SK4382002A3 - 2'-substituted 1,1'-biphenyl-2-carbonamides, method for the production thereof, use thereof as a medicament and pharmaceutical preparations containing said compounds - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31) have the meanings cited in the Claims and are especially suitable as novel antiarrhythmic active agents, in particular for the treatment and prophylaxis of atrial arrhythmia, e.g. atrial fibrillations (AF) or atrial flutter.

Description

The invention relates to compounds of formula I

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ³⁰ and R ³¹ have the meanings given below, the preparations and uses of these compounds, particularly in pharmaceuticals.

BACKGROUND OF THE INVENTION

The compounds of the present invention have not been known hitherto. These compounds act on so-called. The Kv1.5-potassium channel and in the atrium of the human heart inhibit the flow of potassium ions, termed ultra-rapidly activating delayed rectifier. They are therefore particularly suitable as novel antiarrhythmic agents, particularly for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (atrial fibrillation, AF) or atrial flutter (atrial flutter). Atrial fibrillation (AF) and atrial flutter are the most common permanent cardiac arrhythmias. Their incidence increases with age and often has fatal outcomes, such as stroke.

Atrial fibrillation affects approximately 1 million

Americans annually and in the US lead to more than 80,000 cases of stroke each year.

Current class I and III antiarrhythmic drugs reduce the recurrence of AF, but have limited use for their potential proarrhythmic side effects. Therefore, there is a great need to develop better drugs for the treatment of atrial arrhythmias (S. Natell, Am. Heart J. 130, 1995, 1094-1106; "Newer developments in the management of atrial fibrillation").

Most supraventricular arrhythmias have been found to be associated with so-called. “Reentry excitation waves. These occur when the heart tissue has a slow conductivity and at the same time a very short refractory phase. Increasing myocardial refractory time by prolonging potential is a recognized mechanism for ending arrhythmia, respectively. how to prevent it (t. J. Colatsky et al., Drug Dev. Res. 19, 1990, 129-140: "Potassium chanels as targets for antiarrhythmic drug action"). In fact, the length of the action potential is determined by the extent of the repolarizing fluxes of K ⁺ ions that emanate from the cell through different K ⁺ channels. Of particular importance is attributed to a channel called 'delayed rectifier I _K' , which consists of three different components: Ik _r , IK _S and IK _ru .

Most class III antiarrhythmic drugs (e.g., dofetilide, E4031 and d-sotalol) block predominantly or exclusively the rapidly activating IK _f potassium channel, which can be detected in both ventricular and atrial atrial cells. However, these compounds have been shown to exhibit an increased proarrhythmic risk at low or normal heart rates, with particular arrhythmias referred to as "torsades de pointes" (DM Roden, Am. J. Cardiol. 72, 1993, 44B-49B): Current status of class III antiarrhythmic drug therapy). Knowing this high, and in some cases fatal, risk at a lower heart rate, it has been found that the efficacy of IK _r- blockers fails in tachycardia where efficacy would be needed ("negative use-dependence").

While some of these disadvantages it might be possible to overcome the blockage slowly activating components (IK _S), the effectiveness of such blocking agents has not been established because there are no known clinical studies _with channel-blockers IK.

"Especially fast activating and very slowly inactivating component of the channel" delayed rectifier IK _ru (= ultra-rapidly activating delayed rectifier), which corresponds Kvl.5 channel, plays a particularly important role for the repolarization time in the human atrium. Therefore, inhibition of IK _ur- potassium outward current means compared to inhibition of IK _f and resp. IK _{S is a} particularly effective method for prolonging atrial action potential and thus for ending or preventing atrial arrhythmias. According to mathematical models of human action potential should be a positive effect of the blockade of IK _ur particularly pronounced precisely under the pathological conditions of chronic atrial fibrillation (M. Courcemanche, RJ Ramirez, S. Natta Cardiovascular Reasearch 1999, 42, 477-489: "Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model).

In contrast to IK _f and IK _S , which also occur in the human heart chamber, IK _ur plays an important role in the human atrium, but none in the chamber. For this reason, in contrast to IKf or IK _S blockade, the risk of proarrhythmic action is already precluded in inhibiting IK _ur -attack (Z. Wang et al., Circ. Res. 73, 1993, 1061-1076): "sustained Depolarisation" -Induced Outward Current in Human Atrial Myocytes; G. - R. Li et al., Circ. Res. 78, 1996, 689-696: "Evidence for Two Components of Delayed Rectifier K ^{+ -} Current in Human Venticular Myocytes; GJ Amos et al., J. Physiol. 491, 1996, 31-50: “Differences between Outward Currents of Human Atrial and Subepicardial Ventricular Myocytes.

Antiarrhythmic agents acting through selective blockade of the IK _ur or Kv1.5 channel are not yet available on the market. Although many pharmaceutical active substances (such as tedisamil, bupivacaine or sertindole) have been described as having a blocking effect on the Kv1.5 channel, in this case the blocking of Kv1.5 is only a side effect in addition to the other main effects of these substances.

WO 98 04 521 claims aminoindanes as potassium channel blockers that block Kv1.5. WO 98 18 475 and WO 98 18 476 claim the use of various pyridazinones and phosphine oxides as antiarrhythmic agents to act through blockade of IK _ur . However, the same compounds were originally described as immunosuppressants (WO 96 25 936). The compounds disclosed in these patent applications are structurally quite different from the compounds of the present invention.

Recently, it has surprisingly been found that the described 2'-substituted 1,1'-biphenyl-2-carboxamides are potent blockers of the human Kv1.5 channel. and can therefore be used as novel antiarrhythmic agents having a particularly advantageous safety profile. The compounds of the invention are particularly suitable for the treatment of supraventricular arrhythmias, for example fibrillation or atrial flutter.

The compounds of the invention can be used to terminate persistent fibrillation or atrial flutter and restore sinus rhythm (cardioversion). In addition, these compounds reduce the susceptibility to new fibrillations (maintenance of sinus rhythm, prophylaxis).

The compounds of the invention have not been known hitherto. Some structurally related compounds have been described in the literature (Helv. Chim. Acta 1994 (70) 70 and references therein), but the peptide compounds disclosed therein (e.g. Compound A) are not known to block the potassium channel. Moreover, due to the many peptide bonds, such compounds should have too low metabolic stability to be used as antiarrhythmic agents.

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Compound A

Another similar compound (compound B) is disclosed in European patent application EP 0620216. Compound B and all other compounds mentioned in the cited application are characterized in that they have a special substituent in the R (3) position (e.g. benzoyl (1,2,2,4-tetrahydroisoquinoline), which is not included in the compounds of the present patent application. The compounds disclosed in EP 0620216 act as vasopressin antagonists and thus have a completely different biological activity to the Kv1.5 channel blockers described in the present invention.

Compound B

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

(I)

N β

In which:

R ¹ is C (O) OR ⁹ , SO ₂ R ¹⁰ , COR ¹¹ , C (O) NR ¹² R ¹³ or C (S) NR ¹² R ¹³ ;

R ⁹ is C _x H ₂ -R ¹⁴ ;

x is 0, 1, 2, 3 or 4, wherein x cannot be 0 when R ¹⁴ is OR ¹⁵ or SO ₂ Me;

R ¹⁴ is an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F _{5 /} C 3 F 7, CH ₂ F, CHF ₂ , OR ¹⁵ , SO ₂ Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, naphthyl, biphenylyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1, 2 or 3 substituents, selected from: fluorine, chlorine, bromine, iodine, CF ₃ , OCF 3, NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl, containing 1, 2, 3 or 4 carbon atoms; u is 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹⁵ is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, a cycloalkyl group, an iodine atom, CN, a group containing 3, 4, 5 or 6 carbon atoms, a CF 3 group or a phenyl group which is unsubstituted or substituted by 1, 2 or by substituents selected from:

fluorine, chlorine, bromine, CF 3, NO 2,

COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino group, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ;

R ¹³ is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or CF 3;

R ² is H, alkyl having 1, 2, 3 or 4 carbon atoms or CF _3;

R ³ is C _y H _2y -R ¹⁶ ;

y is 0, 1, 2, 3 or 4, wherein y cannot be 0 when R ¹⁶ is OR ¹⁷ or SO ₂ Me;

R ¹⁶ is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF 3, group C2F5 group, C3F7 group, CH 2 F, CHF 2, oR ^17, a group of SO2 Me, phenyl, nafzylová, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, The phenyl, naphthyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH 2, COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy. a group containing 1, 2, 3 or 4 carbon atoms; dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹⁷ is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or a 4-pyridyl group, wherein the phenyl group is 2-, 3- or

The 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO; CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R ³ is CHR ¹⁸ R ¹⁹ ;

R ¹⁸ is a hydrogen atom or a C group _of H ₂ -R ¹⁶ , wherein R ¹⁶ is as previously defined;

z is Ο, 1, 2 or 3;

R ¹⁹ is COOH, CONH 2, CONR ²⁰ R ²¹ , COOR ²² , CH 2 OH;

R ( ²⁰⁾ is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms;

C _in H _{2 in} -CF ₃ or C _w H _2w -phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2 , 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3; w is 0, 1, 2 or 3;

R ²¹ 'is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

R ²² is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms;

R ¹ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms, or a CF ₃ group;

or

R ₃ and R ₄ together form a chain of 4 or 5 methylene groups in which the methylene group may be replaced by -O-, -S-, -NH-, -N (methyl) - or -N (benzyl) -;

R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , NO ₂ , CN, COOMe, CONH 2, COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

R ( ³⁰⁾ , R ( ³¹⁾ independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R ³⁰ , R ³¹ together form a chain of 2 methylene groups;

as well as their pharmaceutically acceptable salts.

Preferred are compounds of formula I in which

R ¹ is C (O) OR ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or C (O) NR ¹² R ¹³ ;

R ⁹ is C _x H ₂ -R ¹⁴ ;

x is 0, 1, 2, 3 or 4;

wherein x cannot be 0 when R ¹⁴ is OR ¹⁵ ;

R ¹⁴ is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , C ₂ F ₅ , OCF ₃ , OR ¹⁵ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, furyl, thienyl group and the nitrogen heteroaromate is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ ,

NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, or 4 atoms carbon, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹⁵ is an alkyl group having 1, 2, 3, 4 or 5 carbon atoms, a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, a C1a group, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, OH, alkyl containing 1, 2 3, 4 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ;

R ¹³ is a hydrogen atom, an alkyl group containing 1, 2, 3 or 4 carbon atoms, or a CF ₃ group;

R ² is H, alkyl having 1, 2, 3 or 4 carbon atoms or CF _3;

R ³ is C _y H ₂ -Y ¹⁶ ;

y is 0, 1, 2, 3 or 4, wherein y cannot be 0 when R ¹⁶ is OR ¹⁷ ;

R ¹⁶ is alkyl having 1, 2, 3 or carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , C2F5, OR ¹⁷ , phenyl a group, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, an alkyl group containing 1, 2, 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group;

R ¹⁷ 'is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or

A 4-pyridyl group, wherein the phenyl group is 2-, 3- or 3-pyridyl;

The 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

or

R ³ is CHR ¹⁸ R ¹⁹ ;

R ¹⁸ is hydrogen or C _of H ₂ -R ¹⁶ , wherein R ¹⁶ is as previously defined;

z is 0, 1, 2 or 3;

'R ¹⁹ ''is CONH ₂ , CONR ²⁰ R ²¹ , COOR ²² , CH ₂ OH;

R is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms;

C _in H _{2 in} -CF 3 or C _w H _2w -phenyl, wherein the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

R ²¹ is a hydrogen atom or an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms;

R ²² is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms;

R ⁴ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms, or a CF ₃ group;

R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , NO ₂ , CN, COOMe, CONH 2, COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino. group;

R ( ³⁰⁾ and R ( ³¹⁾ independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms;

or

R ³⁰ and R ³¹ together form a chain of 2 methylene groups;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I wherein

is C (O) OR ⁹ , C (O) NR ¹² R ¹³ ; group SO ₂ R ¹⁰ , groups and COR ¹¹ or R ⁹ is C _x H ₂ -R ¹⁴ ; x is 0, 1, 2, 3 or 4. where x cannot be 0, when R ¹⁴ means a group OR ¹⁵ ; R ¹⁴ is a cycloalkyl group containing 8 or 9 carbon atoms, CF ₃ , 3 4 5 group 6, 7, OR ^15,

phenyl, furyl, thienyl or nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine , chlorine, bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ¹⁵ is alkyl. a group containing 1 or 2 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, a CF ₃ group or a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from: fluorine , chlorine, bromine, CF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms , dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ;

R ¹³ is hydrogen;

R ² is H or alkyl having 1, 2, or 3 carbon atoms;

R ³ is CHR ^{1 S} R ¹⁹ ;

R ¹⁸ is hydrogen or C _of H ₂ -R ¹⁶ ;

z is 0, 1, 2 or 3;

R ¹⁹ is CONH 2, CONR ²⁰ R ²¹ , COOR ² or CH 2 OH;

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R‘ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, a group

C _in H _{2 in} -CF ₃ or C 1 H 2 _w -phenyl wherein the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

R ²¹ . is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

R ²² is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms;

R ¹⁶ is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR ⁿ , phenyl, furyl , a thienyl group or a nitrogen heteroaromate having 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, atom bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH 2, COMe, NH ₂ , OH, alkyl containing 1, 2 or 3 carbon atoms, alkoxy containing 2 or 2 atoms carbon, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ¹⁷ is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms,

CF ₃ , phenyl or 2-, 3- or 4-pyridyl, wherein the phenyl or 2-, 3- or 4-pyridyl group may be substituted

The 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , CF ₃ , CN, COOMe, CONH 2, COMe, OH an alkyl group containing 1, 2, 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, a methylsulfonylamino group;

R ⁴ is a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms;

R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH , alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ³⁰ and R ³¹ independently of one another are hydrogen or methyl;

or

R ³⁰ and R ³¹ together form a chain of 2 methylene groups;

as well as their pharmaceutically acceptable salts.

Particularly preferred are also compounds of formula I in which:

R ¹ is C (O) OR ⁹ , SO 2 R ¹⁰ , COR ¹¹ or C (O) NR ¹² R ¹³ ;

R ⁹ is C _x H ₂ -R ¹⁴ ;

x is 0, 1, 2, 3 ^; -or 4 wherein x cannot be 0 when R ¹⁴ is a group OR ¹⁵ ; R ¹⁴ is alkyl a group containing 1, 2, 3 or

carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF 3, OR ¹⁵ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , CN, CN COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ¹⁵ 'is an alkyl group containing 1 or 2 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms;

CF ₃ or phenyl which is unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, bromine, CF ₃ , CN, COOMe, CONH ₂ , COMe, OH, an alkyl group containing 1, 2 or 3 carbon atoms, an alkoxy group containing 1 or 2 carbon atoms, a dimethylamino group, a sulfo-arnoyl group, a methylsulfonyl group, a methylsulfonylamino group;

R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ;

R ¹³ is hydrogen;

R ² is H or alkyl having 1, 2, or 3 carbon atoms;

R ³ is C _y H _2y -R ¹⁶ ;

y is 0, 1, 2, 3 or 4, wherein y cannot be 0 when R ¹⁶ is OR ¹⁷ ;

R ¹⁶ is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR ¹⁷ , phenyl, furyl , a thienyl group or a nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, atom bromine, CF ₃ , OCF ₃ , CN, COOMe,

CONH ₂ , COMe, NH ₂ , OH, alkyl containing 1, 2 or 3 carbon atoms, alkoxy containing 2 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino;

R ¹⁷ is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or

A 4-pyridyl group, wherein the phenyl group is 2-, 3- or 3-pyridyl;

The 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from: fluorine, chlorine, bromine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R ⁴ is a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms;

R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH , an alkyl group containing 1, 2 or 3 carbon atoms, an alkoxy group containing 1 or 2 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group or a methylsulfonylamino group;

R ³⁰ and R ³¹ independently of one another are hydrogen or methyl;

or

R ³⁰ and R ³¹ together form a chain of 2 methylene groups;

as well as their pharmaceutically acceptable salts.

Particularly preferred are compounds of formula I wherein

R ¹ is C (O) OR ⁹ , SO ₂ R ¹⁰ , COR ¹¹ or C (O) NR ¹² R ¹³ ;

R ⁹ is C _x H ₂ -R ¹⁴ ;

x is 0, 1, 2 or 3;

R ¹⁴ is an alkyl group having 1, 2, 3 or 4 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, a CF ₃ group, a phenyl group or a pyridyl group, phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, CF ₃ , OCF ₃ , OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy a group containing 1 or 2 carbon atoms;

R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ;

R ¹³ is hydrogen;

R ² is H;

R ³ is C _y H _2y -R ^16; y is 0, 1 or 2;

R ¹⁶ is an alkyl group having 1, 2 or 3 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, an OF ₃ group, a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, CF ₃ , OCF ₃ , OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;

R ⁴ is hydrogen;

R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, CF ₃ , CH ₃ , COOMe, CONH ₂ , NH ₂ , OH, alkyl containing 1, 2 or 3 carbon atoms or an alkoxy group containing 1 or 2 carbon atoms;

R ³⁰ and R ³¹ independently of one another are hydrogen or methyl;

or

R ³⁰ and R ³¹ together form a chain of 2 methylene groups;

as well as their pharmaceutically acceptable salts.

Very particularly preferred are compounds of formula I wherein

R ¹ is C (O) OR ⁹ or COR ¹¹ ;

R ⁹ is C 11 H _2x -R ¹⁴ ;

x is 0, 1, 2 or 3;

R ¹⁴ is a cycloalkyl group containing 5 or 6 carbon atoms or a phenyl group, wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from: fluorine, chlorine, CF ₃ , OCF ₃ , alkyl containing 1, 2 or 3 carbon atoms and an alkoxy group containing 1 or 2 carbon atoms;

R ¹¹ is defined as R ⁹ ;

R ² is H;

R ³ is C _y H _2y -R ¹⁶ ;

y is 0, 1 or 2;

R ¹⁶ is an alkyl group containing 1, 2 or 3 carbon atoms, a cycloalkyl group containing 5 or 6 carbons, a CF ₃ group, a phenyl group or a pyridyl group, the phenyl and pyridyl groups being unsubstituted or substituted by 1 or 2 substituents , selected from: fluorine, chlorine, CF ₃ , OCF ₃ , alkyl containing 1,

2 or 3 carbon atoms and an alkoxy group which: contains 1 or 2 carbon atoms; R ⁴ is hydrogen; R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, CF ₃ , an alkyl group containing 1, 2 or 3

carbon atoms or an alkoxy group containing 1 or 2 carbon atoms;

R ³⁰ and R ³¹ are hydrogen;

as well as their pharmaceutically acceptable salts.

The alkyl groups and the alkylene groups may be straight-chain or branched. The same applies to the alkylene radicals of the formulas C _x H _2x, C _y H _2y, C _z H _{2z, C} H _2v and C _w H _{2 watts} Alkyl groups and alkylene groups may also be unbranched or branched even when substituted or when contained in other substituents, for example in an alkoxy group or in a fluorinated alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 3,3-dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, or nonadecosyl group. Examples of alkylene groups include divalent groups derived from said alkyl groups such as methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene , 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1, 6-hexylene, etc.

Cycloalkyl groups can also be branched. Exemplary cycloalkyl groups having 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl a group, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl, cycloheptyl, cyclooctyl, etc.

Nitrogen heteroaromatics containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are especially 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl a group, 1-, 3-, 4-or 5-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl or 1,2,3-triazol-5-yl 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl, 1- or 5-tetrazolyl, 2-, 4- or

5-oxazolyl, 3-, 4- or 5-isoxazolyl,

1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl , 1,3,4-oxadiazol-2-yl or 1,3,4-oxadiazol-5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or

5-isothiazolyl, 1,3,4-thiadiazol-2-yl or

1,3.4-Thiadiazol-5-yl

1,2,4-thiadiazol-5-yl 1,2,3-thiadiazol-5-yl

1,2,4-thiadiazol-3-yl 1,2,3-thiadiazol-4-yl or or

2-, 3- or 4-pyridyl group, group, group, group, 2-, 4-, 5- or 6-pyrimidinyl, 3- or

4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-,

5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3- , 4-, 5-, 6-, 7- or. 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7 or 8-quinazolinyl, 3-, 4 -, 5-, 6-, 7- or

8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, or 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Also included are the corresponding n-oxides, such as 1-oxy-2-, 3- or 4-pyridyl.

Particularly preferred nitrogen heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Pyridyl means both 2-, 3- and 4-pyridyl. Thienyl represents both 2- and 3-thienyl. Furyl means both 2- and 3-furyl.

Monosubstituted phenyl groups may be substituted at the 2, 3 or 4 position, disubstituted at the 2,3, 2,4, 2,5,

2,6, 3,4 or 3,5 trisubstituted at 2,3,4, 2,3,5,

2.3.6, 2.4.5, 2.4.6 or 3.4.5. The analogous situation also applies logically to nitrogen heteroaromates or to a thiophene or furyl group.

In the case of two or three times the substitution of a group, the substituents may be the same or different.

When R ³ and R ⁴ together form a chain of 4 or 5 methylene groups, some of which may be replaced by -O-,

-S-, -NH-, etc., then these residues together with the nitrogen atom of formula I form a five or six membered nitrogen heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine, and the like.

When the compounds of formula I contain one or more acidic or basic groups, or one or more basic heterocycles, the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts. Thus, compounds of the formula I which contain acidic groups, for example one or more COOH groups, can be used in the form of their own salts, for example as alkali metal salts, preferably sodium or potassium salts, or as alkaline earth metal salts such as calcium or magnesium salts, or ammonium salts, for example as salts with ammonia or organic amines or amino acids. Compounds of formula I which contain one or more basic, i. protonatable groups or containing one or more basic heterocyclic rings may also be used in the form of their own physiologically acceptable acid salts, with inorganic or organic acids, for example, as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malic acid salts, gluconates, etc. If the molecules of the compounds of the formula I contain both acidic and basic groups at the same time, the invention, in addition to the above-mentioned salt forms, also relates to the internal salts, so-called. betaine. Salts can be prepared from the compounds of formula I by conventional methods, for example by mixing with an acid or base in a solvent or dispersant, or also from other salts by ion exchange.

The compounds of formula (I) may exist in stereoisomeric forms if appropriate substitution occurs. When the compounds of formula I contain one or more asymmetric centers, these centers may independently have the S configuration or the R configuration. The invention relates to all possible stereoisomers, for example enantiomers or diastereomers, as well as mixtures of two or more stereoisomeric forms, for example enantiomers and / or diastereoisomers, in any ratios.

For example, enantiomers are enantiomerically pure forms, both levorotatory and dextrorotatory antipodes, as well as mixtures of both enantiomers in different ratios, or in the form of racemates.

The individual stereoisomers may be prepared, if desired, by resolution of their mixture using conventional methods or, for example, by stereoselective synthesis. In the presence of movable hydrogen atoms, the present invention also includes all tautomeric forms of the compounds of formula I.

The compounds of formula (I) may be prepared by a variety of chemical processes which are also within the scope of the invention. Some typical routes are shown in Reaction Schemes 1, 2, 3 and 4. The substituents R ¹ to R ⁸ used in the schemes are as defined herein, unless otherwise indicated.

For example, the compound of formula (I) according to Scheme 1 is obtained by starting from the diphene formula of anhydride acid derivatives II, which are commercially available or described in the literature. Reduction of compounds II with sodium borohydride and subsequent reaction with potassium phthalimide as described in the literature (Tetrahedron 45 (1989) 1365-1376) affords the biphenylcarboxylic acids of formula IV. Condensation with amines of general formula HNR ³ R ⁴ followed by hydrazinolysis of phthalimide affords aminomethyl compounds of the formula

VI, which by reaction with the appropriate derivative of formula R ³ -X invention compounds of formula I wherein R ² is a hydrogen atom and R ^1,

R ³ ,

R ⁴ , R ⁵ ,

R ^6,.

R '

R ^D are as defined above. Alkylation with suitable alkylating agents of formula RY, wherein Y is a nucleophagic leaving group such as chlorine, bromine or iodine, gives the corresponding compounds of formula I wherein R ⁴ is an alkyl group having 1 to 4 carbon atoms.

Alternatively, biphenylcarboxylic acids of formula IV can be converted by hydrazinolysis to aminocarboxylic acids of formula VII, which are then reacted with an amine group with compounds of formula

R ^x -X and R ² -Y followed by amidation of the carboxylic acid with amines of formula HNR ³ R ^{4 are} converted to compounds of formula I according to the invention (Scheme 2).

In some cases, it may be appropriate to prepare, in accordance with the above methods, the compounds of formula Ia according to the invention (Scheme 3) in which R ^{9 is a} readily cleavable moiety such as a tert-butyl group or a benzyl group. After cleavage of the corresponding protecting group, for example trifluoroacetic acid to Boe or catalytic hydrogenation to a benzylcarbonyl group, compounds of formula IX are obtained which can then be converted into other compounds of formula I according to the invention by reaction with compounds of formula R ^x -X.

Another possibility for the preparation of the compounds of the invention is palladium catalyzed condensation of phenylbromide or iodide of formula X with phenylboronic acid of formula XI (Suzuki coupling; Scheme 4), which can be carried out, for example, in the presence of Pd [(PPh) ₃ ] ₄ as a catalyst. and 1,2-dimethoxyethane as solvent. If R ⁹ is a readily cleavable moiety, such as a tert-butyl or benzyl group, the compounds of formula Ib can then be converted to other compounds of formula I according to the invention, as described also in Scheme 3.

Necessary boronic acids of formula XI can be obtained from compounds of formula XII, wherein Z is hydrogen, bromine or iodine, by ortho-lithiation or by halogen-metal exchange and subsequent reaction with trimethylborate.

The reactions of compounds of formula VI, VII and IX with compounds of formula R ¹ -X correspond to the known conversion of an amine into a carboxamide, sulfonamide, carbamate, urea or thiourea derivative. Substituent X is a suitable nucleophage leaving group such as fluorine, chlorine, bromine, imidazolyl or O-succinimide, etc.

For the preparation of compounds of formula I or VIII wherein R ¹ is C (O) OR ⁹ , i.e. carbamates, for example, compounds of formula R ¹ -X where X is chlorine or O-succinimide, i.e. chloroformates or succinimide carbonates, are used.

For the preparation of compounds of formula I or VIII, where R ¹ is CO ₂ R ¹⁰ , i.e. sulfonamides, compounds of formula R ⁴ -X, where X is a chlorine atom, i.e. sulfonyl chlorides, are generally used.

For the preparation of compounds of formula I or VIII wherein R ¹ is COR ¹¹ , i.e. carboxylic acid amides, for example, compounds of formula R ¹ -X where X is chlorine, imidazolyl or acetoxyl, i.e. carboxylic acid chlorides, imidazolides of carboxylic acids, are used. acids or mixed anhydrides. They can be employed, free acids of formula R ¹ OH in the presence of suitable condensing agents such as carbodiimides or uronium salts such as TOTU.

For the preparation of the compounds I or VIII, wherein R ¹ is CONR ¹² R ¹³ or C (S) NR ¹² R ^13, i.e. ureas or thioureas, instead of the compound of formula R ¹ -X can also be used a compound of formula R ¹² N ( = C = O) or R ¹² N (= C = S), i.e. isocyanates or thioisocyanates.

The above reactions of compounds of formula IV or VIII with amines of formula HNR ³ R ⁴ correspond to the known conversion of carboxylic acid to carboxamide. Many methods are known in the literature for carrying out this reaction. Particular preference is given to reacting by activation of a carboxyl group, for example dicyclohexylcarbodiimide (DCC), optionally by addition of hydroxybenzotriazole (HOBT) or dimethylaminopyridine (DMAP), or O - {[cyano (ethoxycarbonyl) methylene] amino) -1,1,3,3,3 -tetramethyluronium tetrafluoroborate (TOTU). However, it is possible to synthesize reactive acid derivatives, for example acid chlorides, by reacting carboxylic acids of formula IV or VIII with inorganic acid halides such as SOCl ₂ by known methods, or to prepare imidazolides of acids by reaction with carbonyldiimidazole, then reacting them with amines of formula HNR ³ R ⁴ , optionally in the presence of an auxiliary base.

In all of the preparation methods used, it may be appropriate to temporarily protect functional groups in the molecule at certain reaction stages. The technique of protecting groups is common to the skilled person. The selection of a protecting group for a given group and the method for its introduction and cleavage are described in the literature and can be easily applied to a given case.

Scheme 1:

N2H4

R ¹ -X

2. R ² -Y

HNR ³ R ⁴

-►

I

Scheme 2:

HNR ³ R ⁴

-►

I

Scheme 3:

I

Scheme 4:

Á

1. tert-BuLi

B (OMe) 3

XII

The compounds of the formula I according to the invention and their physiologically acceptable salts can be used as medicaments for animals, preferably mammals and in particular for humans, alone, in mixtures with one another or in the form of pharmaceutical compositions.

The present invention also relates to the compounds of formula I and their physiologically acceptable salts for use as medicaments, their use in the therapy and prophylaxis of the diseases mentioned, and their use in the preparation of medicaments for this purpose and medicaments that block the K ⁺ channel. Furthermore, the present invention relates to pharmaceutical compositions which contain as an active ingredient an effective amount of at least one compound of formula I and / or pharmaceutically acceptable salts thereof in addition to the usual pharmaceutically acceptable carriers and excipients. The pharmaceutical compositions usually contain from 0.1 to 90% by weight of the compounds of the formula I and / or their physiologically acceptable salts. The pharmaceutical compositions can be prepared in a known manner. For this purpose, the compounds of the formula I and / or their physiologically acceptable salts are mixed with one or more solid or liquid galenic carriers and / or auxiliaries and, if necessary, other active substances to form a dosage form or dosage form which: may then be used as a therapeutic in human or veterinary medicine.

The pharmaceutical compositions containing the compounds of the formula I according to the invention and / or their physiologically acceptable salts can be administered orally, parenterally, for example intravenously, rectally, by inhalation or topically, with the preferred application depending on the individual case, e.g. to be treated.

Suitable adjuvants for the desired formulation of the medicament will be selected by one of ordinary skill in the art. In addition to solvents, gelling agents, suppository bases, tabletting agents and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavoring agents, preservatives, solubilizers, depotants, buffers or colorants can be used.

The compounds of formula (I) may also be combined with other active ingredients to provide a beneficial therapeutic effect. For example, in the treatment of cardiovascular diseases, combinations with cardiovascular active agents are possible and advantageous. Such combination partners that are suitable for the treatment of cardiovascular diseases may be, for example, other antiarrhythmic drugs such as class I, class II or class III antiarrhythmics, such as IK _S or IK _r channel blockers such as dofetilide or blood pressure lowering agents, as ACE inhibitors (eg enalapril, captopril, ramipril), angiotensin K ⁺ channel antagonists, alpha- and beta-receptor blockers, but also sympathomimetic and adrenergic compounds, Na ⁺ / H ⁺ exchange inhibitors, calcium channel antagonists, inhibitors phosphodiesterases, and other substances with a positive inotropic effect, such as foxglove glycosides or diuretics.

For oral use, the active compounds are admixed with suitable excipients such as carriers, stabilizers or inert diluents and formulated into suitable dosage forms such as tablets, dragees, push-fit capsules, or aqueous, alcoholic or oily solutions by conventional methods. As an inert carrier, for example, gum arabic, magnesium, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, in particular corn starch. The preparation can be carried out with both dry and wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions, or mixtures thereof. Other excipients which are also suitable for other dosage forms are, for example, polyethylene glycols and polypropylene glycols.

For subcutaneous or intravenous administration, the active compounds in a solution, suspension or emulsion are mixed, as appropriate, with customary substances, such as wetting agents, emulsifiers, or other excipients, as appropriate. The compounds of formula (I) and their physiologically acceptable salts can be lyophilized and the lyophilizates obtained used, for example, for the preparation of preparations for injection or infusion. Suitable solvents are, for example, water, saline or alcohols, for example ethanol, propanol. glycerin; in addition sugar solutions such as glucose or mannitol, or ^; mixtures of the various solvents mentioned above.

Suitable pharmaceutical formulations for application in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of the formula I or their physiologically acceptable salts in a pharmaceutically acceptable solvent, in particular ethanol or water, or in a mixture of such solvents. If desired, the formulations may contain other pharmaceutical excipients such as surfactants, emulsifiers, stabilizers and propellant. Such compositions usually contain the active ingredient in a concentration of about 0.1 to 10% by weight, in particular 0.3 to 3% by weight.

The dosage of the active compound of the formula I or a physiologically acceptable salt thereof administered depends on the case and, as usual, the dosage should be adjusted to be optimal for the case. It naturally depends on how often the composition is administered, on the efficacy and duration of action of the particular compounds to be used for therapy or prophylaxis, but also on the type and severity of the disease being treated, as well as the sex, age, weight and individual response whether it is an acute therapy or a prophylaxis. The daily dose of a compound of formula I when administered to a patient weighing about 75 kg will generally be 0.001 mg / kg body weight to 100 mg / kg body weight, preferably 0.01 mg / kg body weight to 20 mg / kg body weight. The dose may be administered in the form of a single dose or may be divided into multiple, for example two, three or four, individual doses. Particularly in the treatment of acute cases of cardiac rhythm disorders, for example in an intensive care unit, injection or infusion, such as long-term infusions, may be advantageous.

DETAILED DESCRIPTION OF THE INVENTION

List of abbreviations

CDI 'carbonyldiimidazole

DIC diisopropylcarbodiimide

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

EDAC N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride

HOBT 1-hydroxy-1H-benzotriazole

HPLC high performance liquid chromatography

MS (ES +) mass spectrum (electrospray)

THE tetrahydrofuran

TOTU 0 - {[cyano (ethoxycarbonyl) methylene] amino] -1,1,3,3-tetramethyluronium tetrafluoroborate

mp melting point (unless otherwise stated, melting points of impure products; melting points of the pure compounds may be considerably higher).

Precursor 1: 7H-Dibenzo [c, e] oxepin-5-one

To a suspension of 50.0 g (0.22 mol) of diphosphonic anhydride in 220 ml of dimethylformamide was added portionwise at 5 ° C 9.0 g (0.24 mol) of sodium borate over 10 minutes. The mixture was stirred for 1 hour at room temperature and then poured into water

220 ml of 6M hydrochloric acid are added, 750 ml of water are added and stirred for 2 hours. The precipitated precipitate is suctioned off to obtain

35.0 g of 7H-dibenzo [c, e] oxepin-5-one, mp 131 ° C.

Step 2: 2'-Phthaloimidomethylbiphenyl-2-carboxylic acid

A mixture of 35 g (0.17 mol) of 7H-dibenzo [c, e] oxepin-5-one and 30.8 g (0.17 mol) of phthalimidkalia in 330 ml of dimethylformamide is heated at 170 ° C for 18 hours. After cooling, the precipitated precipitate is filtered off with suction and introduced into 160 ml of glacial acetic acid. Mix. The mixture was stirred for 1 hour and then diluted with 650 ml of ice-water. The precipitated product is filtered off with suction and dried under vacuum. 44.8 g of 2'-phthalimidomethylbiphenyl-2-carboxylic acid are obtained, m.p. 198 ° C.

Step 3: 2'-Aminomethylbiphenyl-2-carboxylic acid

To a suspension of 10.0 g (28 mmol) of 2'-phthalimidomethylbiphenyl-2-carboxylic acid in 450 mL of methanol was added 20 mL of hydrazine hydrate and the mixture was heated at 40 ° C for 1.5 h. The reaction mixture is concentrated and the residue is extracted into 250 ml of methylene chloride. After filtration of the undissolved 2,3-dihydrophthalazine-1,4-dione, the mother liquor is concentrated to give 4.8 g of 2'-aminomethylbiphenyl-2-carboxylic acid.

General rule for the synthesis of mixed succinimidocarbonates from alcohols (pre-stages 4a to 4k)

To a solution of the corresponding alcohol (19.5 mmol) and DMAP (1.2 g, 9.8 mmol) in methylene chloride (30 mL) and acetonitrile (30 mL) was added disuccinimidocarbonate (5.0 g, 19.5 mmol) portionwise at 0 ° C. The reaction mixture is stirred for 2.5-10 hours at room temperature and then 25 ml of water are added. The organic phase is washed twice more with water, dried and concentrated. The corresponding succinimidocarbonate is obtained, mostly as a crystalline solid.

Preface 4a:

According to the general procedure, 3.2 g of 4-fluorobenzyl-N-succinimidocarbonate are obtained; mp 89 ° C (ether).

Pre-stage 4b:

From 11.7 mmol of 4-trifluoromethylbenzyl alcohol, 2.3 g of 4-trifluoromethylbenzyl-N-succinimidocarbonate was obtained according to the general formula; mp 102 ° C (ether).

Preface 4c:

From 10.5 mmol of α-methyl-4- (trifluoromethyl) benzyl alcohol, 1.6 g of α-methyl-4- (trifluoromethyl) benzyl-N-succinimidocarbonate was obtained according to the general formula; mp 115 ° C (ether).

Pre-stage 4d:

Starting from 19.5 mmol of 4,4,4-trifluorobutanol, 4.0 g of 4,4,4-trifluorobutyl-N-succinimidocarbonate was obtained according to the general formula; mp 72 ° C (ether).

Pre-stage 4e:

Starting from 26.3 mmol of α-methyl-3- (trifluoromethyl) benzyl alcohol, 5.1 g of α-methyl-3- (trifluoromethyl) benzyl-N-succinimidocarbonate was obtained according to the general formula; mp 77 ° C (ether).

Pre-stage 4f:

Starting from 31.6 mmol of α-methyl-2,6-difluorobenzyl alcohol, 1.6 g of α-methyl-2,6-dofluorobenzyl-N-succinimidocarbonate is obtained according to the general formula; mp 108 ° C (ether).

Pre-stage 4g:

Starting from 25 mmol of α-methyl 2- (trifluoromethyl) benzyl alcohol, 3.5 g of α-methyl 2- (trifluoromethyl) -benzyl -N-succinimidocarbonate was obtained according to the general formula.

Preheat 4h:

3.5 g of (S) -α-methylbenzyl-N-succinimidocarbonate are obtained from 25 mmol of (S) -1-phenylethanol as a general rule.

Pre-stage 4i:

3.5 g of (R) -α-methylbenzyl-N-succinimidocarbonate are obtained from 25 mmol of (R) -1-phenylethanol as a general rule.

Preface 4j:

4.3 g of α-methyl-4-fluorobenzyl-N-succinimidocarbonate are obtained from 25 mmol of α-methyl-4-fluorobenzyl alcohol as a general rule.

Pre-stage 4k:

Starting from 9.8 mmol of (S) -1-phenyl-1-butanol, 1.7 g of (S) -α-propylbenzyl-N-succinimidocarbonate are obtained according to the general formula.

Step 5a: 2'-Aminomethylbiphenyl-2-carboxylic acid phenethylamide

From 2'-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after activation of CDI and reaction with phenethylamine, 2'-phthioimidomethylbiphenyl-2-carboxylic acid phenethylamide is obtained, m.p. 156 [deg.] C.

5.0 g (10.9 mmol) of this product are dissolved in 200 ml of methanol, 5 ml of hydrazine hydrate are added and the mixture is stirred for 1 hour at 40 ° C. The reaction mixture was concentrated and the residue was extracted into methylene chloride. After filtering off the resulting 2,3-dihydrophthalazine-1,4-dione, the mother liquor is concentrated and the residue is purified by flash chromatography in methylene chloride-methanol (20: 1) to give 3 g of phenethylamide acid.

2'-aminomethylbiphenyl-2-carboxylic acid.

Step 5b: 2'-Aminomethylbiphenyl-2-carboxylic acid benzylamide

From 2'-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after conversion to the acid chloride with thionyl chloride and reaction with benzylamine, the acid benzylamide is obtained. 2'-phthalimidomethylbiphenyl-2-carboxylic acid. The product (1.2 g; 2.7 mmol) was dissolved in 55 mL of methanol, 1.35 mL of hydrazine hydrate was added and the mixture was stirred at 40 ° C for 1 h. The reaction mixture was concentrated and the residue was extracted into methylene chloride. After filtration of the resulting 2,3-dihydrophthalazine-1,4-dione, the mother liquor is concentrated and the residue is purified by flash chromatography in methylene chloride-methanol (30: 1) to give 0.49 g of 2'-aminomethylbiphenyl-2 benzylamide. carboxylate.

Step 5c: 2'-Aminomethylbiphenyl-2-carboxylic acid isopentylamide

Reaction of 3 g (8.4 mmol) of 2'-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2) with isopentylamine in the presence of HOBT and DIC afforded 3.2 g of 2'-phthalimidomethylbiphenyl-2-carboxylic acid isopentylamide, m.p. 165 [deg.] C. The product was dissolved in 100 mL of methanol and 5 mL of hydrazine hydrate was added. The reaction mixture was stirred for 1 hour at 40 ° C, then cooled and filtered. The filtrate was concentrated and the residue was extracted into methylene chloride. After washing with water, drying and evaporation of the solvent, 1.8 g of 2'-aminomethylbiphenyl-2-carboxylic acid isopentylamide is obtained.

Precedence 5d: 2'-Aminomethylbiphenyl-2-kyrboxylic acid 2- (2-pyridyl) ethylarnide

Treatment of 10 g (28 mmol) of 2'-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2) with 2- (2-pyridyl) ethylamine in the presence of HOBT and DIC gives 13 g of 2- (2-pyridyl) ethylamide of 2'- phthaloimidomethylbiphenyl-2-carboxylic acid, m.p. 155 ° C. The product is suspended in 300 ml of methanol and 20 ml of hydrazine hydrate are added. The reaction mixture was stirred for 1 hour at 40 ° C, then cooled and filtered. The filtrate was concentrated and the residue was extracted into ethyl acetate. The product was extracted twice with 2M hydrochloric acid to enter the aqueous phase. The aqueous phase was then basified with potassium carbonate and extracted twice with ethyl acetate. After washing with water, drying and concentration, 7.3 g of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid are obtained.

Step 6: 2 (Benzyloxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid

To a solution of 2'-aminomethylbiphenyl-2-carboxylic acid (455 mg, 2 mmol) (pre-step 3) and sodium bicarbonate (336 mg, 4 mmol) in dioxane (5 mL) and water (5 mL) was added dropwise at 0 ° C. mmol) of benzyl N-succinimidocarbonate in 2.5 ml of dioxane and stirred for 4 hours at room temperature. The mixture was concentrated in vacuo, the residue diluted with water, acidified and extracted with ethyl acetate. 590 mg of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid are obtained.

Step 7: 2 '- (tert-butoxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid

To a solution of 12.0 g (53 mmol) of 2'-aminomethylbiphenyl-2-carboxylic acid (precursor 3) in 130 ml of 1,4 dioxane and 65 ml of water is added 65 ml of 1M sodium hydroxide and, after complete dissolution, 12.6 g. g (58 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for 2 hours at room temperature, then concentrated in vacuo, the residue diluted with water and extracted twice with methylene chloride. The aqueous phase was acidified with 1 M acidic potassium sulfate and extracted with ethyl acetate. After thorough evaporation, addition of n-heptane and addition overnight, the product precipitated. Yield 7.6 g of 2 '- (tert-butoxycarbonylaminomethyl) biphenyl-2-carboxylic acid, m.p. 136 ° C.

General regulation for the cleavage of the protecting group Boe

To a solution of trifluoroacetic acid in dichloromethane (30%) was added N-Boc protected aminomethylbiphenyl derivative (1 g per 10 mL solution). The reaction mixture is stirred for 30 minutes at room temperature and then the solvent is removed by rotary evaporation under vacuum. The residue was extracted into ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and the solvent is evaporated off under vacuum to give the corresponding 2'-aminomethylbiphenyl-2-carboxylic acid amide.

Step 8a: 2'-Aminomethylbiphenyl-2-carboxylic acid (2,4-difluorobenzyl) amide

The compound was obtained from the Boc-protected compound (Example 8c) according to the general formula. Alternatively, the compound can also be isolated directly in the form of trifluoroacetate and treated further.

Next pre-stages 8:

Analogously, the corresponding amines are liberated from the Boc-protected compounds of Examples 8d to 8o and 10a to 10o.

General rule for the conversion of aminoethyl biphenyls to carbamates by reaction with succinimidocarbonates (examples 1a to 1u)

To a solution of the 2'-aminomethylbiphenyl (0.45 mmol) and sodium bicarbonate (38 mg, 0.45 mmol) in dioxane (2 mL) and water (2 mL) was slowly added succinimidocarbonate (0.45 mmol) in dioxane (2 mL). The reaction mixture is stirred for 2-12 hours at room temperature, concentrated, diluted with water, extracted with ethyl acetate and the organic phase washed with water. After drying and evaporation of the solvent, the corresponding carbamate is obtained.

Example 1a

2 '- (4-Trifluoromethylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.45 mmol of 2'-amincmethylbiphenyl-2-carboxylic acid fehethylamide and 4-trifluoromethylbenzyl-N-succinimidocarbonate (precursor 4b) yields 226 mg of 2 '- (4-trifluoromethylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxy-biphenyl-2-carboxy) . MS (ES < + >): m / z = 533 (M + 1).

Example 1b

2 '- (Benzyloxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.3 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide and benzyl-N-succinimidocarbonate gave, as a general rule, 66 mg of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide as an oil. MS (ES < + >): m / z = 456 (M + 1).

Example 1c

2 (Methylsulfonylethyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.45 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and methylsulfonylethyl N-succinimide carbonate generally yields 164 mg of 2 '- (methylsulfonylethyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid as an oil. MS (ES +): m / z = 481 (M + 1).

Example 1d

2'- (4-Trifluoromethylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide (0.3 mmol) (precursor 5d) and 4-trifluoromethylbenzyl-N-succinimidocarbonate (precursor 4b) gave 170 mg of 2- (2- pyridyl) 2 '- (4-trifluoromethylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid ethylamide. MS (ES < + >): m / z = 534 (M + 1).

Example le

2 '- (4-Fluorobenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and 4-fluorobenzyl-N-succinimidocarbonate (preceded 4a) yields 150 mg of 2- (2- 2 '- (4-fluorobenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid pyridyl) ethylamide MS (ES +):

484 (M + 1).

Example 1f

(±) -2 '- (α-Methyl-4- (trifluoromethyl) benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and α-methyl-4- (trifluoromethyl) benzyl-N-succinimidocarbonate (preceded 4c) affords the general formula 170 mg of 2 '- (α-methyl-4- (trifluoromethyl) benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide as racemate. MS (ES < + >): m / z = 548 (M + 1).

Example 1g

(S) -2 (α-Methyl-4- (trifluoromethyl) benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

The (S) -enantiomer was obtained from the corresponding (Example 1f) by preparative HPLC on a 250 x 4.6 Chiralpakom AD column (n-hexane-ethanol-isopropanol 0.3% trifluoroacetic acid / 0.3% diethylamine).

racemate filled (10: 1: 1,

Example 1h

(R) -2 '- (α-Methyl-4- (trifluoromethyl) benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

The (A) -enantiomer was obtained from the corresponding racemate (Example 1f) by preparative HPLC on a 250 x 4.6 column packed with Chiralpak AD in n-hexane-ethanol-isopropanol (10: 1: 1, 0.3% trifluoroacetic acid / 0). , 3% diethylamine).

Example li

2 '- (4,4,4-Trifluorobutyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) arylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and 4,4,4-trifluorobutyl-N-succinimidocarbonate (preceded 4d) gives 140 mg of 2 as a general rule. 2 '- (4,4,4-Trifluorobutyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (2-pyridyl) ethylamide. MS (ES < + >) = 486 (M + 1).

Example 1j

(S) -2 '- (α-Methyl-benzyloxycarbonyl-amiriomethyl) -biphenyl-2-carboxylic acid 2- (2-pyridyl) -ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and (S) -α-methylbenzyl-N-succinimidocarbonate (preceded 4h) gives 60 mg of 2 as a general rule. (S) -2 '- (α-methyl-benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (2-pyridyl) ethylamide.

MS (ES < + >): m / z = 480 (M + 1).

Example Ik

(R) -2'-α-Methyl-benzyloxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid 2- (2-pyridyl) -ethylamide

Reaction with 0.3 mmol of 2- (2-methylbiphenyl-2-carboxylic acid)

-pyridyl) ethylamide (step 5d) and 2'-amino (R) -α-methylbenzyl50

The N-succinimidocarbonate (pre-step 4i) gave 60 mg of 2- (2-pyridyl) ethylamide (R) -2'-α-methylbenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide.

MS (ES < + >): m / z = 480 (M + 1).

Examples 11 to 11

According to the general formula and analogously to Examples 1a to 1k, the following compounds were prepared from the respective precursors:

Prikl.č. precursors structure MS (ES): m / z = 11 5d 4g 548 Y 0 , Ά OL · A ° M Y at lm 5d + 4e M 548 1 χθ n A XX M ln 5d-4f xo 516 Ý and ltlt ° A la F M lo 8a + 4i xo F. ABOUT 501 A AXAX R ° M la U M lp 8 + 4c Ila x yy ^f 569 ιΠ U LO ra ° • ^N ^ Ax F, C-Ά M

Prikl.č. precursors structure MS IES +): m / z = Iq 8a + 4k λ α-οσ 'X ^A Xi' 529 lr 5D + 4k 508 ls 8a + 4a ₀ α / χΑ 505 (T. t. 104 ° C) lt 8a + 4d , 0 οχα ' 5 07 (T. t. 11ÝC) lu O ° ^An Xj 452

General rule for the preparation of carbamates by reaction of aminoethyl biphenyls with chloroformates (Examples 2a to 2m)

To a solution of 0.3 mmol of the appropriate 2'-aminomethylbiferyl and 37 mg (0.36 mmol) of triethylamine in 6 ml of methylene chloride is slowly added dropwise a solution of 0.32 mmol of the corresponding chloroformate in 1 ml of methylene chloride at 5 ° C. The reaction mixture is stirred overnight at room temperature, then poured into water and the organic phase is washed once more with water. After concentration, the residue is purified by flash chromatography.

Example 2a

Methyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

2'- (butoxycarbonyl-amino-

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and butyl chloroformate affords 69 mg of 2- (2-pyridyl) ethylamide of 2 '(- butoxycarbonyl-). aminomethyl) biphenyl-2-carboxylic acid as an oil. MS (ES +): 432 (M + 1).

Example 2b 2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 0.27 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) and benzyl chloroformate gives, as a general rule, 44 mg of 2 '- (benzyloxycarbonyl-aminomethyl) biphenyl-2-yl- 2-carboxylic acid, m.p. 112 [deg.] C. MS (ES +): mlz = 431 (M + 1).

Example 2c

2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.24 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and benzyl chloroformate yields, as a general rule, 59 mg of 2- (2-pyridyl) ethylamide of 2 '- (benzyloxycarbonyl- aminomethyl) biphenyl-2-carboxylic acid, m.p. 140 [deg.] C. (heptane-ethyl acetate). MS (ES < + >): m / z = 466 (M + 1).

Example 2d 2 '- (Butoxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) with butyl chloroformate affords 66 mg of 2'- (butoxycarbonylaminomethyl) biphenyl (3-methylbutyl) amide as a general rule. -2-carboxylic acid in the form of a resin. MS (ES < + >) m / z = 397 (M + 1).

Example 2e 2 '- (2-Chlorobenzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (pre-step 5c) and 2-chlorobenzylchloroformate (0.34 mmol) and 2-chlorobenzyloxycarbonyl- (2-chlorobenzyloxycarbonyl) amide gives 75 mg (3-methylbutyl) amide. aminomethyl) biphenyl-2-carboxylic acid in the form of a resin. MS (ES +): mlz = 465 (M + 1).

Example 2f Nyl-2-carboxylic acid (3-methylbutyl) amide

2 '- (methoxycarbonyl-aminomethyl) -bife-

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (pre-step 5c) and methyl chloroformate affords 29 mg of (3-methylbutyl) amide as a general rule after extraction with ethyl acetate and purification by flash chromatography. 2'-methoxycarbonylaminomethyl) biphenyl-2-carboxylic acid in the form of a resin. MS (ES < + >): m / z = 355 (M + 1).

Example 2g 2 '- (Phenoxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 0.34 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) and phenyl chloroformate according to the general procedure, extraction with ethyl acetate and purification by flash chromatography gave 55 mg of (3-methylbutyl) amide (2-Phenoxycarbonylaminomethyl) biphenyl-2-carboxylic acid in the form of a resin. MS (ES +): mlz = 417 (M + 1).

Example 2h 2 '- (4-Carbomethoxyphenoxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

ABOUT

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (pre-5c) and (4-carbomethoxy) phenyl chloroformate (0.34 mmol) gave, after extraction with ethyl acetate and purification by flash chromatography, 77 mg (3- 2 '- (4-carbomethoxyphenoxycarbonylaminomethyl) biphenyl-2-carboxylic acid methylbutyl) amide as a resin. MS (ES < + >): m / z = 475 (M + 1).

Example 2i

2 '- (2,2-Dimethylpropoxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.45 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precaution 5a) and neopentyl chloroformate gives, after extraction with ethyl acetate and purification by flash chromatography, 156 mg of phenethylamide · 2 '- (2,2-dimethylpropoxycarbonylaminomethyl). biphenyl-2-carboxylic acid. MS (ES < + >): m / z = 445 (M + 1).

Example 2j to 2m

The following compounds were obtained in an analogous manner to Examples 2a to 2i:

Prikl.č. structure MS (ES): m / z = MP: 2J Vi 0 Ά 'klA-Jy 491 2k _n o CX / Xr ' 473 107 21 n Yr ^F THREE ₀ UaJU 503 123 2 m A F) 482

General rule for the conversion of aminomethylbiphenyls to sulfonamides by reaction with sulfonic acid chlorides (Examples 3a to 3t)

To a solution of the appropriate 2'-aminomethylbiphenyl (0.61 mmol) and triethylamine (74 mg, 0.73 mmol) in methylene chloride (5 mL) at 0 ° C was slowly added the corresponding sulfonic acid chloride (0.66 mmol) dropwise. The reaction mixture is stirred for 12 hours at room temperature and then concentrated in vacuo. The residue is stirred for 2 hours with 25 ml of water and the crystallized product is filtered off with suction.

Example 3a

2'-2 (Trifluoromethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-trifluoromethylphenylsulfonyl chloride yielded generally 272 mg of 2 '- (3-trifluoromethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide, m.p. 145 ° C. MS (ES < + >): m / z = 539 (M < + >)

Example 3b

2 '- (4-Acetylphenylsulfonyl-aminomethyl) -biphenyl-2-carboxylic acid phenethylamide

Ο

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 4-acetylphenylsulfonyl chloride generally affords 258 mg of 2'- (4-acetylphenylsulfonylaminomethyl) -biphenyl-2-carboxylic acid phenethylamide; mp 145 ° C. MS (ES - +): m / Z = 513 (M + 1).

Example 3c

2 '- (3-Nitrophenylsulfonyl-aminomethyl) -biphenyl-2-carboxylate phenethylamide

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-nitrophenylsulfonyl chloride gave 272 mg of 2 '- (3-nitrophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide as a general rule, m.p. 145 ° C. MS (ES < + >): m / z = 516 (M + 1).

Example 3d

2 '- (Phenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and phenylsulfonyl chloride yielded 224 mg of 2 '- (phenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide according to the general procedure, m.p. 154 [deg.] C. MS (ES +): mlz = 471 (M + 1).

Example 3e

2 '- (3-Fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 3-fluorophenylsulfonyl chloride generally yields 221 mg of 2 '- (3-fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide, m.p. 153 [deg.] C. MS (ES < + >): m / z = 489 (M + 1).

Example 3f

2 '- (4-Ethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide

Reaction of 0.61 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid phenethylamide (precursor 5a) and 4-ethylphenylsulfonyl chloride generally yields 250 mg of 2 '- (4-ethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid phenethylamide, m.p. 136 ° C. MS (ES < + >): m / z = (M + 1).

Example 3g

2 '- (3-Trifluoromethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide

Reaction of 0.28 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and 3-trifluoromethylphenylsulfonyl chloride generally yielded 131 mg of 2 '- (3-trifluoromethylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide, m.p. 126 ° c. MS (ES +): m / z = 525 (M + D < + >).

Example 3h

2 '- (3-Acetylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide

Reaction of 0.28 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and 3-acetylphenylsulfonyl chloride gave, as a general rule, 110 mg of 2 '- (3-acetylphenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide. 182 [deg.] C. MS (ES < + >): m / z = 499 (M + 1).

Example 3i

2 '- (3-Nitrophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide

Reaction of 0.28 mmol of benzylamide and 3-nitrophenylsulfonyl yield 115 mg of biphenyl-2-carboxylic acid benzylamide (precursor 5b) chloride according to the general formula 2 '- (3-nitrophenylsulfonylaminomethyl) -biphenyl-2-carboxylic acid, m.p. 175 ° C. MS (ES +): mlz = 502 (M + 1).

Example 3j

2 '- (Phenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide

Reaction of 0.28 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and phenylsulfonyl chloride gave, as a general rule, 95 mg of 2 '- (phenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide, m.p. Mp 162 ° C. MS (ES < + >): m / z = 457 (M + 1).

Example 3k

2 '- (3-Fluorophenylsulfonyl-aminomethyl) -biphenyl-2-carboxylic acid benzylamide

Reaction of 0.28 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5b) and 3-fluorophenylsulfonyl chloride generally yields 112 mg of 2 '- (3-fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid benzylamide, tt 147 ° C. MS (ES +): mlz = 475 (M + 1).

Example 31 1- (2-Methylbutyl) amide of 2-carboxylic acid

2 '- (phenylsulfonyl-aminomethyl; -bife-

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) and phenylsulfonyl chloride (0.34 mmol) and phenylsulfonyl chloride generally yields 100 mg of 2 '- (phenylsulfonylaminomethyl) biphenyl-2- carboxyl, mp 127 [deg.] C. MS (ES +): mlz = 437 (M + 1).

Example 3m 2 '- (4-Fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

F,

ABOUT

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (pre-step 5c) and 4-fluorophenylsulfonyl chloride (0.34 mmol) yields, as a general rule, 122 mg of 2 '- (4-fluorophenylsulfonyl) amide aminomethyl) biphenyl-2-carboxylic acid, m.p. Mp 149 ° C. MS (ES +): m / z = 455 (M + 1) < + >

Example 3n 2 '- (3-Fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (3-methylbutyl) (prec. 5c) and 3-fluorophenylsulfonyl chloride generally yields 118 mg of 2 '- (3-) - (3-methylbutyl) amide. fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid, m.p. 141 ° C. MS (ES < + >): m / z = 455 (M + 1).

Example 3o 2 '- (Isopropylsulfonylaminomethyl) biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (pre-5c) and isopropylsulfonyl chloride (0.34 mmol) and general purification by flash chromatography gave 16 mg of (3-methylbutyl) amide.

2 '- (isopropylsulfonyl-aminomethyl) biphenyl-2-carboxylic acid as an oil. MS (ES +): mlz = 403 (M + 1).

Example 3p

2 '- (Phenylsulfonyl-aminomethyl) -biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and phenylsulfonyl chloride gave, as a general rule, 117 mg of 2- (2-pyridyl) ethylamide of 2 '- (phenylsulfonyl-) aminomethyl) biphenyl-2-carboxylic acid, m.p. 131 ° C. MS (ES +): mlz = 472 (M + 1).

Example 3q

2 '- (4-fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

F

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and 4-fluorophenylsulfonyl chloride gives, as a general rule, 106 mg of 2- (2-pyridyl) ethylamide of 2 '- ( 4-fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid, m.p. 130 [deg.] C. MS (ES +): mlz = 490 (M + 1).

Example 3r

2 '- (3-Fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and 3-fluorophenylsulfonyl chloride gives, as a general rule, 102 mg of 2- (2-pyridyl) ethylamide of 2 '- ( 3-fluorophenylsulfonylaminomethyl) biphenyl-2-carboxylic acid, m.p. Mp 123 ° C. MS (ES +): m / z = 490 (M + D < + >).

Example 3s

2 '- (Isopropylsulfonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide (0.3 mmol) (preceded 5d) and isopropylsulfonyl chloride yields 40 mg of 2- (2-pyridyl) ethylamide 2 'according to the general procedure followed by extraction with ethyl acetate. - (isopropylsulfonylaminomethyl) biphenyl-2-carboxylic acid in the form of an oil. MS (ES < + >): m / z = 438 (M + 1).

Analogously to Examples 3a to 3s, the following compound was prepared:

Prikl.č. structure MS (ES): m / z = 3 tons Π í? ° * u 539

General rule for the preparation of carboxamides by reaction of aminomethylbiphenyls with carboxylic acid chlorides (Examples 4a to 41)

To a solution of 0.34 mmol of the appropriate 2'-aminomethylbiphenyl and 41 mg (0.41 mmol) of triethylamine in 5 ml of methylene chloride at 0 ° C was slowly added dropwise 0.36 mmol of the corresponding carboxylic acid chloride. The reaction mixture is stirred for 3 hours at room temperature and then concentrated in vacuo. The residue is stirred with 25 ml of water and the precipitated product is filtered off with suction or isolated by extraction with ethyl acetate.

Example 4a 2 '- (Benzoylamino-methyl) biphenyl-2- (3-methylbutyl) carboxylic acid amide

Reaction of 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) and benzoyl chloride (0.34 mmol) and benzoyl chloride gave, as a general rule, 75 mg of 2 '- (benzoylaminomethyl) biphenyl-2- carboxylic acid,

mp 147 ° C. MS (ES < + >): m / z = 401 (M + 1).

Example 4b

2- (2-Pyridyl) carboxylic acid ethylamide

2 '- (benzoyiaminometyl) biphenyl-2-

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide with 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and benzyl chloride gave the general formula 98 mg of 2- (2-pyridyl) ethylamide of 2 '- ( benzoyiaminometyl) biphenyl-2-carboxylic acid,

mp 135 ° C. MS (ES < + >): m / z = (M + 1).

Example 4c

2,4'-{[2- (4-methoxyphenyl) acetyl-amino] methyl} biphenyl-2-carboxylic acid difluorobenzylamide

Reaction of 0.5 mmol of 2'-aminomethylbiphenyl-2-carboxylic acid 2,4-difluorobenzylamide (precaution 8a) and methoxyphenylaoethyl chloride gives 160 mg of 2,4-ditluorobenzylamide of 2 '- ([2- (4-methoxyphenyl) acetyl) as a general rule. amino] methyl} biphenyl-2-carboxylic acid, mp 138 DEG C. MS (ES +): m / z = 501 (MH +).

The following compounds were prepared analogously to Examples 4a to 4c:

Prikl.č. structure MS (ES): m / z = MP: (A ^{/ Οχ} Αΐ 0 UL γ ^Ν ^ Ά 4d L 1 I L 480 As. ABOUT N A AJ A n about M Ax ~ / M 4e T h n 466 0 ^ <X A A n 0 L N > A t '> A 0 XX X / ^lN p T N 4f T you 466 and 0 A AA 0 AJ A A 4 g in JV Ύί Ϊ AÄo ^x 481 AJ AA L 1 0 x x 4h o < a- 465 AA / M ΓΓ X 0 '0 at AJ A '' Y'hi 0 ML γ ^Ν ^ 4i I II IJ 480 116'C As xA 0 XX xz \ N Υί AJ A / A 0 UL χ ^Ν ^ AA J ή 1 1 11 il 480 XX \ - 0 Ί% AJ fX ' π JA. 0 X Ίι 4 k AJ 508 A Y / -x JAJ (J t - (y 'T

Prikl.č. structure MS IES +): m / z = MP: 41 478

General recipe for the preparation of ureas by reaction of aminomethylbiphenyls with isocyanates (Examples 5a to 5e)

To a solution of 0.34 mmol of the corresponding 2'-aminomethylbiphenyl and 41 mg (0.4.1 mmol) of triethylamine? in 5 ml of methylene chloride, a solution of 0.36 mmol of the corresponding isocyanate in 0.5 ml of methylene chloride is slowly added dropwise at 0 ° C. The reaction mixture is stirred for 3 hours at room temperature and then concentrated in vacuo. The residue is stirred with 25 ml of water and the precipitated product is filtered off with suction or isolated by extraction with ethyl acetate.

Example 5a 2 '- [(3-phenylureido) methyl] biphenyl-2-carboxylic acid (3-methylbutyl) amide

Reaction of 2, 3-methylbutyl) 2'-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl) amide (precursor 5c) and phenyl isocyanate gives, as a general rule, 85 mg of 2 '- [(3-phenylureido) (3-methylbutyl) amide methyl] biphenyl-2-carboxylic acid, m.p. 194 ° C. MS (ES &lt; + &gt;): m / z = 416 (M + 1).

Example 5b

2 '[(3-phenylureido) methyl] biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.3 mmol of 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (preceded 5d) and phenyl isocyanate gives, as a general rule, 101 mg of 2- (2-pyridyl) ethylamide of 2 '[(3- phenylureido) methyl] biphenyl-2-carboxylic acid, mp: 99 ° C. MS (ES +): m / z = 451 ^(M + 1).

Examples 5c to 5e

The following compounds were prepared analogously from 2- (2-pyridyl) ethylamide of 2'-aminomethylbiphenyl-2-carboxylic acid (precursor 5d) and the corresponding isocyanates:

Pri kí.č. structure MS (ES): m / z = 5c σ ' 0 X 'n hr ABOUT XX 0 -x σύ 465 chiral 5d : 0 ABOUT- II Ί about XA 479 chiral 5e σ í ⁰ L · ä Ύί 0 X 479

General rule for the preparation of amides by reaction of biphenylcarboxylic acids with amines (Examples 6a to 6h)

To a solution of 0.28 mmol of the appropriate biphenylcarboxylic acid, 0.3 mmol of HOBT and 0.3 mmol of DIC in 5 mL of tetrahydrofuran was added dropwise at 0 ° C 0.3 mmol of the appropriate amine, and the mixture was stirred for 12 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with dilute hydrochloric acid and sodium bicarbonate solution. After drying over sodium sulfate and evaporation in vacuo, the corresponding amide is obtained.

Example 6a

2 '- (Benzyloxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid benzylmethylamide

Reaction of 0.28 mmol of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (precursor 6) and benzylmethylamine gives, as a general rule, 89 mg of 2' - (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid benzylmethylamide. MS (ES +): mlz = 465 (M + 1).

Example 6b

2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid cyclohexylamide

Reaction of 0.28 mmol of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (precursor 6) and cyclohexylamine yields as a general rule 99 mg of cyclohexylamide

2 '- (benzyloxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid.

MS (ES &lt; + &gt;): m / z = 443 (M + 1).

Example 6c

2 (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenylamide

Reaction of 0.28 mmol of 2 '- (benzyloxycarbonylaminomethyl) -biphenyl-2-carboxylic acid (precursor 6) and aniline gave, as a general rule, 66 mg of 2' - (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid phenylamide.

MS (ES +): mlz = 437 (M + 1).

Example 6d 2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid {N-methyl-N- [2- (2-pyridyl) ethyl]} amide

Reaction of 0.28 mmol of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (precursor 6) and 2- [2- (methylaminoethyl)] pyridine gave, after general purification by flash chromatography, 54 mg of {N 2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid methyl-N- [2- (2-pyridyl) ethyl]} amide; MS (ES &lt; + &gt;): m / z = 480 (M + 1).

Example 6e

2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid dibutyl

Reaction of 0.28 mmol of 2 (benzyloxycarbonylaminomethyl) -biphenyl-2-carboxylic acid: (pre-step 6) and dibutylamine yields 82 mg of 2 '- (benzyloxycarbonylaminomethyl) dibutylamide according to the general procedure, followed by flash chromatography. ) biphenyl-2-carboxylic acid. MS (ES &lt; + &gt;): m / z

473 (M + 1).

Example 6f

2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide

Reaction of 0.28 mmol of 2 (benzyloxycarbonylaminomethyl) -biphenyl-2-carboxylic acid (precursor 6) and 2- (2-pyridyl) ethylamine yields 85 mg of 2- (2-pyridyl) according to the general formula after flash purification. 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid ethylamide, m.p. 140 ° C (heptane-ethyl acetate). MS (ES &lt; + &gt;): m / z = 466 (M &lt; + &gt;)

D ·

Example 6g 2 (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (2,4-difluorobenzyl) amide

Reaction of 0.28 mmol 2 (benzyloxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid (precursor 6) and 2,4-difluorobenzylamine, the following _General: - <Regulation, after purifying by flash chromatography to yield 99 mg (2,4 difluorobenzyl 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid amide. MS (ES &lt; + &gt;): m / z = 487 (M + 1).

Example 6h 2 '- (Benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (2,2,2-trifluoroethyl) amide

Reaction of 0.28 mmol of 2 (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (precursor 6) and 2,2,2-trifluoroethylamine gave, after general purification by flash chromatography, 19 mg (2,2,2- 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid trifluoroethyl) amide. MS (ES +): mlz = 443 (M + 1).

Example 7a

2- [2- (1-Oxypyridyl)] 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid ethylamide

Ί5

To a solution of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid 2- (2-pyridyl) ethylamide (85 mg, 0.18 mmol) (Example 6f) in 13 mL of methylene chloride was added dropwise at 0 ° C a solution of 47 ° C. mg of m-chloroperbenzoic acid in 2 ml of methylene chloride and the reaction mixture was stirred for 12 hours at room temperature. The organic phase is washed twice with sodium bicarbonate solution, dried over magnesium sulphate and concentrated in vacuo. 79 mg of 2- [2- (1-oxypyridyl)] ethylamide of 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid are thus obtained.

MS (ES &lt; + &gt;): m / z = 482 (M + 1).

Analogously to Example 7a, the following compounds were prepared from the corresponding pyridines:

Pri kl.č. structure MS (ES): m / z = 7b about CA- 4 62 7c 456

General code for the reaction of biphenylcarboxylic acids with amines to form amides (Examples 8a to 8ac)

To a solution of 0.42 mmol of the appropriate biphenylcarboxylic acid, 0.44 mmol of HOBT and 0.44 mmol of EDAC in 5 mL of tetrahydrofuran at 0 ° C was added dropwise 0.44 mmol of the appropriate amine. The reaction mixture is stirred for 4-12 hours at room temperature, diluted with ethyl acetate and then washed with dilute hydrochloric acid and sodium bicarbonate solution. - about drying over

6 MgSO4 and concentration in vacuo gave the corresponding amide.

Example 8a

[2'- (1-Carbamoyl-3-methyl-butylcarbamoyl) -biphenyl-2-ylmethyl] -carbamic acid benzyl ester

Reaction of 0.28 mmol of 2 '- (benzyloxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid (precursor 6) and L-leucinamide hydrochloride in the presence of triethylamine gives, as a general rule, 180 mg of benzyl ester of [2' - (1- carbamoyl-3-methyl-butylcarbamoyl) biphenyl-2-ylmethyl] carbamate. MS (ES &lt; + &gt;): m / z = 474 (M + 1).

Example 8b

2 - {[2'-Benzyloxycarbonyl-aminomethyl) -biphenyl-2-carbonyl] -amino} -3-phenylpropionic acid methyl ester

Reaction of 0.28 mmol of 2'- (benzyloxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid (precursor 6) and L-phenylalanine-methyl ester hydrochloride in the presence of triethylamine gives, as a general rule, 230 mg of methyl 2 - ([2'-benzyloxycarbonyl) ester aminomethyl) -bifeny1-2-carbonyl] -amino} -3-phenylpropionic acid. MS (ES +): mlz = 523 (M + 1).

Example 8c Methyl) biphenyl-2-carboxylic acid (2,4-difluorobenzyl) amide

2 '- (tert-butoxycarbonyl-amino-

Reaction of 10 mmol of 2 '- (tert-butoxycarbonyl-aminomethyl) -biphenyl-2-carboxylic acid (precursor 7) and 2,4-difluorobenzylamine yields 3.8 g of (2,4-difluorobenzyl) -amide as a general rule 2 '- (tert-butoxycarbonylaminomethyl) biphenyl-2-carboxylic acid. MS (ES &lt; + &gt;): m / z = 453 (M + 1).

Examples 8d to 8p

Reaction of 2 '- (tert-butoxycarbonylamino-methyl) biphenyl-2-carboxylic acid (precursor 7) with the corresponding amines analogously to Examples 8a to 8c gives the following products:

Prikl.č. structure MS (ES): m / z = MP: 6c (Y ífY i X TY 413 139 8e about 418 171 8 f i ⁰ γτ ^ν ί 432 161

Príkl.č. structure MS (ES): m / z = MP: 8 g 432 59 8i i ⁰ TM '7'0' ^ 'Ν' ^ ^χ / Υ ° 431 171 8j 4oX-5 ^ ⁿ _? 433 165 8k 421 199 81 χλΑί '' ^ 397 8 m n 8i Α80) ^Γ ^ 461 8N Αλ- ^ ^ Χ ΧΟ 490

Prikl.č. structure MS (ES): m / z = MP: 8o 432

Examples 8p to 8ac

By reacting 2 '- (benzyloxycarbonylaminomethyl) biphenyl-2-carboxylic acid (precursor 6) with the corresponding amines, the following products are obtained analogously to Examples 8a to 8c:

Prikl.č. structure MS (ES): m / z = MP: 8p o m! n. JL ⁰ Tff \ ^N cX ^N u ° 460 119 ° C 8Q _α / o cr ° ^an u ⁰ 480 8R XX o ⁰ iT T ⁰ o ~ ° xr f 489 8s XX F ΟΓ ^λ Ί 0 ° 471

Prikl.č. structure MS (ES): m / z = MP: 8 x 0 YjL JL o Cy Y 494 8 y C 0 A Y ^N Y > A ³ R 460 8t , Shown Y 1 YY ΪΊ RYx • A · J 0 524 M M ! YY 8a.alph , Shown Y Y ΪΊ - ^ N J 466 Y M A 8 čc Ify Y- 1 YY yY m A V ^fJ 466 132 ^: t U YY Ί O 8EC Y --OY IN YIY 1 Y N 474 at IN j 1

General rules for the reaction of aminomethylbiphenyls with isocyanates to form thioureas (Examples 9a to 9i)

To a solution of the corresponding 2'-aminomethylbiphenyl (0.34 mmol) and triethylamine (41 mg, 0.41 mmol) in methylene chloride (5 mL) at 0 ° C was slowly added dropwise a solution of the corresponding isocyanate (0.36 mmol) in methylene chloride (0.5 mL). The reaction mixture is stirred for 3 hours at room temperature, then concentrated in vacuo, the residue is stirred with 25 ml of water and the precipitated product is filtered off with suction or purified by preparative HPLC.

In this way, the following products are obtained inter alia:

Examples 10a to 10ο

Condensation of 2 '- (tert-butyloxycarbonyl-aminomethyl) biphenyl-2-carboxylic acid (precursor 7) with the corresponding amines analogous to those described in Example 6 or 8 gives, inter alia, the following products:

Prikl.č. structure MS (ES): m / z = Λ ίί ^ Ί H X ^N X lOk H Ii (ΐ ° ^N) ii 417 n 101 ' Λ Y γ / "NH 406 H ° 0 10 meters yo YA ^NH 434 The N, N ' H A / 0 Λ Q. H ⁿ a 10η oa ^ Y ° ITI 4 66 H A / ιΓί yp Y _o XA in\ about / U 10ο oA '' H T 412

Examples 11a to 11r

General formula for the conversion of the Boc derivatives of Examples 10 into ureas

To cleave the Boc-protecting group, 1 g of the corresponding compound of Example 10 is added to 10 ml of a 30% solution of three fluoroacetic acid in dichloromethane. The mixture was stirred for 30 minutes at room temperature and then the solvent was removed by rotary evaporation in vacuo. The residue was extracted into ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, filtered and the solvent is dried under vacuum. The 2'-aminomethylbiphenyl-2-carboxylic acid amides obtained are then converted to the corresponding ureas according to the procedure for Examples 5 by reaction with isocyanates.

In this way, the following products are obtained inter alia:

? Ríkl.č. structure MS (ES): m / z = L i Iď r, ^N L T 4 SO Y about' tn F x T F IIb N X T y jO 486 £ θ ' L / -

Prí kl.č. structure MS (ES): m / z = 0 ABOUT llc ^N „ ^N in. y 466 C of ⁴ S-FSJ visas F LLD ' ^N ° x y 504 £ Z ⁰ Ό F F y ď ^r Ile ^N > about 521 VJZ c> N? --about F  Ο-F LLF ° E ^N > f ' y 0 → 439 C ť o? > -N '

Príkl.č. structure MS (ES <: m / z = Cl A LLG _ N Y ^N -> D 0 ^ 437 A F O ~ F IIh y ⁰ ' 561 £ 0 / F J1 -F ^F V Q 11i 'N N ^ about 547 ( J 0 from F ^F in ^F Q LLJ ° u \ y ^c, ~ Cl -0 585

Prikl.č. structure MS (ES): m / z = F F in A LLO _ N Y Y n- r J0 519 Αχ ^{0 <} AA F A AA llp N ° Ύ X-, X O x 502 Ax 0 -n ' UQ Until-. A Al 446 And beyond -x Ax o M

Prikl.č. structure MS (ES -): m / z = F UF ^F \ ABOUT LLR o ^N ABOUT 0, 0 'S'' ^N 597 J o -

General Procedures for the Preparation of the Compounds of the Invention by Solid Phase Synthesis

The amounts given in the regulations always refer to the resin capacity determined by UV-photometry after cleavage of the Fmoc-protective group (see, for example, "The Combinatorial Chemistry Catalog, Novabiochem").

General guideline for condensation of α-Fmoc-amino acids on Rink amide resin

A solution of 1.5 equivalents of DIPEA and 1.5 equivalents of α-Fmoc-amino acid in dimethylformamide (5 ml / g resin) was added to the Rink amide polystyrene resin (1.2 mmol / g capacity) and the mixture was shaken for 12 hours at room temperature. temperature. The resin was then filtered off and washed three times with 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and three times with 10 ml of dichloromethane. Determination of the capacity by the Fmoc method shows a value of 0.9 mmol / g carrier.

Cleavage of the Fmoc protecting group

For cleavage of the Fmoc protecting group, the resin is swelled in dimethylformamide at room temperature for 5 minutes. After addition of dimethylformamide-piperidine (4 ml / g resin;

1: 1) the mixture was shaken at room temperature for 20 minutes. The solution was then aspirated and the procedure repeated. Sampling showed complete conversion by HPLC / MS. After complete reaction, the resin was washed three times with dichloromethane and used directly for condensation.

General rule for the condensation of resin-bound amino acids with 2'-phthalimidomethyl-2-carboxylic acid (pre-stage 2)

To 100 mg of amino acid-bound resin (0.6 0.8 mmol / g) add a solution of 12.2 mg (0.09 mmol) of HOBT, 29.5 mg (0.09 mmol) of TOTO, 16 μΐ (0, 09 mmol) of DIPEA and 0.09 mmol of 2'-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2) in 5 ml of dimethylformamide and the mixture is shaken for 12 hours at room temperature. The resin is filtered off and washed three times with 10 ml of dimethylformamide, one time with 10 ml of toluene, one time with 10 ml of methanol and three times with 10 ml of dichloromethane.

General rule for the cleavage of a phthalimide protecting group on a support

To 1 g of resin bound Fmoc compound is added to 5 ml of a 10% solution of hydrazine in dimethylformamide and the mixture is shaken for 2 hours at room temperature. The resin is filtered off with suction and washed three times with 10 ml of dimethylformamide each. Taking an analytical sample shows (HPLC / MS) complete conversion.

General formula for condensation with sulphonyl chlorides

To 100 mg of functionalized 2'-aminomethylbiphenyl-biphenyl-2-carboxylic acid bound resin was added a solution of 0.16 mL (0.027 mmol) of DIPEA and 0.027 mmol of sulfonyl chloride in 5 mL of DMF and the mixture was shaken for 12 hours at room temperature. The resin is filtered off and washed three times with 10 ml of dimethylformamide, one time with 10 ml of toluene, one time with 10 ml of methanol and three times with 10 ml of dichloromethane.

General rule for cleavage from resin

The resin was suspended in dichloromethane-trifluoroacetic acid (3 mL / 0.1 g resin) and shaken for 1 hour. The resin was filtered off and washed with 1 ml of dichloromethane. The combined solutions are concentrated on a rotary evaporator. The residue is extracted into dichloromethane and purified by chromatography on silica gel in dichloromethane and ethyl acetate, or purified by preparative HPLC.

In this way, the. prepare, among others, the following products ':'

Chiral structure

MS (ES &lt; + &gt;): m / z =

I2d

534 chiral

506 chiral

structure

MS (ES +): m / z = chiral

12h

582 chiral

chiral

Example 13a

2 - {[2'- (Benzyloxycarbonylaminomethyl) biphenyl-2-carbonyl] amino} -4-methylpentanoic acid

This compound is obtained by saponification of the methyl ester of Example 8r with potassium hydroxide in methanol-water at 6 ° C.

Examples 13b to 13e

Condensation of the acid of Example 13a with the corresponding amines according to the general method described in Example 8 affords the following compounds:

Príkl.č. structure MS (ES): m / z = 13b chiral o y'yX'Y MM _δ 550 1 3c chiral o γΥ ^Ν γΜ ^ (Αο ^λ ν ^ζ > Λ ° οΛ cr m 564 13d chiral o ιΎΥο ^λ νύΑ ° cKn MM Ff 556 13e C Π 1 Γ α ± ΓΤ ä about 'A- 544

Hydrogenolytic cleavage of the Z-protecting group in the compound of Example 13c followed by reaction with the corresponding acid chlorides affords the following compounds:

Prikl.č. structure MS (ES): m / z = 13f chiral O J ⁰ o N ^X 0 my 556 13q chiral X ΥΎτ ' ^ν ' [^ ύ ' ⁰ N — 0 Ν ^ 0 564 13h chiral o ^x ο ν ν Λ Λ ^ F FV 592

The following compound is obtained from the compound of Example 8z analogously to Examples 13a to 13e by hydrolysis and reaction with isopropylamine:

Prikl.č. structure MS (ES): m / z = ° τΑγΎΊ 13i ° N A,> U U A 551

100

General formula for the condensation of (2,4-difluorobenzyl) 2'-aminomethylbiphenyl-2-carboxylic acid amide with carboxylic acids into carboxylamides (Examples 14a to 14f)

A mixture of the appropriate carboxylic acid (0.27 mmol), HOBT (0.27 mmol) and EDAC (0.27 mmol) in 1 mL tetrahydrofuran was stirred for 30 minutes at room temperature. A solution of 2'-aminomethyl-biphenyl-2-carboxylic acid (2,4-difluorobenzyl) amide (9.26 mmol) in tetrahydrofuran (1 ml) was obtained and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with sodium bicarbonate solution and water. After concentration of the organic phase, the products are purified by preparative HPLC.

The following compounds are obtained in this way:

Prikl.č. structure MS (ES): m / z = 14 cc ^ ^N ~ xb ^of 499 14b O ^F 503 14c 0 Ct _x N ^ ^{O'F 0 F} 499 14d 'Er-VS' ⁵ · ' ¹ ? 501 14ε 1 515

101

Prí kl.č. structure MS (ES): m / z = 14 f ₀ a, A ^F -F 521

General Prescription for Suzuki Biphenyl Synthesis by Condensation (Examples 15a to 15b)

To argon saturated dimethoxyethane (10 µl) was added tetrakis-triphenylphosphine palladium (58 mg, 0.05 mmol) and the corresponding bromide (1 mmol). After 10 minutes, 1.5 mmol of the corresponding boronic acid was added and finally 1 ml of 2M sodium carbonate solution (2 mmol) was added. The mixture was refluxed for 18 hours under argon, then cooled and diluted with 30 mL of methylene chloride. It is washed with water and saturated sodium chloride solution, dried over sodium sulphate, the solvent is evaporated and the product is purified by chromatography on silica gel.

Example 15a 2'-tert-Butoxycarbonylaminomethyl) -4-nitrobiphenyl-2-carboxylic acid (3-methylbutyl) amide

According to the general formula of the nitrosubstituted compound, 350 mg of a yellow solid (79% yield) was obtained.

Example 15b

102 2 '- (tert-butoxycarbonylaminomethyl) -4-methoxybiphenyl-2-carboxylic acid (3-methylbutyl) amide

OMe

According to the general formula, the methoxy-substituted oil compound.

170 mg (41% yield) were obtained as a viscous light

Example 16a 2 '- (tert-Butoxycarbonylamino-biphenyl-2-carboxylic acid) (3-methylbutyl) amide

Nitrosubstituted Example 15a (330 mg;

0.75 mmol) was dissolved in ethyl acetate and hydrogenated in the presence of a 10% palladium on charcoal pin at 1 bar hydrogen pressure. After 2 hours, the mixture was filtered through celite and the clear solution was concentrated. Yield 260 mg (84%).

Example 16b 2 '- (Benzyloxycarbonylaminomethyl) -4-hydroxybiphenyl-2-carboxylic acid (3-methylbutyl) amide

103

The methoxy-substituted compound of Example 15b (150 mg; 0.35 mmol) was dissolved in .5. ml of anhydrous methylene chloride and 1.4 ml (1.4 mmol) of a 1 M solution of borontribromide in n-hexane are slowly added to this solution at -70 ° C. After 10 minutes, the reaction mixture was slowly warmed to 0 ° C. After 2 hours at this temperature, the mixture was neutralized with saturated sodium bicarbonate solution, extracted with a total of 40 ml of methylenechoride, dried over sodium sulfate and concentrated. From the obtained crude 2'-aminomethyl-4-hydroxybiphenyl-2-carboxylic acid (3-methylbutyl) amide (88 mg), a portion (30 mg; 0.1 mmol) was dissolved in 3 mL of methylene chloride and 11 mg (0) was added. , 11 mmol) of triethylamine and 27 mg (0.11 mmol) of benzyloxycarbonyloxy succinimide. After 3 hours, the reaction mixture is diluted with methyl chloride, washed with water, the organic phase is dried over sodium sulfate and the product is purified by reverse phase HPLC. 8 mg of 2 '- (benzyloxycarbonylaminomethyl) -4-hydroxybiphenyl-2-carboxylic acid (3-methylbutyl) amide are obtained in the form of a dark oil.

Example 17a (1- [2 '- (3-Methyl-butylcarbamoyl) -biphenyl-2-yl] -ethyl} -carbamic acid tert-butyl ester

104

Dissolve N-Boc- (R) -Phenethylamine (2.2 g; 10 mmol) in 50 mL of anhydrous tetrahydrofuran, cool the solution to -78 ° C and add dropwise 14 mL of a 1.5 M tert-butyllithium solution ( 21 mmol) in pentane. The mixture was warmed to 20 ° C over 2 hours, 4.5 mL (40 mmol) of trimethyl borate was added and the mixture was warmed to room temperature. The mixture was cooled to 0 ° C, acidified to pH 6 with 10% hydrochloric acid, and the aqueous phase was extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried and concentrated. The boronic acid is obtained in the form of a pale yellow, rigid foam which is further processed without further purification.

Suzuki coupling was carried out according to the general procedure (see Example 15) with 1 mmol of 2-bromo-N (3-methylbutyl) benzamide to give 85 mg (0.2 mmol) of the biphenyl derivative after chromatographic purification.

Examples 17b to 17e

Analogously to Example 17a, enantiomer 17b is obtained. By cleavage of the Boc group and conversion to the corresponding carbamates, compounds 17a and 17b are converted to the compounds of Examples 17c to 17c.

17e.

Príkl.č. structure MS (ES &lt; + &gt;;: m / z = '/ P 4.¾ X, / A ί y 0 ' 411 l) jc 0 Λ Ä M 0 445 n at IJ

105

The following compounds were prepared analogously to the procedures described in Examples 1 to 17:

Prikl.č. structure MS (ES): m / z = heehaw and IN yv / 0 18 Y ύυ In n 0 379 1 A 0 C 18b 427 Tii ri LJ M M A 18c ιίΎ 0 LA ΓΪΙ 431 U U A 18d : 0 1 γγ ^ 443 ITF Ύγ RII χγ M

106

107

Prikl.č. structure MS (ES): m / z = 181 XX Χ-, Χ ° 4 87 18 meters , about XXXX ⁰ 395 18n = o CXnY Χ ° ^Λ Χ ⁰ 433 18o Λ X ^ o i o X \ XX 395 18p o CQa ^F o ^A X ^{0 b} 465 1 ôq ⁰ 466

108

Prikl.č. structure MS (ES): m / z = A JA A / ⁿ \ / N 0 1 Y 18r fY ,about II 0 ΐ J 495 U in 1 I 1 A L x. 0 IT lf T LSS . A 0 J 480 AT oX ΓΪ1 X U M F _x P (í A A T n A γ ^Νχ ^ L ^ · 18 tons 487 X. / x 0 íf T Ä M F P tí a A r M about A _γ ο A υ IBU 1 at 489 A Αγχ IL 0 M (A A D 1 1 γζ './ABOUT. And. IL - 0 ΓΤ N \ 18v n 515 AT '' 'M' ' tn M M F. P (í A A r ° VA 0 s γθ A U 18 watts I n 487 x Ar tn 0 M ABOUT Lox A IA. _ (1 χΤχ \ about 473 ll (1 A 1 about Q r 18y the -M - '' · A 0 475

109

Prikl.č. structure MS (ES): m / z = 18z 443 18AA 433 18ab 459 18ac ₀ Ογ ^Ν ^ ΧΚ. -AAn '-'- Ä ⁰ 432 18ad θνί ^ 9χ 478 1 S G Θ N oi-S'O. M (X ^A υ '' 566 18af 1 Π 505

110

Pharmacological experiments

Human Kv1.5 channels are expressed in Xenopus oocytes. Therefore, oocytes from Xenopus laevis are first isolated and cleared of the follicle. Then, in vitro synthesized Kv1.5, which encodes RNA, is injected into these oocytes. After 1-7 days expression of the Kv1.5 protein, Kv1.5 currents are measured on the oocytes by a two-microelectrode voltage-clamp technique. In this case, the Kv1.5 channels are usually activated by voltage jumps of 0 mV and 40 mV, which last for 500 ms. The bath is washed with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl ₂ 1.8 mM, MgCl ₂ 1 mM, HEPES 5 mM (titrated NaOH to pH 7.4). These experiments are carried out at room temperature. A Geneciamp amplifier (Axon Instruments, Foster City, USA) and a MacLab D / A converter and Software (ADInstruments, Castie Hill, Australia) were used to obtain values and analysis. The test compounds of the invention are added at various concentrations to the bath solution. The effect of the compounds is calculated as the percentage inhibition of the control current Kv1.5 that is obtained when no compound is added to the solution. The data is then extrapolated using the Hill equation to obtain inhibitory concentrations of IC50 for the individual compounds.

In this way, the following IC ₅₀ values were obtained for the following compounds:

Example IC50 Example IC50 Example IC ₅₀ Example IC ₅₀ no. [ΜΜ] no. [ΜΜ] no. [ΜΜ] no. [ΜΜ] la 6.1 2 2.6 4a 4.1 6h 3.0 lb 3, 3 2b 0.8 4c 1.4 7a ~ 6, 0 ld ' -1.0 2c 0.7 · · 4d 1.8 8a 0, 3 le 0, 5 2d 1.7 4 g 3.4 8b 0.9 lf 0.4 2e 3.4 4h 1.8 8d 6, 4 ig 0.4 2f 7.1 4i 4.7 8j 4.5 lh 4.3 2 g 3.3 4J 7.1 8k 3, 1 when 1.7 2h 2.5 4k 2.2 81 3, 5 lj 0.2 2i 3.3 41 0.8 8 m 5.2 lk 2.4 2J 2.5 5a 4.5 8N 3.7 11 1.4 2k 3.8 5c 7.8 80 8.4 lm 0.7 2 m 2.6 5d 1.9 8p 1.4 ln 1.4 3d 1.7 5e 7.2 8Q 7.3 lo 4.4 3k 2.4 6a 4.4 8R 1.0 lr 0.8 31 2.6 6b 1.8 8s 1.0 ls 1.7 3p 1.9 6c 2.5 8x 3.3 lt 1.3 3r 1.5 6d 3, 1 8y 2.8 lu 0, 8 3 3.0 6e 3, 6 8t 1.6 8a.alph 0.8 8AB 1.2 8ac 1, i 9b 3.0 9c 2.0 9f 2.2 9 g 2.2 11 2.3 11b 7.3 LLD 3.3 ng 7.8 IIh 5, 8 111 2.7 11 meters 3.3 LLN 5, 9 LLO 4.4 llp 7.3 12c 11.2 12f 11.3 12 grams 9.1 12h 4.8 121 10, 3 12 meters 7.7 13b -3.0 13c 1.4 13d 0.5 13e 2.8 13f 3.4 i3G 1.1 13h 1.4 13i 1.2 14 3.6 14b 2.7 14d 2.0 14e 0, 8 14f 2.5 15b 3, 1 16b 5.2 18 7.2 18b 0.4 18c 4.2 18d 0.4 18e 1.7 18f 1.3 18 grams 3.9 18h ABOUT 00 18i 0.4 18 j 0.7 18k 3.0 18 meters 2.1 18n 0.4 18o 3, 6 18p 4.7 18q 3.2 18r 0.7 18s 0.9 18U 1.1 18v 0.4 18 watts 5.4 18x 4.6 17d 1.3 17e 1.8 17c 2.1 18y 1.9 18z 1.2 18AA 0.4 18ab 1.1 18ac 10 18ad 0, 3 18af 5.8 18Ah 2.1 18ai 6, 6

112

Claims (17)

Compounds of formula I in which: R ¹ is C (O) OR ⁹ , SO ₂ R ¹⁰ , COR ¹¹ , C (O) NR ¹² R ¹³ or C (S) NR ¹² R ¹³ ; R ⁹ is C _x H ₂ -R ¹⁴ ; x is 0, 1, 2, 3 or 4, wherein x cannot be 0 when R ¹⁴ is OR ¹⁵ or SO ₂ Me; R ¹⁴ is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF ₃ , C ₂ F ₅ , C 3 F 7, CHF ₂ , CH ₂ F, OR ¹⁵ , SO ₂ Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, naphthyl, biphenylyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted with 1, 2 or 3 substituents selected from from the group: fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, NH ₂ group, OH group, alkyl group, which contains 1, 2, 3 or 4 carbon atoms, an alkoxy group which: it contains 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; R ¹⁵ is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, a CF ₃ group or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, iodine, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH , alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; ^Lu R, R ^{and ± 1} and R independently of one another are defined as R ^9; R ¹³ is a hydrogen atom, an alkyl group containing 1, 2, 3 or 4 carbon atoms, or CF ₃ ; R ² is H, alkyl having 1, 2, 3 or 4 carbon atoms or CF _3; R ³ is C _y H _2y -R ¹⁶ ; y is 0, 1, 2, 3 or 4, 114 wherein y cannot be 0 when R ¹⁶ is OR ¹⁷ or SO 2 Me; R ^1c is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, a CF 3 group, C2F5 group, a group of C3F7 group, CH 2 F, CHF ?, ⁱ⁷ is oR group, SO2 Me, phenyl, naphthyl, furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7 , 8 or 9 carbon atoms, wherein the phenyl, naphthyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, atom iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy a group containing 1, 2, 3 or 4 carbon atoms; a ylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group; R 'is a hydrogen atom, an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl, wherein the phenyl or 2-, 3- or the 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl containing 1, 2, 115 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; or R ³ is CHR ¹⁸ R ¹⁹ ; R ^1? is hydrogen or C _of H ₂ -R ¹⁶ , wherein R ¹⁶ is as defined above; z is 0, 1, 2 or 3; R ¹⁹ is COOH, CONH ₂ , CONR ²⁰ R ²¹ , COOR ² , CH ₂ OH; is a hydrogen atom, an alkyl group that contains 1, 2, 3, 4 or 5 carbon atoms; C _in H _{2 in} -CF ₃ or C _w H _2w -phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group of fluorine, chlorine, bromine, iodine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl containing 1, 2, 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; R ²¹ is a hydrogen atom or an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms; 116 R ²² is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms; R ⁴ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms, or a CF ₃ group; or R ³ and R ⁴ together form a chain of 4 or 5 methylene groups in which the methylene group may be replaced by -O-, -S-, -NH-, -N (methyl) - or a group. -N (benzyl) -; R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R ( ³⁰⁾ , R ( ³¹⁾ independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R ^JU , R ³¹ together form a chain of 2 methylene groups; and pharmaceutically acceptable salts thereof. Compounds of formula I according to claim 1, wherein R ¹ is C (O) OR ^9, SO ₂ R ^10, COR ¹¹ or C (0) NR ¹³ R ^P-; R ⁹ is C _x H ₂ -R ¹⁴ ; x is 0, 1, 2, 3 or 4; where x cannot be 0 when R ¹⁴ is OR ¹⁵ ; 117 R ¹⁴ is an alkyl group containing 1, 2, 3 or 4 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF 3, C ₂ F ₅ , OR ¹⁵ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5 , 6, 7, 8 or 9 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted. 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, N0 _2, CN, COOMe, CONH ₂ group, COMe, NH ₂ , contains 1, 2, 3 or 1, dimethylamino, methylsulfonyl, and a group; OH, alkyl having 1 carbon atoms, alkoxy 2, 3 or 4 carbon atoms, sulfamoyl, and methylsulfonylamino is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4 , 5 or 6 carbon atoms, CF ₃ , or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from fluorine, chlorine, bromine, CF 3, NO ₂ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino; R ^u, R ¹¹ and R ¹² independently of one another are defined as R ^9; 118 R ¹³ is a hydrogen atom, an alkyl group containing 1, 2, 3 or 4 carbon atoms, or CF ₃ ; is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or CF ₃ ; is C ₁ H 2 ₁ -R ^1c ; y is 0, 1, 2, 3 or 4, wherein y cannot be 0 when R ¹⁶ is OR ¹ '; R ¹ ® is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, C2F5, OR ^17, phenyl, furyl, thienyl or nitrogen heteroaromate containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or are substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, CF 3, OCF 3, NO 2, CN, COOMe, CONH ₂ , COMe, NH 2, OH an alkyl group containing 1, 2, 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; H ¹⁷ is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4- pyridyl, wherein the phenyl or 2-, 3- or 4-pyridyl group are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of: 119 includes a fluorine atom, a chlorine atom, a bromine atom, a group CF ₂ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; or R ³ is CHR ¹⁸ R ¹⁹ ; R ¹⁸ is hydrogen or C _of H ₂ -R ¹⁶ , wherein R ¹⁶ is as defined in claim 1; z is 0, 1, 2 or 3; R ¹⁹ is CONH 2, CONR ²⁰ R ²¹ , COOR ²² , CH 2 OH; R ²⁰ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, C _in H _{2 in} -CF 3 or C _w H _2w -phenyl, wherein the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine , bromine, CF ₃ , OCF ₃ , NO ₂ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, a methylsulfonylamino group; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; 120 R ²¹ is a hydrogen atom or an alkyl group it contains 1, 2, 3, 4 or 5 carbon atoms; R ² - is alkyl having 1, 2, 3, 4 or 5 carbon atoms; R ⁴ is a hydrogen atom, an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms, or a CF ₃ group; R ^{I ',} R ^c, R and ^R independently of one another are H, F, Cl, Br, CF _3, NO ₂ group, a CN group,. COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R ( ³⁰⁾ and R ( ³¹⁾ independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R ³⁰ and R ^3x together form a chain of 2 methylene groups; and pharmaceutically acceptable salts thereof. Compounds of formula I according to claims 1 or 2, wherein R 'is C (O) OR ^? , SO ₂ R ^u, COR 'or C (O) NR ¹² R ^13; R ^? is C _x H _{2 x} -R ¹⁴ ; x is 0, 1, 2, 3 or 4, wherein x cannot be 0 when R ¹⁴ is OR ¹⁵ ; R ¹⁴ is a cycloalkyl group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR ¹⁵ , phenyl, furyl, thienyl 121 or a nitrogenous heteroaromate containing 3, 4 or Wherein the phenyl, furyl, thienyl and nitrogen heteroaromates are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino ; R ' ³ is an alkyl group containing 1 or 2 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, a group which is substituted by 1 or 2 CF ₃ group or a phenyl unsubstituted group or is a substituent selected from a fluorine atom, a chlorine atom, a bromine atom, a CF ₃ group, a CN group, a COOMe group, a CONH ₂ group, a COMe group, an OH group, an alkyl group containing 1, 2 or 3 carbon atoms, an alkoxy group contains 1 or 2 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group and a methylsulfonylamino group; and R ¹² are independently defined as R ³ ; R ¹ 'is hydrogen; is a hydrogen atom or an alkyl group containing 1, 2 or 3 carbon atoms; R ³ is CHR ¹⁸ R ¹⁹ ; R ¹⁸ is hydrogen or C _of H ₂ -R ¹⁶ ; z is 0, 1, 2 or 3; 122 R ¹⁹ is CONH ₂ , CONR ²⁰ R ²¹ , COOR ²² or CH ₂ OH; R ²⁰ is H, alkyl having 1, 2, 3, 4 or 5 carbon atoms, _the C H _2v -CF ₃ or C _w H _{2 watts} phenyl, wherein the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, chlorine, bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, OH, alkyl containing 1 2 or 3 carbon atoms, an alkoxy group containing 1 or 2 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, a methylsulfonylamino group; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; R ²¹ is a a hydrogen atom or an alkyl group, which It contains 1 2, 3, 4 or 5 carbon atoms; R ²² is a an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms; R ¹⁶ is a an alkyl group containing 1, 2 or 3 atoms carbon, a cycloalkyl group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, a CF ₃ group, OR ¹⁷ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: that includes fluorine, chlorine, bromine, CF ₃ , OCF ₃ , 123 CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino; R 6 is an alkyl group containing 1, 2, 3 or 4 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, a CF ₃ group, a phenyl group or a 2-, 3- or 4-pyridyl group wherein the phenyl or 2-, 3- or 4-pyridyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CF ₃ group, OCF ₃ group, CN, COOMe, CONH:, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl a methylsulfonyl group, a methylsulfonylamino group; R ⁴ is a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms; R ⁵ , R ⁶ , R 'and R ⁹ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , CN, CCCMe, sAcina COMe, NH ₂ , OH, alkyl containing 1, 2 or 3 carbon atoms, an alkoxy group containing 1 or 2 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, a methylsulfonylamino group; R ³⁰ and R ³¹ independently of one another are hydrogen or methyl; or R ³⁰ and R ³¹ together form a chain of 2 methylene groups; 124 and pharmaceutically acceptable salts thereof. Compounds of formula I according to claims 1 or 2, wherein R ¹ is C (O) OR ⁹ , SO 2 R ¹⁰ , COR ¹¹ or C (O) NR ¹² R ¹³ ; R ⁹ is C _x H ₂ -R ¹⁴ ; x is 0, 1, 2, 3 or 4, wherein x cannot be 0 when R ¹⁴ is OR ¹⁵ ; R 'is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR ¹⁵ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and nitrogen heteroaromate are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, Cl, Br, _CF3, a group _OCF3, CN, COOMe, CONH _2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino; is an alkyl group containing 1 or 2 carbon atoms, a cycloalkyl group containing 3, 4, 5 or 6 carbon atoms, a group which is substituted by 1 or 2 CF ₃ group or a phenyl unsubstituted group or is a substituent selected from the group consisting of includes fluorine atom, chlorine atom, bromine atom, CF ₃ group, CN group, COOMe group, 125 CONH ₂ , COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino; R ¹¹ , R ¹¹ and R ¹² are independently defined as R ⁹ ; R ¹³ is hydrogen; R ² is H or alkyl having 1, _2; or 3 carbon atoms; R ³ is C _y H _2y -R ¹⁶ ; y is 0, 1, 2, 3 or 4, wherein y cannot be 0 when R ¹⁶ is OR ¹⁷ ; R ¹⁶ is an alkyl group containing 1, 2 or 3 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF ₃ , OR ¹⁷ , phenyl, furyl, thienyl or nitrogen heteroaromate containing 3, 4 or 5 carbon atoms, wherein the phenyl, furyl, thienyl and the nitrogen heteroaromates are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, CF ₃ , OCF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl, methylsulfonylamino; R ¹⁷ is an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, a cycloalkyl group containing 3, 126 4, 5 or 6 carbon atoms, CF ₃ , phenyl or 2-, 3- or 4-pyridyl, wherein the phenyl or 2-, 3- or 4-pyridyl group are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, CF ₃ group, OCF ₃ group, NO ₂ group, CN group, COOMe group, CONH ₂ group, COMe group, OH group, alkyl group containing 1, 2, 3 or 4 carbon atoms, an alkoxy group containing 1, 2, 3 or 4 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group, and a methylsulfonylamino group; H ⁴ is a hydrogen atom or an alkyl group containing 1 or 2 carbon atoms; R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, chlorine, bromine, CF ₃ , CN, COOMe, CONH ₂ , COMe, NH ₂ , OH an alkyl group containing 1, 2 or 3 carbon atoms, an alkoxy group containing 1 or 2 carbon atoms, a dimethylamino group, a sulfamoyl group, a methylsulfonyl group or a methylsulfonylamino group; R ³⁰ and R ³¹ independently of one another are hydrogen or methyl; or R ³⁰ and R ³¹ together form a chain of 2 methylene groups; and pharmaceutically acceptable salts thereof. Compounds of formula I according to one or more of claims 1, 2 or 4, wherein R ¹ is C (O) OR ^S , SO ₂ R ¹⁰ , COR ⁿ , C (O) NR 11 R ¹³ ; or 127 R ⁹ is C _x H ₂ -R ¹⁴ ; x is 0, 1, 2 or 3; R ¹⁴ is an alkyl group having 1, 2, 3 or 4 carbon atoms, a cycloalkyl group having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, a CF ₃ group, a phenyl group or a pyridyl group, phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , OH, alkyl having 1, 2 or 3 carbon atoms and an alkoxy group containing 1 or 2 carbon atoms; R ¹⁰ , R ¹¹ and R ¹² are independently defined as R ⁹ ; R ¹³ is hydrogen; R ² is H; R ³ is C _y H _2y -R ^16; y is 0, 1 or 2; R ¹⁶ is an alkyl group containing 1, 2 or 3 carbon atoms, a cycloalkyl group containing 5 or 6 carbon atoms, a CF ₃ group, a phenyl group or a pyridyl group, wherein the phenyl group and the pyridyl group are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine, chlorine, CF ₃ , OCF ₃ , OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms; R is hydrogen; 128 R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, CF ₃ , CN, COOMe, CONH ₂ , NH ₂ , OH, alkyl containing 1, 2 or 3 carbon atoms or an alkoxy group containing 1 or 2 carbon atoms; R ³⁰ and R ³¹ independently of one another are hydrogen or methyl; or R ³⁰ and R ³¹ together form a chain of 2 methylene groups; and pharmaceutically acceptable salts thereof. Compounds of formula I according to one or more of claims 1, 2, 4 or 5, wherein: R ¹ is C (O) OR ⁹ or COR ¹¹ ; R ⁹ is C _x H ₂ -R ¹⁴ ; R 2 is 0, 1, 2 or 3; R ¹⁴ is a cycloalkyl group containing 5 or 6 carbon atoms or a phenyl group wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of fluorine atom, chlorine atom, CF ₃ group, OCF ₃ group, alkyl group a group containing 1, 2 or 3 carbon atoms and an alkoxy group containing 1 or 2 carbon atoms; R ¹¹ is defined as R ⁹ ; R ² is H; R ³ is C _y H _2y -R ¹⁶ ; y is 0, 1 or 2; 129 R ¹⁶ is an alkyl group containing 1, 2 or 3 carbon atoms, a cycloalkyl group containing 5 or 6 carbons, a CF ₃ group, a phenyl group or a pyridyl group, the phenyl and pyridyl groups being unsubstituted or substituted by 1 or 2 substituents selected from fluoro, chloro, CF ₃ , OCF ₃ , alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms; R ⁴ is hydrogen; R ⁵ , R ⁶ , R ⁷ and R ⁸ independently of one another are hydrogen, fluorine, CF ₃ , alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms; R ³⁰ and R ³¹ are hydrogen; and pharmaceutically acceptable salts thereof. Compounds of formula I according to one or more of claims 1 to 6 and pharmaceutically acceptable salts thereof for use as medicaments. Pharmaceutical composition, characterized in that it contains an effective amount of at least one compound of the formula I according to one or more of claims 1 to 6, and / or a pharmaceutically acceptable salt thereof, as active ingredient, together with pharmaceutically acceptable carriers and additives, and optionally with one or more other pharmacologically active substances. ^{9 * *} Use of a compound of the formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament having a blocking effect on the K * channel for The treatment and prophylaxis of diseases mediated by the K ^{@ +} channel. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapy and prophylaxis of cardiac rhythm disorders which can be eliminated by prolonging the action potential. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapy and prophylaxis of reentry arrhythmias. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapy and prophylaxis of supraventricular arrhythmias. Use of a compound of formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapy and prophylaxis of atrial fibrillation or atrial flutter. Use of a compound of the formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof for the preparation of a medicament for stopping atrial fibrillation or atrial flutter. A pharmaceutical composition comprising an effective amount of at least one compound of the formula I according to one or more of claims 1 to 5 and / or a pharmaceutically acceptable salt thereof, as well as an IKr-channel blocker as active ingredients, together with pharmaceutically acceptable carriers and ingredients. 131 Pharmaceutical composition, characterized in that it contains an effective amount of at least one compound of the formula I according to one or more of claims 1 to 6 and / or a pharmaceutically acceptable salt thereof and an IKs-channel blocker as active ingredients, together with pharmaceutically acceptable carriers and ingredients. A pharmaceutical composition comprising an effective amount of at least one compound of the formula I according to one or more of claims 1 to 6 - and / or a pharmaceutically acceptable salt thereof and a betabolocator as active ingredients, together with pharmaceutically acceptable carriers and excipients.