . (benzob]thiophen-3-yl)-CH;-CO- 518 ’ 50.6 212 . (2-pyridyl)methyl (benzoph b]thiophene- , -3-yl)-,CH,-CO- 551 60.2 213 . cyclopropyl (benzoph b]thiophen-3-ylj-CH ₂ -CO- ' 500 • 45.0 214 . methyl (benzob]thiophen-3-yl)-CH ₂ -CC- 474 44.3 - '215 ethyl . (benzob]thiophen-3-yl)-CH.,-CO- '488 65.7 216 (2-benzimidazolyl)- methyl (benzob]thiophen.'-3-yl)-CH ₂ -CO- . 590 62.2 217 1-Methoxycarbons! -2-phenylethyl (benzob]thiophen-''--3-yl)-CH ₂ -CO- 622 46.0 '218 .3-phenylpropyl. (2-thienyl)-( _CH2 ) ₄ -CO- 570 37.1 .219. 2-methoxyethyl. (2-thienyl)-(CH ₂ ) ₄ -CÓ- ⁵¹⁰ 82.5 220 ' (2-pyridyl)methyl (2-thienyl)-(OH') ₄ -C0- 543 73.2 ' , 221' cyclopropy1' .. (2-thienyl)-(CH ₂ ) ₄ -CC- 492.. ' 72.3 . 222 . methyl (2-thienyl)-( _CH2 ) ₄ -CO- 466 '76.7 . 223 .. ethyl (2-thienyl) -.(CH ₂ ). ₄ -CQ- . 480 53.8 224 (2-benzimidazolyl)methyl .(2-thienyl)-(CH ₂ ) .-CO- , 582 79.8 225 1-Methoxycarbonyl. -2-phenylethyl (2-thi.enyl) - (CH ₂ ) -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

- 66 •· · « • · ·· • · · • © · • · · · · · ··

99 • 9 9 · • * · · · · · 9

9 9 9

99

Example No. . . R ² R ^x -X . MS (ES-) (M-l)’ Residual activity (%) NCBE at 10 μΜ 228 (2-pyridyl)methyl (3-thienyl)-CH2 _- CO- 501 94.8 229 , cyclopropyl . (3-thienyl)-CH2- _OO- 450 86.7 230 methyl (3-thienyl)-CH ₂ -CO- . 424 68.6 231 ethyl (3-thienyl)-CH2 _- CO- 438 57.8 232 (2-benzimidazolyl)- 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-methoxyethyl -(2-thienyl)-CH2 _- CO- 468. 50.3 238 ί (3,4-dihydroquinazo- lin-2-yl)methyl (2-thienyl)-CH2 _- CO- 554 '54.7 239 methyl . (2-thienyl)-CH2 _- CO- 424 , 56.3 '240 ' ethyl (2-thienyl) -CH ₂ ~CO- . 438 58.0 241 . benzyl phenyl-CH( _NH2 )-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

φφ • * • · φ φ • φ φφ φ *· Φ· • Φ C Φ Φ Φ • φ. > φφ '· Φ Φ « 9 ·

Φ Φ - φ Φ Φ

Φ

ΦΦ ΦΦ • Φ Φ · • Φφφ

Φ Φ Φ Φ

Φ Φ Φ Φ

Φ« ΦΦ

Example No. R ² Ø-X MS . (ES-) (M-1)’ Residual activity (%) NCBE at 10 μΜ 250 (2-thienyl)methyl (2=thienyl)-CH2- _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 -.CH ₂ -CHO- 520 61.0 · 256 . cyclohexylmethyl1 (2-thienyl)-CH2 _- 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-(CH..) ₄ -CO- :. 604 45.3 ²⁶³ 3,4-dichlorobenzyl (2-furvi)-CO-CO- . 566 ' 54.0 . 264 3,4-dichlorobenzyl cyclohexyl-CH ₂ -CH ₂ ~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 -CHQ- 520 57, 9 268 phenyl-CH(COOCHj - . (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

• · · · · · ·

Example No. -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( _COOCH3 )- (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)-CH2 _- CO- 640 36.8 277 . (1-naphthyl)methyl (2-bromophenyl)-CH2 _- 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)-CH2 _- CO- 544 89.0 283 2,4-dichlorobenzyl (4-hydroxyphenyl)'. -ch ₂ -what- . 578 80.0 . '284 (i-naphthyl)methyl (4-hydroxyphenyl)· -ch ₂ -co- 560 52, 9 '285 3-chlorobenzyl (4-hydroxyphenyl)- . -ch ₂ -what- 544'. 5.8,8 286 phenyl-CH( _COOCH3 )- (2 ¹ -thienyl)-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„- • . * from -CH.-CO- ’ 582 63.1 289 (I-naphthyl)methyl (3-thienyl) -CH ₂ - -ch ₂ -co- 564 « 39.2 290 - 3-chlorobenzyl (2-thienyl)-CH2- _{ch2 -} 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 -

Example No. R ² T R ^! -X MS (ES.-) (Μ-l); 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-cyclohexyl1-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-CHl-NH-CO- 539 65.8 304' . 3-methoxybenzyl N-cyclohexyl1 -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-)- _Cn2 -CO- .568/ 88.9 310 (2-naphthyl)methyl . (2-thienyl)-CH ₂ -CO- . 550 47.7 311 3-methylbenzyl (2-thienyl)-CH2 _- CO- 514 .. 10.4' 312 2-methylbenzyl . (2-thienyl) -CH..-CO- . 514' 12.5 .313 (CH ₃ ) ₂ C=CH-CH ₂ -CH ₂ -. -C(CH ₃ )=CH-CH ₂ - (2-thienyl)-CHy-CO-. 546 17.2 314 l-indanyl (2-thienyl)-CH2 _- CO- .526. 14.4

Example No. R ² r ¹ --x MS (ES-) (M-l.)- Residual activity (’% ) NCBE at 10 μΜ. 315 1,2,3,4-tetrahydro- -1-naphthyl (2-thienyl)-CH2 _- CO- 540 23.5 . 316 2-fluorobenzyl (2-thienyl)-CH ₂ -CO- 518 .. 14.4 317 . 3-phenylbenzyl (2-thienyl)-CH2 _- CO- 576 _ 14.5 318 (1,2',3,4-1-tetrahydro-2-furyl)methyl (2-thienyl)-CH2 _- CO- 494 16.4 319 2,3-dichlorobenzyl methoxy-CH ₂ -CH ₂ -CO- 530 38.0 . 320 , (2-naphthyl)methyl methoxy-CH ₂ -CH ₂ -CO- 512 38.8 ,321 . 3-methylbenzyl . methoxy-CH ₂ -CH ₂ -CO- 476 322 2-methylbenzyl. methoxy-CH ₂ -CH ₂ -CO- 476 66.3 323 (CH ₃ ) ₂ C=CH-CH 2 -CH ₂ -c (ch ₃ .) =ch-ch ₂ -. methoxy-CH ₂ -CH ₂ -CO- 508 , 23.6 . . 324 1-indanyl methoxy-CH ₂ -CH ₂ -CO- .488 ' 60.5 325 1,2,3,4-tetrahydro-1-naphthyl methoxy-CH ₂ -CH ₂ -CO- 502 .33.8 326 2-fluorobenzyl methoxy-CH ₂ -CH ₂ -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-CH ₂ -CH ₂ -CO- ' .456 87.0 329 2,'3-dichlorobenzyl.l 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

Example - No. 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-furo1)methyl1 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 ^CO- 538 85.3. ' '343 ,(CH ₃ ) ₂ C=CH-CH2-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-CH ₂ -CH ₂ ~CO- . / . , 564 · 39.8 ·· i 346 2-fluorobenzyl· . phenoxy-CH ₂ -CH ₂ ~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 cyclohexyl-CH ₂ - CO - , 568 50.4 350 (2-naphthyl)methyl , cyclohexyl-CH ₂ -CO- 550 , 351 . 3-methylbenzyl · cyclohexyl-CH,-CO- b ¹ J •514 27.2 352 - 2-methylbenzyl cyclohexyl 1-CH ₂ -CO - 514 .. QQ 0' 353 ' (CH^jO^CH-CiVČH.,- -C (CH ₃ ) =ch-,ch ₂ - ... cyclohexyl - 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 cyclohexyl-CH ₂ -CO- 518 47.4

'•Ύ-Τ ⁷ '-:

Example No. R ² R ^x -X MS (ES-) (Μ-l)’ Residual activity (%) NCBE at 10 μΜ 357 '3-phenylbenzyl cyclohexyl1 - CH ₂ - CO - 576 61.9' 358 (1,2,3,4-tetrahydro-2-furo1)methyl1 ohexy cycle 1 - CH ₂ - CO - 494, from' 55.5 - 359 2,3-dichlorobenzyl cyclopentyl-CH ₂ -CO -. 554 37.9 360 (2-naphthyl)methyl open tyl- CH ₂ - CO - cycle 536 . 36.9 361 . 3-methylbenzyl cyclopentyl-CH ₂ -CO- ¹ 500 29.4 362' . , 2-methylbenzyl cycle open t yl - CH' - CO - 500 '44.4 363 . (CHy.^CH-CÍVCH^ -C (CH ₃ ) =ch-ch ₂ - cyclopentyl-CH ₂ -CO- 532 48.3 '364 1-indanyl cyclopentyl-CH ₂ -CO- 512 52.6 . 365 1,2,3,4-tetrahydro, ··.- -1-naphthyl cyclopentyl-CH ₂ -CO- 526 45.1 ' 366 2-fluorobenzyl cyclopentyl-CH ₂ -CO- 504 38.4 367 3-phenylbenzyl open t yl cycle - 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-methylphenyl-SO ₂ - 590 . 33.7 370 4-tert.butylphenyl . 3,4-dimethoxy-phenyl-SO ₂ - 656 50.1 '371 4-tert-butylphenyl 2,5-dimethoxy-· phenvl-SO^- . · i. 656 ' . 38.6 372 ., 2,4-difluorophenyl 2,3,4,5,6-penta-methylphenyl-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

Example No.' R ² R ^x -X MS (ES-) (M-l)- 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-trichlorophenyl-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-dimethoxy-phenyl-SO ₂ - 625 ' 60,, 8 382 2,3-dichlorophenyl 3,4-dichlorophenyl-^S0 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 - (CH,)-CO- 514 - 63.7 • 389 . benzyl - (2-furyl)-CH..-CO- 484 • 51.5 . 390,. (l-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 -phenylcyclopentyl)methyl (2-thienyl)-CH-. -(CH ₃ )-CO- 582 16.7

Example 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-l-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-chlorophenyl-SO ₂ - -· 645 4.00 5-acetylamino-2-methylphenyl 2,5-dichlorophenyl-S0 ₂ - 679 401 . 4-acetylamine-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-methoxyphenyl-S0 ₂ - 612 408 ' 3-acetylphenyl 2-chlorophenyl-SO ₂ ~ 616 409 ·. 3-acetylphenyl 2-chloro-6-methyl·-' phenyl-SO ₂ - 630 , 410 3-acetylphenyl 4-tert.butylphenyl-SO ₂ - ·. 638 -

Example No. R ² R*-X MS (ES-) (M-l)’ Residual activity (%) NCBE at 10 pM 411 ' 3-acetylphenyl 4-fluorophenyl-'S0 ₂ - 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-SO ₂ - 638 .422 5-chloro-2-methoxyphenyl 2,4,5-trichloro- phenyl-SC.- ' ' . . 706. ' ⁴²³ ·;.·. '. 2-fluorophenyl - .. ·'4-acetyl'aminophenyl-SO ₂ - , 615' 424 1-naphthyl '. ' 4-Acetylamino.' pheryl-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-SO ₂ - 616

Example No. R ² r ³ -x MS (ES-) (M-l)' 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-trichlorophenyl-SO ₂ - 710 436 ' 5-chloro-2-methylphenyl 2,4,5-trichlorophenyl-SO ₂ - 690 437. . 2-fluorophenyl · 2,4,5-trichloro- . phenyl-SO ₂ - 660· 438 2,6-dimethylphenyl1) 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 _z - 676 446' 3, ,4-dimethoxyphenyl .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

Example No. 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-SÓ ₂ ~. 596 454 2, 6-di.isopropyl-phenyl phenyl-S0 ₂ - 624 455 ' 2-bi'phenylyl 4-methyl phenyl 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-methoxyphenyl1 4-chlorophenyl-SO ₂ - 638' ^: 461 2-methoxy-5-methyl- phenyl phenyl-SO ₂ - 584 462 3-methoxy-4-methylphenyl' phenyl-SO..- 584 463 2-methoxyphenyl 4chlorophenyl-SO ₂ - 604 464 _times . 3-hydroxyphenyl 4-chlorophenyl-S0 ₂ - . .590 465· . 3,4-dichlorophenyl 4-chlorophenyl-SO ₂ - ' 642 ' 466 . 3-acetylphenyl 4-chlorophenyl-S0 ₂ - 616 467 '2,6-diethylphenyl 4 -methy 1 pheny 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-SO ₂ - 67.6 .471 2-acetylphenyl 2, 4-.difluorophenyl~S0 ₂ - ' 618 '' 472 1-acetylamino-2-naphthyl 4-methylphenyl-SO ₂ - . 661

• Φ

I « φ· e ·

Example No. 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-methoxyphenyl-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-dimethoxy-phenyl-SO ₂ - 634 :478 2-methyl-1-naphthyl1 phenyl-SO ₂ - • 604 479 2,6-dimethylphenyl 4-ac,ethylamino-phenyl.-SO ₂ - 625 . 430 . 1,3-dihydro-1-oxo-. benzoph c]furan-6-yl 4-chlorophenyl-S0 ₂ - . 630 481 benzyl (5-methyl-2-thienyl)-CH-(CH ₃ )-CO-' • 528 • 62.6 '482 3 - nitrobenzene z.y 1 (2-thienyl)-CH2 _- CO- ' 545 483. neopentyl (2-thienyl)-CH2 _- CO- 480 ' 484 isopropyl (2-thienyl)-CH2 _- CO- .452 485 2-ethoxybenzyl (2-thienyl)-CH2 _- CO- 544 . 486 3-nitrobenzyl .(3-thienyl)-CH2 _- CO- '545 ,487 ^: ·· neopentyl (3-thienyl)-CH2 _- CO- 480 ' .488 isopropyl (3-thienyl)-CH2- _CO = . 452 ' 489 2-ethoxybenzyl (3-'thienyl) _-CH2 -CO- 544 . 490 2,2,2-trifluoroethyl • (3-thienyl) _-CH2 -CO-. . 492 -. ' 491· 2-(3-trifluoro- methylphenyl)ethyl (3-thienyl)-CH2 _- CO- 582 492 3-nitrobenzyl - . (2-fluorophenyl)-CH ₂ -CO- 557' 493 ^1. neopentyl. (2-fluorophenyl)-CH2 _- CO- 492

··

Example No. . R ² R ² -X . MS (ES-) (M-l) Residual activity (%) NCBE at 10 pM 494 isopropyl (2-fluorophenyl)-CH ₂ -CO- 464 495.. , , 2-ethoxybenzyl . (2-fluorophenyl)-CH ₂ -CO- 556- 496 2-(3-trifluoromethyl phenyl)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- me thy 1 phenyl) .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 '

··. from

4« 4 44 44 • 4 44 4 4 4 *

4 4 4 4 44

4 444 44 4

4 4.4 4 4 4 .444 44 44

Example No. R ² R^X ,R ⁷ MS (ES-) (M-l),7 .Residual activity (%) NCBE at 10 μΜ 513 benzyl (2-thienyl)-CH2 _- CO- 4-methyl 514 88.6 514. (1-naphthyl)methyl (2-thienyl)-CH2 _- CO- 4-methyl 564 74.9 515 (2-naphthyl)methyl (2-thienyl)-CH ₂ -CHO- 4-methyl 564 68, 9 .516 2-chlorobenzyl (2-thienyl)-CH ₂ -CO- 4-methyl 548 98.7 517 (2-thienyl)methyl (2-thienyl)-CH2 _- CO- 4-methyl 520 86.2 518 2-phenylethyl (2-thienyl)-CH ₂ -CO- 4-methyl 528 93.5 519· 2-fluorobenzyl (2-thienyl)-CH2 _- CO- 4-methyl 532 95.6 520 2,3-dichlorobenzyl (2-thienyl)-CH2 _- CO- 4-methyl 582 85.9 521 - benzyl (2-thienyl)-. -CH(CH ₃ )-C0- 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(CH ₃ )-CO- . 4-methyl 534 74.0 526 2-phenylethyl (2-thienyl) ^f -CH(CH;)-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 » · · β ·· ··

I · · 4 » β β <

Example No. , 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)-.. -ch ₂ -co- 4-methyl 560 ' 84.0 536 2,3-dichlorobenzyl (4-Chlorophenyl)'- ' -CH..-CO- 4-methyl 610 7.6.3 . 537 benzyl (3-thienyl)-CH2 _- CO- ' 4-methyl 514' 54.4 538. (1-naphthyl)methyl (3-thienyl)-CH2 _- CO- 4-methyl . 564 .80.6 '539. ,(2-naphthyl) methyl. (3-thienyl)-CH2 _- CO- 4-methyl 564 65.2 540 2-chlorobenzyl , (3-thienyl)-CH2 _- 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)-CH2 _- CO- 4-methyl ⁵²⁸ 67.4 . 543 2-fluorobenzyl (3-thienyl)-CH2 _- CO— 4-methyl 532 . 58.3 ' 544 2,3-dichlorobenzyl (3-thienyl)-CH2 _- CO- /4-methyl 582 . θ ² ·,2 545 '..benzyl cyclohexyl - CH ₂ - CO - 4-methyl ' 514 ' 70.1 '546 (1-naphthyl)methyl· cyclohexyl-CH ₂ -CÓ-. 4-methyl 564 ' .63.6 ' 547 . (2-haftyl)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·

Example No. R ² _with 'R ^J -X R ⁷ . MS . (ES-) (M-l)- Residual activity- (%) NCBE at 10 μΜ 552 2, 3-dichlorobenzyl cyclohexyl-CH ₂ -CO- 4-methyl 582 61.5 553 benzyl (2-thienyl)-CH2 _- CO- 5-Chlorine 534 85.7

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

a) 4-bromo-1-bromomethyl-2-chlorobenzene ' · 7. .

7.1 ml of 4-bromo-2-chlorotoluene are dissolved in 20 ml of chlorberisene and at a temperature of 130° C. a mixture of 9.4 g of N-bromosuccinimide and 200 mg of dibenzoyl peroxide is added in portions. The mixture is boiled for 30 minutes under reflux, after cooling it is diluted with 100 ml of dichloromethane and washed once with 50 ml of saturated aqueous sodium sulfite solution and once with 100 ml of saturated aqueous sodium bicarbonate solution. The mixture is dried over sodium sulfate and the solvent is removed in vacuo. 11.0 g of a light yellow oil is obtained.

R _f (1:8 mixture of ethyl acetate and n-heptane) = 0.49.

Mass spectrometry (DCI): 283- (M+H)* . ...

b) .Benzyl-(4-brcm-2-chlorobenzyl)amine;?

765 μΐ of benzylamine are dissolved in 10 ml of anhydrous tetrahydrofuran, at a temperature of 0° C. 1.0 g is added.

• 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 is stirred for 4 hours at room temperature. Then 100 ml of half-saturated aqueous sodium carbonate solution is added and the mixture is extracted three times with 100 ml of ethyl acetate each time. The extract is dried over magnesium sulfate and chromatographed on silica gel, using diisopropyl ether as eluent. 590 mg of a colorless oil is obtained.

R _f (diisopropyl ether) - 0.30,

Mass Spectrometry, (DCI) : 310 (M+H) ⁺

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

580 mg of benzyl-(4-bromo-2-chlorobenzyl)amine are dissolved in 10 ml of anhydrous dichloromethane and then 300 μΐ of pyridine and then 330 mg of 2-thiophen-2-ylacetyl chloride are added. 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. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo. The residue is chromatographed on silica gel using diisopropyl ether as eluent. 490 mg of a colorless oil are obtained.

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

Mass spectrometry (ES) : 434 (M+H) ⁺

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

R _f (diisopropyl ether) = 0.20 ,·

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

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

510 mg of 4'-{[benzyl-(2-thiophen-2-ylacetyl)amino]methyl)-3'-chlorobiphenyl-2-sulfonic acid tert.butylamide and 110 μΐ of anisole are left to stand in 3 ml of trifluoroacetic acid for 18 hours at room temperature. The volatile components are then removed in vacuo, the residue is taken up in 5 ml of toluene and the volatile components are removed again in vacuo. 586 mg of a colorless oil is obtained, which is used further without purification.

R, (diisopropyl ether) = 0.12

Mass spectrometry. (ES) : 511 (M+H) ⁺

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

586 mg of 4'-{[benzyl-(2-thiophen-2-ylacetyl)amino]methyl}-3'-chlorobiphenyl-2-sulfonamide, 372 mg of potassium carbonate and 100 μϊ of a 5M solution of cyanogen bromide in acetonitrile are boiled for 1.5 hours under reflux. After cooling, the entire reaction mixture is chromatographed on silica gel using a mixture of ethyl acetate and methanol in a ratio of 10:1 as eluent. 181 mg of a colorless amorphous solid is obtained. . .

R _f , (mixture of ethyl acetate and methanol in the ratio 10 : 1) =0.22

Infrared spectrum (CN): 2172.5 cm' ¹

Mass spectrometry (ES): 536 (M+H) ⁺ .

Residual NCBE activity at 10 μΜ: 15%

The title compound of Example 555 was synthesized analogously 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 are slowly added to 250 ml of chlorosulfonic acid at a temperature of -10° C. with stirring. The mixture is then stirred at this temperature for a further 30 minutes, allowed to warm to a temperature of 0° C. and poured onto an excess of 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 a vacuum. 63 g of a colourless solid are obtained, which is directly subjected to the next reaction.

b) 2-bromo-5-meth.ylbenzenesulfinic acid'

37.6 g of sodium sulfite are dissolved in 500 ml of water and the solution is heated to 70° C. At this temperature, 62 g of 2-bromo-5-methylbenzenesulfonyl chloride are added in portions. At the same time, a 10M aqueous solution of sodium hydroxide is added dropwise so that the pH of the solution is maintained between pH = 9 and pH = 10. The mixture is then stirred for a further 1.5 hours at 70° C., the solution is filtered and then the pH is adjusted to 0 in an ice bath with saturated aqueous hydrogen chloride solution. 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 with a melting point of 120 to 122° C. are obtained;

• · · ·

- 8.6 Mass spectrometry (ES): .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 is 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 in vacuo over P ₄ O ₁₀ . 54.0 g of the product are obtained, which melts with decomposition at a temperature of 280-290° C.

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 rises to 50° C. The mixture is stirred for 3 hours at 50° C. and then the N,N-dimethylformamide is removed in vacuo. The residue is stirred with 500 ml of water, the mixture is stirred for 1 hour at 0° C. and filtered. The product is washed with water, dried and recrystallized from a mixture of 400 ml of n-heptane and 250 ml of ethyl acetate with activated carbon. 27.0 g of colorless crystals with a melting point of 110-114° C. are obtained.

R _f (mixture of ethyl acetate and n-heptane in the ratio 1:4) = 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 refluxed 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 carbonate solution and once with 50 ml of water. The mixture is dried over sodium sulfate and the solvent is removed in vacuo. The residue is recrystallized from a mixture of 80 ml of

n-heptane and 30 ml of ethyl acetate. 6.9 g of a light yellow solid with a melting point of 120-124° C is obtained.

,R _f (mixture of ethyl acetate and n-heptane in the ratio 1:2) =0.38 Mass spectrometry (DCI): 329 (M+H) ⁺

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

652 μΐ of benzylamine are dissolved in 10 ml of anhydrous tetrahydrofuran and 1.0 g of 1-bromo-4-bromomethyl-2-methanesulfonylbenzene are slowly added 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 100 ml of ethyl acetate each time. The extract is dried over magnesium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using a 1:1 mixture of methyl tert.butyl ether and diisopropyl ether as eluent gives 510 mg of a colorless oil.

R, (diisopropyl ether) = 0.10 . · ,·.'..·

Mass spectrometry (ES) : 354 (M+H) ⁺ '

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

R _f (10:1 mixture of ethyl acetate and methanol) = 0.21

Infrared spectrum. (CN) : 2175.3 cm' ¹

Mass spectrometry (ES): 580 (M+H) ⁺ . ' ^:

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 were dissolved in 20 ml of dichloromethane and at room temperature, 1.4 g of thiophene-2-sulfonic acid chloride were slowly added. The mixture was stirred for 4 hours at room temperature, then diluted with 200 ml of ethyl acetate and washed twice with 100 ml of 5% aqueous sodium hydrogen sulfate solution and twice with 50 ml of saturated aqueous sodium carbonate solution. The mixture was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using diisopropyl ether as eluent gave 1.5 g of a colorless oil.

R _f (diisopropyl ether). = 0.21 , ....

Mass spectrometry (FAB) : 456 · (M+H) ⁺

Further reactions to obtain the compound mentioned in the title of Example 556 are carried out analogously to Example 554 d) to

f).. '

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

R _f (10:1 mixture of ethyl acetate and methanol) = 0.17 Infrared spectrum (CN): 2178.5 cm- ¹ , ,

Mass spectrometry (FAB) : 580 (M+Na)*

Residual NCBE activity at 10 μΜ: 0 %.

The title compound of Example 557 is synthesized analogously to Example 556 from the title compound of Example 555b).

Example 557 ··

4'-{[benzyl(thiophene-2-sulforiyl)amino]methyl}.-3'-methylsulfonylbiphenyl-2-sulfonylcyanamide

N

R _f (10:1 ethyl acetate/methanol) ~ 0.28 Infrared spectrum (CN): 2175.0 cm- ¹ Mass spectrometry (ES): 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 g of 3-hydroxy-4-methylaniline, 24.9 g of 2-bromomethylmethyl ether and 233 g of cesium carbonate are dissolved in 570 ml of N,N-dimethylformamide and the mixture is stirred for 8 hours at 40°C. 3 l of 1.0% aqueous sodium bicarbonate solution are added, the mixture is extracted six times with 750 ml of ethyl acetate. It is then washed twice with 1 l of 10% aqueous sodium bicarbonate solution. The mixture is dried over sodium sulfate and the solvent is evaporated off in vacuo. 32.9 g of yellow oil are obtained, which is used in the subsequent reaction without further purification. - - '

R _f (1:1 mixture of ethyl acetate and n-heptane) = 0.33 ··

- 90 • ·· • * · · · · · · • · · · · · · · · · «· · ’ · · · · · · · ·

b) 4-methyl.1-3-(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 and at a temperature of 0°. C, a solution of '12.5 g of sodium nitrate in 25 ml of water is slowly added dropwise. The solution is stirred for 30 minutes at a temperature of 0° Ca and then slowly added to a solution of 51.9 g of copper bromide in, 4 90 ml of saturated aqueous hydrogen bromide solution, heated to a temperature of 50°' C. The reaction mixture is then slowly heated from 50° C to. 70° C over 6 hours. The mixture is then cooled, extracted, is· four times, each time 500 ml of diethyl ether, washed with 500 ml of saturated aqueous sodium chloride solution and dried ' over sodium sulfate. Chromatography on silica gel using a mixture of ethyl acetate and n-heptane in a ratio of 1:8 gave 15.4 g of a colorless oil.

R _f (1:1 mixture of ethyl acetate and n-heptane) = 0.41. Mass spectrometry (DCI): 245 (M+H) ⁺ · .

c) 4-Bromomethyl-3-(2-methoxy)ethoxybromobenzene 15.3 g of 4-methyl-3-(2-methoxy)ethoxybromobenzene is dissolved in 300 ml of chlorobenzene and a mixture of 1.1.1 g of N-bromosuccinimide and 125 mg of benzoyl peroxide is added portionwise while boiling under reflux. The mixture is boiled under reflux for 24 hours, the solvent is removed in vacuo and then 500 ml of dichloromethane is taken up. The mixture is washed first with 200 ml of saturated aqueous sodium sulfate solution and then with 100 ml of saturated aqueous sodium carbonate solution. The mixture is dried over sodium sulfate and the solvent is removed in vacuo. Chromatographic treatment on silica gel using a mixture of ¹ L ethyl acetate and n-heptane in a ratio of 1.15 as eluent

The reagent yields 12.8 g of a light yellow oil.

R _f (mixture of ethyl acetate and n-heptane in the ratio 1:4) = 0.42 Mass spectrometry (DCI): 323 (M+H) ⁺

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

2.4 ml of benzylamine are dissolved in - 20 ml of anhydrous tetrahydrofuran and 3.2 g are slowly added at 0° C.

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

Workup on silica gel using methyl tert-butyl ether as eluent gives 1.3 g of a colorless oil.

R _f (methyl tert.butyl ether) = .0.20 ^v Mass spectrometry (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 is then diluted with 100 ml of dichloromethane and subsequently washed twice with 50 ml of 5%.

+ aqueous hydrogen sulfate solution. of sodium and then 50 ml.

saturated aqueous sodium carbonate solution. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using diisopropyl ether as eluent gives 900 mg of a colorless oil. R _f (diisopropyl ether) = 0.2.

Mass spectrometry (ES) : 496 (M+H) ⁺ ? · ;

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

- 92 is removed in vacuo. The residue is taken up in 100 ml of toluene and the volatile components are removed once more in vacuo. 56 g of a colorless oil are obtained, which is subjected to further reaction without purification. R _f .(methyl tert. butyl ether) ~ 0.4

g) Dihydroxyboran-2-ylbenzenesulfonic acid dimethylaminomethyleneamide g of dihydroxyboran-2-ylbenzenesulfonamide and 66 ml of dimethylformamide dimethylacetal are dissolved in 200 ml of anhydrous N,N-dimethylformamide and the solution is left to stand for 18 hours at room temperature. The reaction mixture is poured into 1.5 l of water and extracted four times with 500 ml of ethyl acetate each time. The extract is dried over magnesium sulfate and the solvent is removed in vacuo. Crystallization from 100 ml of ethyl acetate gives 5.2 g of colorless crystals which melt with decomposition at 175° C.

R, (ethyl acetate) =0.25 ' '

h) Dimethylaminomethyleneamide {[benzyl(thiophene-2-sulfonyL)amino]methyl}-3'-(2-methoxy)ethoxybiphenyl-2-sulfonic acid

900 mg of benzyl-[4-bromo-2-(2-methoxy)ethoxybenzyl]thiophene-2-sulfonic acid amide, 1.4 g of dihydroxyboran-2-ylbenzenesulfonic 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 is refluxed for 6 hours, then allowed to cool and diluted with 100 ml of ethyl acetate. The mixture is washed twice with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using methyl tert-butyl ether as eluent gives 560 mg of a colorless viscous oil. . ' . '' · 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 0 000

000 00 00 ·· 00

R _f (methyl tert.butyl ether) =0.13 Mass spectrometry (ES): 628 (M+H) ⁺

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

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

R _f (mixture of methyl tert.butyl ether and diisopropyl ether in a ratio of 1:1) = 0.33

Mass spectrometry (ES): 573 (M+H) ⁺ ·.

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

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

R _; (mixture of ethyl acetate and methanol in the ratio 10:1) = 0.13 infrared spectrum (CN): 2175.3 cm ^-1 . ¹ , .

Mass Spectrometry (FAB): 598 (M+H) ⁺

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 is stirred for 12 hours at a temperature of 120° C. The mixture is then cooled and the solvent is removed in vacuo. The residue is taken up in 400 ml of methyl tert.butyl ether and washed three times /each time ' 200 ml of 10%' aqueous sodium hydroxide solution and .once 100 ml of saturated aqueous sodium chloride solution. The mixture is dried over sodium sulfate and the solvent is removed in vacuo. 10.4 g of a light yellow oil are obtained. . . ,

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

Mass spectrometry (DCI) : 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 at reflux temperature a mixture of 10.1 g of N-bromosuccinimide and 200 mg of benzoyl peroxide is added in portions. The mixture is refluxed for 30 minutes, then allowed to cool and diluted with 300 ml of ethyl acetate. The mixture is then washed first once with 100 ml of saturated aqueous sodium sulfite solution and then twice with 100 ml of saturated aqueous sodium sulfite solution each time.

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 is dried over magnesium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using a mixture of ethyl acetate: n-heptane in a ratio of 1:4 as eluent gives 5.2 g of a colorless oil.

R _f (mixture of ethyl acetate and n-heptane in the ratio 1 : .4) = 0.20

Mass spectrometry (DCI): 262 (M+H) ⁺ bl) 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 refluxed 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 carbonate solution and once with 50 ml of water. The mixture is dried over sodium sulfate and the solvent is removed ⁱⁿ vacuo. The residue is recrystallized from a mixture of 80 ml of n-heptane and 30 ml of ethyl acetate, yielding 6.9 g of a light yellow solid with a melting point of 12.0 to 124° C.

R _f (mixture of ethyl acetate and n-heptane in the ratio 1- : 2) = 0;38 Mass spectrometry- (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. The mixture was allowed to cool, diluted with 200 ml of water and the suspension was stirred for 30 minutes at room temperature. The product was then _filtered off _to give 1.8 g of a colorless solid with a melting point of 188-190° C.

Mass spectrometry (ES) 393 (M+H) ⁺ ,

d) . 4-bromo~2-methanesulfonyl bexylamine

1.8' g of 2-(4-bromo-2-methanesulfonylbenzyl)isoindole-1,3-dim?

and 1.5 ml of hydrazine hydrate in 30 ml of ethanol are first stirred for 1 hour at 60° 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 components are filtered off again. The solvent from the filtrate is removed in vacuo, yielding 1.3 g of a light yellow oil.

R _f (10:1 ethyl acetate/methanol) = 0.10 Mass spectrometry (DCI): 26.4 (M+H) ⁺

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 at a temperature of 0° C. a solution of 1.3 g of 2-bromomethyl-4-fluoro-1-(2-methoxyethoxy)benzene in 5. ml of anhydrous tetrahydrofuran is added dropwise. The mixture is stirred for 60 hours at a temperature of /

room temperature, then diluted with 200 ml of ethyl acetate and washed twice with 100 ml of saturated aqueous sodium carbonate solution. The mixture was dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography on silica gel using ethyl acetate as eluent gave 910 mg of a colorless oil.

R. (ethyl acetate) - 0.43

Mass spectrometry (ES): 446 (M+H) ⁺ , ' . Further reactions are carried out 'analogously to,, in example 558f) .to 5.58j) . ' f) . 4'-{[benzyl (thiophene-2-sulfonyl)amino]methyl}-3'-(2-methoxy)ethoxybiphenyl-2-sulfonylcyanamide

R _f (mixture of ethyl acetate and methanol in the ratio 10:1) = 0.33 • Infrared spectrum (CN): 2174.3 cm' ¹

Mass spectrometry (ES): 694 (M+H) ⁺

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

9 9 9 9 99 9 9 9 9 · · . 9 · 9 · · · · 9 · ·

9 9 .'· 9 9 9 9 9 9 9,9

9 99 99 99 9 9 99

- 97 The compound given in the title of Example 560 is synthesized analogously to Example 558.

Example 560

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

R _f (5:1 ethyl acetate/methanol) =0.36 Infrared spectrum (CN): 2175.0 cm ^-1 Mass spectrometry (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-sulfonylcyanamide · '

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

4.4 ml of benzylamine are dissolved in 90 ml of anhydrous tetrahydrofuran and at a temperature of 0° C. 7.6 g of 4'-(bromomethyl)-N-[(dimethylamino)methylene]-(1,1'-biphenyl)-2-sulfonamide (J. Med. Chem. 1995, 38, 2357) are added in portions. The mixture is stirred for

»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 9

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. The mixture is dried over sodium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using a 10:1 mixture of ethyl acetate and methanol as eluent gives 3.8 g of a colorless oil.

R. (10:1 ethyl acetate/methanol) = 0.25 Mass spectrometry (FAB): 408 (M+H) ⁺ .

b) o-tolylacetyl chloride' 4.8 g of o-tolylacetic acid is dissolved in '3.6 ml of SOC1 ₂ ' f

a. the solution is boiled for 12 hours under reflux. The volatile components are removed in vacuo, the residue is then taken up three times with 50 ml of toluene and the volatile components are again removed in vacuo. 6.6 g of a light yellow liquid are obtained, which is used further without purification. , . ’

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

408 mg of (dimethylamino)methyleneamide of 4'-(benzylaminomethyl)biphenyl-2-sulfonic acid are dissolved in :9 ml of anhydrous dichloromethane and at room temperature first 162 μΐ pyridine and then 220 mg of o-tolylacetyl chloride are added. The mixture is stirred for. 24 hours at room temperature,, diluted with 100. ml of dichloromethane· and washed three times with 50. ml of saturated, aqueous sodium carbonate solution.. The mixture is dried over. sodium sulfate, and the solvent is removed in vacuo., Chromatographic treatment on· silica gel using a mixture of ethyl acetate and. n-heptane-in the ratio 2 ·': 1 as eluent gives 330 mg of colorless oil. ,

R _f (2:1 ethyl acetate/n-heptane) - 0.52. Mass spectrometry (FAB): 540 (M+H) ⁺

• 4 4 • · © » e

4 4 • 4 • 4 e

·· 44

44 • 4 4 » • 4 4 4 « 4 9 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 is refluxed for 8 hours and after cooling the pH is adjusted to 5-6 with 6M aqueous sodium hydroxide solution. The mixture is diluted with 70 ml of water and extracted three times with 70 ml of ethyl acetate each time. The extract is dried over sodium sulfate and the solvent is removed in vacuo. 300 mg of a colorless oil is obtained. ' '·'·

R.. (ethyl acetate) = 0.68

Mass spectrometry (ES): 485 (M+H)*

e) 4'-{[benzyl-2-(2-methylphenyl)acetylamino]methyl}bife'. n'yl-2-sul'phyl acamide .

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. 116 μΐ of a 5M solution of cyanogen bromide in acetonitrile are added. The mixture 7 is boiled ' for . 2 . hours under reflux and' after cooling the entire -reaction mixture is chromatographed on silica gel using a mixture of ethyl acetate. and methanol in a ratio of 10 :_ 1 as eluent. The product is obtained

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

R _f (10:1 mixture of ethyl acetate and methanol) = 0.27 Infrared spectrum (CN): 2177.0 cm ^-1 Mass spectrometry (FAB.): 532 (M+Na)*

Residual NCBE activity at 10 μΜ: 16%.

The compounds named in Examples 562 to 568 are synthesized ^analogously to Example 561.

- 100

Example 562 ·

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

R _f (10:1 ethyl acetate/methanol mixture) = 0.30 Infrared spectrum (CN): 2178.0 cm ¹ Mass spectrometry (FAB): 586 (M+Na) ⁺ ''The product melts upon decomposition at 90° C. Residual NCBE activity at 10 μΜ: 33% '

Example. 563.

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

R _f (mixture of ethyl acetate and methanol in the ratio 10:1) =0.26 Infrared spectrum (CN): 2177.0 cm ¹ - - . '

Mass spectrometry (ES): 580 (M+H) ⁺ . ...

The product melts with decomposition at a temperature of 125° C.

Residual activity'. NCBE at 10 μΜ: 46%

Example 564 ·.

-{1-Benzyl-2-(2-trifluoromethylthioferriyl)acetylamino]methyl)biphenyl-2-sulfonylcyanamide. , ...

R, (10:1 ethyl acetate/methanol mixture) = 0.27 Infrared spectrum (CN): 2176.0 cm- ¹ Mass spectrometry (ES): 596 (M+H) ⁺

The product melts with decomposition at a temperature of 122° C. Residual activity of NCBE' at 10 μΜ: 23 %

Example 565 '-([benzyl-2-methylbenzoylamino]methyl]biphenyl-2-sulfonylcyanamide

R, (10:1 mixture of ethyl acetate and methanol)' = 0.22 Infrared spectrum (CN): 2174.0 cm

Mass spectrometry (ES): 496 (M+H) ⁺

The product melts with decomposition at 173° C - .

Residual activity of NCBE, at 10 μΜ: 42%

Example 566

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

• ·

- 102 -

R, (10:1 mixture of ethyl acetate and methanol) = 0.20 Infrared spectrum (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 in

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

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

Example 568 '-{[benzyl-(5-methylthiophen-2-yl)carbonylamino]methyl}biphenyl-2-sulfonyl cyanamide ·

R, .(mixture of ethyl acetate and methanol in the ratio 10 : 1). = 0.16 Infrared spectrum . (CN) ·: 2175.0· cm' ¹ Mass spectrometry (FAB): 524 (M+Na) ⁺

The product melts with decomposition at a temperature of 166° C.

• · · · · · · · · · · · · · · · · · · · · · · · · ' - 103 Residual NCBE activity at 10 μΜ: 70 %

Pharmacological data:

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

Human endothelial cells (ECV-304) are detached from the culture vessels using Trypsin/EDTA buffer (0.05% trypsin and 0.02% EDTA (ethylenediaminetetraacetic acid) in ^phosphate buffer) and after centrifugation at 100 g for 5 minutes are placed in a buffered saline solution (containing 115 mmol/l sodium chloride, 20 mmol/l ammonium chloride, 1 mmol/l potassium chloride, 1 mmol/l calcium chloride, 1 mmol/l sodium

-mmol/l magnesium sulfate, ' 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. sé incubated.. . ..with ,,... 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 a buffer solution free of sodium 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 measurement, in FLIPR (Fluorescent Imaging Plate Reader) 100 μΐ of the above-mentioned cell suspension is pipetted into each well of a 96-well microtiter plate and this microtiter plate is centrifuged at 100 g for 5 minutes. In FLIPR, 100 μΐ of buffer solution is then taken from another prepared microtiter plate and pipetted into each of the 96 wells of the measuring plate. In this case, 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, 0.97 mmol/l disodium phosphate, 0.23 mmol/l sodium dihydrogen phosphate, 5 mmol/l glucose, pH 7.4), containing 50 μΜ HOE 642. For the 0% control, i.e. no pH restoration _, a buffer solution containing no bicarbonate ions and containing sodium, is used. 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 in various concentrations to a solution containing sodium and bicarbonate ions. After addition of the buffer solutions to the stained and acidified cells located in the measuring plate, the increase in fluorescence intensity is measured, which corresponds to the increase in pH value _iZ in each well of the microtiter plate. The kinetics are monitored over a period of 2 minutes at a temperature of 35°. G. - '' . <

The increase in fluorescence intensity for different concentrations of compounds according to the invention is related to both controls and thus the inhibitory effect of these compounds is determined.

Claims (12)

1. Biphenylsulfonylcyanamides of general formula I (i: in which R ¹ represents ' . 1. an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,' 2. an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, -3. alkenyl group, with. 2, 3,. '4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms,’ 4. the group -C.H. -Y, where ' ; nn - has the value 0 or 2, and n has the value 0, 1, 2, 3 or 4, with n not having.. . the value 0 or 1 if nn ' has the value, 2, or _r . 5. the group -C..where - nn ' has the -value 0 or 2, and ·. . h has the value' ¹ !, ,2., 3 or 4, with n having no value' i if nn has the value 2, ..'_; in which 1,. 2 or. 3. hydrogen atoms in the divalent radical .-0 _η Η ₂ „.. _Γπ - are independently replaced by a radical selected from the group consisting of 1. aryl groups with 6, 7, 8, 9, 10, 11,..12, 13 or, 14 carbon atoms, - - . 2nd amino group, NR ²² R ²³ groups, alkoxycarbonyl groups, ² 4. - 106 '5th group COOR ¹⁶ , 6. alkyl groups with 1, 2, , 3 or 4 atoms carbon,· á 7. arylalkylcarbonyl groups with . 6 to 14 atoms carbon in the aryl moiety and 1 to 4 carbon atoms in alkyl moieties,,. means 1. hydrogen atom,. ^; 2. alkyl group with 1, 2,. 3, 4,. 5, 6, - 7 or.8 atoms carbon, 3. alkyl group with 1, 2, 3, 4, 5,' 6, 7 or 8' atoms carbon, in which one to all of the hydrogen atoms* are replaced by fluorine atoms, 4.. an alkenyl group with 2, 3, 4, 5, 6, .7, 8, 9, 10, 11 or 12 carbon atoms, ' 5. an alkynyl group with 2, 3, 4, 5, 6, 7 or 8 carbon atoms,· , ' 7 .. 6. the group -C _n H _2n _ _nn -Z, where ' . nn has the value 0 or 2, and . ‘ . n has the value 0, 1, 2, 3' or 4, with n -not having the value 0 or 1 if nn has the value 2, or 7. group -Ο _π Η. _;π .. _ηη -Ζ, where . . nn· has the value 0,or.2, and ' n ^: has the value щ, .2, 3 or 4, whereby n has the value 1 if nn has the value 2, . ' - in which .there are 1, 2. or 3 hydrogen atoms in the.divalent radical; ^- C _n H _2r ^ _nn - independently of each other replaced ./by a radical selected,, from the group consisting of 1. aryl groups with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, 2. amino group, 3rd group NR ²² R ²³ , - . . '' . 4. alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy moiety, §. groups COOR ¹⁶ , and . . . . ₍ ' - 107 - 6. alkyl groups with 1, 2, 3 or 4 carbon atoms, , the symbols R ³ and R ⁴ independently of each other each represent a hydrogen atom or an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 'the symbols R ⁵ , R ^ž and R ⁷ independently of each other each represent a hydrogen atom, an alkyl group with 1, 2, 3, 4, 5, '6, 7 or 8 carbon atoms, a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl group, a cyano group, a nitro group, a group SO _q -R ⁸ , CO-R ^z: or OR ¹⁰ , , '·. R ⁸ represents an alkyl group with 1, 2, 3, '4, 5, 6, 7 or 8 carbon atoms,' a group NR ⁿ R ¹² ' or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals selected from the group . .. · comprising'^; fluorine, chlorine, bromine' and iodine atoms, a trifluoromethyl group, a methyl group, .. .. . methoxy group, hydroxy group and ..'groups ÇR ⁿ R ¹² , - symbols R ⁹ and R ²¹ independently of each other always represent a hydrogen atom, an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or a group OR ¹³ , R ¹⁰ represents a hydrogen atom, an alkyl group with 1, 2, 3, '4, . 5, . 6, 7 or -8 carbon atoms, which is optionally substituted by an alkoxy group with 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 comprising . fluorine, chlorine,' bromine and iodine atoms, trifluoromethyl group, \ . methyl group, methoxy group, hydroxy group. and groups NR' ^: R ² , '< . symbols R, R ¹² ,. R ¹⁹ and R ²⁰ independently of each other each represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 atoms ·' . ' - - '' , '' .in ' carbon or' alkanoyl group with 1 to 4 carbon atoms, R ¹³ .. means , a hydrogen atom or an alkyl group with. 1, 2, 3, 4, 5, '6, 7 or 8 carbon atoms, X- ’ represents a carbonyl group, -group -CO-NH-, - 108 - -CO-CO-, or a sulfonyl group, the symbols Y and Z independently of each other always mean 1. an aryl group with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, 2. a residue as defined under point 1/, which is substituted by 1,2, 3, 4 or 5 identical or different residues selected from the group consisting of alkyl groups with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, aryl groups of 6, 7, 8, 9, 10, 11, 12, 1.3 or 14 carbon atoms, fluorine, chlorine, bromine and iodine atoms, a trifluoromethyl group, SO _q R ¹⁸ , OR ¹⁶ , NR ¹⁹ R ²⁰ groups, cyano group, nitro group and CO-R ⁹ groups, or on which two radicals together form an fused heterocyclyl radical, ,. 3. a heteroaryl group with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, 4. - a residue defined under point 3·., which is. substituted by 1, 2 or. '3 identical or different residues selected from the group comprising fluorine, chlorine, bromine and iodine atoms,, trifluoromethyl group, methyl group; methoxy group, hydroxy group ..and groups ·' MR ^:: R ^: \ 5.. cycloalkyl group; with 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, - / , 6. : a residue, as defined in point '5., substituted by an aryl group with 6, 7,-8, 9·, 10, 11, 12; 13 or. 14 3. carbon torns, 7th group O-Ø ¹⁴ , / - 8th group OR ¹⁷ , , 9. group -SO ₂ -R ¹⁴ ,/ 10. an arylalkylcarbonyl group, or 11. a heterocyclyl group, · the symbols R ¹⁴ and R ¹⁷ independently of each other always represent 1. hydrogen atom, 2. an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 atoms - 109 • · carbon, 3. an alkenyl group with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12' carbon atoms,. 4. the group -C _n H _2n _ _nr) -phenyl, where nn has the value 0 or 2, and . n- has the value 0, 1, 2, 3 or 4, where n does not have the value 0 or 1 if nn has the value 2, or 5. a residue as defined under point 4., in which the phenyl part is substituted by 1, 2 or 3. identical or different residues selected from the group consisting of alkyl groups - with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, fluorine, chlorine, bromine and iodine atoms, trifluoroethyl group, SO _q R ¹⁵ , -OR ¹⁶ , ^: NR ⁿ R ¹² , cyano group, nitro group and CO-R ⁹ groups, the symbols R ¹⁵ and R ¹⁸ independently of each other each represent an alkyl group with 1, 2, 3 or 4 carbon atoms, alkyl - ·. group -with 1, 2, .3 or 4 . carbon atoms, in which one to. all. hydrogen atoms are replaced by fluorine atoms, or the group NR ¹¹ R ¹² , R ¹⁶ - means 1. hydrogen atom, 'j ¹ 2. an alkyl group with 1, 2, 3 or 4 carbon atoms, . · 3. an alkyl group having 1, 2, 3 or 4 carbon atoms substituted with an alkoxy group having 1 to 4 carbon atoms, 4. an alkyl group with 1, 2, 3 or 4 carbon atoms in which one or all of the hydrogen atoms are replaced by fluorine atoms, .·'·.·5. an aryl group with 6, 7, 8, 9, 10, 11, 12, 13 or 14 .carbon atoms, or ' 6. a radical defined under point 5., which is .substituted-·. by Ί, ^: 2 or 3 identical or., different radicals .selected from the group comprising fluorine,.chlorine, bromine . and iodine atoms, trifluoromethyl group, . groups NR ¹⁹ R ²⁰ ., cyano group and nitro group, symbols R ²² and R ²³ independently, each represent an atom 110 hydrogen or the group CO-OR ²⁴ , R ²⁴ represents a hydrogen atom, an alkyl group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or a group -C _n H _2n -phenyl, where n has the value 1, 2, 3 or 4, and q has independently the value 0, 1 or 2, as well as physiologically acceptable salts thereof. 2. Biphenylsulfonylcyanamides of general formula I according to claim 1, wherein R ¹ represents 1. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, ' 2, an alkyl group with, 1,. 2., 3, 4 or 5 carbon atoms, in which one to. all hydrogen atoms are replaced by fluorine atoms, 7 n / an alkenyl group with 2, 3, 4, 5, 6, 7, 8, 9, 10, or. 12 carbon atoms, the group ~C _n H _2n _ _nn -Y, where has the value. 0 or. 2, and has the value Ό, 71, 2, 3 or 4, where n has no - the value 0. or 1 if nn has the value 2, or', the group -Y, where . - 7 . has the value 0 or 2, and has the value 1, 2, 3 or 4, with n having no value 1 if nn. has the value 2, which are 1,.. 2 or- 3 hydrogen atoms in the divalent replaced by the remainder ⁹ 9, 10, .11, 12, 13 3. 11 4 . n n n 5. n n n in the rest -CH, - independently of the nozzle - ² n .2n-nn.. τττ τΉ r* o rt Xrm o eVnní τί τ z τ o Η vn τ ii τ r< i v ý jOi. Cl ii ý íu z_. O iii-iiy 1. aryl groups -with 6, 7, 8, _: or, 14 carbon atoms, ' 2. amino group, 3. Groups NR ²² R ²³ , and 4..Alkoxycarbonyl groups, -5. 'group COOR ¹⁶ , 6. alkyl groups with . 1, 2, 3 or 4 atoms 111 7. arylalkylcarbonyl groups with 6 to 14 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl portion, R ² means . 1. hydrogen atom, 2. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, 3. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, 4. 'alkenyl group with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, 5. an alkynyl group with 2, 3, 4 or 5 carbon atoms, 6. group ^- C _n H _2n _ _nn -Z, where nn has the value 0 or 2, and an . has the value 0, 1, 2, 3 or 4, with' n not having the value 0 or L if nn has the value 2, or · ·. · 7. group''-C _n H _2n ". _in -Z, where nn ’ has value 0. or 2, and n has .value 1, 2, 3 or 4, with n having no value 1 if n.n. has-value 2, . ' . in which are 1, 2 or 3 hydrogen atoms, in a divalent the residue -C _n H _2n j _nn - ' .independently of each other . replaced by a residue selected from the group consisting of < . ' . ' . 1., aryl groups with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atomsj ' , 2. amino group, . ; ' 3rd group NR ²² R ²³ ,, .'. / 4. alkoxycarbonyl groups with 1 to 4 carbon atoms; in the alkoxy moiety, 5. groups COOR', a'. ... 6. alkyl groups with 1, 2, 3 or 4' . atoms , · .. carbon, > the symbols R ³ and R ⁴ independently of each other. represent- each .hydrogen atom or an alkyl group.with 1,- 2, 3 or .4 carbon atoms, ·. .< • 9 - 112 symbols R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, a fluorine, chlorine or bromine atom, a trifluoromethyl group, a cyano group, a SO-R ⁸ , CO-R ²¹ group or STEED R' represents an alkyl group with 1, 2, 3 or 4 carbon atoms, a group NR ⁿ R ¹² or a phenyl group which is unsubstituted or substituted by 1 or 2 identical or different radicals selected from the group comprising fluorine, chlorine and bromine atoms, trifluoromethyl group, methyl group, methoxy group, hydroxy group and groups NR ^U R ¹² , the symbols R ⁹ and R ²¹ independently of each other each represent a hydrogen atom, an alkyl group with 1,2, 3 or. 4 carbon atoms or the group OR ¹³ , ¹⁰ represents a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, which is - optionally substituted \ by an alkoxy group with · 1 to 4 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1 or 2 identical 'or different radicals selected from the group comprising' fluorine, chlorine and bromine atoms, a trifluoromethyl group, a methyl group, . · a methoxy group, a hydroxy group and., groups NR ⁿ R ¹² , ·' the symbols R ^u , R ¹² , R ¹⁹ and R ²⁰ independently of each other. each represent a hydrogen atom, an alkyl group, with 1,. 2, 3 or 4 carbon atoms or an alkanoyl- group with 1 to 4 carbon atoms, R ¹³ represents a hydrogen atom- or an alkyl group -s , 1.,. 2, 3 or 4 carbon atoms,· · . X represents a carbonyl group, -CO-.NH-, -CO-CO-, or a sulfonyl group. the symbols Y and Z independently of each other mean. each . . ' . 1. a phenyl, 1-naphthyl or 2-naphthyl group, '2. a residue as defined under point 1., which is substituted 1,. 2, 3, 4 or 5 with identical or different residues selected from the group consisting of. alkyl groups with 1, -·· - 113 .2, 3 or 4 .carbon atoms, phenyl, 1-naphthyl and 2-naphthyl group, fluorine, chlorine and bromine atoms, trifluoromethyl group, SO _q R ¹⁸ , OR ¹⁶ , NR ¹⁹ R ²⁰ groups, cyano group and CO-R ^{5 * * * 9 *} groups, or on which two 'residues together form an fused heterocyclyl residue,· 3,. heteroaryl group with 1, 2, 3, 4, 5, 6, 7., 8 or ^Λ 9 carbon atoms, 4. a radical as defined in point 3., which is substituted by 1 or 2 identical or different radicals selected from the group consisting of fluorine, chlorine and bromine atoms, a trifluoromethyl group, a methyl group, a methoxy group, a hydroxy group and the groups NR ^U R ¹² , / 5. a cycloalkyl group with 3, 4, 5, 6, 7, 8, 9- or . 10 carbon atoms', - . · 6. residue/ defined under point 5., substituted. • . phenyl, 1-naphthyl or 2-naphthyl group,... ,7·.· group OR ¹⁴ ., '' ,8. group OR ¹⁷ ·, .. 9. a group -SO..-R ¹⁴ , ' .10. an arylalkylcarbonyl group, or ' 11. a heterocyclyl group, the symbols R ¹⁴ and R ¹⁷ independently of each other always represent ^; 1. hydrogen atom, ' ^f ' 2. alkyl group with 1, 2, 3 or 4 carbon atoms, 3. alkenyl group . sě 2, 3, . 4, 5 or 6 . atoms carbon, - · 4 . o 1/11 r> ΐ rm —V ¹ U _-F q η τ ; 1 Lr Ω SKclP-uxiua ^ _n ^xx 2n-nn ΚναΘ · nn has a value of 0 or 2, and n has the value, 0, 1, 2, 3 or 4, while, n . has no value 0 or 1 if nn has the value 2, ..or 5. a residue 'defined' under point 4., in which the phenyl part is substituted by 1, 2 or 3 identical or r · ¹ different residues selected from the group consisting of alkyl groups, with 1, 2, 3 or 4 carbon atoms, fluorine, chlorine », and bromine atoms, trifluoromethyl group, «9 99 I 9 9 » 9 ·9 - 114 •· 9 groups SO _q R ¹⁵ , OR ¹⁶ , NR ⁿ R ¹² , cyano group ' and groups CO-R ⁹ , the symbols R ¹⁵ and R ¹⁸ independently of each other always represent an alkyl group with 1, 2, . 3 or 4 carbon atoms, an alkyl ' group with 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, or the group NR ^:: R' ² , R ¹⁶ means , ' 1. hydrogen atom,. 2. an alkyl group with 1, 2, 3 or 4 carbon atoms, 3. an alkyl group with 1, 2, 3, or 4 carbon atoms substituted with an alkoxy group with 1 to 4 carbon atoms, 4. an alkyl group with 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine atoms, ' . . 5. a ferri.yl, l-naphthyl. or . 2-naphthyl group, or ·. . . Λ · . ' - ? .. 6. a residue defined under point 5., which is substituted by 1, 2 or 3 identical or different residues selected from the group consisting of fluorine, chlorine and bromine atoms, a trifluoromethyl group, NR ¹⁹ R ²⁰ groups and a cyano group, . the symbols R ²² and R ²³ independently of each other represent, in each case, a hydrogen atom or a group CC—OR ²⁴ , R ²⁴ represents a hydrogen atom, an alkyl group with 1, 2, 3, or 4 carbon atoms, or a group -C _n H _2n ~phenyl, where n has the value 1, 2 or 3, and q has independently the value 0, 1 or 2, as well as physiologically acceptable salts thereof. 3... Biphenylsulfonylcyanamides of general formula I according to claim 1 or/and 2, wherein . R ¹ represents _t 1. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, • 2. an alkenyl group with 2, 3 or 4 carbon atoms, i 44 ·· > »4 < 3. Y ηη η 4. Y - 115 group -C _n H _2n _ _nn -Y, where it represents 1. phenyl group,. 2. the remainder defined under point 1., which is. ^substituted by 1, 2, 3, 4 or 5 identical or different radicals selected from the group consisting of alkyl groups with 1, 2, carbon atoms, fluorine atoms, chlorine atoms, cyano groups, trifluoromethyl groups, 3 or 4 and bromine,, group, hydroxy group, nitro group, 'SO ₂ R ¹⁸ , . OR ^1S , SCF ₃ , NR ¹⁹ R ²⁰ and CO-R ⁹ , , 3rd group OR ¹⁴ ,.. 4. group SC,-R' ⁴ , 5. 1-naphthyl or 2-naphthyl group, 6. a residue defined under point 5., which is substituted by a residue selected from the group consisting of -alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, a trifluoromethyl group and the groups SO ₂ R ¹⁸ , OR ¹⁶ , NR ¹⁹ R ²⁰ and . CO-R ⁹ , 7. heteroaryl group.with 1, 2, 3; 4, 5, 6, 7, 8 or 9 carbon atoms, 8. a residue .'defined under point . 7., - which :is substituted by a residue selected -from the group consisting of fluorine and chlorine atoms, a trifluoromethyl. group, a methyl group, - .methoxy group.! and a dimethylamino group, or . . ·, · .· - . ' ----------atcmv 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 of . 2, or the group -C _n H _2n _ _nn -Y, where e represents 1. phenyl group, Q Γ’χζίτΐ γίλ 1 mrmi «Vnninii 6 or 7 pncemz n. has 2nd group OR , or • · • · ·· ·· »· » 9 9 « » · ·· ·· ·· • · · 9 9 9 9 9 9.9 9 · · - 116 n n 3. a heteroaryl group, has the value 0 or 2, and , has the value 1, 2 or 3, wherein n does not have the value 1 if nn has the value 2, in which 1, 2 or '3 hydrogen atoms in the divalent radical ~C _n H _2n _ _nn - are independently replaced by a radical selected from the group consisting of 1.,aryl groups.with 6, 7, 8, 9, 10, 1-1, 12,: 13 or 14 carbon atoms, 2. amino group, 3. groups NR ²² R ²³ , 4. alkyl groups . with 1 , 2, . : carbon, means 1. hydrogen atom, , ’ 2·· alkyl group with 1, 2, ³ >. 4 or. 3 . an alkyl group with 1, 2, 3, 4-. or in, which are one to all atoms fluorine atoms, 4. an alkenyl group with 2, 3, 4, 5, 10 Carbon atoms, '5. an alkynyl group with 2, 3, 4 or 6. the group -C _n H _2n _ _nn -Z, where From represents .. 1. phenyl group,' 3 or 4 atoms 9 or 2. the remainder' defined under point 1., which is Si η Ο+·τ·Ηη/^ττόη 1 O r\ QO h Q ^- ' ? rm τ τ“\ Vs »7 <1 ί 1 n Srm τ LXXJ O l__LLUOV CUl Λ- f 2- O >— J ii % lil _U iiCU.U i. U V-Á-L J- ii J/ ULL residues selected from the group consisting of alkyl groups with 1, _: 2, 3 or 4 atoms, carbon, phenyl group,' fluorine, chlorine and bromine atoms, trifluoromethyl group, SO ₂ R ¹⁸ groups, OR ¹⁶ , nitro group, cyano group and NR ¹⁹ R ²⁰ and CO-R ⁹ groups, or on which · two. residues together form a methylenedioxy group, '' 3'. 1-naphthyl or 2-naphthyl group, ~ 'ŮOŮ27.7-; :/-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 00 - 117 4. a residue defined under point 3., which is substituted by a residue selected from the group comprising alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl group, SO ₂ R ¹⁸ , OR ¹⁶ , nitro group, cyano group and NR ¹⁹ R ²⁰ and CO-R ⁹ groups, 5. a heteroaryl group with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, ¹ ..- + 6.. a residue defined under point 5., which is substituted by a residue selected from the group consisting of fluorine and chlorine atoms, -trifluoromethyl group, methyl group, methoxy group, hydroxy group and dimethylamino group, 7. a cycloalkyl group with 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, or 8. -a residue, -defined under point 7., which is ----- . substituted by a .phenyl group, nn has the value 0 or 2., and . n has the value 0, 1, 2 or 3, with n having no value 0 or 1 if nn has the value 2, 7. the group -C„H......,,-Z, where Z represents. 1. a phenyl group, or 2 - a residue as defined in point 1, which is substituted by 1, 2 or 3 identical or different residues selected from the group consisting of alkyl Γ' Iri i τ » 7 O O νΛ b". s. /1 -"v 4" τ τ i 1". Ί i 1 »· ·» -. £7 _ — ...... o. x _r . x , o · nexu ί aukjiiiy iun.xjs.iij iSuyiuVOu group, fluorine chlorine atoms, trifluoromethyl (, group, SO ₂ R ¹⁸ , OR ¹⁶ , nitro group, cyano group and NR ¹⁹ R ²⁰ groups a. CO-R ⁹ , ' ( nn '-· has the value 0 or 2, and . , n . / has the value 1, 2 or .3, with n not having the value 1 if nn has. the value 2, in which, there are 1, 2 or 3 hydrogen atoms in the divalent ,1: - 118 of the residue -C _n H _2n _ _nn - independently replaced by a residue selected from the group consisting of 1. alkoxycarbonyl groups, with 1 to 4 carbon atoms in the alkoxy moiety, 2nd group COOR ¹ 3. alkyl groups with carbon, or '· the group -C _n H _2n -OR ¹⁷ ,· where has the value 0, 1, 2 or 3, 3 or 4 atoms 1, the symbols R ³ and R ⁴ each represent a hydrogen atom or a methyl group, the symbols R ⁵ , R ⁶ and R ⁷ independently of each other . each represent a hydrogen atom, an alkyl group with 1, 2, 3' or 4 carbon atoms, a fluorine atom. . or <chlorine atom, a trifluoromethyl .. group, a cyano group, a SO ₂ -R ⁸ , CO-R ²¹ or OR ¹⁰ group, R ⁸ represents an alkyl group having 1, 2, 3 or 4 carbon atoms, a dimethylamino group or a phenyl group which is unsubstituted or substituted by a radical selected from the group consisting of fluorine and chlorine atoms. , , trifluoromethyl group, methyl group, methoxy group, hydroxy group and dimethylamino group, the symbols R ⁹ 'and . R ²¹ independently of each other always represent a hydrogen atom, a methyl group or a group OR ¹³ , .1 ¹⁰ means a hydrogen atom, an alkyl group with 1, 2, 3 or 4/ carbon atoms,., ..which . is optionally substituted by an alkoxy group with 1 to 4 carbon atoms, -or a phenyl group which is unsubstituted or substituted ^Rn and ^R12 are each independently a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms or an alkanoyl group with 1 to 4 carbon atoms, R ¹³ represents a hydrogen atom or an alkyl group with 1, 2, 3 or 4 carbon atoms, • · 119 X - represents a carbonyl group, a -CO-CO-, -NH-CHO- or a sulfonyl group, R ¹⁴ represents 1. hydrogen atom, 2. an alkyl group with 1, 2, 3 or 4 carbon atoms, 3. an alkenyl group with 2, 3, 4, 5 or 6 carbon atoms, 4. the group -C _n íí _2n _ _nn -phenyl, where nn has the value 0 or 2, and n has the value 0, 1, 2, 3 or 4, with n not having the value 0 or 1 if nn has the value 2, or 5. a residue as defined under point 4., in which - the phenyl part is substituted, 1, 2 or _: 3. with the same' or ' - different residues selected ·- from the group consisting of 1 alkyl groups with 1, 2, 3 or '4 carbon atoms, fluorine, chlorine and bromine atoms, trifluoromethyl group, : groups. . SO_R ¹⁵ , OR. ^fe , .NR ^U R ¹² ,. cyano group and- -groups CO-R ⁹ , R ¹⁵ ' means an alkyl group with 1, 2, 3 or 4 carbon atoms or a dimethylamino group, R ¹⁶ , ; means , ·.. · i . hydrogen atom, '', , 2. alkyl, a group with 1, 2, 3 or 4 carbon atoms,. ^{6 * * * *} 3. an alkyl group with 1, 2, 3 or 4 carbon atoms substituted by an alkoxy group with 1 to 4 carbon atoms, 6. a residue defined ..under point 5., which is substituted by 1, · 2 or 3 identical or different residues selected from the group consisting of fluorine, chlorine and bromine atoms, a trifluoromethyl group, . groups NR ¹⁹ R ²⁰ . and a cyano group, , • · • ·· ·· ·« • · · · - · · · · · • · · · . ·· · - 120 R ¹⁷ represents 1. hydrogen atom, 2. an alkyl group with 1, 2, 3 or 4 carbon atoms, 3. an alkenyl group with 2, 3 or 4 carbon atoms, 4. the group -C _n H _2n _ _nn -phenyl, where nn has the value .0 or 2, and n has the value 0, 1/2, 3 or 4, with n not having the value 0 or 1 if nn has the value .2, or 5/ a residue as defined under point 4, in which the phenyl part is substituted by a residue selected from the group consisting of alkyl groups with -1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, trifluoromethyl group, SO _q R ¹⁵ -, OR ¹⁶ , NR ^U R ¹² -, cyano group and CO-R ⁹ - groups. R ¹⁸ represents an alkyl group with 1, 2, 3 or 4 carbon atoms, an alkyl group with 1, 2, 3 or 4 carbon atoms in which one or all of the hydrogen atoms are replaced by fluorine atoms, or the group NR ^U R ¹² , the symbols R ¹ independently of each other always represent an atom .... , . hydrogen, an alkyl group with 1, 2, 3 or 4 carbon atoms or an alkanoyl group with 1 to 4 carbon atoms, the symbols , R ²² , and R ²³ independently . of each other. represent , in each case a hydrogen atom, or the group CQ-OR ²⁴ , , R ²⁴ represents a hydrogen atom, an alkyl group with 1, 2, 3 or 4 carbon atoms, or a group -C..H.. _n -phenyl, where n. has . . ; the value of 1 or 2, and . q has an independent value of 0, i or 2, as well as physiologically acceptable salts thereof. . ’. 4. Biphenylsulfonyl cyanamides of the general formula I according to one or more of claims 1 to 3, wherein R ^{1 1} 'represents 7 . 1. an alkyl group with 1, 2, 3, 4 or 5 carbon atoms, 2. an alkenyl group with 2, 3 or 4 carbon atoms, 3rd group ~C _n H _2n _ _nn ~Y, where [ - , č - -- -121 ϊ·. ¢. Y represents 1. phenyl group, 2. a residue as defined under point 1., which is substituted by 1, 2, 3, 4 or 5 identical or different residues selected from the group consisting of alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine, chlorine and bromine atoms, cyano group, trifluoromethyl group, hydroxy group, nitro group, SQ groups₂R¹⁸, .OCH₃, OCF₃, ' SCF₃, N(CH ₃ ) ₂ , NH-CO-CH ₃ , CO-R ⁹ , phenoxy and phenoxy groups substituted once or more by » ¹ halogen, . 3- group OR ¹⁴ , or 4. the group SO ₂ ~R ¹⁴ , nn has the value 0 or 2, and n·' has the value Ό, 1, 2, 3 or' 4, where n does not have . ..the value 0. or. ;.l if, nn has the value 2, or < 4. group -C _n H _2n _ _nn -Y, where Y represents 1. phenyl group., 2. a group OR ¹⁴ , or '3. a heteroaryl group, preferably a thienyl group, 'nn has the value 0 or 2, and . < has the value. 1, 2 or 3, where n does not have the value 1 if nn .has. the value 2, . ’ j ' . in which is the sky CL C CJILLy \ Ί Ί TT «Λ ΤΛ Z' ΤΊΠ in aZíiciLt residue ^- C _n H _2n _ _nn - independently of each other 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 or a phenylacetyl group 2. amino group, , 3. groups ŇR ²² R ²³ ,' and ' 4. alkyl groups with ’ 1 > 2, 3 or 4 carbon atoms, , · · · · · · · · · · • · · · · « · · • · ·· · 122 5. the group -C _n H _2n -Y, where. Y represents , 1. 1-naphthyl or 2-naphthyl group, 2. a residue defined under point 1., which is substituted by a residue selected from the group comprising alkyl groups with 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, a trifluoromethyl group and the groups SO ₂ R ¹⁸ , OCH ₃ , N(CH ₃ ) ₂ and CO-R ⁹ , 3. - heteroaryl group with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably a thienyl, benzothiophenyl, indolyl or furyl group, 4. a radical as defined in point 3., which is substituted by a radical selected from the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group and a dimethylamino group, or a cycloalkyl group having 3, 4, 5, 6 or ¹⁷ carbon atoms, and n is 0, 1, 2, 3 or 4, or . . '; 6. the group -C _n H.,„-OR ^: where n has the value 0, 1 or 2, . R ² means ' , · 1. an alkyl group with 1, . 2, 3, . 4 or 5 carbon atoms, 2. ‘an alkyl group with 1, 2, 3, 4 or 5 carbon atoms,’ in which one to all of the hydrogen atoms are replaced by a 3. alkenyl' group with 2, 3,4,5,6, 7, 8, 9 or 10 carbon atoms, 4 . alkynyl group.se 2, ' 3, 4 or 5 carbon atoms, 5. of the group -C _n H _2n . _nn -Z, where From represents ·* . 1.. a phenyl group, 2. a defined residue. under point 1., which is , , substituted by 1, 2 or 3 of a kind or different • · - 123 residues selected from the group consisting of alkyl groups with 1, 2, 3 or 4 carbon atoms, phenyl group, fluorine, chlorine and bromine atoms, trifluoromethyl group, SO ₂ R ¹⁸ groups, -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy group, hydroxy group, nitro group, cyano group, N(CH ₃ ) ₂ groups, -NH-CO-CH ₃ , CO-R ⁹ , phenoxy group and phenoxy groups substituted once or more by halogen, or on which two residues together form a 'methylenedioxy group, nn . has the value 0 or 2, and . . n has the value 0, 1, 2’or 3, with n having no value 0 or 1 if nn has the value 2, .. 6. group ~C _n H _2n _ _nn -Z, where . Z represents i. .phenyl group, or . .2 .. -. residue: def inovahý . under ..point - 1., which , is substituted by 1, 2 or 3 identical.or. different residues selected from the group comprising alkyl groups with 1, 2, 3 or 4 carbon atoms, phenyl group, .atoms . fluorine and chlorine, trifluoromethyl'' group, , groups. SO ₂ R ¹⁸ , -OCH ₃ , -O (C ₂ H ₄ ) OCH ₃ , ethoxy group, hydroxy group, nitro group, cyano group,. groups Ç(.CH ₃ ) ₂ and CO-Ø ⁹ , , - . Π · rvs —i h /Λ z~J r i i lUO likJ UliU ΛΧ - . if nn has In which j is 1, nn has the value 0. or 2, and TO r> z“\ z“\ J »»» ·, z^ λ η X - 1«. zJ ·»". z·. X » * Π xr ncbu sj _r pxxtídLiZ ii iicma uuuuuuu x value 2, . 2 or 3 hydrogen atoms in the divalent radical,, _π - independently of each other replaced by a radical selected from the group consisting of; ' 1-alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy moiety, 2.. groups, COOR ¹⁶ , and. 3. alkyl groups with- 1, 2, 3 or. 4 atoms - 124 - carbon, 7. group -C _n H _2n -Z, where Z represents 1. 1-naphthyl or 2-naphthyl group, 2. a residue as defined in point 1., which is substituted by a residue selected from the group consisting of alkyl groups of 1, 2, 3 or 4 carbon atoms, fluorine and chlorine atoms, trifluoromethyl group, SO ₂ R ¹⁸ groups, O'CH ₃ , -O (C ₂ H ₄ )OCH ₃ , ethoxy group, hydroxy group, nitro group, cyano group, N(CH ₃ ) ₂ groups, -NHCOCH ₃ and CO-R ⁹ , 3. a heteroaryl group with 1, 2,.3, 4, 5, 6, 7, 8 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]...furanyl, and quinazolinyl, for example 3,4-dihydroquinazolinyl, groups, - . 4. a residue . defined under point 3., which, is substituted by a residue ...selected from the group consisting of fluorine and chlorine atoms, trifluoromethyl - '' group, '' methyl group, methoxy group, .hydroxy group and dimethylamino group, . . 5. a cycloalkyl group with 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably a cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or indanyl group, or 6. a residue as defined in point 5, which is substituted by a phenyl group, preferably a phenylcyclopentyl group, and n has the value 0, 1, 2 or 3, or 8. the group -C _n H _2n -OR ^1,7 , where , , n has the value 2 or 3, the symbols R ³ and R ⁴ always represent a hydrogen atom, - 125 - 9' · the symbols R ⁵ , R ⁶ and R ⁷ independently of each other always represent a hydrogen atom, an alkyl group with 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 represents a methyl group or a dimethylamino group, the symbols R ⁹ and R ²¹ independently of each other each represent a hydrogen atom, a methyl group or a group 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 residue selected from the group consisting of fluorine and chlorine atoms, a trifluoromethyl group, a methyl group, a methoxy group and a dimethylamino group, R ¹³ represents a hydrogen atom or an alkyl group with 1/ 2, 3. or 4 carbon atoms, X represents a'carbonyl group,. ' -group. —CO-CO--, -NH-CO-. or a sulfonyl group, R ¹⁴ represents 1. atom. of hydrogen., ' . ... 2. a methyl or ethyl group,· . 3. an alkenyl ¹ group with 2, 3, 4,·. 5 or· 6 atoms. • carbon, preferably an allyl group, 4. the group -C _n H. _;n ~ phenyl, where n. has. value 0 or 1, 5. a residue defined under point 4., in which the phenyl part is substituted by a residue selected from the group consisting of an alkyl group with carbon, fluorine and chlorine atoms, >15' of, j neoo.+ atoms, a trifluoromethyl group, the groups SO ₂ R ¹⁵ , OCH ₃ , N(CH ₃ ) ₂ and CO-R ⁹ , or 6. an alkenyl group with 2, 3 or 4 carbon atoms, R ¹⁰ represents a methyl group or a dimethylamino group, ^R1fa represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms. R ¹⁷ represents· . 1. a hydrogen atom, 126 2. methyl group, 3. the group -C _n H _2n -phenyl, where n has the value 0 or 1, '4. the residue defined under point 3., in which' the phenyl part is substituted by a residue selected from the group comprising alkyl groups with 1, 2, 3 or 4 carbon atoms, . fluorine and chlorine atoms, -trifluoromethyl group, groups SO ₂ R ¹⁵ , -OCH ₃ , N(CH ₃ ) ₂ and CO-R ⁹ , or 5.. an alkenyl group with 2, 3 or 4 carbon atoms,. R ²² and R ²³ independently of each other each represent ^a hydrogen atom or a CO-OR ²⁴ group, and R ²⁴ represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, or a -C _n 1 n _{2 n} -phenyl group, where n has the value 1 or 2, as well as physiologically acceptable salts thereof. 5. Biphenylsulfonylcyanamides of the general formula I according to one or more of claims 1 to 4, which correspond to the general formula _ lá · ' .. . v ' in which the radicals X- and R ¹ . to R ⁷ have the meanings defined in claims 1 to 4, as well as their physiologically acceptable salts. - , ''' - · ' * , . 6. Biphenylsulfonylcyanamides of the general formula I- according to one or more of claims 1 to 5 or/and their physiologically acceptable salts for use as a medicament. ·· · • · ·· • · · • Φ ·· ► · · « • · · « - 127 7. A pharmaceutical composition, characterized in that it contains an effective amount of biphenylsulfonylcyanamide of the general formula I according to one or more of claims 1 to 5 and/or a physiologically acceptable salt thereof. 8. Pharmaceutical composition according to claim 7, characterized in that it further contains an effective amount of an inhibitor of the sodium/hydrogen exchange system or/and an active substance from another group of substances acting on the heart and blood circulation or/and their physiologically acceptable salts. ,9. Biphenylsulfonyl cyanamides of the general formula .1 according to one or more of claims 1 to 5 or/and their physiologically acceptable salts for use as inhibitors of the Na ⁺ -dependent bicarbonate/chloride exchange system. ' . - 10 Biphenyl sulionyl cyanamides of the general formula I-·caccording to one or more of claims. 1 to 5. or/and their physiologically acceptable salts for use for . therapy or/and. prophylaxis of heart infarction, . angina pectoris,' diseases caused by ischemic conditions,, impaired respiratory stimulation, ischemic conditions, heart, ischemic, conditions of the peripheral and central 'nervous system, and apoplexy, ischemic conditions of peripheral organs/, and limbs., diseases whose primary or secondary cause is cellular, proliferative, or. for the treatment of shock conditions, or for use in surgical operations and organ transplantations, or for the preservation and storage of transplants for surgical procedures. 11. 'Biphenylsulfonylcyanamides of the general formula . I. according to . one or . more of claims 1 ' to 5 or/and · their physiologically acceptable . . salts for use in the therapy or./and . prophylaxis of cancer. 12. Pharmaceutical composition according to claim 7 or/and 8 rg—-rt:. - 128 - ·· φφ • · • φφ • · . φ · φφ ·· φφ φφ φ · · » φ φ φ φ • · © β • Φ · · ΦΦΦ for use in the therapy or/and 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, ischemic conditions of peripheral organs and limbs, diseases whose primary or secondary cause is . cell proliferation, or . for the treatment of . shock conditions/ or for use in surgical operations and organ transplantations, or for the preservation and storage of transplants for surgical procedures. - 13. Pharmaceutical composition according to claim 7 or/and 8 for use in the therapy or/and prophylaxis of cancer.