HRP20020264A2 - 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

Description

The invention relates to compounds of formula I,

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in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31 ) have the following meanings, both in their production and their use, especially in medicines.

Compounds of formula I were not known until now. They act on the so-called Kvl.5 potassium channels and in the human heart atrium inhibit the potassium current, which is designated as "ultra-rapidly activating delayed rectifier". Therefore, these compounds are particularly suitable as new antiarrhythmic active substances, especially for the treatment and prophylaxis of atrial arrhythmias, eg atrial flutter (atrial fibrillation, AF) or atrial flutter (atrial flutter).

Atrial fibrillation (AF) and atrial flutter are the most common cardiac arrhythmias. These phenomena are increasingly common in old age and often lead to fatal consequences, such as stroke. AF hits approx. 1 million Americans annually and each year leads to more than 80,000 strokes in the USA. Class I and III antiarrhythmics that are currently used reduce the rate of AF recurrence, however, due to their possible proarrhythmic side effects, they are only used to a limited extent. Therefore, there is a great medical need for the development of better drugs for the treatment of atrial arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094 -1106; "Newer developments in the management of atrial fibrillation").

Most supraventricular arrhythmias have been shown to be caused by so-called "Reentry" excitation waves. Such reentries appear when the heart tissue has slow conduction and at the same time very short periods of refraction. Increasing the myocardial refraction time by prolonging the action potential is a recognized mechanism for interrupting arrhythmias, i.e. for preventing their occurrence (T.J. Colatsky et al., Drug Dev. Res. 19, 1990, 129-140; "Potassium channels as targets for antiarrhythmic drug action") . The length of the action potential is determined mainly by the "measure of the repolarizing" K+ current that exits the cells through various K+ channels. At the same time, the so-called "delayed rectifier" IK, which consists of 3 different components: IKr, IKS and IKur, is of particular importance.

Most of the known class III antiarrhythmics (eg, dofetilide, E4031 and d-sotalol) block predominantly or exclusively the fast-acting IKr potassium channels, which can be found in both human ventricular cells and the atria. However, these compounds have been shown to have an increased risk of proarrhythmia at a low or normal heart rate, with arrhythmias designated as "Torsades de pointes" being particularly observed (D.M. Rođen, Am. J. Cardiol. 72, 1993, 44B- 49B; "Current status of class III antiarrhythmic drug therapy"). In addition to this high risk, which is partially fatal at a lower frequency, it would be necessary for IKr-blockers to prove their effectiveness under conditions of tachycardia, where the effect is really needed ("negative use-dependence").

While some of these drawbacks can probably be overcome with slow-acting component (SKB) blockers, their efficacy has not been known until now, as no clinical studies with IKs-channel blockers have been known.

The components of the delayed rectifier IKur (= ultra-rapidly activating delayed rectifier), which are activated "especially quickly" and are deactivated very slowly, and which correspond to channel Kvl.5, it has a special role for the duration of repolarization in the human atrium. For this reason, compared to inhibiting IKr or Iks, inhibition of the outgoing potassium current IKur represents a particularly effective method for prolonging the atrial action potential and thus for terminating or preventing atrial arrhythmias. Mathematical models of the human action potential show that the positive effect of IKur blockade should be especially pronounced under the pathological conditions of chronic atrial fibrillation (M. Courtemanche, R.J. Ramirez, S. Nattel, Cardiovascular Research 1999, 42, 477-489; "Ionic targets for drug therapy and atrial fibrillation-induced electrical - remodeling: insights from a mathematical model").

Contrary to IKr and IKS, which also occur in the human ventricle, IKur has a significant role in the human atrium, but not in the ventricle. Therefore, when inhibiting the IKur current, the risk of a proarrhythmic effect on the ventricle is immediately excluded, which is the opposite of IKr or IKS blockade (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 Ventricular Myocytes"; G. J. Amos et al., J. Physiol . 491, 1996, 31-50: "Differences between outward currents of human atrial and subepicardial ventricular myocytes").

Antiarrhythmics that work through selective blockade of the IKur current, that is, the Kvl.5 channel, were not available on the market until now. Blocking action on Kvl.5 channels has been described for numerous pharmaceutical active substances (eg tedisamil, bupivacaine or sertindole), but here Kvl.5 blockade represents only a secondary effect, in addition to other main effects of the substance.

In WO 98 04521 the subject of patent claims are amino-indanes as potassium channel blockers, which block Kvl.5 channels. In patent applications WO 98 18475 and WO 98 18476, the subject of the patent claims is the use of various pyridazinones and phosphine oxides as antiarrhythmics, which act through IKuz blockade. However, the same compounds were previously described as immunosuppressive (WO 96 25936). The compounds that were described in the mentioned patent applications are structurally completely different from the compounds according to the invention of this application.

It has now surprisingly been found that the 2'-substituted 1,1'-biphenyl-2-carbonamides described herein are potent blockers of human Kv1.5 channels. Therefore, they can be used as new antiarrhythmics with a particularly favorable safety profile. They are particularly suitable compounds for the treatment of supraventricular arrhythmias, eg atrial flutter or atrial flutter.

These compounds can be used to stop existing atrial fibrillation or flutter to re-prolong sinus rhythm (cardio version). In addition, these substances reduce the possibility of the occurrence of new flutter stimuli (sinus rhythm formation, prophylaxis).

The compounds of the invention were not known until now. Some structurally related compounds are described in Helv. Chem. Acta 1994 (70) 70 and in the literature cited there. However, the peptide compounds described there (eg compound A) are not known to have any potassium channel blocking activity. In addition, due to the numerous peptide bonds, such compounds would have to have too low a metabolic stability to be used as antiarrhythmics.

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Another similar compound (compound B) is mentioned in the European patent application EP 0620216. Compound B and all other compounds from that application are characterized by the fact that those in the R(3) position carry special substituents (e.g. benzoyl-1,2,3, 4-tetrahydroisoquinoline), which are not included in the compounds according to the invention in this application. The compounds listed in EP 0620216 act as vasopressor antagonists and thus have a completely different biological effect than the Kvl.5 channel blockers described here.

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The proposed invention relates to compounds of formula I,

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where

R(1) is C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13);

R(9) is CxHx-R(14);

x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15) or SO2Me;

R(14) is alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, cyclo-alkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3, C2F5 , C3F7, CH2F, CHF2, OR(15), SO2Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms,

wherein phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted by si, 2 or 3 substituents selected from the group they comprise. F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C- atoms, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino;

R(15) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

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

R(13) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(2) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(3) is CyH2y-R(16);

y is 0, 1, 2, 3 or 4,

where i cannot be O if R(16) represents OR(17) or SO2Me;

R(16) is alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3, C2F5, C3F7 , CH2F, CHF2, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms,

wherein phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2 , COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl,

wherein phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

R(3) is CHR(18)R(19);

R(18) is hydrogen or C2H2z-R(16), wherein R(16) is as defined above;

z is 0, 1, 2 or 3;

R(19) is COOH, CONH2, CONR(20)R(21), COOR(22), CH2OH;

R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or CwH2w-phenyl,

wherein the phenyl ring is unsubstituted or substituted by si, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, 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 with 1, 2, 3, 4 or 5 carbon atoms;

R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(4) is hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;

or

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

R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, J, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl s 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

R(30) and R(31) independently represent hydrogen or alkyl with 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.

Preferred compounds of formula I are those in which

R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);

R(9) is CxH2x-R(14);

x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15);

R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, C2F5, OR(15), phenyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms,

wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2 , OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms , dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

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

R(13) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(2) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3;

R(3) is CyH2y-R(16);

y is 0, 1, 2, 3 or 4, wherein y cannot be 0 if R(16) represents OR(17);

R(16) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, C2F5, OR(17), phenyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5% 6, 7, 8 or 9 C-atoms,

wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2 , OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3-, or 4-pyridyl, wherein phenyl or 2-, 3-, or 4-pyridyl unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH , alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamail, methylsulfonyl and methylsulfonylamino; or

R(3) is CHR(18)R(19);

R(18) is hydrogen or CzH2z-R(16), wherein R(16) is as defined above in claim 1;

z is 0, 1, 2 or 3;

R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH;

R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or CwH2w-phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consist of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-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 with 1, 2, 3, 4 or 5 carbon atoms;

R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(4) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, CF3;

R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

R(30) and R(31) independently represent hydrogen or alkyl with 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 compounds of formula I are those in which

R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);

R(9) is CxH2x-R(14);

x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15);

R(14) is cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(15), phenyl, furyl, thienyl or heteroaromatic containing N with 3, 4 or 5 C-atoms ,

wherein phenyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3,OCF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1 , 2 or 3 C-atoms, 1- or 2-C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) is alkyl with 1 or 2 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl , Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 C-atoms, alkoxy with 1 or 2 C-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 hydrogen or alkyl with 1, 2 or 3 carbon atoms;

R(3) is CHR(18)R(19);

R(18) is hydrogen or CzH2z-R(16);

z is 0, 1, 2 or 3;

R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH;

R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or CwH2w-phenyl,

wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, or 3 C -atom, 1 or 2 C-atom alkoxy, 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 with 1, 2, 3, 4 or 5 carbon atoms;

R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(17), phenyl, furyl, thienyl or heteroaromatic which contains N with 3, 4 or 5 C-atoms, whereby phenyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN .

R(17) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl,

wherein phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4) is hydrogen or alkyl with 1 or 2 carbon atoms;

R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms, 1- or 2-C-alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

R(30) and R(31) independently represent 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 compounds of formula I are also those in which

R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);

R(9) is CxH2x-R(14);

x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15);

R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(15), phenyl, furyl, thienyl or N-containing heteroaromatic with 3, 4 or 5 C-atoms, wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3 , CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 C-atoms, alkoxy with 1 or 2 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) is alkyl with 1 or 2 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl , Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 C-atoms, alkoxy with 1 or 2 C-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 hydrogen, alkyl with 1, 2 or 3 carbon atoms;

R(3) is C1H21-R(16);

y is 0, 1, 2, 3 or 4, wherein y cannot be 0 if R(16) represents OR(17);

R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(17), phenyl, furyl, thienyl or heteroaromatic which contains N with 3, 4 or 5 C-atoms,

wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms, 1- or 2-C-alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, whereby phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCP3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(4) is hydrogen or alkyl with 1 or 2 carbon atoms; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms, 1- or 2-C-alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;

R(30) and R(31) independently represent hydrogen or methyl; or

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

as well as their pharmaceutically acceptable salts.

Particular preference is given to those compounds of formula I in which

R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);

R(9) is CxH2x-R(14);

x is 0, 1, 2 or 3;

R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, phenyl or pyridyl, wherein phenyl and pyridyl are unsubstituted or are substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms;

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

R(13) is hydrogen;

R(2) is hydrogen;

R(3) is CyH2y-R(16);

y is 0, 1 or 2;

R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 5 or 6 C-atoms, CF3, phenyl or pyridyl,

wherein phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms;

R(4) is hydrogen;

R(5), R(6), R(7) and R(8) independently represent hydrogen, F, CF3, CN, COOMe, CONH2, NH2, OH, alkyl with 1, 2 or 3 C-atoms or alkoxy with 1 or 2 carbon atoms;

R(30) and R(31) independently represent 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 compounds of formula I are those in which

R(1) is C(O)OR(9) or COR(11);

R(9) is CxH2x-R(14);

x is 0, 1, 2 or 3;

R(14) is cycloalkyl with 5 or 6 C-atoms or phenyl, whereby phenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C -atoms and 1 or 2 C-atom alkoxy;

R(11) is defined as R(9);

R(2) is hydrogen;

R(3) is CyH2y-R(16);

y is 0, 1 or 2;

R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 5 or 6 C-atoms, CF3, phenyl or pyridyl,

wherein phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms;

R(4) is hydrogen;

R(5), R(6), R(7) and R(8) independently represent hydrogen, F, CF3, alkyl with 1, 2 or 3 C-atoms or alkoxy with 1 or 2 C-atoms;

R(30) and R(31) represent hydrogen;

as well as their pharmaceutically acceptable salts.

Alkyl residues and alkylene residues can have a straight or branched chain. This also applies to alkylene radicals of the formulas CxH2x, CyH2y, CzH2z, CvH2v and CwH2w. Alkyl radicals and alkylene radicals can also have a straight or branched chain if they are substituted or if they are found in other radicals, for example in an alkoxy radical or in a fluorinated alkyl radical. Examples of alkyl radicals are 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, nonadecyl, eicosyl. Divalent residues derived from these residues, for example 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. are examples of alkylene radicals.

Cycloalkyl residues can also be branched. Examples of cycloalkyl radicals with 3 to 11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl, cyclo-heptyl, cyclooctyl, etc.

Examples of heteroaromatics containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are in particular 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl , 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or - 5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2 ,4-oxadiazol-3-oder 5-yl, 1,3,4-oxadiazol-2-yl or –5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1 ,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3 - or 4-pyridyl, 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-benz-imidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7 - or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, -7- or 8-quinazolinyl, 3- , 4-, 5-, 6-, 7- or 8-cinolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Also included are the corresponding N-oxides of these compounds, i.e. 1-oxy-2-, 3- or 4-pyridyl.

Of the N-containing heterocycles, pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl are particularly preferred.

Pyridyl is both 2-, 3-, and also 4-pyridyl. Thienyl is both 2- and 3-thienyl. Furyl is both 2- and 3-furyl.

Monosubstituted phenyl residues can be substituted in position 2, 3 or 4, disubstituted in positions 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5, and trisubstituted in positions 2,3,4 , 2,3,5, 2,3,6, 2,4,5, 2,4,6 or 3,4,5. The corresponding applies in the same sense also analogously for heteroaromatics containing N, thiophene or furyl residues.

In di- or trisubstitution of the residue, the substituents can be the same or different.

If R(3) and R(4) together form a chain of 4 or 5 methylene groups, one methylene group of which can be replaced by -O-, -S-, -NH-, etc., then these residues together with the nitrogen atom of formula I form a 5- or 6-membered nitrogen-containing heterocycle, such as pyrrolidine, piperidine, morpholine, thiomorpholine, etc.

If the compounds of formula I contain one or more acidic or basic groups, i.e. one or more basic heterocycles, then the invention also includes corresponding physiologically or toxicologically tolerable salts, especially pharmaceutically usable salts. Thus, the compounds of formula 1 bearing acidic groups, e.g. one or more COOH groups, can be used, for example, as salts of alkali metals, preferably sodium or potassium salts, or as salts of alkaline earth metals, e.g. calcium or magnesium salts, or as ammonium salts , eg as a salt with ammonia or organic amines or amino acids. Compounds of the formula I which carry one or more basic groups, i.e. groups that can be protonated, or one or more basic heterocyclic rings, then they can also be used in the form of their physiologically tolerable acid addition salts with inorganic or organic acids, for example as hydrochlorides . Salts from the compounds of formula I can be obtained by usual procedures, for example by combining an acid or a base in a solvent or dispersing agent or also by anion exchange from other salts.

With certain substitution, the compounds of formula I can also exist in stereoisomeric forms. If the compounds of formula I contain one or more centers of asymmetry, they can independently have an S- or R-configuration. The invention includes all possible stereoisomers, eg enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, eg enantiomers and/or diastereomers, in any ratio. Enantiomers belong to the invention, for example, also in enantiomerically pure form, and also as left- or right-pointing antipodes, and also in the form of a mixture of two enantiomers in the most varied proportions or in the form of a racemate. Individual stereoisomers can be produced as desired by separating the mixture by conventional procedures or, for example, by stereoselective synthesis. In the case of the presence of mobile hydrogen atoms, the proposed invention also covers all tautomeric forms of the compounds of formula I.

Compounds of formula I can be produced by various chemical processes, which also fall within the scope of the proposed invention. Several typical pathways are shown as reaction sequences designated below as Schemes 1, 2, 3 and 4. The residues R(1) to R(8) used herein are in each case defined as above unless otherwise specified. otherwise.

Thus, for example, the compound of formula I is obtained according to scheme 1 by starting from the diphenic acid anhydride derivative of formula II, as precursor II, which is commercially available, that is, which is known from the literature. Reduction of compound II with sodium borohydride is followed by conversion with potassium phthalimide, as described in Tetrahedron 45 (1989) 1365-1376, to give the biphenylcarboxylic acid of formula IV. Connection with an amine of the formula HNR(3)R(4) and then hydrazinolysis of phthalimide gives an aminomethyl compound of the formula VI, from which, by conversion with the corresponding derivative of the formula R(1)-X, a compound of the formula I of the invention is obtained, in which the formula R(2) is hydrogen, and R(1), R(3), R(4), R(5), R(6), R(7) and R(8) are as defined above. Final alkylation with a suitable alkylating agent of formula R(2)-Y, where Y is a nucleophilic leaving group, eg Cl, Br or J, gives the corresponding compound of formula I, where R(2) is alkyl with 1 to 4 C-atoms.

Alternatively, the biphenyl carboxylic acid of the formula IV can also be converted by hydrazinolysis to the amino carboxylic acid of the formula VII, which is then converted by the reaction of the amino group with the compounds of the formulas R(1)-X and R(2)-Y and then by amidation of the carboxylic acid with the amine of the formula HNR( 3)R(4) can translate into a compound according to the invention of formula I (scheme 2).

In most cases, it is advisable to first produce the compounds of formula 1a according to the invention (Scheme 3), in which R(9) represents a residue that can be easily cleaved, such as tert-butyl or benzyl, by the previously mentioned methods. After removal of the appropriate protective group, e.g. with trifluoroacetic acid if it is a Boe group or catalytic hydrogenation if it is a benzyloxy-carbonyl residue, compounds of the formula IX are obtained, which are then converted again with compounds of the formula R(1)- X can be converted into other compounds of formula I according to the invention.

Another possibility for the preparation of the compounds according to the invention consists in coupling phenyl bromide or iodide of formula X with phenylboronic acid of formula XI with a palladium catalyst (Suzuki coupling; scheme 4), which can be carried out, for example, in the presence of Pd[(PPh)3]4 as catalyst, sodium carbonate as base and 1,2-di-methoxyethane as solvent.

If R(9) represents a residue that can be easily cleaved off, such as tert-butyl or benzyl, then compounds of formula lb can be converted into other compounds of formula I according to the invention, as described above and in scheme 3.

The necessary boric acid of the formula XI can be obtained from the compound of the formula XII, in which Z represents hydrogen, bromine or iodine, by ortholithiation, i.e. by metal-halogen exchange from the reaction with the trimethyl ester of boric acid.

The above conversions of compounds of formulas VI, VII and IX with compounds of formula R(1)-X correspond to known conversions of amines into derivatives of carboxylic acid amides, sulfonic acid amides, carbamates, urea or thiourea. The residue X here represents a suitable nucleophilic starting group, such as JT, Cl, Br, imidazole, O-succinimide, etc.

For the preparation of compounds of the formula I or VIII in which R(1) represents C(O)OR(9), i.e. a carbamate, compounds of the formula R(1)-X are used, for example, in which both X represent chlorine or O-succinimide, i.e. chloroformate or succinimido-carbonate.

For the preparation of compounds of formula I or VIII in which R(1) means SO2R(10), i.e. sulfonamide, as a rule, compounds of the formula R(1)-X in which X has the meaning of chlorine, i.e. sulfonic acid chloride, are used.

For the preparation of compounds of formula I or VIII in which R(1) has the meaning COR(11), i.e. amide of a carboxylic acid, for example, compounds of the formula R(1)-X in which X represents chlorine, imidazole or acetoxy, i.e. carboxylic acid chloride, are used acids, carboxylic acid imidazolide or mixed anhydride. However, free acids of the formula R(1)-OH can also be used in the presence of a suitable condensing agent such as carbodiimides or uronium salts as TOTU.

For the preparation of compounds of formula I or VIII in which R(1) represents CONR(12)R(13) or C(S)NR(12)R(13), i.e. urea or thiourea, instead of compounds of formula R(1)-X compounds of the formula R(12)N(=C=O) or R(12)N(=C=S) can also be used, i.e. isocyanates or thioisocyanates.

The above conversions of compounds of formula IV or VIII with amines of formula HNR(3)R(4) correspond to known conversions of a carboxylic acid into a carboxylic acid amide. Numerous methods are described in the literature for carrying out these reactions. They can be particularly advantageously carried out by activating a carboxylic acid, e.g. with dicyclohexylcarbodiimide (DCC), if necessary with the addition of hydroxybenzotriazole (HOBT) or dimethylaminopyridine (DMAP) or with O-[(cyano-(ethoxycarboniT)methylene)amino]-1,1 ,3,3-tetramethyluronium tetrafluoroborate (TOTU). However, it is also possible to first synthesize reactive acid derivatives using known methods, for example an acid chloride by reacting a carboxylic acid of formula IV or VIII with an inorganic acid halide, such as SOCl2, or an acid imidazolide by reacting with carbonyldiimidazole, which then reacts with an amine with the addition of an auxiliary base of the formula HNR(3)R(4).

In all procedures, it may be necessary at certain stages of the reaction to temporarily protect the functional groups in the molecule. Such protecting groups are known to the expert. The choice of protective groups that may come into consideration and the procedures for their introduction are described in the literature and can be adapted to the individual case without difficulty if necessary.

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The compounds of the formula I according to the invention and their physiologically tolerable salts can therefore be used on animals, primarily mammals, and especially humans, as drugs alone or as mixtures with each other or in the form of pharmaceutical preparations. The subject of the proposed invention are also compounds of formula I and their physiologically tolerable salts for use as medicine, their use in the therapy and prophylaxis of the mentioned diseases and their use for the production of medicines for this purpose and medicines that act by blocking K+ channels. A further subject of the proposed invention are pharmaceutical preparations which, as an active ingredient, contain an effective dose of at least one compound of formula I and/or its physiologically tolerable salt, in addition to the usual pharmaceutical carriers and excipients. Pharmaceutical preparations normally contain from 0.1 to 90 wt. % of the compound of formula I and/or its physiologically tolerable salt. The production of pharmaceutical preparations can be carried out in a known manner. For this purpose, the compounds of formula I and/or their physiologically tolerable salts are combined with one or more solid or liquid galenic carriers and/or auxiliary substances, and if desired, in combination with other active substances of the drugs, a form suitable for administration or a form for dosage that can then be used as a medicine in human medicine or in veterinary medicine.

Medicines containing the compounds according to the invention of formula I, and/or their physiologically tolerable salts, can be administered orally, parenterally, e.g. intravenously, rectally, by inhalation or topically, whereby the preferred application depends on the individual case, e.g. on the respective picture of the disease that wants to be treated.

Based on his professional knowledge, the expert can know which excipient will be the most favorable for the desired drug formulation. In addition to solvents, gel forming agents, suppository bases, tablet excipients and other active substance carriers, for example, antioxidants, dispersants, emulsifiers, antifoaming agents, flavor correctors, preservatives, dissolution enhancers can be used , agents for achieving a depot effect, buffers or dyes.

To achieve a useful therapeutic effect, compounds of formula I can also be combined with other active substances of drugs. Thus, for the treatment of diseases of the heart and circulation, favorable combinations with drugs for the heart and circulation are possible. As such, for the treatment of diseases of the heart and blood flow, as favorable participants in combinations, other antiarrhythmics, such as class I, class II or class III antiarrhythmics, such as IKS or IKr channel blockers, e.g. dofetilide, or other blood pressure lowering agents such as AGE inhibitors (for example enalapril, captopril, ramipril), angiotensin-antagonists, K+ channel activators, as well as alpha- and beta-receptor blockers, but also compounds that act sympathomimetic and otherwise, and inhibitors Na+/H+ exchangers, calcium channel antagonists, phosphodiesterase inhibitors and other substances that have an inotropic positive effect, such as digitalis glycosides or diuretics.

For the oral form of administration, the active compounds are mixed with suitable additives such as carriers, stabilizers or inert diluents and processed by usual methods into a form suitable for administration, such as dragee tablets, plug-in capsules, aqueous, alcoholic or oily solutions.

Gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, can be used as inert carriers. At the same time, the preparation can be produced as a dry or as a wet granulate. Suitable oil carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or liver oil. Solvents for aqueous or alcoholic solutions include, for example, water, ethanol or sugar solutions or their mixtures. Other auxiliaries, also for other forms of application, are eg polyethylene glycols and polypropylene glycols.

For subcutaneous or intravenous application, the active compounds, optionally with substances customary for this purpose such as agents for promoting dissolution, emulsifier or other auxiliary substances, are translated into a solution suspension or emulsion. The compounds of formula I and their physiologically tolerable salts can also be lyophilized and the obtained lyophilizate can be used, for example, for the preparation of injection or infusion preparations. Suitable solvents include, for example, water, physiological salt solution or alcohols, for example ethanol, propanol, glycerin, and in addition also sugar solutions such as glucose or mannitol solutions, or also mixtures of the various mentioned solvents.

Suitable pharmaceutical formulations for administration in aerosol or spray form are, for example, solutions, suspensions or emulsions of the active substance of formula 1 or its physiologically tolerable salts in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or in a mixture of such solvents. If necessary, the formulation may contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, as well as propellant gas. Such a preparation contains an active substance usually in a concentration of approx. 0.1 to 10, especially from approx. 0.3 to 3 mass percent.

The dosage of the active substance of formula I or its physiologically tolerable salt that is administered depends on the individual case and is usually adapted to the circumstances of the individual case for optimal effect. Thus, it depends, of course, on the frequency of administration and on the strength of action, duration of action and also on the type and severity of the disease being treated, as well as on the sex, age, weight and individual reaction of the treated person or animal and on whether it is an acute or prophylactic therapy. Typically, a daily dose of a compound of formula I when administered to a patient with severe approx. 75 kg is from 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 can be given as a single dose or divided into several, eg two, three or four single doses. In particular, when treating an acute case of cardiac arrhythmia, for example in an intensive care unit, parenteral administration by injection or infusion, eg by continuous intravenous infusion, may also be appropriate.

Experimental part

List of abbreviations

CDI carbonyldiimidazole,

DIC diisopropylcarbodiimide,

DMAP 4-dimethylaminopyridine,

DMF N,N-dimethylformamide,

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

EE ethyl ester of acetic acid,

F. p. melting point (unless otherwise stated, melting points refer to the crude crude product; the melting point of the pure substance in question may be well above this),

HOBT 1-hydroxy-1H-benzotriazole,

i. Vak. in a vacuum,

LM solvent,

Me methyl,

RT room temperature,

THF tetrahydrofuran,

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

Pre-stage 1:

7H-dibenzo[c,e]oxepin-5-one

To a suspension of 50.0 g (0.22 mol) of diphenic anhydride in 220 ml of DMF at 5°C, 9.0 g (0.24 mol) of sodium borate was added in portions over 10 minutes. It is stirred for 1 h at room temperature and then the reaction mixture is poured onto 220 ml of 6M hydrochloric acid, diluted with 750 ml of water and stirred for another 2 h. The secreted precipitate is sucked off and 35.0 g of 7H-dibenzo[c,e]oxepin-5-one is obtained; tal. 131°C.

Pre-stage 2:

2'-phthaloimidomethyl-biphenyl-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 potassium phthalimide in 330 ml of DMF is heated for 18 h at 170°C . When it cools down, the separated precipitate is sucked off and placed in 160 ml of glacial acetic acid. It is stirred for 1 h and then diluted with 650 ml of ice water and the secreted product is sucked off and dried in a vacuum. 44.8 g of 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid are obtained; tal. 198°C.

Pre-stage 3:

2'-aminomethyl-biphenyl-2-carboxylic acid

A suspension of 10.0 g (28 mmol) of 2-phthaloimidomethyl-biphenyl-2-carboxylic acid in 450 ml of methanol was mixed with 20 ml of hydrazine hydrate and heated for 1.5 h at 40°C. The reaction mixture is concentrated and the residue is taken up in 250 ml of methylene chloride. The undissolved 2,3-dihydro-phthalazine-1,4-dione was filtered off and the mother liquor was concentrated to give 4.8 g of 2'-aminomethyl-biphenyl-2-carboxylic acid.

General rule for the synthesis of mixed succinimidocarbonates from alcohol (pre-steps 4a - 4k)

To a solution of 19.5 mmol of the corresponding alcohol and 1.2 g (9.8 mmol) of DMAP in 30 ml of methylene chloride and 30 ml of acetonitrile at 0°C, 5.0 g (19.5 mmol) are added in portions of di-succinimi-docarbonate. After stirring for 2.5 to 10 h at room temperature, 25 ml of water is added and the organic phase is washed 2 more times with water. After drying and concentration, the corresponding succinimido carbonate is obtained, usually as a crystalline solid.

Pre-stage 4a:

In accordance with the general regulation, 3.2 g of 4-fluoro-benzyl-N-succinimidocarbonate was obtained; tal. 89°C (ether).

Pre-stage 4b:

2.3 g of 4-trifluoromethylbenzyl-N-succinimidocarbonate was obtained from 11/7 mmol of 4-trifluoromethylbenzylalcohol in accordance with the general regulation; tal. 102°C (ether).

Preliminary stage 4c:

1.6 g of α-methyl-4-(trifluoromethyl)benzyl-N-succinimidocarbonate was obtained from 10.5 mmol of α-methyl-4-(trifluoromethyl)-benzyl alcohol in accordance with the general regulation; tal. 115°C (ether).

Pre-degree 4d:

4.0 g of 4,4,4-trifluorobutyl-N-succinimidocarbonate was obtained from 19.5 mmol of 4,4,4-trifluorobutanol in accordance with the general regulation; tal. 72°C (ether).

Pre-stage 4e:

5.1 g of α-methyl-3-(trifluoromethyl)benzyl-N-succinimidocarbonate were obtained from 26.3 mmol of α-methyl-3-(trifluoromethyl)-benzyl alcohol in accordance with the general regulation; tal. 77°C (ether).

Pre-stage 4f:

1,6 α-methyl-2, 6-difluorobenzyl-N-succinimidocarbonate was obtained from 31.6 mmol of α-methyl-2,6-difluorobenzylalcohol in accordance with the general regulation; tal. 108°C (ether).

Pre-degree 4g:

3.5 g of α-methyl-2-(trifluoromethyl)benzyl-N-succinimidocarbonate were obtained from 25 mmol of α-methyl-2-(trifluoromethyl)-benzyl alcohol in accordance with the general regulation.

Pre-degree 4h:

3.5 g of (S) α-methyl-benzyl-N-succinimidocarbonate was obtained from 25 mmol of (S)-1-phenylethanol in accordance with the general regulation.

Pre-stage 4i:

3.5 g of (R)-α-methyl-benzyl-N-succinimidocarbonate was obtained from 25 mmol of (R)-1-phenylethanol in accordance with the general regulation.

Pre-degree 4j:

4.3 g of α-methyl-4-fluorobenzyl-N-succinimidocarbonate were obtained from 25 mmol of α-methyl-4-fluorobenzyl alcohol in accordance with the general regulation.

Pre-degree 4k:

1.7 g of (S)-α-propyl-benzyl-N-succinimidocarbonate was obtained from 9.8 mmol of (S)-1-phenyl-1-butanol in accordance with the general regulation.

Preliminary stage 5a:

2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide

From 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid (pre-step 2), after activation with GDI and conversion with phenethylamine, 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid-phenethylamide was obtained; tal. 156°C.

5.0 g (10.9 mmol) of the product were dissolved in 200 ml of methanol and mixed with 5 ml of hydrazine hydrate. After stirring for 1 h at 40°C, the reaction mixture was concentrated and the residue was taken up in methylene chloride. When the resulting 2,3-dihydro-phthalazine-1,4-dione is filtered off, the mother liquor is concentrated and the residue is purified by vacuum chromatography with methylene chloride/methanol 20:1. 3 g of 2'-amino-methyl-biphenyl-2-carboxylic acid-phenethylamide is obtained.

Pre-stage 5b:

2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide

From 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid (pre-step 2), after conversion to the acid chloride with thionyl chloride and conversion with benzylamine, 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid-benzylamide was obtained. 1.2 g (2.7 mmol) of the product was dissolved in 55 ml of methanol and mixed with 1.35 ml of hydrazine hydrate. After stirring for 1 h at 40°C, the reaction mixture was concentrated and the residue was taken up in methylene chloride. When the resulting 2,3-dihydro-phthalazine-1,4-dione is filtered off, the mother liquor is concentrated and the residue is purified by vacuum chromatography with methylene chloride/methanol 30:1. 0.49 g of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide is obtained.

Pre-level 5c:

2'-aminomethyl-biphenyl-2-carboxylic acid-isopentylamide

From 3 g (8.4 mmol) of 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid (pre-stage 2) by reaction with isopentylamine in the presence of HOBT and DIC, 3.2 g of 2'-phthaloimidomethyl-biphenyl-2 was obtained -carboxylic acid-isopentylamide; tal. 169°C. The product is dissolved in 100 ml of methanol and mixed with 5 ml of hydrazine hydrate. After stirring for 1 h at 40°C, the cooled reaction mixture is filtered. The filtrate is concentrated and the residue is taken up in methylene chloride. After washing with water, drying and concentration, 1.8 g of 2'-aminomethyl-biphenyl-2-carboxylic acid isopentyl-amide is obtained.

Pre-degree 5d:

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

From 10 g (28 mmol) of 2'-phthaloimidomethyl-biphenyl-2-carboxylic acid (pre-stage 2) by reaction with 2-(2-pyridyl)-ethylamine in the presence of HOBT and DIC, 13 g of 2'-phthaloimidomethyl was obtained -biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; tal. 155°C. The product is suspended in 300 ml of methanol and mixed with 20 ml of hydrazine hydrate. After stirring for 1 h at 40°C, the cooled reaction mixture is filtered. The filtrate is concentrated and the residue is taken up in EE. The product is extracted twice with 2M hydrochloric acid into the aqueous phase. The aqueous phase is then made alkaline with potassium carbonate and extracted twice with EE. After washing with water, drying and concentration, 7.3 g of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide are obtained.

Pre-stage 6:

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

To a solution of 455 mg (2 mmol) of 2'-aminomethyl-biphenyl-2-carboxylic acid (pre-step 3) and 336 mg (4 mmol) of sodium hydrogen carbonate in 5 ml of dioxane and 5 ml of water at 0°C, 500 mg (2 mmol) of benzyl-N-succinimidocarbonate dissolved in 2.5 ml of dioxane. After stirring for 4 h at room temperature, it is concentrated in vacuo, diluted with water, acidified and extracted with ethyl acetate. 590 mg of 2'(benzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid is obtained.

Pre-stage 7:

2'-(tert-butoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid

To a solution of 12.0 g (53 mmol) of 2'-aminomethyl-biphenyl-2-carboxylic acid (pre-step 3) in 130 ml of 1,4-dioxane and 65 ml of water, 65 ml of 1 M sodium alkali is added and after complete dissolution, 12.6 g (58 mmol) of di-tert-butyldicarbonate. After stirring for 2 h at room temperature, it is concentrated in vacuo, diluted with water and extracted twice with methylene chloride. The aqueous phase is acidified with potassium hydrogen sulfate solution and extracted with ethyl acetate. After maximum concentration, n-heptane is added and allowed to stand overnight. The product is precipitated and 7.6 g of 2'-(tert-butoxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid is obtained; tal. 136°C.

General regulation for breaking off the protective group Boe

The N-Boc protected derivative of aminomethyl-biphenyl (1 g per 10 ml of solution) is added to a solution of trifluoroacetic acid in dichloromethane (30% alcohol). The mixture was stirred for 30 minutes at room temperature and then the solvent was removed on a rotary evaporator under vacuum. The residue is taken up in acetic ester and washed with saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate, the solvent is removed in vacuo and the corresponding amide of 2'-aminomethyl-biphenyl-2-carboxylic acid is obtained.

Preliminary stage 8a:

2'-Aminomethyl-biphenyl-2-carboxylic acid-(2,4-difluorobenzyl)-amide

This compound was obtained from the Boc-protected compound (Example 8c) according to the general procedure. Alternatively, the compound can also be isolated directly as the trifluoroacetate and reacted further.

Further steps 8:

Analogously, the corresponding amines were released from the Boc-protected compounds of examples 8d–8o and 10a–10o.

General rule for the conversion of aminomethylbiphenylene with succinimidocarbonates into carbamates (examples 1a to 1u)

To a solution of 0.45 mmol of the corresponding 2'-aminomethyl-biphenyl and 38 mg (0.45 mmol) of sodium hydrogen carbonate in 2 ml of dioxane and 2 ml of water, 0.45 mmol of the corresponding succinimidocarbonate dissolved in 2 ml of dioxane is slowly added dropwise. It is stirred for 2 to 12 h at room temperature, concentrated, diluted with water, extracted with EE and the organic phase is washed with water. After drying and concentration, the corresponding carbamate is obtained.

Example 1a:

2'-(4-trifluoromethylbenzyloxycarbonyl-amino-methyl)-biphenyl-2-carboxylic acid-phenethylamide

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226 mg of 2'-(4-trifluoromethylbenzyl- oxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-phenethylamide. MS (ES+): m/z 533 (M+1).

Example 1b:

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

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66 mg of 2'-{benzyloxycarbonyl-aminomethyl}-biphenyl-2-carboxylic acid- was obtained from 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide and benzyl-N-succinimidocarbonate in accordance with the general working regulations. phenethylamide as an oil. MS (ES+): m/z = 456 (M+1).

Example 1c:

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

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164 mg of 2'-(methylsulfonylethyloxycarbonyl-aminomethyl)-biphenyl-2- carboxylic acid-phenethylamide as an oil. MS (ES+): m/z = 481 (M+1).

Example 1d:

2'-(4-trifluoromethylbenzyloxycarbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

From 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (preliminary step 5d) and 4-trifluoromethylbenzyl-N-succinimidocarbonate (preliminary step 4b) in accordance with the general working regulations, it was obtained 170 mg of 2'-(4-trifluoromethylbenzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide. MS (ES+): m/z = 534 (M+1).

Example 1e:

2'-(4-fluorobenzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethifamide

[image]

From 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (pre-step 5d) and 4-fluoro-benzyl-N-succinimidocarbonate (pre-step 4a) in accordance with the general working regulation 150 mg of 2'-(4-fluoro-benzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide were obtained. MS (ES-r): m/z = 484 (M+1).

Example 1f:

(±)-2'-(α-methyl-(trifluoromethyl)-benzyloxy-carbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethyl-amide

[image]

From 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (pre-step 5d) and α-methyl-4-(trifluoromethyl)-benzyl-N-succinimidocarbonate (pre-step 4c) in accordance with the general procedure, 170 mg of 2'-(α-methyl-4-(trifluoromethyl)-benzyloxy-carbonyl-aminomethyl)biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide were obtained as a racemate. MS (ES+): m/z = 548 (M+1).

Example 1g:

(S)-2'-(α-methyl-4-(trifluoromethyl)-benzyloxy-carbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

The S-enantiomer was obtained from the corresponding racemate (Example 1f) by preparative HPLC over a Chiralpak AD 250x4.6 column with n-hexane/ethanol/isopropanol (10:1:1, each containing 0.3% trifluoroacetic acid/diethyl- amine) as a solvent.

Example 1h:

(R)-2'(α-methyl-4-(trifluoromethyl)-benzyloxy-carbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethyl-amide

[image]

The R-enantiomer was obtained from the corresponding racemate (Example 1f) by preparative HPLC over a Chiralpak AD 250x4.6 column with n-hexane/ethanol/isopropanol (10:1:1, with 0.3% trifluoroacetic acid/diethylamine) as solvent.

Example 1i:

2'-(4,4,4-trifluorobutyloxycarbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethyl-amide

[image]

From 0.3 mmol of 2-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (pre-step 5d) and 4,4,4-trifluorobutyl-N-succinimidocarbonate (pre-step 4d) in accordance with the general working procedure by prescription, 140 mg of 2'-(4,4,4-trifluorobutyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide were obtained. MS (ES+): m/z = 486 (M+1).

Example 1j:

(S)-2'-(α-methyl-benzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

From 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (pre-step 5d) and (S)-α-methyl-benzyl-N-succinimidocarbonate (pre-step 4h) in accordance with the general procedure, 60 mg of (S)-2'-(α-methyl-benzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide was obtained. MS (ES+): m/z = 480 (M+1).

Example 1k:

(R)-2'-(α-methyl-benzyloxycarbonyl-amino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

From 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (pre-step 5d) and (R)-α-methyl-benzyl-N-succinimidocarbonate (pre-step 4i) in accordance with the general procedure, 60 mg of (R)-2'-(α-methyl-benzyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide was obtained. MS (ES+): m/z = 480 (M+1).

Examples 1l-1u

In accordance with the general work regulations and analogously to examples 1a-1k, the following compounds were obtained from the corresponding preliminary steps:

[image]

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General rule for the conversion of aminomethylbiphenylene with chloroformic acid ester into carbamates (examples 2a to 2m):

To a solution of 0.3 mmol of the corresponding 2'-amino-methyl-biphenyl and 37 mg (0.36 mmol) of triethylamine in 6 ml of methylene chloride, 0.32 mmol of the corresponding chloroformic acid ester dissolved in 1 ml of methylene chloride at 5°C. It is left to stir overnight at room temperature, the reaction mixture is poured over water and the organic phase is washed once more with water. The residue after concentration is purified by vacuum chromatography.

Example 2a:

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

[image]

69 mg of 2' was obtained from 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (preliminary step 5d) and chloroformic acid-butyl ester in accordance with the general procedure -(butoxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide as an oil. MS (ES+): m/z = 432 (M+1).

Example 2b:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

44 mg of 2' was obtained from 0.27 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (preliminary step 5c) and chloroformic acid-benzyl ester in accordance with the general procedure -(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 112°C. MS (ES+): m/z = 431 (M+1).

Example 2c:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

59 mg of 2' was obtained from 0.24 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (preliminary step 5d) and chloroformic acid-benzyl ester in accordance with the general procedure -(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethyl-amide; tal. 140°C (heptane/EE). MS (ES+): m/z = 466 (M+1).

Example 2d:

2'-(butoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

66 mg of 2' was obtained from 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (preliminary step 5c) and chloroformic acid-butyl ester in accordance with the general procedure -(butoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as a resin. MS (ES+): m/z = 397 (M+1).

Example 2e:

2'-(2-chlorobenzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

From 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (pre-step 5c) and chloro-formic acid-(2-chlorobenzyl)-ester in accordance with the general working regulation obtained is 75 mg of 2'-(2-chlorobenzyloxy-carbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as a resin. MS (ES+): m/z = 465 (M+1).

Example 2f:

2'-(Methoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

From 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (pre-step 5c) and chloro-formic acid-methyl ester in accordance with the general procedure and then extraction with EE and purification by vacuum chromatography afforded 29 mg of 2'-(methoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as a resin. MS (ES+): m/z = 355 (M+1).

Example 2g:

2'-(phenoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

From 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (pre-step 5c) and chloro-formic acid-phenyl ester in accordance with the general working regulation and then extraction with EE and purification by vacuum chromatography gave 55 mg of 2'-(phenoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as a resin. MS (ES+): m/z = 417 (M+1).

Example 2h:

2'-(4-carbomethoxy-phenoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

From 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (pre-step 5c) and chloroformic acid-(4-carbomethoxy)-phenyl ester in accordance with the general working regulation and then extraction with EE and purification by vacuum chromatography afforded 77 mg of 2'-(4-carbomethoxy-phenoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as a resin. MS (ES+): m/z = 475 (M+1).

Example 2i:

2'-(2,2-dimethylpropoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-phenethylamide

[image]

156 mg of 2'- (2,2-dimethylpropoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-phenethylamide. MS (ES+): m/z = 445 (M+1).

Examples 2j - 2m

Analogous to examples 2a - 2i, the following compounds were obtained:

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General rule for the conversion of aminomethylbiphenylene with sulfonic acid chlorides to sulfonamides (examples 3a to 31)

Into a solution of 0.61 mmol of the corresponding 2'-amino-methyl-biphenyl and 74 mg (0.73 mmol) of triethylamine in 5 ml of methylene chloride at 0°C, 0.66 mmol of the corresponding sulfonic acid chloride was slowly added dropwise. After stirring for 12 h at room temperature, the reaction mixture is concentrated in vacuo, the residue is mixed with 25 ml of water for 2 h and the crystallized product is suctioned off.

Example 3a:

2'-(3-trifluoromethylphenylsulfonyl-aminomethyl)-biphenyl-2-carboxylic acid-phenethylamide

[image]

272 mg of 2'-(3-trifluoromethyl-phenylsulfonyl-) was obtained from 0.61 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide (pre-step 5a) and 3-trifluoro-methyl-phenylsulfonyl chloride in accordance with the general working regulations. amino-methyl)-biphenyl-2-carboxylic acid-phenethylamide; tal. 145°C. MS (ES+): m/z = 539 (M+1).

Example 3b:

2'-(4-acetylphenylsulfonyl-aminomethyl)-biphenyl-2-carboxylic acid-phenethitamide

[image]

258 mg of 2'-(4-acetylphenylsulfonyl-aminomethyl)- was obtained from 0.61 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide (pre-stage 5a) and 4-acetylphenyl-sulfonyl chloride in accordance with the general working regulations. biphenyl-2-carboxylic acid-phenethylamide; tal. 145°C. MS (ES+): m/z = 513 (M+1).

Example 3c:

2'-(3-nylrophenylsulfon.yl-aminomethyl)-biphenyl-2-carboxylic acid-phenethylamide

[image]

272 mg of 2'-(3-nylrophenylsulfonyl-aminomethyl)- was obtained from 0.61 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide (pre-stage 5a) and 3-nitrophenyl-sulfonyl chloride in accordance with the general working regulations. biphenyl-2-carboxylic acid-phenethylamide; tal. 145°C. MS (ES+): m/z = 516 (M+1).

Example 3d:

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

[image]

224 mg of 2'-(phenylsulfonyl-aminomethyl)-biphenyl-2-carboxylic acid was obtained from 0.61 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide (preliminary step 5a) and phenylsulfonyl chloride in accordance with the general working instructions -phenethylamide; tal. 154°C. MS (ES+): m/z = 471 (M+1).

Example 3e:

2'-(3-fluorophenylsulfonyl-aminomethyl)-biphenyl-2-carboxylic acid-phenethylamide

[image]

221 mg of 2'-(3-fluorophenylsulfonyl-aminomethyl)- was obtained from 0.61 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-phenethylamide (pre-step 5a) and 3-fluorophenyl-sulfonyl chloride in accordance with the general working regulations. biphenyl-2-carboxylic acid-phenethylamide; tal. 153°C. MS (ES+): m/z = 489 (M+1).

Example 3f:

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

[image]

250 mg of 2'-(4-ethylphenylsulfonyl-aminomethyl)- biphenyl-2-carboxylic acid-phenethylamide; tal. 163°C. MS (ES+): m/z =499 (M+1).

Example 3g:

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

[image]

From 0.28 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide (preliminary step 5b) and 3-trifluoromethyl-phenylsulfonyl chloride, in accordance with the general working regulations, 131 mg of 2'-(3-trifluoromethylphenyl-sulfonyl- amino-methyl)-biphenyl-2-carboxylic acid benzylamide; tal. 126°C. MS (ES+): m/z = 525 (M+1).

Example 3h:

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

[image]

From 0.28 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide (preliminary step 5b) and 3-acetylphenyl-sulfonyl chloride, in accordance with the general working regulations, 110 mg of 2'-(3-acetylphenylsutphonyl-aminomethyl)- biphenyl-2-carboxylic acid-benzylamide; tal. 182°C. MS (ES+): m/z = 499 (M+1).

Example 3i:

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

[image]

115 mg of 2'-(3-nitrophenylsulfonyl-aminomethyl) was obtained from 0.28 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide (preliminary step 5b) and 3-nitrophenyl-sulfonyl chloride in accordance with the general procedure. -biphenyl-2-carboxylic acid-benzylamide; tal. 175°C. MS (ES+): m/z 502 (M+1).

Example 3j:

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

[image]

95 mg of 2'-(phenylsulfonyl-aminomethyl)-biphenyl-2-carboxylic acid was obtained from 0.28 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide (preliminary step 5b) and phenylsulfonyl chloride in accordance with the general procedure acid-benzylamide; tal. 162°C. MS (ES+): m/z = 457 (M+1).

Example 3k:

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

[image]

112 mg of 2'-(3-fluorophenylsulfonyl-aminomethyl)- were obtained from 0.28 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-benzylamide (pre-step 5b) and 3-fluorophenyl-sulfonyl chloride in accordance with the general working regulations. biphenyl-2-carboxylic acid-benzylamide; tal. 147°C. MS (ES+): m/z = 475(M+1).

Example 3l:

2'-(phenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

100 mg of 2'-(phenylsulfonylamino -methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 127°C. MS (ES+): m/z = 437 (M+1).

Example 3m:

2'-(4-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

122 mg of 2'-( 4-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 149°C. MS (ES+): m/z = 455 (M+1).

Example 3n:

2'-(3-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

118 mg of 2'-{ 3-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 141°C. MS (ES+): m/z = 455 (M+1).

Example 3o:

2'-(isopropylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

16 mg of 2'- (isopropylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide as an oil. MS (ES+): m/z = 403 (M+1).

Example 3p:

2'-(phenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

117 mg of 2'-(phenylsulfonylamino -methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; tal. 130°C. MS (ES+): m/z = 472 (M+1).

Example 3q:

2'-(4-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

106 mg of 2'-(4 -fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; Tal. 130°C. MS (ES+): m/z = 490 (M+1).

Example 3r:

2'-(3-fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

102 mg of 2'-(3 -fluorophenylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; tal. 123°C. MS (ES+): m/z = 490 (M+1).

Example 3s:

2'-(isopropylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

40 mg of 2' was obtained from 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (preparative step 5d) and isopropylsulfonyl chloride in accordance with the general procedure and then extraction with EE -(isopropylsulfonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide as an oil. MS (ES+): m/z =438 (M+1).

Analogous to examples 3a - 3s, the following compound was obtained:

[image]

General rule for the conversion of aminomethylbiphenylene with carboxylic acid chlorides into carbonamides (examples 4a to 4l):

In a solution of 0.34 mmol of the corresponding 2'-amino-methyl-biphenyl and 41 mg (0.41 mmol) of triethylamine in 5 ml of methylene chloride at 0°C, 0.36 mmol of the corresponding sulfonic acid chloride is slowly added dropwise. After stirring for 3 h at room temperature, the reaction mixture is concentrated in vacuo, the residue is mixed with 25 ml of water and the secreted product is suctioned off or isolated by extraction.

Example 4a:

2'-(benzoylamino-methyl)-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

75 mg of 2'-(benzoylamino-methyl) was obtained from 0.34 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide (preliminary step 5c) and benzoyl chloride in accordance with the general procedure )-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 147°C. MS.(ES+): m/z = 401 (M+1).

Example 4b:

2'-(benzoylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

98 mg of 2'-(benzoylamino-methyl) was obtained from 0.3 mmol of 2'-aminomethyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (preliminary step 5d) and benzoyl chloride in accordance with the general procedure )-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; tal. 135°C. MS (ES+): m/z = 436 (M+1).

Example 4c:

2'-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid-2,4-difluoro-benzylamide

[image]

160 mg of 2'-{[2 -(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid-2,4-difluoro-benzyl-amide; tal. 138°C. MS (ES+): m/z = 501 (M+1).

Analogous to examples 4a - 4c, the following compounds were obtained:

[image]

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General rule for the conversion of aminomethylbiphenylene with isocyanates to urea (examples 5a-5e):

In a solution of 0.34 mmol of the corresponding 2-amino-methyl-biphenyl and 41 mg (0.41 mmol) of triethylamine in 5 ml of methylene chloride at 0°C, slowly add 0.36 mmol of the corresponding isocyanate dissolved in 0.5 ml of methylene. chloride. After stirring for 3 h at room temperature, the reaction mixture is concentrated in vacuo, the residue is mixed with 25 ml of water, the excreted product is suctioned off or isolated by extraction with EE.

Example 5a:

2'-[(3-phenyl-ureido)-methyl]-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

[image]

85 mg of 2'-[(3 -phenyl-ureido)-methyl-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide; tal. 194°C. MS (ES+): m/z = 416 (M+1).

Example 5b:

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

[image]

101 mg of 2'-[(3 -phenyl-ureido)-methyl]-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide; tal. 99°C. MS (ES+): m/z = 451 (M+1).

Examples 5c - 5e

Analogously, the following compounds were obtained from 2'-amino-methyl-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethyl-amide (pre-step 5d) and the corresponding isocyanate:

[image]

General rule for the conversion of biphenylcarboxylic acids with amines into amides (examples 6a-6h):

In a solution of 0.28 mmol of the corresponding biphenylcarboxylic acid, 0.3 mmol of HOBT and 0.3 mmol of DIC in 5 ml of THF at 0°C, 0.3 mmol of the respective amine is added dropwise and mixed for 12 hours at room temperature. The reaction mixture was diluted with EE and washed with dilute hydrochloric acid and sodium bicarbonate solution. After -drying over magnesium sulfate and concentrating in a vacuum, the corresponding amide is obtained.

Example 6a:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-benzyl-methylamide

[image]

89 mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2 was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (preliminary step 6) and benzyl-methylamine in accordance with the general work regulations -carboxylic acid-benzyl-methylamide. MS (ES+): m/z = 465 (M+1).

Example 6b:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-cyclohexylamide

[image]

99 mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2 was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (pre-stage 6) and cyclohexylamine in accordance with the general working regulations -carboxylic acid-cyclohexylamide. MS (ES+): m/z = 443 (M+1).

Example 6c:

2'-(Benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-phenylamide

[image]

66 mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (preliminary step 6) and aniline in accordance with the general working regulations phenylamide acid. MS (ES+): m/z = 437 (M+1).

Example 6d:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-{N-methyl-N-[2-(2-pyridyl)-ethyl]}-amide

[image]

54 mg were obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (pre-step 6) and 2-[2-(methylaminoethyl)]pyridine in accordance with the general working procedure and then cleaning by vacuum chromatography 2'-(Benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-{N-methyl-N-[2-(2-pyridyl)-ethyl]}-amide. MS (ES+): m/z =480 (M+1).

Example 6e:

2'-(Benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-dibutylamide

[image]

82 mg of 2'-(benzyloxycarbonylamino) was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (preliminary step 6) and dibutylamine in accordance with the general work instructions and then by vacuum chromatography purification -methyl)-biphenyl-2-carboxylic acid-dibutylamide. MS (ES+): m/z = 473 (M+1).

Example 6f:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide

[image]

85 was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (preliminary step 6) and 2-(2-pyridyl)-ethylamine in accordance with the general procedure and then purified by vacuum chromatography. mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide. Tal. 140°C (heptane/EE); MS (ES+): m/z=466(M+1).

Example 6g:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(2,4-difluorobenzyl)-amide

[image]

From 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (pre-step 6) and 2,4-difluorobenzylamine. in accordance with the general working regulation and then cleaning by vacuum chromatography, 99 mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(2,4-difluorobenzyl)-amide was obtained. MS (ES+): m/z = 487 (M+1).

Example 6h:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(2,2,2-trifluoroethyl)-amide

[image]

19 mg of 2 was obtained from 0.28 mmol of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (preparative step 6) and 2,2,2-trifluoroethylamine in accordance with the general working procedure and then cleaning by vacuum chromatography '-(Benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-(2,2,2-trifluoroethyl)-amide. MS (ES+): m/z = 443 (M+1).

Example 7a:

2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-[2-(1-oxypyridyl)]-ethylamide

[image]

A solution of 85 mg (0.18 mmol) of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-(2-pyridyl)-ethylamide (example 6f) in 13 ml of methylene chloride at 0°C was added dropwise 47 mg of m-chloroperbenzoic acid dissolved in 2 ml of methylene chloride and the reaction mixture was stirred for 12 h at room temperature. The organic phase is washed twice with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. 79 mg of 2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carboxylic acid-2-[2-(1-oxypyridyl)]-ethylamide are obtained. MS (ES+): m/z = 482 (M+1).

Analogous to example 7a, the following compounds were obtained from the corresponding pyridines:

[image]

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General rule for the conversion of biphenylcarboxylic acid with amines into amides (examples 8a - Sac):

To a solution of 0.42 mmol of the corresponding biphenylcarboxylic acid, 0.44 mmol of HOBT and 0.44 mmol of EDAC in 5 ml of THF at 0°C, 0.44 mmol of the corresponding amine is added dropwise and mixed for 4 to 12 h at room temperature. The reaction mixture was diluted with E.E and washed with dilute hydrochloric acid and sodium bicarbonate solution. After drying over magnesium sulfate and concentrating in a vacuum, the corresponding amide is obtained.

Example 8a:

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

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180 mg of [2'-(1-carbamoyl -3-methyl-butylcarbamoyl)-biphenyl-2-ylmethyl]-carbamic acid-benzyl ester. MS (ES+): m/z = 474 (M+1).

Example 8b:

2-{[2'-(benzyloxycarbonylamino-methyl)-biphenyl-2-carbonyl]-amino}-3-phenyl-propionic acid methyl ester

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230 mg of 2-{[2 '-(Benzyloxycarbonylamino-methyl)-biphenyl-2-carbonyl]-amino}-3-phenyl-propionic acid methyl ester. MS (ES+): m/z = 523 (M+1).

Example 8c:

2'-(tert-butoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid -(2, 4-difluorobenzyl)-amide

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From 10 mmol of 2'-(tert-butoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (pre-step 7) and 2,4-difluorobenzylamine in accordance with the general regulation, 3.8 g of 2'-(tert-butoxycarbonylamino- methyl)-biphenyl-2-carboxylic acid -(2,4-difluorobenzyl-amide. MS (ES+): m/z =453 (M+1).

Examples 8d-8p

From 2'-(tert-butoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (pre-stage 7) and the corresponding amines, analogously to examples 8a - 8c, the following products were obtained:

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Examples 8p - 8ac

The following products were obtained from 2'-(benzifoxycarbonylamino-methyl)-biphenyl-2-carboxylic acid (pre-step 6) and the corresponding amines analogously to examples 8a - 8c:

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General rule for the conversion of aminomethylbiphenylene with isothiocyanates to thioureas (examples 9a - 9i)

To a solution of 0.34 mmol of the corresponding 2'-amino-methyl-biphenyl and 41 mg (0.41 mmol) of triethylamine in 5 ml of methylene chloride at 0°C, slowly add 0.36 mmol of the corresponding isothiocyanate dissolved in 0.5 ml methylene chloride. After stirring for 3 h at room temperature, the reaction mixture is concentrated in a vacuum, the residue is mixed with 25 ml of water and the secreted product is suctioned off or purified by preparative HPLC.

In this way, among others, the following products were obtained:

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Examples 10a - 10o

By connecting 2'-(tert-butyloxycarbonyl-aminomethyl)-biphenyl-2-carboxylic acid (pre-step 7) with the corresponding amines, analogously to the procedure described in example 6 or 8, the following products were obtained, among others:

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Examples 11a - 11r

General regulation for the conversion of Boc-derivatives from example 10 into urea

To remove the Boe protecting group, 1 g of the corresponding compound from example 10 is added to 10 ml of a 30% solution of TFA in dichloromethane. The mixture was stirred for 30 min at room temperature and the solvent was removed on a rotary evaporator under vacuum. The residue is taken up in acetic ester and washed with saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate, filtered and the solvent is removed under vacuum. The resulting 2'-aminomethyl-biphenyl-2-carboxylic acid amide is then converted with isocyanate into the corresponding urea according to the procedure of Example 5.

In this way, among other things, the following products were obtained:

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General regulation for the preparation of compounds according to the invention by synthesis on a solid phase

The amounts stated in the regulations always refer to the loading of the resin as determined UV-photometrically after removal of the Fmoc protecting group (see for example "The Combinatorial Chemistry Catalog", Novabiochem).

General rule for connecting α-Fmoc-amino acid to Rink-amide resin

K Rink - amide polystyrene resin (added 1.2 mmol/g) is added to a solution of 1.5 equivalents each of HOB-aT, TOTU, DIPEA and α-Fmoc amino acid in DMF (5 ml/g resin) and the mixture is allowed to shake for 12 h at room temperature. The resin is filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane. By determining the load according to the Fmoc method, an amount of 0.9 mmol/g of the carrier is obtained.

Cleavage of the Fmoc protecting group

To remove the Fmoc protecting group, the resin is first swollen for 5 min in DMF at room temperature. After the addition of the DMF/piperidine solution (4 ml/g of resin, 1:1), it was shaken for 20 min at room temperature. The solution is sucked off and the procedure is repeated. Complete conversion is confirmed by separation of the analytical sample and analysis by HPLC/MS. After complete conversion, the resin is washed three times with dichloromethane and used directly for bonding.

General working procedure for the connection of a resin-bound amino acid with 2'-phthalimidomethyl-biphenyl-2-carboxylic acid (prestage 2)

A solution of 12.2 mg (0.09 mmol) HOBT, 29.5 mg (0.09 mmol) TOTU- a, 16 μl (0.09 mmol) of DIPEA and 0.09 mmol of 2'-phthalimidomethyl-biphenyl-2-carboxylic acid (pre-step 2) in 5 ml of DMF and the mixture is allowed to shake for 12 h: at room temperature . The resin is filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

General rule for removing the phthalimido protecting group from the support

5 ml of a 10% solution of hydrazine in DMF was added to 1 g of resin loaded with an Fmoc-protected amino compound and the mixture was allowed to shake for 2 h at room temperature. The resin is sucked off. Then the resin is washed three times with 10 ml each of DMF and with dichloromethane. Complete conversion is confirmed by separation of the analytical sample and analysis by HPLC/MS.

General regulation for connection with sulfonic acid chloride

A solution of 0.16 ml (0.027 mmol) of DIPEA and 0.027 mmol of sulfonic acid chloride in 5 ml of DMF was added to 100 mg of resin loaded with functionalized 2'-aminomethyl-biphenyl-2-carboxylic acid and the mixture was allowed to shake for 12 h at room temperature. The resin is filtered off and washed 3 times with 10 ml of DMF, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml of dichloromethane.

General work regulation for separation from resin

For separation, the resin is suspended in dichloromethane/trifluoroacetic acid (3 ml/0.1 g resin) and shaken for 1 h. The resin is then filtered off and washed with 1 ml of dichloromethane. After separation, the combined solution is concentrated on a rotary evaporator. The residue is taken up in dichloromethane and chromatographed over silica gel with dichloromethane and ethyl acetate or purified by preparative HPLC.

In this way, among other things, the following products were obtained:

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Example 13a:

2-[[2r-(benzyloxycarbonylamino-methyl)-biphenyl-2-carbonyl]-amino}-4-methyl-pentanoic acid

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This compound was obtained from the methyl ester of Example 8r by saponification. with potassium hydroxide in methanol/water at 60°C.

Examples 13b - 13e

By connecting the carboxylic acid from example 13a with the corresponding amines in accordance with the general procedure described in example 8, the following compounds were obtained:

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By hydrogenolytic separation of the Z-protecting group from the compound from example 13 c and then by conversion with the appropriate acid chlorides, the following compounds were obtained:

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Starting with the compound from example 8, analogously to examples 13a - 13e, the following compound was obtained by hydrolysis and reaction with isopropylamine:

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General rule for the connection of 2'-amino-methyl-biphenyl-2-carboxylic acid-(2,4-difluorobenzyl)-amide with a carboxylic acid to form carbonamides (examples 14a-14f):

0.27 mmol of the corresponding carboxylic acid was mixed with 0.27 mmol of HOBT and 0.27 mmol of EDAC in 1 ml of THF for 30 min at room temperature. Then 0.26 mmol of 2'-amino-methyl-biphenyl-2-carboxylic acid-(2,4-difluorobenzyl)amide-trifluoroacetate dissolved in 1 ml of THF was added and stirred overnight at room temperature. The reaction mixture was diluted with EE and washed with sodium bicarbonate solution and water. After concentrating the organic phase, the product is purified via preparative HPLC.

The following compounds were produced in this way:

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General rule for the synthesis of biphenylene by Suzuki coupling (examples 15a - 15b)

Dimethoxyethane (10 ml) was degassed with argon and then 58 mg (0.05 mmol) of tetrakis-triphenylphosphine-palladium and 1 mmol of the corresponding bromide were added. After 10 minutes, 1.5 mmol of the corresponding boric acid and finally 1 ml of a 2 molar solution of sodium carbonate (2 mmol) are added. It is heated for 18 h under reflux and under argon, cooled and diluted with 30 ml of methylene chloride. The mixture is washed with water and a saturated solution of table salt. It is dried over sodium sulfate, concentrated and purified by chromatography over silica gel.

Example 15a:

2'-(tert-butoxycarbonylamino-methyl)-4-nitro-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

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In accordance with the municipal regulation, 350 mg (79% yield) of the nitro-substituted compound was obtained as a yellow solid.

Example 15b:

2'-(t-butoxycarbonylamino-methyl)-4-methoxy-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

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In accordance with the general procedure, 170 mg (41% yield) of the methoxy-substituted compound was obtained as a viscous light oil.

Example 16a:

2'-(tert-butoxycarbonylamino-methyl)-4-amino-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

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330 mg (0.75 mmol) of the nitro-substituted compound from Example 15a was dissolved in ethyl acetate and hydrogenated with a teaspoonful of 10% palladium on charcoal under a hydrogen atmosphere (1 bar). After 2 h, it is filtered through celite and the clear solution is concentrated. Yield: 260 mg (84%).

Example 16b:

2'-(benzyloxycarbonylamino-methyl)-4-hydroxy-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide

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150 mg (0.35 mmol) of the methoxy-substituted compound from example 15b is dissolved in 5 ml of anhydrous methylene chloride and at -70°C it is slowly mixed with 1.4 ml (1.4 mmol) of a 1 molar solution of boron tribromide in n - hexane. After 10 minutes, the reaction mixture is slowly heated to 0°C. After 2 h at that temperature, it is neutralized with a saturated solution of sodium hydrogen carbonate, extracted with a total of 40 ml of methylene chloride, dried over sodium sulfate and concentrated. From the obtained crude product (88 mg) of 2'-aminomethyl-4-hydroxy-biphenyl-2-carboxylic acid (3-methyl-butyl)-amide, 30 mg (0.1 mmol) were dissolved in 3 ml of methylene chloride and mixed with 11 mg (0.11 mmol) of triethylamine and 27 mg (0.11 mmol) of benzyloxycarbonyloxysuccinimide. After 3 h, it is diluted with methylene chloride, washed with water, the organic phase is dried over sodium sulfate and purified using RP-HPLC. 8 mg of 2'-(benzyl-oxycarbonyl-amino-methyl)-4-hydroxy-biphenyl-2-carboxylic acid-(3-methyl-butyl)-amide is obtained as a dark oil.

Example 17a:

{1-[2'-(3-methyl-butylcarbamoyl)-biphenyl-2-yl]-ethyl}-carbamic acid-tert-butyl ester

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2.2 g (10 mmol) of N-boc-(R)-phenethylamine were dissolved in 50 ml of anhydrous THF, cooled to -78°C and mixed dropwise with 14 ml (1.5 M solution in pentane, 21 mmol) tert-butyl-lithium. It is heated to -20°C for 2 hours, then 4.5 ml (40 mmol) of boric acid-trimethyl ester is added and it is heated to room temperature. The solution is cooled to 0°C, acidified with 10% HCl to pH 6, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with saturated NaCl solution, dried and concentrated. Boric acid is obtained as a light yellow: solid foam that is used without further cleaning.

The Suzuki coupling is carried out in accordance with the general procedure (see example 15) with 1 mmol of 2-bromo-N-(3-methyl-butyl)-benzamide and after chromatographic purification, 85 mg (0.2 mmol) of biphenyl is obtained.

Examples 17b - 17e

Analogous to example 17a, enantiomer 17b was obtained. By removing the Boc group and converting them into the corresponding carbamates, compounds 17a and 17b were converted into compounds from examples 17c - 17e.

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Analogous to the procedure described in examples 1 to 17, the following compounds were produced:

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Pharmacological tests

Human Kvl.5 channels were expressed in xenopus oocytes. For this purpose, oocytes from Kenopus laevis were first isolated and defolliculated. Then, in vitro synthesized RNA encoding Kvl.5 was injected into these oocytes. After 1-7 days of Kvl.5 protein expression, the Kvl.5 current was measured in these oocytes using the Voltage-Clamp Technique with two micro-electrodes. voltage jumps at 0 mV and 40 mV lasting 500 ms. The bath was washed with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl2 1.8 mM, MgCl2 1 mM, HEPES 5 mM (titrated with NaOH to pH 7 ,4). These experiments were performed at room temperature. A Geneclamp amplifier (Axon Instruments, Foster City, USA), a MacLab D/A converter and a computer program (ADInstruments, Castle Hill, Australia) were used for data collection and analysis. substances according to the invention, and different concentrations were added to the bath with the solution. The effect of the substance was calculated as the percentage of inhibition of Kvl.5 of the control current, when there was no substance in the solution. To determine the inhibitory concentrations IC50, for the substance in question, these data were then extrapolated using the Hill equation.

In this way, the following IC50 values were determined for the following listed compounds:

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Claims (17)

1. Compounds of formula I, [image] indicated by that R(1) is C(O)OR(9), SO2R(10), COR(11), C(O)NR(12)R(13) or C(S)NR(12)R(13); R(9) is CxHx-R(14); x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15) or SO2Me; R(14) is alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, cyclo-alkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3, C2F5 , C3F7, CH2F, CHF2, OR(15), SO2Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, naphthyl, biphenylyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group they comprise. F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C- atoms, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; R(15) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(10), R(11) and R(12) are independently defined as R(9); R(13) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3; R(2) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3; R(3) is CyH2y-R(16); y is 0, 1, 2, 3 or 4, where i cannot be O if R(16) represents OR(17) or SO2Me; R(16) is alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3, C2F5, C3F7 , CH2F, CHF2, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2 , COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(17) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, wherein phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; or R(3) is CHR(18)R(19); R(18) is hydrogen or C2H2z-R(16), wherein R(16) is as defined above; z is 0, 1, 2 or 3; R(19) is COOH, CONH2, CONR(20)R(21), COOR(22), CH2OH; R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or CwH2w-phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, J, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1 , 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, 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 with 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms; R(4) is hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms or CF3; or R(3) and R(4) together form a chain of 4 or 5 methylene groups, one methylene group of which can be replaced by -O-, -S-, -NH-, -N(methyl)- or -N( benzyl)-; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, J, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl s 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30) and R(31) independently represent hydrogen or alkyl with 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. 2. Compounds of formula I according to claim 1, characterized in that R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13); R(9) is CxH2x-R(14); x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15); R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, C2F5, OR(15), phenyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted- or substituted with 1, 2 or 3 a substituent selected from the group consisting of F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C- atoms, dimethylamino, sulfamoyl, methylsulfonyl, and methylsulfonylamino; R(10), R(11) and R(12) are independently defined as R(9); R(13) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3; R(2) is hydrogen, alkyl with 1, 2, 3 or 4 carbon atoms or CF3; R(3) is CyH2y-R(16); y is 0, 1, 2, 3 or 4, wherein y cannot be O if R(16) represents OR(17); R(16) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, C2F5, OR(17), phenyl, furyl, thienyl or heteroaromatic containing N with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C-atoms, wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2 . R(17) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3-, or 4-pyridyl, wherein phenyl or 2-, 3-, or 4-pyridyl unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH , alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; or R(3) is CHR(18)R(19); R(18) is hydrogen or CzH2z-R(16), wherein R(16) is as defined above in claim 1; z is 0, 1, 2 or 3; R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH; R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or CwH2w-phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 , 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, 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 with 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms; R(4) hydrogen or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, CF3; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30) and R(31) independently represent hydrogen or alkyl si, 2 or 3 C-atoms; or R(30) and R(31) together form a chain of 2 methylene groups; as well as their pharmaceutically acceptable salts. 3. Compounds of formula I according to claims 1 or 2, characterized in that R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13); R(9) is CxH2x-R(14); x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15); R(14) is cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(15), phenyl, furyl, thienyl or heteroaromatic containing N with 3, 4 or 5 C-atoms , wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl si, 2 or 3 C-atoms, 1- or 2 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) is alkyl with 1 or 2 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl , Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 C-atoms, alkoxy with 1 or 2 C-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 hydrogen or alkyl with 1, 2 or 3 carbon atoms; R(3) is CHR(18)R(19); R(18) is hydrogen or CzH2z-R(16); z is 0, 1, 2 or 3; R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH; R(20) is hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3 or C„H2w-phenyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, or 3 C -atom, 1 or 2 C-atom alkoxy, 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 with 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkyl with 1, 2, 3, 4 or 5 carbon atoms; R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(17), phenyl, furyl, thienyl or heteroaromatic which contains N with 3, 4 or 5 C-atoms, whereby phenyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN . R(17) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, wherein phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F,- Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH , alkyl with 1, 2, 3 or 4 C-atoms, alkoxy with 1, 2, 3 or 4 C-atoms, dimethylamino, sulfamyl, methylsulfonyl and methylsulfonylamino; R(4) is hydrogen or alkyl with 1 or 2 carbon atoms; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms, 1- or 2-C-alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30) and R(31) independently represent hydrogen or methyl; or R(30) and R(31) together form a chain of 2 methylene groups; as well as their pharmaceutically acceptable salts. 4. Compounds of formula I according to claims 1 or 2, characterized in that R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13); R(9) is CxH2x-R(14); x is 0, 1, 2, 3 or 4, wherein x cannot be 0 if R(14) represents OR(15); R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 1, 8 or 9 C-atoms, CF3, OR(15), phenyl, furyl, thienyl or N-containing heteroaromatic with 3, 4 or 5 C-atoms, wherein phenyl, furyl, thienyl and N-containing heteroaromatic are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3,OCF3 , CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 C-atoms, alkoxy with 1 or 2 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl - and methylsulfonylamino; R(15) is alkyl with 1 or 2 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms7 CF3 or phenyl, which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 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 hydrogen, alkyl with 1, 2 or 3 carbon atoms; R(3) is CyH2y-R(16); y is 0, 1, 2, 3 or 4, wherein y cannot be 0 if R(16) represents OR(17); R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, OR(17), phenyl, furyl, thienyl or heteroaromatic which contains N with 3, 4 or 5 C-atoms, whereby phenyl, furyl, thienyl and heteroaromatic containing N are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN , COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms, alkpxy with 1 or 2 C-atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(17) is alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, whereby phenyl or 2-, 3- or 4-pyridyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCP3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl with 1, 2, 3 or 4 C-atoms, 1, 2, 3 or 4 C-atom alkoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(4) is hydrogen or alkyl with 1 or 2 carbon atoms; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkM with 1, 2 or 3 C-atoms, 1- or 2-C-alkoxy, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30) and R(31) independently represent hydrogen or methyl; or R(30) and R(31) together form a chain of 2 methylene groups; as well as their pharmaceutically acceptable salts. 5. Compounds of formula I according to one or more claims 1, 2 or 4, characterized in that R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13); R(9) is CxH2x-R(14); x is 0, 1, 2 or 3; R(14) is alkyl with 1, 2, 3 or 4 C-atoms, cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 C-atoms, CF3, phenyl or pyridyl, wherein phenyl and pyridyl are unsubstituted or are substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms; R(10), R(11) and R(12) are independently defined as R(9); R(13) is hydrogen; R(2) is hydrogen; R(3) is CyH2y-R(16); y is 0, 1 or 2; R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 5 or 6 C-atoms, CF3, phenyl or pyridyl, wherein phenyl and pyridyl are "unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms ; R(4) is hydrogen; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, CF3, CN, COOMe, CONH2, NH2, OH, alkyl with 1, 2 or 3 C-atoms or alkoxy with 1 or 2 carbon atoms; R(30) and R(31) independently represent hydrogen or methyl; or R(30) and R(31) together form a chain of 2 methylene groups; as well as their pharmaceutically acceptable salts. 6. Compounds of formula I according to one or more claims 1, 2, 4 or 5, characterized in that R(1) is C(O)OR(9) or COR(11); R(9) is CKH2x-R(14); x is 0, 1, 2 or 3; R(14) is cycloalkyl with 5 or 6 C-atoms or phenyl, - wherein phenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C-atoms and 1- or 2-C-alkoxy; R(11) is defined as R(9); R(2) is hydrogen; R(3) is CyH2y-R(16) ;. y is 0, 1 or 2; R(16) is alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 5 or 6 C-atoms, CF3, phenyl or pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C-atoms and alkoxy with 1 or 2 C-atoms; R(4) is hydrogen; R(5), R(6), R(7) and R(8) independently represent hydrogen, F, CF3, alkyl with 1, 2 or 3 C-atoms or alkoxy with 1 or 2 C-atoms; R(30) and R(31) represent hydrogen; as well as their pharmaceutically acceptable salts. 7. Compounds of formula I according to one or more claims 1 to 6 and their pharmaceutically acceptable salts, characterized in that they are used as medicine. 8. Pharmaceutical preparation, characterized in that it contains as an active substance an effective amount of at least one compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier and, if necessary, with one or more other pharmacological active substances. 9. Use of a compound of formula I according to one or more claims 1 to 6 and/or a pharmaceutically acceptable salt thereof, characterized in that it is used for the production of a drug, which acts by blocking K+ channels, for the therapy and prophylaxis of diseases caused by with K+ channels. 10. Use of the compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, indicated by the fact that it is used for the production of a drug for the therapy and prophylaxis of heart rhythm disorders, which disorders can be removed by prolonging the action potential. 11. Use of the compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, characterized in that it is used for the production of a drug for the therapy and prophylaxis of reentry-arrhythmias. 12. Use of the compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, characterized in that it is used for the production of a drug for the therapy and prophylaxis of supraventricular arrhythmias. 13. Use of the compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, characterized in that it is used for the production of a drug for the therapy and prophylaxis of atrial fibrillation or atrial flutter. 14. Use of the compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, characterized in that it is used for the production of a drug for stopping atrial fibrillation or atrial flutter (cardio version). 15. Pharmaceutical preparation, characterized in that it contains as an active substance an effective amount of at least one compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, as well as an IKr channel blocker, together with pharmaceutically acceptable carriers and additional substances . 16. Pharmaceutical preparation, characterized in that it contains as an active substance an effective amount of at least one compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salts, as well as an IKS channel blocker, together with pharmaceutically acceptable carriers and additional substances . 17. Pharmaceutical preparation, characterized in that it contains as an active substance an effective amount of at least one compound of formula I according to one or more claims 1 to 6 and/or its pharmaceutically acceptable salt, as well as a beta blocker, together with pharmaceutically acceptable carriers and additional substances.