Indorsement benzopyrrole, the method of production thereof, and also containing pharmaceutical compositions

 

(57) Abstract:

The present invention relates to indorsement benzylammonium formula I

in which R(8) denotes 1 or-indaily residue of formula II, or 2-indaily the rest of the formula III

and where R(1) and R(2) denote independently from each other R(20)-CrH2r,

R(20) denotes N, CH3CH2F, cycloalkyl with 3, 4, 5, 6 C-atoms, phenyl, or N-containing heterocycle with 5 C-atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of HE, metoxygroup, r denotes zero, 1, 2, 3, 4, 5, 6, 7 or 8, or R(1) and R(2) together denote a chain of 5 methylene groups, of which one CH2-group replaced by-O-. Compounds particularly suitable as antiarrhythmic biologically active substances of a new type, particularly for the treatment and prevention of atrial arrhythmias, such as atrial fibrillation (trialno flicker AF) or atrial flutter (trialno atrial flutter). Also described is a method of obtaining compounds and farmcampsite. 3 N. and 9 C.p. f-crystals, 4 PL.

The invention relates to compounds of the formula I

in which R(8) denotes the), R(6) R(7), R(9) R(10) R(11) R(12) R(13) R(14) R(15) have the following values

their production and their use, particularly in medicines.

Compounds according to the invention act on the so-called Kv1.5-potassium channel and inhibit the flow of potassium, referred to as “sverhbystro activating a slow detector” in the atrium of the person. So connection is the most suitable as antiarrhythmic biologically active substances of a new type, particularly for the treatment and prevention of atrial arrhythmias, such as atrial fibrillation (trialno flicker AF) or atrial flutter (trialno flutter).

Atrial fibrillation (AF) and atrial flutter are the increase of prolonged cardiac arrhythmias. Their occurrence increases with age and often leads to fatal consequences, such as bleeding in the brain. AF affects about 1 million Americans annually and results annually in the United States to more than 80,000 hemorrhages in the brain. Antiarrhythmic agent of class I and III used in the present time, reduce the degree of recurrence of AF, but, due to their potential prioritiesin side effects, are only of limited use. Therefore, in meam.Heart J., 130, 1995, 1094 -1106, “Newer developments in the management of atrial fibrillation”).

It was shown that most supraventricular arrhythmias due to so-called circulations wave excitation. Such circulation of excitation occur when the tissue of the heart has a slow conductivity and at the same time is very short refractory phases. Increased myocardial refractory time by lengthening of the action potential is known mechanism to stop or prevent arrhythmia (T. J. Colatsky et al., Drug Dev. Res., 19, 1990, 129 - 140, “Potassium channels as targets for antiarrhythmic drug action”). The duration of the action potential depends largely on the size repolarizing TO+stream, which through different+-channels is directed from the cell. It is particularly great importance is attributed to the so-called “slow detector” Itothat consists of 3 different components: IKrIKsand IKur.

The most well-known antiarrhythmic agent of class III (e.g., dofetilide, E and d-sotalol) block, predominantly, or exclusively, rapidly activating potassium channel IKrthat is how in the cells of the ventricle of the human heart, and in pretrazivac increased proaritmicski risk and especially was observed arrhythmia, called piruetas tachycardia (Pointes de pointes) (D. M. Roden, Am.J.Cardiol., 72, 1993, 44B-49B, “Current status of class III antiarrhythmic drug therapy”). In addition, high, partly the risk of death at low frequency, for IKr-blocker installed weakening the effectiveness in terms of tachycardia, which needs directly impact ("inverse").

While some of these disadvantages may be overcome by using blocker slowly activating component (IKs), their effectiveness is still not proven, since no known clinical studies blockers IKschannels.

“Especially rapidly activating and slowly inactivating components of the delayed detector IKurthat match Kv1.5-channel, play a particularly important role for the duration of the depolarization in the atrium of the person.

Inhibition of IKurthe flow of potassium out is, thus, compared with the inhibition of IKror ICsespecially effective way to extend trialing action potential and thereby stopping or preventing trialing arrhythmias.

In proty the AET significant role in the atrium of the person, but not in the ventricle. Based on this, the inhibition of IKurstream, in contrast to the blockade of IKror ICsfrom the very beginning , avoid the risk proaritmicheskimi steps in the ventricle (Z. Wang et al., Circ. Res., 73, 1993, 1061-1076, "Sustained Depolarisation-Induced Outward Current in Human Atrial Myocites"; 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").

Selective blockers IKuror v1.5-channel in the literature so far has not been described. Although many pharmaceutical biologically active substances (for example, tedisamil, bupivacaine or sertindole) described a blocking effect on the Kv1.5-channel, still Kv1.5-blockade is presented only as a side effect, along with other main activities of the substances. In WO 9804521 as blockers potassium channel describes aminoindane that block Kv1.5-channel. However, for these compounds is also described equipotential activity on v1.3-channel.

Blockade Kv1.3-channel, which plays a role in T-lymphocytes of man, leads to immunosuppressive, in the form of side effects, chronically not desirable to use antiaritmichesky the e antiarrhythmic drugs, which must act through the blockade of IKur. However, these compounds initially (WO 9625936) also described as immunosuppressive funds, so that their medical applicability for the treatment of atrial arrhythmias is questionable.

It was shown that the compounds according to the invention are potent blockers v1.5-channel person. Therefore they can be used as an antiarrhythmic agent of a new type with a particularly preferred level of security. In particular, the compound suitable for the treatment of supraventricular arrhythmias, such as atrial fibrillation or atrial flutter.

Compounds according to the invention of the formula I have so far been not known. Some structurally similar indanone derivatives described in applications EP 258096 and EP 374054. However, the compounds differ from the compounds according to the invention of this application is the fact that in these applications R(9) is a primary amine substituent. In addition, there is described exclusively unsubstituted sulfonamides (R1 and R2=H), while in this application it was shown that substituted sulfonamides are particularly effective blockers Kv1.5-channel.

This invention concerns connected to the remainder of formula III

and where R(1) and R(2) denote independently from each other R(20)-CrH2rand one CH2group group CrH2rmay be replaced by-O-, -CH=CH-, -C=C-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -NR(21) -, or-CONR(21);

R(21) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(20) denotes N, CH3CH2F, CHF2, CF3C2F5C3F7cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, NR(22)R(23), -CONR(22)R(23), -OR(24), -COOR(24), phenyl, or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, hydroxymethyl, hydroxyethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(22) R(23) denote independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(22) R(23) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(24) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

r of the seat is and CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(3), R(4), R(5) R(6) denote independently from each other hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, CN, CF3, NO2, OR (25) or NR(26) R(27);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, fluorinated alkyl residue of the formula-CxH2CFyH3-yor phenyl, nezameshchenny or replaced 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

x denotes 0, 1, 2 or 3;

y denotes 1, 2 or 3;

R(26) R(27) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(26) R(27) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen, OR(28) or OCOR(28);

R(28) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(10) who appoints, independently from each other hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, -CN, -CF3- 2F5- 3F7, -N3, -NO2, -Y-CsH2s-R (29), phenyl, thienyl, furyl or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl, thienyl, furyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

Y represents-O-, -CO-, -CO-O -, - O-CO-, -S-, -SO-, -SO2-, -O-SO2-, -SO2NR(30)-, -CONR(30) -, or-NR(30)CO-, and linking with the main structure is as necessary through the atom, standing left;

R(30) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

s denotes the zero, 1, 2, 3, 4, 5 or 6;

R(29) denotes hydrogen, methyl, CF3C2F5WITH3F2cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, OR(31), -COOR(31), -NR(32)R(33), -CONR(32)R(33), phenyl, or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from groupcalifornia group, methylsulfonyl group and methylsulfonylamino;

R(31) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(32) and R(33) denote independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(32) and R(33) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(CH3)- or-N(benzyl)-group

as well as their physiologically compatible salts.

Preferred are the compounds of formula I, with the above values, and, however, at least one of the residues R(1) or R(2) is not hydrogen.

Especially preferred are the compounds of formula I in which R(8) is 1 or-indaily residue of formula II, or 2 - indaily residue of formula III, where R(1) denotes hydrogen;

R(2) denotes R(20)-CrH2rand one of CH2-group grouprH2rmay be replaced by-O-, -CH=CH-, -SS-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -NR(21) -, or-CONR(21);

R(21) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(20) denotes CH3CH2F, CHF2, CF3WITH2F5WITH3F7cycloalkyl with 3, 4, 5, 6, 7 or 8 C-ATO the N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, hydroxymethyl, hydroxyethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(22) R(23) denote independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(22) R(23) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(24) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

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

R(3), R(4), R(5) R(6) denote, independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, CN, CF3, NO2, OR (25) or NR(26)R(27);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, fluorinated alkyl residue of the formula-CxH2CFyH3-yor phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group, methylsulfonylamino from each other, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(26) R(27) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen, OR(28) or OCOR(28);

R(28) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(10) R(11) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(12) R(13) R(14) R(15) denote, independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, -CN, -CF3, -C2F5- 3F7, -N3, -NO2, -Y-CsH2s-R(29), phenyl, thienyl, furyl or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl, thienyl, furyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

Y represents-O-, -CO-, -CO-O -, - O-CO-, -S-, -SO-, -SO2-, -O-SO2-, -SO2NR(30)-, -CONR(30) - IS CLASS="ptx2">R(30) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

s denotes the zero, 1, 2, 3, 4, 5 or 6;

R(29) denotes hydrogen, methyl, CF3C2F5WITH3F7cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, OR(31), -COOR(31), -NR(32)R(33), -CONR(32)R(33), phenyl, or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(31) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(32) and R(33) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(32) and R(33) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(CH3)- or-N(benzyl) groups;

as well as their physiologically compatible salts.

Especially preferred are the compounds of formula I in which R(8) is 1-indaily residue of formula II, i.e. the compounds of formula Ia

where R(1) denotes hydrogen;

R(2) Obrestad-O-, -CH=CH-, -SS-, -CO-, -CO-O-, -O-CO-, -S-, -SO-, -SO2-, -NR(21) -, or-CONR(21);

R(21) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(20) denotes CH3CH2F, CHF2, CF3WITH2F5WITH3F7cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, NR(22)R(23), -CONR(22)R(23), -OR(24), -COOR(24), phenyl, or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, hydroxymethyl, hydroxyethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(22) R(23) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(22) R(23) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(24) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

r denotes zero, 1, 2, 3, 4 or 5;

R(3), R(4), R(5) R(6) denote, independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, CN, CFthe STATCOM formula-CxH2CFyH3-yor phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

x denotes 0, 1, 2 or 3;

y denotes 1, 2 or 3;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen, OR(28) or OCOR(28);

R(28) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(10) R(11) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(12) R(13) R(14) R(15) denote, independently of one another, hydrogen, F, C1, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, -CN, -CF3, -C2F5- 3F7, -NO2, -Y-CsH2s-R(29), phenyl, thienyl, furyl or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl, thienyl, furyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl the2NR(30)-, -CONR(30) -, or-NR(30)CO-, and linking to the main structure occurs, as needed, through the atom, standing left;

R(30) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

s denotes the zero, 1, 2, 3, 4, 5 or 6;

R(29) denotes hydrogen, methyl, CF3C2F5C3F7cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, OR(31), -COOR(31), -NR(32)R(33), -CONR(32) R(33), phenyl, or N-containing heterocycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents, selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, NH2HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(31) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

R(32) and R(33) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(32) and R(33) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(CH3)- or-N(benzyl) groups;

as well as their physiologically compatible salts.

Specifically preferred compounds of formula Ia

where R(1) about the>, CF3cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, -CONR(22)R(23), -OR(24), -COOR(24) or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, NO2CN, HE, methyl, ethyl, hydroxymethyl, hydroxyethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(22) R(23) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms

or R(22) R(23) together denote a chain of 4 or 5 methylene groups, of which one CH2group can be replaced by-O-, -S-, -NH-, -N(methyl) -, or-N(benzyl) groups;

R(24) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

r denotes zero, 1, 2, 3, 4 or 5;

R(3), R(4), R(5) R(6) denote, independently of one another, hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, CN, CF3, NO2or or (25);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms, fluorinated alkyl residue of the formula-CxH2CFyH3-yor phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, NO2CN, HE, methyl, ethyl, metox the

x denotes 0, 1, 2 or 3;

y denotes 1, 2 or 3;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen or(28);

R(28) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(10) R(11) denote, independently of one another, hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(12) R(13) R(14) R(15) denote, independently of one another, hydrogen, F, CL, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, CN, CF3, -NO2or-Y-CsH2s-R(29);

Y represents-O-, -CO-, -CO-O -, - O-CO-, -S-, -SO-, -SO2-, -O-SO2-, -SO2NR(30)-, -CONR(30) -, or-NR(30)CO-, and linking to the main structure occurs, as needed, through the atom, standing left;

R(30) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

s represents zero, 1, 2, 3, 4 or 5;

R(29) denotes hydrogen, methyl, CF3, -OR(31), -COOR(31), -NR(32)R(33), -CONR(32)R(33) or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, NO2CN, HE, methyl, ethyl, metoxygroup, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(31) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

2group can be replaced by-O-, -S-, -NH-, -N(CH3)- or-N(benzyl)-group

as well as their physiologically compatible salts.

Alkyl residues and alkylene residues can be unbranched or branched. This also applies to alkilinity the remnants of the formula CrH2rCsH2sand CxH2. Alkyl residues and alkylene residues can also be unbranched or branched, if they are substituted or contained in other residues, such as CNS residue or allylmercaptan residue, or fluorinated alkyl residue. Examples of alkyl residues 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, Needell, eicosyl. Examples alkilinity residues are divalent residues of these residues, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butylene, 1,5-pentile, 2,2-dimethyl-1,3-propylene, 1,6-hexylen and so on.

Cycloalkenyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclohexyl, 3-methylcyclobutene, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cycloheptyl, cyclooctyl and so on.

To N-containing heterocycles with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms are particularly aromatic systems: 1-, 2-or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-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 - or-5-yl, 1,3,4-oxadiazol-2-yl or-5-yl, 2-, 4-or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-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-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-indazole, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethanolic, 2-, 4-, 5-, 6-, 7- or 8-hintline, 3-, 4-, 5-, 6-, 7- or 8-chinoline, 2-, 3-, 5-, 6-, 7- or 8-honokalani, 1-, 4-, 5-, 6-, 7- or 8-phthalazine.

Especially preferred are N-containing heterocycles: pyrrolyl, imidazolyl, hinely, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Thienyl seat is izlesene - in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position. This also applies to N-containing heterocycles or tofanelli balances.

When you double the substitution of one residue substituents may be the same or different.

If the compounds of formula I contain one or more acidic or basic groups, or one or more basic compounds, the invention also includes the corresponding physiologically or toxicologically tolerated salts, in particular pharmaceutically applicable salt. Thus, the compounds of formula I, which have acid groups, for example one or more COOH groups, can be used, for example, in the form of alkali metal salts, preferably sodium salts or potassium, or alkaline earth salts of metals, for example salts of calcium or magnesium, or ammonium salts, for example as salts with ammonia or organic amines or amino acids. The compounds of formula I which have one or more primary, i.e. protonium, groups, or one or more of the basic heterocyclic rings can also be applied in the form of their physiologically compatible acid additive salts with inorganic or organic acids, such as hydrochloride, phosphate is whether the compounds of formula I contain in the molecule at the same time acidic and basic groups, the invention includes, in addition to the described forms salts, also internal salts, the so-called betaines. Salts of compounds of formula I can be obtained by conventional means, for example a compound with acid or base in a solvent or dispersant, or by anion exchange from other salts.

The compounds of formula I with the appropriate substitution may exist in stereoisomeric form. If the compounds of formula I contain one or more centers of asymmetry, they may, independently from each other, to have the S-configuration or R-configuration. The invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereometric form, such as enantiomers and/or diastereomers in any ratio. Thus, the invention includes enantiomers, for example, in pure enantiomeric form as levogyrate, and programada antipodes and also in the form of mixtures of both enantiomers in different ratios or in the form of racemates. In the presence of CIS/TRANS-isomerism to the invention also include both the CIS-form and TRANS form and mixtures of these forms. Getting the individual stereoisomers may occur if desired, the presence of mobile hydrogen atoms, the invention also includes all tautomeric forms of compounds of formula I.

The compounds of formula I can be obtained by various chemical methods, which are also included within this invention. For example, the compound of the formula I get the fact that the carboxylic acid of formula IV

where R(1), R(2), R(3), R(4), R(5) R(6) have the above values,

subjected to the interaction per se known method for the amidation reaction with an amine of the formula Va or Vb

where R(7), R(9) R(10) R(11) R(12) R(13) R(14) R(15) have the above values.

For carrying out these reactions in the literature describes many ways. Especially preferably, they may be performed by activation of the carboxylic acid, for example, dicyclohexylcarbodiimide (DCC), if necessary with the addition of hydroxybenzotriazole (NOVT) or dimethylaminopyridine (DMAP), or O-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium-tetrafluoroborate (TOTU). But also primarily known methods can be synthesized reactive derivatives of acids, for example the chloride, by reaction of carboxylic acids of the formula IV with inorganic acid halides, such as SOCl2or imidazoline acids by interacting with the carbonyl of the interaction with amines of the formula Va or Vb.

Amines of formula Va or Vb or known from the literature, or can similarly be obtained by known methods, for example by reductive amination of the corresponding 1-indanone or by epoxidation of the corresponding 1H-indenol and subsequent disclosure of epoxy cycle with the amine of the formula R(7)-NH2.

Carboxylic acids of formula IV can, for example, be obtained from chlorosulfonyl compounds of formula VI

by reaction with an amine of the formula R(1)R(2)NH in a suitable inert solvent, such as diethyl ether, THF or acetone and, if necessary, in the presence of an auxiliary base, such as triethylamine.

Chlorosulfonyl the compounds of formula VI or known from the literature, or can similarly be obtained by known methods, for example by chlorsulfuron correspondingly substituted benzoic acid with chlorosulfonic acid.

In all ways it may be appropriate at certain stages of the reaction temporarily protected functional groups in the molecule. Such protecting groups are known to the specialist. The choice of protective groups for groups taken into consideration, and the method of its introduction, use the additional cases.

Thus, the compounds of formula I according to the invention and their physiologically compatible salts can be used as medicines for animals, preferably mammals, especially for humans individually, in mixtures with one another or in the form of pharmaceutical compositions. The object of the present invention are also the compounds of formula I and their physiologically compatible salts for use as pharmaceuticals, their use in the treatment and prevention of these diseases and their application to obtain drugs and medicines action blocking TO+-channel. Further, an object of the present invention are pharmaceutical compositions which contain as an active component an effective dose of at least one of the compounds of formula I and/or one of its physiologically compatible salts along with the usual pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions usually contain from 0.1 to 90 wt.% compounds of the formula I and/or their physiologically compatible salts. Obtaining pharmaceutical compositions can to make itself known methods. In addition, Saeima or liquid galenovye carriers and/or excipients and, if it is desired, in combination with other medicinal biologically active substances in a suitable form of injection or dispensing, which can then be used as drugs in medicine or veterinary medicine.

Medicines which contain compounds of the formula I according to the invention and/or their physiologically compatible salts can be used orally, parenterally, for example intravenously, rectally, by inhalation, or locally, preferably the application depends on the specific case, for example, from the clinical picture of the disease under treatment.

The specialist, on the basis of his special knowledge, you know which excipients suitable for the desired pharmaceutical finished forms. In addition to solvents, geleobrazovanie, suppositories, excipients for tablets and other carriers of biologically active substances can be used, for example, antioxidants, dispersing funds, emulsifiers, defoamers, substances, correcting flavor, preservatives, co-solvents, the means to achieve the effect, buffer substances or dyes.

The compounds of formula I for which mi biologically active substances. So, for the treatment of diseases of the circulatory heart is possible preferred combinations with substances, activating the blood circulation of the heart. As components of combinations of this type are preferred for diseases of the circulatory heart, take into account, for example, other antiarrhythmic agent, such antiarrhythmic agent of class I, class II or class III, as, for example, blockers ICsor IKrchannel, such as dofetilide, or substances that reduce blood pressure like ACE inhibitors (e.g. enalapril, captopril, ramipril), antagonists of angiotensin, activators+channel, as well as alpha - and beta-receptor blockers, and adrenergic and adrenergichesky active compounds and inhibitors of PA+/N+exchange, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotrope active substances as, for example, digitalis glycosides or diuretics.

For oral forms of application of active compound is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and by conventional techniques result in suitable forms of administration, such as tablets be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Thus the composition may be in the form of dry and wet granulate. As oily carriers or solvents take into account, for example, vegetable or animal oils as sunflower oil or cod-liver oil. As solvents for aqueous or alcohol solutions take into account, for example, water, ethanol or solutions of sugars or mixtures thereof. Other auxiliary substances, also for other forms of application are, for example, glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active compound is administered, if desired, with the usual substances, such as co-solvents, emulsifiers or other auxiliaries, in solution, suspension or emulsion. The compounds of formula I and their physiologically compatible salts can also be lyophilisate and lyophilisate containing them, to use, for example, for injection or infusion preparations. As solvents take into account, for example, water, physiological salt solution, the sludge is Anita, or a mixture of the mentioned solvents.

As pharmaceutical preparative ready-made forms for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of biologically active substances of the formula I or their physiologically compatible salts in one pharmaceutically not calling a doubt a solvent such as especially ethanol, or water, or mixtures of such solvents. Preparative ready form may also contain, as needed, other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as a blowing gas. One such composition comprises a biologically active substance is usually in a concentration of from about 0.1 to 10, especially from about 0.3 to 3 wt.%.

Dosage introduce biologically active substances of formula I or its physiologically compatible salt depends on the specific case and usually chosen for optimum performance in specific conditions. So naturally, it depends on the frequency of administration, the strength and duration of action of the compounds used, depending on the circumstances, for therapy or prevention, and also on the nature and STI person or animal, being treated, and the treated whether the acute form of the disease or prevents. The daily dose of the compounds of formula I when administered to a patient weighing about 75 kg is from 0.001 to 100 mg/kg body weight, preferably from 0.01 to 20 mg/kg of body weight. The dose may be administered as a single dose or divided into several, for example two, three or four, one-time dose. In particular in the treatment of acute cases of cardiac arrhythmias, for example, at the first aid station can also be preferably parenteral administration by injection or infusion, for example by prolonged intravenous infusion.

Experimental part

List of abbreviations:

DMF - N,N-dimethylformamide,

EA - ethyl ester acetic acid,

So pl. - melting point (if not indicated otherwise, the specified melting point of the crude crude product, melting point of the respective pure substances can be clearly above)

NAVT - 1-hydroxy-1H-benzotriazole,

in HAC. - in vacuum,

Rast. a solvent

CT room temperature,

THF is tetrahydrofuran,

TOTU - O-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetrame the>0.2 mol of substituted benzoic acids contribute in 135 ml of chlorosulfonic acid and the reaction mixture 4 hours and heated at 120C. After cooling, was poured onto 800 g of ice, and then stirred for 1 hour and afterwards released product.

This way, synthesized, including the following, 3-chlorosulfonylbenzoic acid, are shown in table 1.

A common method of interaction 3-chlorosulfonylbenzoic acid (formula VI) with amines to sulfonamides of formula IV (a)

To a solution of 30 mmol of the corresponding amine in 20 ml diethyl ether or methylene chloride) is added 10 mmol of the corresponding 3-chlorosulfonylbenzoic acid and the reaction mixture was stirred over night at room temperature. After adding 20 ml of ether (or methylene chloride) and 20 ml of water the organic phase is extracted with 2 times with diluted hydrochloric acid and then 2 times with saturated sodium bicarbonate solution. After acidification bicarbonate extract precipitated product of the formula IV and allocate or by suction, or by extraction with EA.

This way, synthesized, including the following, sulfonamides of formula IV, are shown in table 2.

Overall int)

3 mmol amine of the formula HNR(1)R(2) is dissolved in 20-50 ml of diethyl ether and mixed with 1 mmol dissolved in ether 3-chlorosulfonylbenzoic acid (formula VI). Stirred for 30 minutes at room temperature, install with 2 M hydrochloric acid to pH 1, and divide phase. The organic phase is dried, filtered and evaporated in vacuum. The precipitate is boiled with 5 ml of thionyl chloride for 40 min under reflux. Then removed in vacuum, the excess thionyl chloride and repeatedly evaporated together with the toluene. The product, thus obtained, are included into the ether or dichloromethane, are added to a solution of 1 mmol of aminoindane (formula II or III) and 1 mmol of base Hunga in ether and stirred for 20 minutes at room temperature. Then install with 2 M Hcl pH equal to 1, and divide phase. The organic phase is dried, filtered and evaporated in vacuum. The crude product is purified using flash chromatography.

General methods of synthesis of compounds of formula I according to the invention of the sulfonamides of formula IV (option)

1 mmol of the compound of formula IV is boiled with 5 ml of thionyl chloride and 40 minutes under reflux. Then removed in vacuum, the excess thionyl chloride and repeatedly evaporated together with the toluene. Product recip is more to fully develop at room temperature. After concentration of the reaction mixture the residue purified preparative HPLC.

General methods of synthesis of compounds of formula I according to the invention of the sulfonamides of formula IV (option D)

To the solution or suspension of 1 mmol of compounds of formula IV in THF added from 1.15 to 1.40 mmol of carbonyldiimidazole and the reaction mixture is stirred 3 hours at room temperature. After adding 1.1 to 1.5 mmol of 1 - or 2-aminoindane formula Va or Vb is stirred over night at room temperature and then the reaction mixture was concentrated in vacuo. Sediment contribute in EA and washed with diluted hydrochloric acid and sodium bicarbonate solution. After concentrating the organic phase under vacuum the residue is dissolved in isopropanol and the product are planted by the addition of water. After extraction and drying obtain the compounds of formula I with a purity >90% (partially contaminated with up to 10%, corresponding belindamulvaney).

General methods of synthesis of compounds of formula I according to the invention of the sulfonamides of formula IV (option E)

1 mmol of the compound of formula IV in the presence of 1 mmol TOTU, 1 mmol Foundation Hunga subjected to interaction with 1 mmol of 1 - or 2-aminoindane formula Va or Vb in DMF. Photomaterial on kieselgel-RP18.

General methods of synthesis of compounds of formula I according to the invention of the sulfonamides of formula IV (option F)

To a solution of 1.4 mmol of compounds of formula IV, 0.21 g (1.55 mmol) NOWT and 0,19 g (1.55 mmol) of diisopropylcarbodiimide in 15 ml of THF added at 0C 1.55 mmol 1 - or 2-aminoindane formula Va or Vb, and the reaction mixture was stirred over night at room temperature. After filtering off precipitated sludge filtrate was concentrated in vacuo, making EA and extracted with sodium bicarbonate solution.

According to the General methods (options b, C, D, E or F) was synthesized, including the following, the compounds of formula I, which are shown in table 3.

Connections that are not specified melting point, allocated in the form of oils or amorphous vitreous products. Compounds for which there is no reference to the used variant of the synthesis, was obtained by analogy with the described methods, however, with slight variations, as, for example, different solvents, different reagent combinations, etc. Using a certain way in any case is not an urgent necessity, as a rule, can be used all the options.

Example 97

A solution of 100 mg 4-fluoro-N-indan-1-yl-3-(3-methylbutanoyl)benzamide (example 41), 26 mg of phenol and 100 mg of potassium carbonate in 4 ml of N, N-dimethylacetamide was heated for 6 hours at 100C. After addition of water and extraction of the precipitated product obtained 82 mg of 4-phenoxy-N-indan-1-yl-3-(3-methylbutanoyl)benzamide, so pl. 73S.

Example 98

A solution of 100 mg 4-fluoro-N-indan-1-yl-3-(3-methylbutanoyl)benzamide (example 41), 29 mg of benzylamine and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated for 6 hours at 100C. After adding water, extraction with EA and chromatographic separation obtained 33 mg of 4-benzylamino-N-indan-1-yl-3-(3-methylbutanoyl)benzamide.

Example 99

From 100 mg of 2-chloro-N-indan-1-yl-5-(3-methylbutanoyl)benzamide (example 42) analogously to example 97 received 75 mg of 2-phenoxy-N-indan-1-yl-5-(3-methylbutanoyl)benzamide.

Pharmacological studies

Kv1.5-channels of human expressed in Xenopus oocytes. First, oocytes were isolated from Xenopus Iaevis, and separated follicles. Then in these oocytes in vitro were injected synthesized RNA encoding Kv1.5. After 1-7 days Kv1.5-protein expression in oocytes was measured Kv1.5 flows through me is agenia duration 500 MS to 0 and 40 mV. The bath was washed with a solution of the following composition: NaCl 96 mm, KCl 2 mm, CaCl21.8 mmol, MgCl21 mmol, HEPES 5 mmol (titrated with NaOH to pH 7.4). These experiments were performed at room temperature. To retrieve the data and analysis used Geneclamp amplifier (Axon Instruments, Foster City, USA) and MacLab D/A Converter and software (ADInstruments, Castle Hill, Australia). Compounds according to the invention were tested because they were added to the bath at different concentrations of the solution. Efficiency was calculated as percentage of inhibition of Kv1.5 is a control flow that is received, if the solution did not add any substance. The data is then extrapolated using the hill equation to determine the concentration braking IC50the relevant substances.

This way for the following compounds was determined values IC50in table 4.

1. Indorsement benzopyrene formula I

in which R(8) denotes 1 or-indaily residue of formula II, or 2-indaily the rest of the formula III:

R(1) and R(2) denote independently from each other R(20)-CrH2r;

R(20) denotes N, CH3CH2F, cycloalkyl with 3, 4, 5 or 6 C-atoms, a is 1 or 2 substituents, selected from the group consisting of HE, metoxygroup;

r= 0, 1, 2, 3, 4, 5, 6, 7 or 8;

or R(1) and R(2) together denote a chain of 5 methylene groups, of which one CH2group can be replaced by-O-;

R(3), R(4), R(5) R(6) denote independently from each other hydrogen, F, CL, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, NO2, OR(25) or NR(26) R(27);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or phenyl,

R(26) R(27) denote independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen,

R(10) R(11) denote hydrogen

R(12) R(13) R(14) R(15) denote independently from each other hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C-atoms, -Y-CsH2s-R(29),

Y represents-O-,

s = 0;

R(29) denotes hydrogen, methyl,

as well as their physiologically compatible salts.

2. The compounds of formula I on p. 1, and at least one of the residues R(1) or R(2) does not denote hydrogen.

3. The compounds of formula I under item 1 or 2, in which R(8) denotes 1 or-indaily residue of formula II, or 2-indaily the rest of the formula III, and R(1) denotes hydrogen; R(2) denotes R(20)-CrH2 5 C-atoms, and phenyl and N-containing heterocycle unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of HE, metoxygroup; r= 0, 1, 2, 3, 4, 5, 6, 7 or 8;

R(3), R(4), R(5) R(6) denote independently from each other hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, NO2, OR(25) or NR(26)R(27);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms

R(26) R(27) denote independently from each other hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen;

R(10) R(11) denote hydrogen;

R(12) R(13) R(14) R(15) denote independently from each other hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C-atoms, -Y-CsH2s-R(29),

Y represents-O-;

s = 0;

R(29) denotes hydrogen, methyl, as well as their physiologically compatible salts.

4. The compounds of formula I according to one or more paragraphs.1-3, in which R(8) denotes a 1-indaily residue of formula II, which are compounds of formula Ia:

where R(1) denotes hydrogen;

R(2) denotes R(20)-CrH2r;

R(20) denotes CH3CH2F, cycloalkyl with 3, 4, 5 or 6 C-atoms, phenyl, or N-containing heterocycle with 5 C-atoms, being the her of IT, metoxygroup;

r= 0, 1, 2, 3, 4 or 5;

R(3), R(4), R(5) R(6) denote independently from each other hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, NO2or or (25);

R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms;

R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms;

R(9) denotes hydrogen;

R(10) R(11) denote hydrogen;

R(12) R(13) R(14) R(15) denote independently from each other hydrogen, F, Cl, Br, alkyl with 1, 2, 3, 4 or 5 C-atoms, -Y-CsH2s-R(29);

Y represents-O-;

s = 0;

R(29) denotes hydrogen, methyl,

as well as their physiologically compatible salts.

5. The compounds of formula 1A according to one or more paragraphs.1-4, where: R(1) denotes hydrogen; R(2) denotes R(20)-CrH2r; R(20) denotes CH3CH2F, cycloalkyl with 3, 4, 5 or 6 C-atoms or phenyl, unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of HE, metoxygroup; d= 0, 1, 2, 3, 4 or 5; R(3), R(4), R(5) R(6) denote independently from each other hydrogen, F, CL, Br, I, alkyl with 1, 2, 3, 4 or 5 C-atoms, NO2or or (25); R(25) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms; R(7) denotes hydrogen or alkyl with 1, 2, 3 or 4 C-atoms; R(9) denotes hydrogen; R(10) R(11) denote vodor theH2s-R(29); Y represents-O-; s = 0; R(29) denotes hydrogen, methyl, as well as their physiologically compatible salts.

6. Method of producing compounds of the formula I according to one or more paragraphs.1-5, characterized in that the carboxylic acid of formula IV

where R(1), R(2), R(3), R(4), R(5) R(6) have the meanings given in paras.1-5,

subjected to amidation reaction by means of an amine of the formula Va or Vb

where R(7), R(9) R(10) R(11) R(12) R(13) R(14) R(15) have the meanings given in paras.1-5.

7. The compounds of formula I according to one or more paragraphs.1-5 and/or their physiologically compatible salts, suitable for medicinal products with a blocking K+channel action for the treatment and prevention of disease due to K+channel.

8. The compounds of formula I according to one or more paragraphs.1-5 and/or their physiologically compatible salts, suitable for medicinal product for the treatment or prevention of cardiac arrhythmias, which can be stopped by lengthening of the action potential.

9. The compounds of formula I according to one or more paragraphs.1-5 and/or their physiologically compatible salts, suitable for medicinal product for the treatment or profilin PP.1-5 and/or their physiologically compatible salts, suitable for the production of pharmaceuticals for therapy or prophylaxis of supraventricular arrhythmias.

11. The compounds of formula I according to one or more paragraphs.1-5 and/or their physiologically compatible salts, suitable for medicinal product for the treatment or prevention trialing flicker or trialing utter.

12. Pharmaceutical composition having a blocking K+-channel effect, containing an effective amount of at least one of the compounds of formula I according to one or more paragraphs.1-5 and/or its physiologically compatible salts as biologically active ingredients together with pharmaceutically acceptable carriers and additives and, if necessary, one or more other biologically active pharmacological substances.

 

Same patents:

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

The invention relates to compounds of the formula I

< / BR>
in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

< / BR>
R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to a method of purification of isoquinoline, which is that fraction of isoquinoline obtained by processing bituminous coal tar, containing approximately 1 wt.% quinoline and approximately 8 wt.% rinaldina, cooled to a temperature 4-18oWith and spend suspension crystallization by centrifugation mother liquor

The invention relates to a method for producing 1-substituted 3,3-dimethyl-3,4-dihydroisoquinolines formula (I), where R=OMe; Me; X=Me; SMe; Ph; CH2COOEt; CH2CONH2who is that in an environment of concentrated sulfuric acid at the same time introducing somelady aldehyde, 1,2 - or 1,4-dimethoxy- (or dimethyl) substituted benzene, NITRILES of the formula RCN where R=Me; SMe; Ph; CH2COOEt; CH2CONH2) at a molar ratio of reagents, respectively, 1:1:1

The invention relates to Bioorganic chemistry, specifically to an improved method for producing orginalny derived aminomethanesulfonic General formula

ArgNHwhere R1H, R2CH3; C2H5; n, i= C3H7; n-, i-, t-C4H9; C5H11; C8H17;; -CHor R1R2CH3;

C2H5; C3H7; n-, i-C4H9; or

NR1R2=O;;which are used in biotechnology as CR - and fluorogenic substrates in the determination of the enzymatic activity of proteases and analysis of complex mixtures and can be used to synthesize other derivatives based on them, used for the same purposes

The invention relates to thiosulfonate formulas

< / BR>
< / BR>
or

< / BR>
< / BR>
< / BR>
where R1represents a radical having a length greater than the saturated chain of four carbon atoms, and shorter than the saturated chain from eighteen carbon atoms, and in rotation around the axis passing through the position 1, associated with the SO2and position 4 6-membered ring or through position 1, associated with the SO2group and associated with the Deputy position 3 or 5 of the 5-membered ring, defines a three-dimensional volume, the largest size in which the width is approximately one phenyl ring up to three phenyl rings in a direction transverse to the axis of rotation; R2means hydrido,1-C6alkyl, phenyl-C1-C4alkyl, heteroaryl-C1-C4alkyl, C2-C4alkyl substituted amino; C2-C4alkyl, substituted monosubstituted amino or disubstituted amino, where-C6) alkyl, C5-C8cycloalkyl and C1-C6alkylsulphonyl, or where two of the substituent and the nitrogen to which they are attached, together form pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, and other pyrimidinyl

The invention relates to new derivatives of sulfonamides of General formula I, where R1- [(A1)CH2]c[(A2)CH2]b[(A3)CH2]andC-, each of a, b and C is 1; each of the A1AND2and a3independently selected from H, (C1-C5)alkyl and phenyl or substituted phenyl; R2and R3independently (C1-C6)alkyl, or R2and R3together form a 3-7-membered cycloalkyl, tetrahydropyran-4-ilen ring or bicyclical formula

< / BR>
where the asterisk denotes a carbon atom common to R2and R3; Q - (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl, where each (C6-C10, WITH6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryloxy(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl,

(C6-C10)aryl(C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C6-C10)aryl(C1-C6)alkoxy(C6-C10)aryl possibly substituted on any of the ring carbon atoms capable of forming additional links, one or more than one substituents on the ring, independently selected from fluorine, chlorine, bromine, (C1-C6)alkyl, (C1-C6)alkoxy, PERFLUORO (C1-C3)alkyl, PERFLUORO(C1-C3)alkoxy and (C6-C10)aryloxy; and Y is hydrogen or (C1-C6)alkyl

The invention relates to sulphonilecarbomide acids of the formula

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and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

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where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

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

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

The invention relates to derived hydroxyethylaminophenol formulas I, II, III, where R is phenyl-C1-C8alkoxycarbonyl, where phenyl may be substituted C1-C8alkoxy; chinainternational, mono - or di-C1-C8alkylamino-C1-C8alkanoyl; R' is H, C1-C8alkyl; R1- H, C1-C8alkyl, C2-C8alkenyl, -C(O)NH2CH2C(O)NH2, -CH2C(O)NHCH3C(CH3)2(SCH3), amino acid side chain, such as glycine; R1'and R1"both - H; R2- phenyl-C1-C8alkyl; R3- H, C1-C8alkyl, C1-C8alkoxy-C1-C8alkyl, C2-C8alkenyl; R4- C1-C8alkyl, phenyl, methoxyphenyl; R6Is H; Y Is O; x = 1, 2; t = 0 or 1

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

The invention relates to benzoylpyridine General formula (I)

(I)

where R(1) means hydrogen or R(5) - SOm,

m means 0, 1 or 2,

R(5) means (C1-C8)-alkyl,

R(2) means-CF2R(14), -CF[R(15)][R(16)],

R(14) means (C1-C4)-alkyl,

R(3) is defined as R(1),

R(4) means hydrogen, -(CH2)s-(CF2)t-CF3,

s denotes 0 or 1, t is 0, 1 or 2,

and their pharmaceutically compatible salts
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