2'-substituted 1,1'-byphenylcarbonamides, methods for production thereof, uses as drugs and pharmaceutical compositions containing the same

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

 

The invention relates to compounds of formula (I):

where R(1), R(2), R(3), R(4), R(5), R(6)R(7)R(8), R(30) R(31) have the meanings stated below, their reception and their applications, especially in medicine.

Proposed according to the invention the compounds of formula (I) is still not known. They affect so-called Kv1.5 potassium channel and inhibit referred to as "sverhbystro activated slow cleaner" potassium current in human atrium. Connections are therefore highly suitable as a new kind of anti-arrhythmic biologically active substances, in particular for the treatment and prevention of atrial arrhythmias, such as atrial fibrillation (atrial fibrillation, AF) or atrial flutter (atrial utter).

Atrial fibrillation (AF) and atrial flutter are the most common atrial arrhythmia. Their occurrence increases with age and often leads to fatal consequences, such as apoplexy. AF affects approximately 1 million Americans each year and leads to more than 80000 apoplectic strokes each year in the United States. The currently adopted antiarrhythmic agent of class I and class III reduce the frequency of re-occurrence of AF, but because of their potential prioritiesin pomocnitekstovi find only limited application. Consequently, in medicine there is a great need in getting the best medicines for the treatment of atrial arrhythmias (S.Nattel, Am. Heart J., 130, 1094-1106 (1995); "Newer (developments in the management of atrial fibrillation").

It is shown that most supraventricular arrhythmias dependent on the so-called "circulating" waves of excitation. This circulation occurs when the tissue of the heart has a slow conductivity and at the same time is very short refractory periods. The increase in myocardial refractory time by lengthening of the action potential is a recognized mechanism for termination of arrhythmias or, respectively, to prevent their occurrence (T.J.Colatsky and others, Drug Dev. Res., 19, 129-140 (1990): "Potassium channels as targets for antiarrhythmic drug action"). The duration of the action potential is essentially determined by the amount repolarizing K+-currents that flow through the different+-channels of the cells. Especially great importance is attributed to the so-called "slow purifier" Ik, which consists of three different components: IKr, IKsand IKur.

Most of the known antiarrhythmic drugs class III (e.g. dofetilide, E and d-sotalol) block predominantly or exclusively quickly activated potassium channel IKrthat can be in the cell is x ventricle person, and also in the atrium. However, it turned out that these compounds in small or normal frequency of cardiac contractions have increased prioritiesin risk, and in particular see arrhythmia, denoted as pirueta tachycardia (D.M.Roden, Am. J.Cardiol. 72, 44B-49B (1993): "Current status of class III antiarrhythmic drug therapy"). Along with this high, partly fatal risk at low frequency, for IKr-blockers installed the weakening of activity in conditions of tachycardia, which is directly necessary action ("negative dependence on use").

While some of these shortcomings could be overcome blockers slowly activated component (IKs), their effectiveness is still not proven as unknown no clinical studies with blockers IKschannels.

"Especially quickly activated and very slowly inactiveusers slow component cleaner IKur(=sverhbystro activated slow purifier), which corresponds to the Kv1.5 channel, plays a particularly important role in relation to the duration of repolarization in the human atrium. Inhibition directed to the periphery of potassium current IKurcompared with the inhibition of IKror, respectively, the IKsthus, is particularly is particularly effective method of lengthening the atrial action potential and thus the termination, accordingly, prevention of atrial arrhythmias. A mathematical model of human action potential shows that the positive effect of the blockade of IKurshould be particularly expressed directly in pathological conditions of chronic atrial fibrillation (.Courtemanche, R.J.Ramirez, S.Nattel, Cardiovascular Research, 42, 477-489 (1999): "Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model").

In contrast to the IKrand IKsthat are also in the ventricle man, IKur, however, plays a significant role in the human atrium, but not in the ventricle. On this basis, when the inhibition of IKur-current, in contrast to the blockade of IKror IKsfrom the outset excluded risk proaritmicheskimi effects on ventricular (Z.Wang and others, Circ. Res. 73, 1061-1076 (1993): "Sustained Depolarisation-Induced Outward Current in Human Atrial Myocytes"; G.-R. Li and others, Circ. Res., 78, 689-696 (1996): "Evidence for Two Components of Delayed Rectifier K+-Current in Human Ventricular Myocytes"; G.J.Amos and others, J.Physiol., 491, 31-50 (1996): "Differences between outward currents of human atrial and subepicardial ventricular myocytes").

Antiarrhythmic agent that act by selective blockade of IKur-current or Kv1.5 channel, still, however, not available for sale. For numerous pharmaceutical biologically active substances (as, for example, tedisamil, bupivacaine or sertindole), however, described inhibitory effects on Kv1.5 channel,however, Kv1.5-blockade in this case, accordingly, represents the only side effects along with other key actions of substances.

In the application WO-9804521 claimed aminoindane as blockers of potassium channels that block Kv1.5 channel. In applications WO-9818475 and WO-9818476 describes the use of different pyridazinones and phosphine oxides as antiarrhythmic drugs, which should be affected by blockade of IKur. The same compounds originally described, but also as immunosuppressants (WO-9625936). Described in these applications, the compounds have the structure of a completely different kind than proposed according to the invention the connection.

Unexpectedly, it was shown that described in the present application is 2’-substituted 1,1’-biphenyl-2-carbonamide are potent blockers of human Kv1.5 channel. Therefore, they can be used as a new kind of antiarrhythmic drugs with particularly favorable safety profile. Compounds particularly suitable for the treatment of supraventricular arrhythmias, such as atrial fibrillation or atrial flutter.

Connections can be used for termination of the existing atrial fibrillation or atrial flutter for restoring sinus rhythm (cardioversion). Moreover, substances reduce the predisposition to the emergence of a new flicker (the achievement is of sinus rhythm, prevention).

Proposed according to the invention compounds have so far been unknown. Some structurally related compounds described in Helv. Chim. Acta, (70) 70 (1994) and cited in the literature. For the peptide compounds (e.g., compound A), however, is not known to block potassium channel activity. Moreover, such connections because of the numerous peptide bonds must have too low metabolic stability for use as an antiarrhythmic agent.

Connection And

Another similar connection (connection) specified in the application EP 0620216. Connection and all other connections of this application are characterized in that in the position R (3) they contain a special Deputy (for example, benzoyl-1,2,3,4-tetrahydroisoquinoline), which in the case of proposed according to the invention of compounds of the present application is not provided. Specified in EP 0620216 compounds act as antagonists of vasopressin and yet have completely different biological activity than that described in this case blockers Kv1.5 channel.

Connection

The present invention relates to compounds of formula (I):

where:

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

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15) or SO2CH3;

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5C3F7CH2F, CHF2, OR(15), SO2CH3, phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, F3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl, which is unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

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

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

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

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

and y cannot mean 0 when R(16) mean OR(17) or SO2CH3;

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5With2F7CH2F, CHF2, OR(17), SO2CH3, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, F3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino ;

R(17) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl;

moreover, phenyl or 2-, 3 - or 4-pyridyl nezamisimaya substituted by one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, F3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

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

R(18) means a hydrogen atom or a CzH2z-R(16), and

R(16) has the above meaning;

z is 0, 1, 2 or 3;

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

R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, WithvH2v-CF3or CwH2wis phenyl;

moreover, the phenyl ring is unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, F3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 carbon atoms;

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

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

or

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

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, I, CF3, NO2CN, SOON3, N2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31), independently of one another, mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

or

R(30) R(31) together mean a chain of two methylene groups;

and their pharmaceutically acceptable salts.

Preferred compounds of formula (I), where:

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

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3C2F5, OCF3, OR(15), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, NO2CN, SOON3, CONH2The PINES 3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl, which is unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, NO2CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

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

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

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

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

and y cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3C2F5, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted with one two or three substituents, selected from the group consisting of F, Cl, Br, CF3, F3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

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

moreover, phenyl or 2-, 3 - or 4-pyridyl neelamani or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, F3, NO2CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

or

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

R(18) means a hydrogen atom or a CzH2z-R(16)and R(16) has the above meaning;

z is 0, 1, 2 or 3;

R(19) means CONH2, CONR(20)R(21), COOR(22), CH2IT;

R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, CvH2v-CF3orwH2wis phenyl;

moreover, the phenyl ring is unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, F3, NO2CN, SOON3, CONH2 The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 carbon atoms;

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

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

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, CF3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31), independently of one another, mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

or

R(30) R(31) together mean a chain of two methylene groups;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula (I), where:

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

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) means cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, furyl, thienyl or N-containing heteroa the automatic balance 3, 4 or 5 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3, F3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1 or 2 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

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

R(18) means a hydrogen atom or a CzH2z-R(16);

z is 0, 1, 2 or 3;

R(19) means CONH2, CONR(20)R(21), COOR(22) or CH2IT;

R(20) means a hydrogen atom, alkyl with 1, 2, 3, 4 or 5 carbon atoms, WithvH2v-CF3orwH2wis phenyl;

the dryer is the emotional ring unsubstituted or substituted by one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, OCF3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

v means Of, 1, 2 or 3;

w stands for O, 1, 2 or 3;

R(21) means a hydrogen atom or alkyl with 1, 2, 3, 4 or 5 carbon atoms;

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

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3, F3CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

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

moreover, phenyl or 2-, 3 - or 4-pyridyl unsubstituted or substituted one, two or three substituents, selected the C group, consisting of F, Cl, Br, CF3, F3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4) means a hydrogen atom or alkyl with 1 or 2 carbon atoms;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, CF3CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31), independently of one another, mean a hydrogen atom or methyl;

or

R(30) R(31) together mean a chain of two methylene groups;

and their pharmaceutically acceptable salts.

Especially preferred are also the compounds of formula (I), where:

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

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

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

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted who or substituted by one or two substituents, selected from the group consisting of F, Cl, Br, CF3, F3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) denotes alkyl with 1 or 2 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, CF3or phenyl, which is unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms;

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

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

and cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents, vybere the diversified group, consisting of F, Cl, Br, CF3, F3CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

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

moreover, phenyl or 2-, 3 - or 4-pyridyl unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, F3, NO2CN, SOON3, CONH2The PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4) means a hydrogen atom or alkyl with 1 or 2 carbon atoms;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, CF3CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulphonyl or methylsulfonylamino;

R(30) R(31), independently of one another, mean a hydrogen atom or methyl;

or

R(30) R(31) together mean a chain of two methylene groups;

and their pharmaceutically acceptable salts.

In the highest art is the penalty preferred compounds of formula (I), where:

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

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

x represents 0, 1, 2 or 3;

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl and pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3HE, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

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

y means 0, 1 or 2;

R(16)denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl or pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3HE, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, CF3CN, SOON3, CONH2, NH2HE, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;

R(30) R(31), independently of one another, mean a hydrogen atom or methyl;

or

R(3) and R(31) together mean a chain of two methylene groups;

and their pharmaceutically acceptable salts.

Particularly preferred compounds of formula (I), where:

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

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

x represents 0, 1, 2 or 3;

R(14) means cycloalkyl with 5 or 6 carbon atoms or phenyl;

and phenyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(11) is specified for R(9) value;

R(2) means a hydrogen atom;

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

y means 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl and pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, CF3, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;

R(30) R(31) denote a hydrogen atom;

and their pharmaceutically acceptable salts.

Alkyl residues and alkylene residues may be linear or branched. This applies also for the to alkilinity the remnants of the formula C xH2CyH2yCzH2zCvH2vand CwH2w. Alkyl residues and alkylene residues may be linear or branched, if they substituted or contained in other residues, such as CNS 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. Produced from these divalent residue remains, as, 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-pentile, 2,2-dimethyl-1,3-propylene, 1,6-hexylen etc. are examples alkilinity residues.

Cycloalkyl residues can also be branched. Examples cycloalkyl residues 3-11 carbon atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, 2-methylcyclohexyl, 3-methylcyclobutene, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, mental, cycloheptyl, cyclooctyl etc.

As the N-containing heteroaromatic residues with 1, 2, 3, 4, 5, 6, 7, 8 or 9 and what Ohm carbon have value in particular 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 - or-5-yl; 2-, 4 - or 5-thiazolyl; 3-, 4 - or 5-isothiazolin; 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-cinnoline; 2-, 3-, 5-, 6-, 7 - or 8-honokalani; 1-, 4-, 5-, 6-, 7 - or 8-phthalazine. Next, we mean the corresponding N-oxides of these compounds, therefore, for example, 1-hydroxy-2-, 3 - or 4-pyridyl.

Particularly preferred N-containing heterocyclic residues pyrrolyl, imidazolyl, hinely, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

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

Monosubstituted phenyl residues can be substituted in 2-, 3 - or 4-position; disubstituted - in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions; tizanidine - in 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-positions. The corresponding value is also DL the N-containing heteroaromatic residues, thiophene or fueling balance.

In the case of di-, respectively, tizamidine residue substituents may be the same or different.

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

If the compounds of formula (I) contain one or more acidic groups or basic character, respectively, one or more basic compounds, the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically applicable salt. Thus, the compounds of formula (I)containing acid groups, e.g. one or more COOH groups, can be applied, for example, in the form of alkali metal salts, preferably sodium salts or potassium, or in the form of salts of alkaline-earth metals, for example, salts of calcium or magnesium, or ammonium salts, such as salts with ammonia or organic amines or amino acids. The compounds of formula (I)containing one or more primary, i.e. protonium, groups, or one or more basic heterocycles, can emanate also in the form of their physiologically acceptable additive salts with inorganic or organic acids, for example, in the form of hydrochloride, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malatov, gluconate, etc. If the compounds of formula (I) contain both acid groups and the main character in the molecule, the invention are described along with the salt forms, internal salt, the so-called betaines. Salts of compounds of formula (I) can be obtained by conventional means, for example, by combining with the acid, respectively, a base in a solvent or dispersant or other salts by anion exchange.

The compounds of formula (I) with the appropriate substitution may be present in stereoisomeric forms. If the compounds of formula (I) contain one or more asymmetric centers, independently from each other, they can have the S-configuration or R-configuration. The invention includes all possible stereoisomers, such as enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms such as enantiomers and/or diastereomers, in all ratios. The invention therefore include, for example, enantiomers in pure enantiomeric form, in the form of levogyrate, and also in the form of programada antipodes, or in the form of mixtures of both enantiomers in different ratios or in the form of racemates. Individual stereo the Windows in the desirable case can be obtained by separation of the mixture by conventional methods or, for example, by stereoselective synthesis. In the presence of mobile hydrogen atoms to the present invention also includes all tautomeric forms of the compounds of formula (I).

The compounds of formula (I) receive different chemical methods, which also belong to the present invention. Some typical ways of synthesis presented in indicated below in schemes 1, 2, 3 and 4 of the reaction sequences. The residues R(1)-R(8) are, respectively, the same as above, if not specified otherwise.

For example, the compound of formula (I) are obtained according to scheme 1 of the derivatives of the anhydride givenaway acid of formula (II) as commercially available, respectively, are known from the literature of the parent compounds. The recovery of the compounds of the formula (II) with sodium borohydride and subsequent interaction with phthalimide potassium, as described in Tetrahedron, 45, 1365-1376 (1989), leads to biphenylcarbonic acids of the formula (IV). By reacting with amines of the formula HNR(3)R(4) with subsequent hydrazinolysis phthalimide get aminomethyl compounds of formula (VI), which by introducing into engagement with suitable derivatives of the formula R(1)-X get proposed according to the invention the compounds of formula (I), where R(2) denotes the hydrogen atom and R(1), R(3), R(4), R(5), R(6)R(7) and R(8) are higher than the values shown. Subsequent alkylation with a suitable alkylating means of the formula R(2)-Y, where Y means nucleofuge delete a group, such as Cl, Br or I, leads to the corresponding compounds of formula (I), where R(2) denotes alkyl with 1-4 carbon atoms.

Alternatively, biphenylcarbonic acid of formula (IV) by hydrazinolysis can be turned into aminocarbonyl acid of the formula (VII), which are then due to the reaction of the amino group with compounds of formula R(1)-X and R(2)-Y, followed by amidation of carboxylic acids with amines of the formula HNR(3)R(4) turn in the proposed according to the invention the compounds of formula (I) (scheme 2).

In some cases it may be appropriate first to receive one of the above methods proposed according to the invention the compounds of formula (Ia) (scheme 3)in which R(9) is easily tseplyalsya the rest, as, for example, tert-butyl or benzyl. After removal of the respective protective groups, for example, using triperoxonane acid for the BOC-group, or by catalytic hydrogenation to benzyloxycarbonylamino balance, obtain the compounds of formula (IX), which then again by introducing into an interaction with compounds of formula R(1)-X can be transformed into other proposed according to the invention the compounds of formula (I).

Another opportunity to receive the Oia proposed according to the invention compounds is catalyzed by palladium reaction combinations of panelbased or iodide of the formula (X) with phenylboronic acid of formula (XI) (reaction mix by Suzuki; scheme 4), which can be realized, for example, in the presence of Pd[(RS6H5)3]4as a catalyst, sodium carbonate as a base and 1,2-dimethoxyethane as a solvent.

If R(9) means easy tseplyalsya the rest, as, for example, tert-butyl or benzyl, the compounds of formula (Ib) then, as described above and in scheme 3, can be transformed into other proposed according to the invention the compounds of formula (I).

Required boranova acid of formula (XI) can be obtained from compounds of formula (XII), in which Z denotes a hydrogen atom, bromine or iodine, by the introduction of lithium in the ortho-position, respectively, of the exchange of halogen, metal, with subsequent interaction with trimethylamin ester of boric acid.

The above interaction between the compounds of formulae (VI), (VII) and (IX) with compounds of formula R(1)-X correspond to the well-known conversion of amine to amide derivative of carboxylic acid, amide sulfonic acids, carbamate, urea or thiourea. The remainder of X means suitable nucleofuge delete the group, such as F, Cl, Br, imidazolyl, O-operations group.

To obtain the compounds of formula (I) or (VIII)in which R(1) means C(O)OR(9), therefore, carbamates, using, for example, the compounds of formula R(1)-X, in which X is a chlorine atom or O-operations group, sledovatel is but chloroformiate or succinimidylester.

To obtain the compounds of formula (I) or (VIII)in which R(1) means SO2R(10)therefore, sulfonamides, as a rule, use the compounds of formula R(1)-X, in which X denotes a chlorine atom, therefore, the anhydrides of sulfonic acids.

To obtain the compounds of formula (I) or (VIII)in which R(1) means COR(11), therefore, amides of carboxylic acids, are used, for example, the compounds of formula R(1)-X, in which X denotes a chlorine atom, imidazolyl or acetochlor, therefore, carboxylic acid anhydrides, imidazolides carboxylic acids or mixed anhydrides. However, you can also use free acid of the formula R(1)-OH in the presence of a suitable condensing means, as carbodiimide or oranjevyi salt, as TOTU.

To obtain the compounds of formula (I) or (VIII)in which R(1) means CONR(12)R(13) or C(S)NR(12)R(13)therefore, ureas or thioureas, instead of the compounds of the formula R(1)-X it is also possible to use compounds of the formula R(12)N(=C=O), or R(12)N(=C=S), therefore, isocyanates or thioisocyanate.

The above interaction between the compounds of formulae (IV) or (VIII) with amines of the formula HNR(3)R(4) correspond to the well-known transformation of the carboxylic acid in the carboxylic acid amide. For these reactions the literature describes numerous ways. Especially prefer is Ino can be done by activating carboxylic acid, for example, using dicyclohexylcarbodiimide (DCC), if necessary, with the addition of hydroxybenzotriazole (NOVT) or dimethylaminopyridine (DMAP), or with O-[(cyano(ethoxy-carbonyl)methylene)amino]-1,1,3,3-tetramethylethylenediamine (TOTU). But first, can be synthesized by known methods reactive derivatives of acids, for example anhydrides of the acids, by introducing into the interaction of carboxylic acids of the formula (IV) or (VIII) with inorganic halogenide acids, such as SOCl2or imidazoline acid by introducing into the interaction with the carbonyl diimidazol, which are then, if necessary, adding a secondary basis, enter into interaction with amines of the formula HNR(3)R(4).

In the case of all methods may be appropriate at certain stages of the reactions temporary protection of functional groups in the molecule. Such methods with the use of protective groups known to the specialist. The choice of protective groups for the groups and methods for their introduction and removal are described in the literature and, if necessary, can be easily used in a particular case.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Proposed according to the invention the compounds of formula (I) and their physiologically acceptable salts, thus, can be applied in the case of an animal, preferably in the case of a mammal, and in particular in the case of a man as drugs individually, as 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 acceptable salts for use as pharmaceuticals, their use for the treatment and prevention of these paintings diseases and their application to obtain drugs for this purpose and medicines with blocking To+-channel effect. Further, an object of the present invention are pharmaceutical compositions, which as active constituent parts contain an effective dose of at least one of the compounds of formula (I) and/or its physiologically acceptable salt along with conventional, pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions usually contain 0.1 to 90 wt.% compounds of formula (I) and/or their physiologically acceptable salts. The pharmaceutical compositions can prepare itself known. For this purpose the compounds of formula (I) and/or their physiologically acceptable salts instead of the ones with one or more, solid or liquid, galenovye carriers and/or excipients and, if desired, in combination with other biologically active substances of medicines brought to suitable forms of applications, or a single dose, which can then be used as medicinal products in human medicine or animal.

Medicines that contain proposed according to the invention the compounds of formula (I) and/or their physiologically acceptable salts can be administered orally, parenterally, for example intravenously, rectally, by inhalation, or locally, preferably the introduction depends on the specific case, for example, from the corresponding picture of the manifestations of the disease to be treated.

What excipients suitable for the desired composition of the medicinal product, the specialist is known on the basis of his expert knowledge. Besides solvents, gel-forming components, the basics of suppositories, auxiliary materials for the production of tablets and other carriers of biologically active substances can be used, for example, antioxidants, dispersants, emulsifiers, defoamers, improves the taste of the ingredients, preservatives, agents, dissolution, means to achieve a depot effect, buffer substances or dyes.

To achieve the Oia useful therapeutic effects of the compounds of formula (I) can also be combined with other medicinal biologically active substances. Thus, in the treatment of cardiovascular diseases possible combinations with active against cardiovascular substances. As such useful for cardiovascular disease component combinations are used, for example, other antiarrhythmic agent, such as antiarrhythmic agent of class I, class II or class III, as, for example, blockers IKs- or IKrchannels, such as dofetilide, or, further, blood pressure-lowering substances, such as ACE inhibitors (e.g. enalapril, captopril, ramipril), antagonists of angiotensin, activators To+channels and blockers alpha - and beta-receptors, however, also sympathomimetic and adrenergichesky active compounds and inhibitors of Na+/H+exchange, calcium channel antagonists, phosphodiesterase inhibitors and other positively inotrope active substances as, for example, digitalis glycosides or diuretics.

For oral use, the active compounds are mixed with suitable for this purpose additives, as carriers, stabilizers or inert diluents, and by conventional methods lead to suitable forms of applications, such as tablets, pills, detachable capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, Magne is s, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This preparation can be carried out both as dry and as wet granules. As oily carriers or solvents are used, for example, vegetable or animal oils as sunflower oil or cod-liver oil. As solvents for aqueous or alcohol solutions are used, 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 compounds in the desired case, along with the usual for this purpose substances as agents of dissolution, emulsifiers or other auxiliaries, transferred into a solution, suspension or emulsion. The compounds of formula (I) and their physiologically acceptable salts can also be liofilizirovanny and received lyophilizate be used, for example, for the preparation of drugs for injection or infusion. As the solvent used, for example, water, physiological sodium chloride solution or alcohols, e.g. ethanol, propanol, glycerin, along with this also solutions of sugars, as glucose or mannitol, or a mixture of various specified the s solvents.

As pharmaceutical compositions 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 acceptable salts in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or mixtures of such solvents. If necessary, the composition may also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as the propellant. This composition contains biologically active substance is usually in a concentration of from about 0.1 wt.% up to 10 wt.%, in particular from about 0.3 wt.% up to 3 wt.%.

Dosage introduce biologically active substances of the formula (I), its physiologically acceptable salts, depends on the specific case and must be adapted, as usual, for the optimal actions in the circumstances of a particular case. So, it depends, of course, on the frequency of administration and on the strength and duration used for the treatment or prevention of compounds, but also on the nature and intensity of treatable diseases, as well as gender, age, weight and individual responsiveness curable person or animal and enter whether in the acute or preventive care is automatic. Usually a daily dose of a compound of formula I when administered to a patient weighing approximately 75 kg is from about 0.001 mg/kg body weight to 100 mg/kg body weight, preferably from 0.01 mg/kg body weight to 20 mg/kg of body weight.

Dose can be administered as a single dose or divided into several, for example two, three or four doses. In particular in the treatment of acute cases of cardiac arrhythmias, for example, in the ICU, it may be preferable parenteral administration by injection or infusion, for example, by prolonged intravenous infusion.

Experimental part

List of abbreviations

CDICarbonyldiimidazole
DICDiisopropylcarbodiimide
DMAP4-dimethylaminopyridine
DMFN,N-dimethylformamide
EDACN-ethyl-N’-(3-dimethylaminopropyl)carbodiimide
ITThe ethyl acetate
TPLthe melting temperature (unless otherwise noted, the above melting point

untreated raw foods; the melting temperature of the respective pure substances can be significantly higher)
NOT1-hydroxy-1H-benzotri the ol
in HAC.in the vacuum
LMSolvent
MeMethyl
RTroom temperature
THFTetrahydrofuran
TOTUO-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyleneglutaric

Preliminary stage 1:

7H-Dibenzo[C,e]oxepin-5-he

To a suspension of 50.0 g (0.22 mol) of the anhydride givenaway acid in 220 ml of dimethylformamide at a temperature of 5°C for 10 minutes portions added 9.0 g (0.24 mol) boronate sodium. After stirring for 1 hour at room temperature, the reaction mixture was poured into 220 ml of 6M hydrochloric acid, diluted with 750 ml of water and additionally stirred for 2 hours. The precipitation is filtered off under vacuum and get 35,0 g 7H-dibenzo[C,e]oxepin-5-it; TPL 131°C.

Phase 2:

2’-Phthalimidomethyl-2-carboxylic acid

A mixture of 35 g (to 0.17 mol) 7H-dibenzo[C,e]oxepin-5-she and 30.8 g (to 0.17 mol) phthalimide potassium in 330 ml of dimethylformamide is heated for 18 hours at a temperature of 170°C. After cooling, the precipitated precipitate is filtered under vacuum and bring in 160 ml of glacial acetic acid. After stirring for 1 hour, diluted with 650 ml of ice water and you AVSI precipitated product is filtered under vacuum and dried in vacuum. Get to 44.8 g of 2’-phthalimidomethyl-2-carboxylic acid; TPL 198°C.

Phase 3:

2’-Aminomethylphenol-2-carboxylic acid

A suspension of 10.0 g (28 mmol) of 2’-phthalimidomethyl-2-carboxylic acid in 450 ml of methanol is mixed with 20 ml of hydrazine hydrate is added and heated for 1.5 hours at a temperature of 40°C. the Reaction mixture was concentrated and the residue is treated with 250 ml dichloromethane. After filtering off insoluble 2,3-dihydrophenazine-1,4-dione mother liquor concentrate and obtain 4.8 g of 2’-aminomethylphenol-2-carboxylic acid.

General methods of synthesis of mixed succinimidylester of alcohols (preliminary stage 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 dichloromethane and 30 ml of acetonitrile at a temperature of 0°With portions add 5.0 g (of 19.5 mmol) disuccinimidyl. After stirring for 2.5 hours to 10 hours at room temperature, add 25 ml of water and the organic phase is still 2 times washed with water. After drying and concentrating receive appropriate succinimidylester, often in the form of a solid crystalline substance.

Preliminary stage 4A:

According to the General method obtain 3.2 g of 4-terbisil-N-succinimidylester; TPL 89°C (ether).

Preliminary stage 4b:

11,mmol 4-triftormetilfosfinov alcohol, respectively, a shared approach to obtain 2.3 g of 4-trifloromethyl-N-succinimidylester; TPL 102°C (ether).

Preliminary stage 4C:

From 10.5 mmol α-methyl-4-(trifluoromethyl) benzyl alcohol, respectively, a shared approach to obtain 1.6 g α-methyl-4-(trifluoromethyl)benzyl-N-succinimidylester; TPL 115°C (ether).

Preliminary stage 4d:

From a 19.5 mmol 4,4,4-triptoreline respectively a shared approach to obtain 4.0 g 4,4,4-trifloromethyl-N-succinimide-carbonate; TPL 72°C (ether).

Preliminary stage 4E:

Out of 26.3 mmol α-methyl-3-(trifluoromethyl)benzyl alcohol, respectively, a shared approach to get a 5.1 g α-methyl-3-(trifluoromethyl)benzyl-N-succinimidylester; TPL 77°C (ether).

Preliminary stage 4f:

Out of 31.6 mmol α-methyl-2,6-differenziava alcohol, respectively, a shared approach to obtain 1.6 g α-methyl-2,6-diferensial-N-succinimidylester; TPL 108°C (ether).

Preliminary stage 4g:

25 mmol α-methyl-2-(trifluoromethyl)benzyl alcohol, respectively, a shared approach to obtain 3.5 g α-methyl-2-(trifluoromethyl)benzyl-N-succinimidylester.

Preliminary stage 4h:

Of 25 mmol (S)-1-phenylethanol respectively a shared approach to obtain 3.5 g (S)-α-methylbenzyl-N-succinimidylester.

Preliminary stage 4i:

Of 25 mmol (R)-1-phenylethanol respectively a shared approach to obtain 3.5 g of (R)-α-methylbenzyl-N-succinimidylester./p>

Preliminary stage 4j:

25 mmol α-methyl-4-fermentelos alcohol, respectively, a shared approach to obtain 4.3 g α-methyl-4-terbisil-N-succinimidylester.

Preliminary stage 4k:

From 9.8 mmol (S)-1-phenyl-1-butanol, respectively, a shared approach to obtain 1.7 g (S)-α-propylbenzyl-N-succinimidylester.

Preliminary stage 5A:

Penetrated 2’-aminomethylphenol-2-carboxylic acid

From 2’-phthalimidomethyl-2-carboxylic acid (phase 2) after activation with CDI and administration in cooperation with phenethylamines get penetrated 2’-phthalimidomethyl-2-carboxylic acid; TPL 156°C.

5.0 g (10.9 mmol) of the product is dissolved in 200 ml of methanol and mixed with 5 ml of hydrazine hydrate is added. After stirring for 1 hour at a temperature of 40°the reaction mixture is concentrated and the residue is treated with dichloromethane. After filtering off the resulting 2,3-dihydrophenazine-1,4-dione, the mother liquor is concentrated and the residue purified by flash chromatography using a mixture of dichloromethane and methanol in a ratio of 20:1. Get 3 g of phenethylamine 2’-aminomethylphenol-2-carboxylic acid.

Preliminary stage 5b:

Benzylated 2’-aminomethylphenol-2-carboxylic acid

From 2’-phthalimidomethyl-2-carboxylic acid (pedwar the tion stage 2) after you put in the acid chloride using thionyl chloride and administration in cooperation with benzylamine get benzylated 2’-phthalimidomethyl-2-carboxylic acid. 1.2 g (2.7 mmol) dissolved in 55 ml of methanol and mixed with 1.35 ml of hydrazine hydrate is added. After stirring for 1 hour at a temperature of 40°the reaction mixture is concentrated and the residue is treated with dichloromethane. After filtering off the resulting 2,3-dihydrophenazine-1,4-dione, the mother liquor is concentrated and the residue purified by flash chromatography using a mixture of dichloromethane and methanol in the ratio of 30:1. Get 0,49 g benzylamine 2’-aminomethylphenol-2-carboxylic acid.

Preliminary stage 5C:

Isopentylamine 2’-aminomethylphenol-2-carboxylic acid

3 g (8.4 mmol) of 2’-phthalimidomethyl-2-carboxylic acid (phase 2) by entering into interaction with isopentylamine in the presence of NEWT and DIC obtain 3.2 g of isopentylamine 2’-phthalimidomethyl-2-carboxylic acid; TPL 169°C. the Product is dissolved in 100 ml of methanol and mixed with 5 ml of hydrazine hydrate is added. After stirring for 1 hour at a temperature of 40°the cooled reaction mixture is filtered. The filtrate is concentrated and the residue is treated with dichloromethane. After washing with water, drying and concentrating obtain 1.8 g of isopentylamine 2’-aminomethylphenol-2-carboxylic acid.

Preliminary stage 5d:

2-(2-Pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid

10 g (28 mmol) of 2’-phthalimidomethyl-2-carboxylic acid (phase 2) by entering into interaction with 2-(2-pyridyl)ethylamine in the presence of NEWT and DIC obtain 13 g of 2-(2-pyridyl)ethylamide 2’-phthalimidomethyl-2-carboxylic acid; TPL 155°C. the Product is suspended in 300 ml of methanol and mixed with 20 ml of hydrazine hydrate is added. After stirring for 1 hour at a temperature of 40°the cooled reaction mixture is filtered. The filtrate is concentrated and the residue is treated with ethyl acetate. The product is extracted 2 times with 2M hydrochloric acid in the aqueous phase. Then the aqueous phase is alkalinized with potassium carbonate and extracted 2 times with ethyl acetate. After washing with water, drying and concentration gain of 7.3 g of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid.

Preliminary stage 6:

2’-(Benzyloxycarbonylamino)biphenyl-2-carboxylic acid

To a solution of 455 mg (2 mmol) of 2’-aminomethylphenol-2-carboxylic acid (phase 3) and 336 mg (4 mmol) of sodium bicarbonate in 5 ml of dioxane and 5 ml of water at a temperature of 0°With added dropwise a solution of 500 mg (2 mmol) benzyl-N-succinimidylester in 2.5 ml of dioxane. After stirring for 4 hours at room temperature, concentrated in vacuo, diluted with water, acidified and extracted utilized the volume. Obtain 590 mg of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

Preliminary stage 7:

2’-(tert-Butoxycarbonylamino)biphenyl-2-carboxylic acid

To a solution of 12.0 g (53 mmol) of 2’-aminomethylphenol-2-carboxylic acid (phase 3) in 130 ml of 1,4-dioxane and 65 ml of water, add 65 ml of 1M sodium hydroxide solution and after complete dissolution type of 12.6 g (58 mmol) of di-tert-BUTYLCARBAMATE. After stirring for 2 hours at room temperature, concentrated in vacuo, diluted with water and extracted 2 times with dichloromethane. The aqueous phase is acidified with 1M solution of potassium hydrosulfate and extracted with ethyl acetate. After a significant degree of concentration, addition of n-heptane and standing overnight, the product precipitates, and obtain 7.6 g of 2’-(tert-butoxycarbonylamino)biphenyl-2-carboxylic acid; TPL 136°C.

A General method of removal of the BOC-protective group:

To 30%of the resultant solution triperoxonane acid in dichloromethane added N-Boc-protected aminomethylpyridine derivative (1 g per 10 ml solution). The mixture is stirred for 30 minutes at room temperature and then the solvent is removed under vacuum in a rotary evaporator apparatus. The residue is treated with ethyl acetate and washed with a saturated solution of sodium bicarbonate. The PR is onicescu phase is dried over magnesium sulfate, the solvent is removed in vacuum and obtain the corresponding amides of 2’-aminomethylphenol-2-carboxylic acid.

Preliminary stage 8A:

(2,4-Diferensial)amide 2’-aminomethylphenol-2-carboxylic acid

The connection is obtained from the BOC-protected compound (example 8C) according to the General method. Alternatively, the connection can also select directly in the form of triptoreline and enter into interaction further.

Further preliminary stage 8:

Similarly from the BOC-protected compounds of examples 8d-8o and 10A-10o release the corresponding amines.

General methodology for the interaction of aminomethylphenol with succinimidylester to obtain carbamates

(examples 1a-1u)

To a solution of 0.45 mmol of the corresponding 2’-aminomethylphenol and 38 mg (0.45 mmol) of sodium bicarbonate in 2 ml of dioxane and 2 ml of water is slowly added dropwise a solution of 0.45 mmol of the corresponding succinimidylester in 2 ml of dioxane. Stirred for 2-12 hours at room temperature, concentrated, diluted with water, extracted with ethyl acetate and the organic phase is washed with water. After drying and concentrating receive the corresponding carbamates.

Example 1A

Penetrated 2’-(4-triftormetilfosfinov-carbonylmethyl)biphenyl-2-carboxylic acid

0.45 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid and 4-trifloromethyl-N-succinimidylester (phase 4b) according to the General method obtain 226 mg phenethylamine 2’-(4-triftoratsetilatsetonom)biphenyl-2-carboxylic acid.

Mass spectrum (ei e spray with the formation of positive ions) [MS (ES+)]: m/z=533 (M+1).

Example 1b

Penetrated 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.3 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid and benzyl-N-succinimidylester according to the General method obtain 66 mg of phenethylamine 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid in the form of oil.

MS (ES+): m/z=456 (M+1).

Example 1C

Penetrated 2’-(methylsulfonylmethane)biphenyl-2-carboxylic acid

0.45 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and methylsulfonylmethyl-N-succinimidylester according to the General method obtain 164 mg of phenethylamine 2’-(methylsulfonylmethane)biphenyl-2-carboxylic acid in the form of oil.

MS (ES+): m/z=481 (M+1).

Example 1d

2-(2-Pyridyl)ethylamide 2’-(4-triftoratsetilatsetonom)biphenyl-2-carbon is acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and 4-trifloromethyl-N-succinimidylester (phase 4b) according to the General method obtain 170 mg of 2-(2-pyridyl) ethylamide 2’-(4-triftoratsetilatsetonom)-biphenyl-2-carboxylic acid.

MS (ES+): m/z=534 (M+1).

Example 1E

2-(2-Pyridyl)ethylamide 2’-(4-forbindelsesindstillinger)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and 4-terbisil-N-succinimidylester (phase 4A) according to the General method receive 150 mg of 2-(2-pyridyl)ethylamide 2’-(4-forbindelsesindstillinger)biphenyl-2-carboxylic acid.

MS (ES+): m/z=484 (M+1).

Example 1f

2-(2-Pyridyl)ethylamide (±)-2’-(α-methyl-4-(trifluoromethyl)benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and α-methyl-4-(trifluoromethyl)benzyl-N-succinimidylester (phase 4C) according to the General method obtain 170 mg of 2-(2-pyridyl)ethylamide 2’-(α-methyl-4-(trifluoromethyl)benzyloxycarbonylamino ethyl)biphenyl-2-carboxylic acid in the form of a racemate.

MS (ES+): m/z=548 (M+1).

Example 1g

2-(2-Pyridyl)ethylamide (S)-2’-(α-methyl-4-(trifluoromethyl)benzyloxycarbonylamino)biphenyl-2-carboxylic acid

The S-enantiomer is obtained from the corresponding racemate (example 1f) by preparative high performance liquid chromatography (HPLC) on a column Chiralpak AD size 250×4,6 using the mixture of n-hexane, ethanol, and isopropanol (10:1:1; 0.3% triperoxonane acid/diethylamine) as solvent.

Example 1h

2-(2-Pyridyl)ethylamide (R)-2’-(α-methyl-4-(trifluoromethyl)benzyloxycarbonylamino)biphenyl-2-carboxylic acid

The R-enantiomer is obtained from the corresponding racemate (example 1f) by preparative HPLC on a column Chiralpak AD size 250×4,6 using the mixture of n-hexane, ethanol, and isopropanol (10:1:1; 0.3% triperoxonane acid/diethylamine) as solvent.

Example 1i

2-(2-Pyridyl)ethylamide 2’-(4,4,4-triftormetilfullerenov)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and 4,4,4-trifloromethyl-N-succinimidylester (preliminary stage 4d) according to the General method obtain 140 mg of 2-(2-pyridyl)-ethylamide 2’-(4,4,4-thrift butyloxycarbonyl)biphenyl-2-carboxylic acid.

MS (ES+): m/z=486 (M+1).

Example 1j

2-(2-Pyridyl)ethylamide (S)-2’-(α-methylbenzyloxycarbonyl)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and (S)-(α-methylbenzyl-N-succinimidylester (preliminary stage 4h) according to the General method given 60 mg of 2-(2-pyridyl)-ethylamide (S)-2’-(α-methylbenzyloxycarbonyl)biphenyl-2-carboxylic acid.

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

Example 1k

2-(2-Pyridyl)ethylamide (R)-2’-(α-methylbenzyloxycarbonyl)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and (R)-α-methylbenzyl-N-succinimidylester (preliminary stage 4i) according to the General method given 60 mg of 2-(2-pyridyl)ethylamide (R)-2’-(α-methylbenzyloxycarbonyl)biphenyl-2-carboxylic acid.

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

Examples 1l-1u

According to the General method and is similar to examples 1a-1k are provided the following compounds from the corresponding compounds obtained in the preliminary stages:

General methodology for the interaction of aminomethylphenol with esters harmor is vinoy acid to obtain carbamates

(examples 2A-2m):

To a solution of 0.3 mmol of the corresponding 2’-aminomethylphenol and 37 mg (0.36 mmol) of triethylamine in 6 ml of dichloromethane at a temperature of 5°C is added slowly dropwise a solution of 0.32 mmol of the corresponding ether of Harborview acid in 1 ml of dichloromethane. Stand under stirring over night at room temperature, the mixture was poured into water and the organic phase is washed again with water. After concentration the residue is purified by flash chromatography.

Example 2A

2-(2-Pyridyl)ethylamide 2’-(butoxycarbonylamino)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and butyl ether of Harborview acid according to the General method obtain 69 mg of 2-(2-pyridyl)ethylamide 2’-(butoxycarbonylamino)-biphenyl-2-carboxylic acid in the form of oil.

MS (ES+): m/z=432 (M+1).

Example 2b

(3-Methylbutyl)amide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.27 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and benzyl ether of Harborview acid according to the General method obtain 44 mg of (3-methylbutyl)amide 2’-(benzyloxycarbonylamino)-biphenyl-2-carboxylic sour the s. TPL 112°C.

MS (ES+): m/z=431 (M+1).

Example 2C

2-(2-Pyridyl) ethylamide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

Of 0.24 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and benzyl ether of Harborview acid according to the General method obtain 59 mg of 2-(2-pyridyl)ethylamide 2’-(benzyloxycarbonylamino)-biphenyl-2-carboxylic acid. TPL 140° (heptane/ethyl acetate).

MS (ES+): m/z=466 (M+1).

Example 2d

(3-Methylbutyl)amide 2’-(butoxycarbonylamino)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and butyl ether of Harborview acid according to the General method obtain 66 mg of (3-methylbutyl)amide 2’-(butoxycarbonylamino)biphenyl-2-carboxylic acid in the form of resin.

MS (ES+): m/z=397 (M+1).

Example 2E

(3-Methylbutyl)amide 2’-(2-chlorobenzylidenemalononitrile)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and 2-chlorobenzylamino ether Harborview acid according to the General method receive 75 mg (3-methylbutyl)amide 2’-(2-chlorobenzonitrile the said;") biphenyl-2-carboxylic acid in the form of resin.

MS (ES+): m/z=465 (M+1).

Example 2f

(3-Methylbutyl)amide 2’-(methoxycarbonylaminophenyl)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and methyl ether of Harborview acid according to the General methodology followed by extraction with ethyl acetate and purification by flash chromatography obtain 29 mg of (3-methylbutyl)amide 2’-(methoxycarbonylaminophenyl) biphenyl-2-carboxylic acid in the form of resin.

MS (ES+): m/z=355 (M+1).

Example 2g

(3-Methylbutyl)amide 2’-(phenoxycarbonylamino)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and phenyl ether Harborview acid according to the General methodology followed by extraction with ethyl acetate and purification by flash chromatography obtain 55 mg (3-methylbutyl)amide 2’-(phenoxycarbonylamino)biphenyl-2-carboxylic acid in the form of resin.

MS (ES+): m/z=417 (M+1).

Example 2h

(3-Methylbutyl)amide 2’-(4-carbomethoxybiphenyl)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and (4 carbomethoxy)phenyl E. the Ira Harborview acid according to the General methodology followed by extraction with ethyl acetate and purification by flash chromatography receive 77 mg (3-methylbutyl)-amide 2’-(4-carbomethoxybiphenyl)biphenyl-2-carboxylic acid resin.

MS (ES+): m/z=475 (M+1).

Example 2i

Penetrated 2’-(2,2-dimethylpropanolamine)biphenyl-2-carboxylic acid

0.45 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and neopentanoate according to the General methodology followed by extraction with ethyl acetate and purification by flash chromatography obtain 156 mg of phenethylamine 2’-(2,2-dimethylpropanolamine)biphenyl-2-carboxylic acid.

MS (ES+): m/z=445 (M+1).

Examples 2j-2m

Similar to examples 2a-2i receive the following connections:

Example No.StructureMC (ES+): m/z=TPL
2j491 
2k473107
2l503123
2m482 

General methodology for the interaction of aminomethylphenol with anhydrides of sulfonic acids to obtain sulfonamides

(examples 3A-3t):

To a solution of 0.61 mmol with the corresponding 2’-aminomethylphenol and 74 mg (0.73 mmol) of triethylamine in 5 ml dichloromethane at a temperature of 0° With slowly added dropwise 0.66 mmol of the corresponding sulfonic acid chloride. After stirring for 12 hours at room temperature the reaction mixture was concentrated in vacuo, the residue is stirred with 25 ml of water for 2 hours and vegascasinoonline the product is filtered under vacuum.

Example 3A

Penetrated 2’-(3-triftormetilfullerenov)biphenyl-2-carboxylic acid

From 0.61 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and 3-triftormetilfullerenov according to the General method get 272 mg phenethylamine 2’-(3-triptoreline-sulfoaluminate)biphenyl-2-carboxylic acid. TPL 145°C.

MS (ES+): m/z=539 (M+1).

Example 3b

Penetrated 2’-(4-acetylpenicillamine)biphenyl-2-carboxylic acid

From 0.61 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and 4-acetylphenylalanine according to the General method obtain 258 mg phenethylamine 2’-(4-acetylpenicillamine)-biphenyl-2-carboxylic acid. TPL 145°C.

MS (ES+): m/z=513 (M+1).

Example 3C

Penetrated 2’-(3-nitrophenylacetylene)biphenyl-2-carboxylic acid

From 0.61 mmol f is methylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and 3-nitrophenylacetonitrile according to the General method get 272 mg phenethylamine 2’-(3-nitrophenylacetylene)-biphenyl-2-carboxylic the acid. TPL 145°C.

MS (ES+): m/z=516 (M+1).

Example 3d

Penetrated 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid

From 0.61 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and phenylsulfonylacetate according to the General method obtain 224 mg of phenethylamine 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid. TPL 154°C.

MS (ES+): m/z=471 (M+1).

Example 3e

Penetrated 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid

From 0.61 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and 3-perpenicularity according to the General method obtain 221 mg of phenethylamine 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid. TPL 153°C.

MS (ES+): m/z=489 (M+1).

Example 3f

Penetrated 2’-(4-ethylphenethylamine)biphenyl-2-carboxylic acid

From 0.61 mmol of phenethylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5A) and 4-ethylphenethylamine according to the General method receive 250 mg of phenethylamine 2’-(4-ethylphenethylamine)biphenyl-2-carboxylic acid. TPL 163°C.

MS (ES+): m/z=499 (M+1).

Example 3g

Benzylated 2’-(3-triptoreline liposolubility)biphenyl-2-carboxylic acid

From 0.28 mmol of benzylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5b) and 3-triftormetilfullerenov according to the General method obtain 131 mg of benzylamine 2’-(3-triftormetilfullerenov)biphenyl-2-carboxylic acid. TPL 126°C.

MS (ES+): m/z=525 (M+1).

Example 3h

Benzylated 2’-(3-acetylpenicillamine)biphenyl-2-carboxylic acid

From 0.28 mmol of benzylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5b) and 3-acetylphenylalanine according to the General method obtain 110 mg of benzylamine 2’-(3-acetylpenicillamine)biphenyl-2-carboxylic acid. TPL 182°C.

MS (ES+): m/z=499 (M+1).

Example 3i

Benzylated 2’-(3-nitrophenylacetylene)biphenyl-2-carboxylic acid

From 0.28 mmol of benzylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5b) and 3-nitrophenylacetonitrile according to the General method obtain 115 mg of benzylamine 2’-(3-nitrophenylacetylene)biphenyl-2-carboxylic acid. TPL 175°C.

MS (ES+): m/z=502 (M+1).

Example 3j

Benzylated 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of benzylamine 2’-AMI is methylbiphenyl-2-carboxylic acid (preliminary stage 5b) and phenylsulfonylacetate according to the General method obtain 95 mg of benzylamine 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid. TPL 162°C.

MS (ES+): m/z=457 (M+1).

Example 3k

Benzylated 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid

From 0.28 mmol of benzylamine 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5b) and 3-perpenicularity according to the General method obtain 112 mg of benzylamine 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid. TPL 147°C.

MS (ES+): m/z=475 (M+1).

Example 3l

(3-Methylbutyl)amide 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and phenylsulfonylacetate according to the General method receive 100 mg (3-methylbutyl)amide 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid. TPL 127°C.

MS (ES+): m/z=437 (M+1).

Example 3m

(3-Methylbutyl) amide 2’-(4-fortuneloungeonline)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and 4-perpenicularity according to the General method obtain 122 mg of (3-methylbutyl)amide 2’-(4-fortuneloungeonline)-biphenyl-2-carboxylic acid. TPL 149°C.

MS (ES+): m/z=455 (M+1).

Example 3n

(3-Methylbutyl)s is d 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and 3-perpenicularity according to the General method obtain 118 mg (3-methylbutyl)amide 2’-(3-fortuneloungeonline)-biphenyl-2-carboxylic acid. TPL 141°C.

MS (ES+): m/z=455 (M+1).

Example 3o

(3-Methylbutyl)amide 2’-(isopropylaminomethyl)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and isopropylacetanilide according to the General method followed by purification by flash chromatography receive 16 mg (3-methylbutyl)amide 2'-(isopropylaminomethyl)biphenyl-2-carboxylic acid in the form of oil.

MS (ES+): m/z=403 (M4-1).

Example 3p

2-(2-Pyridyl)ethylamide 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and phenylsulfonylacetate according to the General method obtain 117 mg of 2-(2-pyridyl)ethylamide 2’-(phenylcarbonylamino)biphenyl-2-carboxylic acid. TPL 131°C.

MS (ES+): m/z=472 (M+1).

Example 3q

2-(2-Pyridyl)ethylamide 2’-(4-perpenicular-aminomethyl)biphenyl-2-carboxylic acid is you

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and 4-perpenicularity according to the General method obtain 106 mg of 2-(2-pyridyl)ethylamide 2’-(4-fortuneloungeonline)-biphenyl-2-carboxylic acid. TPL 130°C.

MS (ES+): m/z=490 (M+1).

Example 3r

2-(2-Pyridyl)ethylamide 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and 3-perpenicularity according to the General method obtain 102 mg of 2-(2-pyridyl)ethylamide 2’-(3-fortuneloungeonline)biphenyl-2-carboxylic acid. TPL 123°C.

MS (ES+): m/z=490 (M+1).

Example 3s

2-(2-Pyridyl)ethylamide 2’-(isopropylaminomethyl)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and isopropylacetanilide according to the General method and by subsequent extraction with ethyl acetate receive 40 mg of 2-(2-pyridyl)ethylamide 2’-(isopropylaminomethyl)-biphenyl-2-carboxylic acid in the form of oil.

MS (ES+): m/z=438 (M+1).

Analogously to examples 3A-3s get the following connection:

Example No.StructureMS (ES+): m/z=
3t539

General methodology for the interaction of aminomethylphenol with carboxylic acid anhydrides to obtain carbonamide

(examples 4A-4l)

To a solution of 0.34 mmol of the corresponding 2’-aminomethylphenol and 41 mg (0.41 mmol) of triethylamine in 5 ml dichloromethane at a temperature of 0°slowly added dropwise 0.36 mmol of the corresponding sulfonic acid chloride. After stirring for 3 hours at room temperature the reaction mixture was concentrated in vacuo, the residue is stirred with 25 ml of water and precipitated precipitated product is filtered off under vacuum or allocate by extraction with ethyl acetate.

Example 4A

(3-Methylbutyl)amide 2’-(benzoylamino)biphenyl-2-carboxylic acid

From 0.34 mmol (3-methylbutyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and benzoyl chloride according to the General method receive 75 mg (3-methylbutyl)amide 2’-(benzoylamino)biphenyl-2-carboxylic acid. TPL 147°C.

MS (ES+): m/z=401 (M+1).

Example 4b

2-(2-Pyridyl)ethylamide 2’-(benzoylamino)biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-feast of the deal)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and benzoyl chloride according to the General method obtain 98 mg of 2-(2-pyridyl)ethylamide 2’-(benzoylamino)biphenyl-2-carboxylic acid. TPL 135°C.

MS (ES+): m/z=436 (M+1).

Example 4C

2,4-Differentiated 2’-{[2-(4-methoxyphenyl)-acetylamino]methyl}biphenyl-2-carboxylic acid

Of 0.5 mmol (2,4-diferensial)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 8A) and 4-methoxyphenylacetylene according to the General method obtain 160 mg of 2,4-differentiated 2’-{[2-(4-methoxyphenyl)acetylamino]-methyl}biphenyl-2-carboxylic acid. TPL 138°C.

MS (ES+): m/z=501 (M+1).

Analogously to examples 4A-4C receive the following connections:

General methodology for the interaction of aminomethylphenol with isocyanates to obtain urea (examples 5A-5e)

To a solution of 0.34 mmol of the corresponding 2’-aminomethylphenol and 41 mg (0.41 mmol) of triethylamine in 5 ml dichloromethane at a temperature of 0°slowly add dropwise a solution of 0.36 mmol of the appropriate isocyanate in 0.5 ml of dichloromethane. After stirring for 3 hours at room temperature the reaction mixture was concentrated in vacuo, the residue is stirred with 25 ml of water and precipitated precipitated product is filtered off under vacuum or allocate by extraction with ethyl acetate.

Example 5A

3-Methylbutyl)amide 2’-[(3-phenylurea)methyl]biphenyl-2-carboxylic acid

From 0.34 mmol (3-METI is butyl)amide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5C) and phenylisocyanate according to the General method obtain 85 mg (3-methylbutyl)amide 2’-[(3-phenylurea)methyl]biphenyl-2-carboxylic acid. TPL 194°C.

MS (ES+): m/z=416 (M+1).

Example 5b

2-(2-Pyridyl)ethylamide 2’-[(3-phenylurea)methyl]biphenyl-2-carboxylic acid

From 0.3 mmol of 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and phenylisocyanate according to the General method obtain 101 mg of 2-(2-pyridyl)ethylamide 2’-[(3-phenylurea)methyl]biphenyl-2-carboxylic acid. TPL 99°C.

MS (ES+): m/z=451 (M+1).

Examples 5C-5e

In a similar manner from 2-(2-pyridyl)ethylamide 2’-aminomethylphenol-2-carboxylic acid (preliminary stage 5d) and the corresponding isocyanates receive the following connections:

Example No.StructureMS (ES+) m/z=
5C465
5d479
5th479

General methodology for interaction biphenylcarbonic acids with amines to obtain amides (examples 6a-6h)

To a solution of 0.28 mmol appropriate biphenylcarbonic acid, 0.3 mmol of NEWT and 0.3 mmol DIC in 5 ml of tetrahydrofuran at a temperature of 0°With added dropwise 0.3 mmol appropriate Amina stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid and a solution of sodium bicarbonate. After drying over magnesium sulfate and concentration in vacuo receive the corresponding amide.

Example 6A

Benzylmethylamine 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and benzylmethylamine according to the General method obtain 89 mg of benzylmethylamine 2’-(benzyloxycarbonylamino) biphenyl-2-carboxylic acid.

MS (ES+): m/z=465 (M+1).

Example 6b

Cyclohexylamin 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and cyclohexylamine according to the General method to get 99 mg cyclohexylamine 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=443 (M+1).

Example 6C

Pentamid 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and aniline according to the General method obtain 66 mg phenylamide the 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=437 (M+1).

Example 6d

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

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and 2-[2-(methylaminomethyl)]pyridine according to the General method and by further purification using flash chromatography receive 54 mg {N-methyl-N-[2-(2-pyridyl)ethyl]}amide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

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

Example 6E

Dibutylated 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and dibutylamine according to the General method and by further purification using flash chromatography obtain 82 mg of dibutylamine 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=473 (M+1).

Example 6f

2-(2-Pyridyl)ethylamide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and 2-(2-pyridyl)ethylamine according to General method and by further purification using flash chromatography receive the 85 mg of 2-(2-pyridyl)ethylamide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid. TPL 140° (heptane/ethyl acetate).

MS (ES+): m/z=466 (M+1).

Example 6g

(2,4-Diferensial)amide 2’-(benzyloxycarbonylamino)bifeng-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and 2,4-differentiatin according to the General method and by further purification using flash chromatography to get 99 mg (2,4-diferensial)amide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=487 (M+1).

Example 6h

(2,2,2-Triptorelin)amide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and 2,2,2-triptorelin according to the General method and by further purification using flash chromatography obtain 19 mg (2,2,2-triptorelin)amide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=443 (M+1).

Example 7a

2-[2-(1-Oxypyridine)]ethylamide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid

To a solution of 85 mg (0.18 mmol) of 2-(2-pyridyl)ethylamide 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (example 6f) in 13 ml of dichloromethane at a temperature of 0°add the drop wise addition of a solution of 47 mg m-chlormadinone acid in 2 ml of dichloromethane and the reaction mixture is stirred for 12 hours at room temperature. The organic phase is washed 2 times with a solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. Obtain 79 mg of 2-[2-(1-oxypyridine)]ethylamide 2’-[benzyloxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=482 (M+1).

Analogously to example 7a from the corresponding pyridines receive the following connections:

Example No.StructureMS (ES+): m/z=
7b482
7C496

General methodology for interaction biphenylcarbonic acids with amines to obtain amides (examples 8A-8ºc)

To a solution of 0.42 mmol appropriate biphenylcarbonic acid, 0.44 mmol NOWT and 0.44 mmol EDAC in 5 ml of tetrahydrofuran at a temperature of 0°With added dropwise 0.44 mmol of the corresponding amine and stirred for 4-12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid and a solution of sodium bicarbonate. After drying over magnesium sulfate and concentration in vacuo receive the corresponding amide.

Example 8A

Benzyl ether [2’-(1-carbarnoyl-3-methylbutanoyl)biphenyl-2-yl is etil]carbamino acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and L-latinamericancupid/triethylamine according to the General method receive 180 mg benzyl ether [2’-(1-carbarnoyl-3-methylbutanoyl)biphenyl-2-ylmethyl]carbamino acid.

MS (ES+): m/z=474 (M+1).

Example 8b

Methyl ester 2-{[2’-(benzyloxycarbonylamino)biphenyl-2-carbonyl]amino]-3-phenylpropionic acid

From 0.28 mmol of 2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and the hydrochloride of the methyl ester of L-phenylalanine/triethylamine according to the General method obtain 230 mg of methyl ester of 2-{[2'-(benzyloxycarbonylamino)biphenyl-2-carbonyl]amino}-3-phenylpropionic acid.

MS (ES+): m/z=523 (M+1).

Example 8C

(2,4-Diferensial)amide 2’-(tert-butoxycarbonylamino)biphenyl-2-carboxylic acid

10 mmol of 2’-(tert-butoxycarbonylamino)biphenyl-2-carboxylic acid (phase 7) and 2,4-differentiatin according to the General method obtain 3.8 g of (2,4-diferensial)amide 2’-(tert-butoxycarbonylamino)biphenyl-2-carboxylic acid.

MS (ES+): m/z=453 (M+1).

Examples 8d-8p

2’-(tert-butoxycarbonylamino)biphenyl-2-Carbo the OIC acid (preliminary stage 7) and the corresponding amines analogously to examples 8A-8C receive the following products:

Examples 8P-8ºc

2’-(benzyloxycarbonylamino)biphenyl-2-carboxylic acid (phase 6) and the corresponding amines analogously to examples 8A-8C receive the following products:

General methodology for the interaction of aminomethylphenol with isothioscyanates to get thioureas (examples 9a-9i):

To a solution of 0.34 mmol of the corresponding 2’-aminomethylphenol and 41 mg (0.41 mmol) of triethylamine in 5 ml dichloromethane at a temperature of 0°slowly add dropwise a solution of 0.36 mmol of the corresponding isothiocyanate in 0.5 ml of dichloromethane. After stirring for 3 hours at room temperature the reaction mixture was concentrated in vacuo, the residue is stirred with 25 ml of water and precipitated precipitated product is filtered off under vacuum or purified by preparative HPLC.

Thus obtained, in particular, the following products:

Examples 10A-10o

By the reaction of a combination of 2’-(tert-butoxycarbonylamino)biphenyl-2-carboxylic acid (phase 7) with the corresponding amines as described in example 6 or 8 methods get, particularly, the following products:

Examples 11a-11r

A General method of conversion of BOC-derivatives according to examples 10 to ureas

For removal of the BOC-protective group 1 g of the corresponding compounds according to example 10 is added to 10 ml of 30%aqueous solution triperoxonane acid in dichloromethane. The mixture is stirred for 30 minutes at room temperature and the solvent is removed in a vacuum rotary evaporator. The residue is treated with ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and the solvent is removed in vacuum. Received amides of 2’-aminomethylphenol-2-carboxylic acid then according to the method of examples 5 enter into interaction with isocyanates upon receipt of the corresponding ureas.

Thus obtained, in particular, the following products:

A General method of obtaining the proposed according to the invention compounds by solid-phase synthesis

Quantitative data techniques include, respectively, is always to load the resin, which determine Fotometricheskii after removal of Fmoc-protective group (see, for example, The Combinatorial Chemistry Catalog, Novabiochem).

General methods of combination reaction α-Fmoc-amino acids with amide resin Rinca

To aminopenicillins resin Rinca (load of 1.2 mmol/g) add a solution of 1.5 equivalent of NEWT, TOTU, and DIPEA α-Fmoc-amino acid in dimethylformamide (5 ml/g resin) and the mixture was incubated with shaking for 12 hours at room temperature. The resin is filtered off and washed with 3 times 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml dichloromethane. The definition of load Fmoc-method gives the load of 0.9 mmol/g carrier.

The removal of Fmoc-protective group

For removal of Fmoc-protective group of the resin previously subjected to swell for 5 minutes in dimethylformamide at room temperature. After adding a solution of dimethylformamide/piperidine (4 ml/g resin; in the ratio 1:1) and shaken for 20 minutes at room temperature. The solution is filtered under vacuum and the process is repeated. Banding in the case of analytical sample shows the complete transformation according to a study by HPLC/mass spectrometry. After complete conversion of the resin three times washed with dichloromethane and used directly in the reaction combinations.

General methods of combination reaction associated with resin amino acid with 2’-telememedicine the-2-carboxylic acid (phase 2)

To 100 g loaded amino acid (0.6-0.8 mmol/g) resin add a solution of 12.2 mg (0.09 mmol) NOWT, 29,5 mg (0.09 mmol) of TOTU, 16 μl (0.09 mmol) DIPEA and 0.09 mmol of 2'-phthalimidomethyl-2-carboxylic acid (phase 2) in 5 ml of dimethylformamide and the mixture was incubated with shaking for 12 hours at room temperature. The resin is filtered off and washed with 3 times 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml dichloromethane.

A General method of removal of phthalimides protective troupe from media

To 1 g of the resin loaded with Fmoc protected-group aminoguanidinium, add 5 ml of 10%aqueous solution of hydrazine in dimethylformamide and the mixture was incubated with shaking for 2 hours at room temperature. The resin is filtered off under vacuum. Then the resin was washed with three times 10 ml of dimethylformamide and dichloromethane. Banding in the case of analytical sample shows the complete transformation according to a study by HPLC/mass spectrometry.

General methods of combination reaction with anhydrides of sulfonic acids

To 100 mg of the resin loaded with functionalized 2’-aminomethylphenol-2-carboxylic acid, add a solution of 0.16 ml (or 0.027 mmol) DIPEA and 0.027 mmol sulfonic acid chloride in 5 ml of dimethylformamide and the mixture was incubated with shaking for 12 the aces at room temperature. The resin is filtered off and washed with 3 times 10 ml of dimethylformamide, once with 10 ml of toluene, once with 10 ml of methanol and 3 times with 10 ml dichloromethane.

A General method of removal of the resin

For removal of the resin is suspended in dichloromethane/triperoxonane acid (3 ml/0.1 g resin) and shaken for 1 hour. The resin is filtered off and washed with 1 ml dichloromethane. The combined solution after removal of concentrate in the rotor hub. The residue is treated with dichloromethane and using dichloromethane and ethyl acetate chromatographic on silica gel and purified by preparative HPLC.

Thus obtained, in particular, the following products:

Example 13A

2-{[2’-(Benzyloxycarbonylamino)biphenyl-2-carbonyl]amino}-4-methyl-pentane acid

The connection is obtained from the methyl ester obtained according to example 8r, by saponification with potassium hydroxide in a mixture of methanol and water at a temperature of 60°C.

Examples 13b-13e

By the reaction of a combination of carboxylic acid according to example 13A with the corresponding amines according to the specified in example 8 General methodology given the following connections:

By cleavage by hydrogenolysis of the Z-protective group from compounds according to example 13C and the subsequent introduction into engagement with the corresponding anhydrides of the acids have the following connections:

Based on the compounds according to example 8z, similar to the methods of examples 13A-13th, by hydrolysis and administration in cooperation with isopropylamino get the following connection:

Example No.StructureMS (ES+): m/z=
13i551

General methods of combination reaction (2,4-diferensial)amide 2’-aminomethylphenol-2-carboxylic acid with carboxylic acids to obtain carbonamides (examples 14a-14f)

The appropriate carboxylic acid in an amount of 0.27 mmol together with 0.27 mmol NOWT and 0.27 mmol EDAC in 1 ml of tetrahydrofuran is stirred for 30 minutes at room temperature. Then add a solution of 0.26 mmol of triptoreline (2,4-diferensial)amide 2’-aminomethylphenol-2-carboxylic acid in 1 ml of tetrahydrofuran and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with sodium hydrogen carbonate solution and water. After concentration org the clinical phase products are purified by preparative HPLC.

Thus get the following connections:

Example No.StructureMS (ES+): m/z=
14a499
14b503
14C499
14d501
14515
14f521

General methods of synthesis of biphenyl by the reaction of a combination according to Suzuki (examples 15A-15b)

In an argon atmosphere to dimethoxyethane in the amount of 10 ml added 58 mg (0.05 mmol) of tetrakis-(triphenylphosphine)palladium and 1 mmol of the corresponding bromide. After 10 minutes add 1.5 mmol of the corresponding Bronevoy acid and, finally, 1 ml of 2M solution of sodium carbonate (2 mmol). Refluxed in an argon atmosphere for 18 hours, cooled and diluted with 30 ml dichloromethane. The mixture is washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified by chromatography on forces is the Kagel.

Example 15A

(3-Methylbutyl)amide 2’-(tert-butoxycarbonylamino)-4-nitrobiphenyl-2-carboxylic acid

According to the General method obtain 350 mg (yield 79%) is substituted by a nitro-group connection in a solid yellow color.

Example 15b

(3-Methylbutyl)amide 2’-(tert-butoxycarbonylamino)-4-methoxybiphenyl-2-carboxylic acid

According to the General method obtain 170 mg (yield 41%) substituted by methoxy group connection in the form of a viscous light oil.

Example 16A

(3-Methylbutyl)amide 2’-(tert-butoxycarbonylamino)-4-aminobiphenyl-2-carboxylic acid

330 mg (0.75 mmol) is substituted by a nitro-group of compounds according to example 15A was dissolved in ethyl acetate and after making at the tip of the spatula 10%palladium-on-coal hydronaut in an atmosphere of hydrogen (1 bar). After 2 hours, filtered through celite and the clear solution concentrated. Yield: 260 mg (84%).

Example 16b

(3-Methylbutyl)amide 2’-(benzyloxycarbonylamino)-4-hydroxybiphenyl-2-carboxylic acid

150 mg (0.35 mmol) substituted by methoxy group of the compounds according to example 15b is dissolved in 5 ml of anhydrous dichloromethane and at a temperature of -70°slowly mixed with 1.4 ml (1.4 mmol) of 1M dissolve the and tribromide boron in n-hexane. After 10 minutes the reaction mixture is slowly heated to a temperature of 0°C. After incubation for 2 hours at this temperature, neutralized with saturated solution of sodium bicarbonate, extracted in whole with 40 ml of dichloromethane, dried over sodium sulfate and concentrated. The obtained crude product (88 mg) (3-methylbutyl)amide 2’-aminomethyl-4-hydroxybiphenyl-2-carboxylic acid 30 g (0.1 mmol) is dissolved in dichloromethane, mixed with 11 mg (0.11 mmol) of triethylamine and 27 mg (0.11 mmol) of benzyloxycarbonylglycine. After 3 hours, diluted with dichloromethane, washed with water, the organic phase is dried over sodium sulfate and purified by HPLC with reversed phase. Receive 8 mg (3-methylbutyl)amide 2’-(benzyloxycarbonylamino)-4-hydroxybiphenyl-2-carboxylic acid in the form of a dark oil.

Example 17A

tert-Butyl ether ({1-[2’-(3-methylbutanoyl)biphenyl-2-yl]ethyl}carbamino acid

2.2 g (10 mmol) N-Boc-(R)-phenethylamine dissolved in 50 ml of anhydrous tetrahydrofuran, cooled to a temperature of -78°With dropwise and mixed with 14 ml (1.5 m solution in pentane; 21 mmol) of tert-utility. For 2 hours, heated to a temperature of -20°With, then add 4.5 ml (40 mmol) trimethylol ester of boric acid and heated to room temperature. The solution ohla who give up temperature 0° C, acidified to pH equal to 6 using 10%Hcl, the aqueous phase is extracted with dichloromethane, the combined organic phases are washed with saturated solution of sodium chloride, dried and concentrated. Get Bronevoy acid as light yellow solid foam, which is used without further purification.

The reaction mix by Suzuki carried out according to the General method (see example 15) with 1 mmol of 2-bromo-N-(3-methylbutyl)benzamide and after chromatographic purification obtain 85 mg (0.2 mmol) of biphenyl.

Examples 17b-e

Similarly to the method of example 17A receive enantiomer according to example 17b. By removal of the BOC-group and translated into the corresponding carbamates of compounds according to examples 17A and 17b converted into compounds according to the examples 17c-e.

Similar to that described in examples 1-17 methods receive the following connections:

Pharmacological studies

Kv1.5 channels of a person expressed in Xenopus oocytes. First, oocytes were isolated from Xenopus laevis and depolymerase. Then in these oocytes were injected by injection synthesized in vitro encoding Kv1.5 RNA. After the expression of Kv1.-protein within 1-7 days in the oocytes was measured Co-current method fixed bias voltage to the two electrodes. Kv1.5 channels at the same time, usually activated with lasting 500 MS voltage steps to 0 mV and 40 mV. The bath was washed with a solution of the following composition: 96 mm NaCl, 2 mm KCl, 1.8 mm CaCl2, 1 mmol MgCl2, 5 mmol HEPES (titrated with NaOH solution to pH=7,4). These experiments were performed at room temperature. To increase (largest) data and analysis used Geneclamp amplifier (Axon Instruments, Foster City, USA) and the Converter MacLab D/A and software (ADInstruments, Castle Hill, Australia). Proposed according to the invention substances tested so that they are in different concentrations were injected into the electrolyte. The effect of the substances was calculated as the inhibition percentage of the control current Kv1.5, which was obtained when the solution did not add any substance. Data is then extrapolated according to the hill equation to determine the inhibitory concentration IR50for the relevant substances.

Thus, for the following compounds (see table) has identified the following values IR50:

1. The compounds of formula (I):

where

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

R(9) implies Cx H2x-R(14);

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15) or SO2CH3;

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3C2F5With3F7CH2F, F2, OR(15), SO2CH3, phenyl, naphthyl, biphenylyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

moreover, phenyl, naphthyl, biphenylyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2SOON3The PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms;

R(15) means phenyl;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

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

y means 0, 1, 2, 3 or 4;

and cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF3With2F5With3F7CH2F, CHF2, OR(17), phenyl, naphthyl, furyl, thienyl or N-containing the s heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, I, CF3, F3, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms or phenyl;

or

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

R(18) implies CzH2z-R(16)and R(16) has the above meaning;

z is 0, 1, 2 or 3;

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

R(20) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, WithvH2v-CF3orwH2wis phenyl;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom;

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

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

or

R(3) and R(4) together imply a chain of 4 or 5 methylene groups, of which one methylene group may be replaced by-S-,

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, I, NO2, NH2HE, alkyl with 1, 2, 3 or 4 atom is mi carbon alkoxy with 1, 2, 3 or 4 carbon atoms, sulfamoyl;

R(30) R(31), independently of one another, mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

and their pharmaceutically acceptable salts.

2. The compounds of formula (I) according to claim 1, in which

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

R(9) meansxH2-R(14);

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3C2F5, OR(15), phenyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

and phenyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, NO2SOON3The PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms,

R(15) means phenyl,

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

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

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

and cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3C2F5, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3, F3, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl with 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms

or phenyl,

or R(3) means CHR(18)R(19);

R(18) implies CzH2z-R(16)and R(16) is specified in claim 1 value;

z is 0, 1, 2 or 3;

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

R(20) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms, WithvH2v-CF3or CwH2wis phenyl;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom;

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

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

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, NO2, NH2HE, alkyl C1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms, sulfamoyl;

R(30) R(31), independently of one another, mean a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

and their pharmaceutically acceptable salts.

3. The compounds of formula (I) according to claim 1 or 2, in which

R(1) means C(O)OR(9), SO2R(10), COR(11), or

C(O)NR(12)R(13);

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) means cycloalkyl with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted one, two or three substituents selected from the group consisting of F, Cl, Br, CF3SOON3The PINES3, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms;

R(15) - phenyl;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

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

R(18) implies CzH2z-R(16);

z is 0, 1, 2 or 3;

R(19) means N2, CONR(20)R(21), COOR(22), CH2IT;

R(20) means alkyls 1, 2, 3, 4 or 5 carbon atoms, WithvH2v-CF3orwH2wis phenyl;

v is 0, 1, 2 or 3;

w stands for 0, 1, 2 or 3;

R(21) means a hydrogen atom, R(22) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms;

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3, F3, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) denotes alkyl with 1, 2, 3 or 4 carbon atoms or phenyl;

R(4) means a hydrogen atom or alkyl with 1 or 2 carbon atoms;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1 or 2 carbon atoms, sulfamoyl,

R(30) R(31), independently of one another, mean a hydrogen atom or methyl,

and their pharmaceutically acceptable salts.

4. The compounds of formula (I) according to claim 1 or 2, in which R(1) means C(O)OR(9), SO2R(10), COR(11), or C(O)NR(12)R(13);

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

x represents 0, 1, 2, 3,or 4

moreover, x may not indicate 0 when R(14) mean OR(15);

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, Br, CF3SOON3The PINES3, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms;

R(15) means phenyl;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

R(3) meansyH2y-R(16);

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

and cannot mean 0 when R(16) mean OR(17);

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or N-containing heteroaromatic residue with 3, 4 or 5 carbon atoms;

and phenyl, furyl, thienyl and N-containing heteroaromatic residue unsubstituted or substituted by one or two substituents, wybir is feasible from the group consisting of F, Cl, Br, CF3, F3, alkyl with 1, 2 or 3 carbon atoms, alkoxyl with 1 or 2 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(17) denotes alkyl with 1, 2, 3, 4 or 5 carbon atoms or phenyl;

R(4) means a hydrogen atom or alkyl with 1 or 2 carbon atoms;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, Cl, Br, NH2HE, alkyl with 1, 2 or 3 carbon atoms, alkoxy with 1 or 2 carbon atoms, sulfamoyl,

R(30) R(31), independently of one another, mean a hydrogen atom or methyl;

and their pharmaceutically acceptable salts.

5. The compounds of formula (I) according to one or more of claims 1, 2 or 4, in which

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

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

x represents 0, 1, 2 or 3;

R(14) denotes alkyl with 1, 2, 3 or 4 carbon atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl and pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(10)R(11) R(12)independently of one another, are specified for R(9) value;

R(13) means a hydrogen atom;

R(2) means a hydrogen atom;

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

y means 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl and pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, NH2HE, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;

R(30) R(31), independently of one another, mean a hydrogen atom or methyl;

and their pharmaceutically acceptable salts.

6. The compounds of formula (I) according to one or more of claims 1, 2, 4, or 5, in which

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

R(9) meansxH2-R(14);

x represents 0, 1, 2 or 3;

R(14) means cycloalkyl with 5 or 6 carbon atoms or phenyl;

and phenyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(11) is specified for R(9) value;

R(2) means a hydrogen atom;

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

y means 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 carbon atoms, cycloalkyl with 5 or 6 carbon atoms, CF3, phenyl or pyridyl;

moreover, the phenyl and pyridyl unsubstituted or substituted by one or two substituents selected from the group consisting of F, Cl, CF3, F3, alkyl with 1, 2 or 3 carbon atoms and alkoxyl with 1 or 2 carbon atoms;

R(4) means a hydrogen atom;

R(5), R(6)R(7) and R(8)independently of one another, mean a hydrogen atom, F, alkyl with 1, 2 or 3 carbon atoms or alkoxy with 1 or 2 carbon atoms;

R(30) R(31) denote a hydrogen atom,

and their pharmaceutically acceptable salts.

7. The compounds of formula (I) according to one or more of claims 1 to 6 and their pharmaceutically acceptable salts are suitable for use as drugs with antiarrhythmic activity.

8. The compounds of formula (I) according to one or more of claims 1 to 6 and/or their pharmaceutically acceptable salts, suitable for medicinal products with a blocking K+channel action for the treatment and prevention of mediated+channel diseases.

9. The compounds of formula (I) according to one or more of claims 1 to 6 and/or their pharmaceutically acceptable salts, suitable for medicinal product on the I treatment or prevention of cardiac arrhythmias, that can be eliminated by lengthening of the action potential.

10. The compounds of formula (I) according to one or more of claims 1 to 6 and/or its pharmaceutically acceptable salts, suitable for medicinal products for treatment or prevention of recurrent arrhythmias.

11. The compounds of formula (I) according to one or more of claims 1 to 6 and/or its pharmaceutically acceptable salts, suitable for medicinal product for the treatment or prophylaxis of supraventricular arrhythmias.

12. The compounds of formula (I) according to one or more of claims 1 to 6 and/or its pharmaceutically acceptable salts, suitable for medicinal products for treatment or prevention of atrial fibrillation or atrial flutter.

13. The compounds of formula (I) according to one or more of claims 1 to 6 and/or its pharmaceutically acceptable salts, suitable for medicinal products for termination of atrial fibrillation or atrial flutter (cardioversion).



 

Same patents:

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 the use of compounds of the type of retinoids as active agents in cosmetic compositions or pharmaceutical compositions intended for the treatment of disorders or diseases associated with sverrehelena receptors PPK and/or hypervitaminosis A

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

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:

< / BR>
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 imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

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where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to heterocyclic compounds of the formula I, values radicals cm

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

The invention relates to products derived from histamine and, in particular, the condensation products of histamine or methylsiloxanes histamine and amino acids, the method of their preparation and use as active principle in areas such as therapy and cosmetology, as well as the factor (agent), improving the stability of compositions used in therapy, cosmetology, agriculture and food industry (region)

The invention relates to new heterocyclic compounds having therapeutic activity, methods and intermediate compounds for their production, pharmaceutical preparations containing these compounds, and to the medical use of these compounds

The invention relates to the field of organic chemistry, in particular to methods of synthesis of heterocyclic compounds and can be used in the production of imidazole needed to obtain drugs and sorbents

The invention relates to thiosulfonate formulas

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or

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< / 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 certain disubstituted acids benzenaminium
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