Ortho-substituted nitrogen-containing bis-aryl compounds for using as potassium channel inhibitors and pharmaceutical compositions comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

 

This invention relates to ortho, ortho-substituted nitrogen-containing bizarely compounds of formula I,

in which:

A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen, CH or CR(5),

moreover, at least one of these groups denotes nitrogen, and at least 4 groups represent CH;

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

R(9)R(10)R(11) R(12) independently of one another denote CxH2x-R(14);

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

moreover, x cannot be 0 if R(14) denotes OR(15) or SO2Me;

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3C2F5C3F7CH2F, CHF2, OR(15), SO2Me, phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic cycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 C-atoms, cloacal 3, 4, 5 or 6 C-atoms, CF3or phenyl, unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(13) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or CF3;

R(2) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or CF3;

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

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

and y cannot be 0 if R(16) denotes OR(17) or SO2Me;

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9, 10 or 11 C-atoms, CF3C2F5C3F7CH2F, CHF2, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic cycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(17) Ref is no hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or 2-, 3 - or 4-pyridyl,

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

or

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

R(18) denotes hydrogen or CzH2z-R(16)and R(16) is defined as above;

z is 0, 1, 2 or 3;

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

R(20) denotes hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

R(21) denotes hydrogen or alkyl with 1, 2, 3, 4 or 5 C-atoms;

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

R(4) about the mean hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C-atoms or CF3;

or

R(3) and R(4) together denote 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)groups;

R(5) denotes, independently of one another, F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group or methylsulfonylamino, and if several residues A1-A8 are set to CR(5), residues of R(5) are defined independently from each other.

R(30) R(31) denote, independently of one another, hydrogen or alkyl with 1, 2 or 3 C-atoms;

or

R(30) R(31) together represent oxygen or a chain of 2 methylene groups,

and their pharmaceutically acceptable salts.

Preferred compounds of formula 1,

in which:

A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen, CH or CR(5), and at least one of these groups denotes nitrogen, and at least 4 groups represent CH;

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

R(9)R(10)R(11) R(12) independently of one another denote CxH2x-R(14);

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

moreover, x cannot be 0 if R(14) denotes OR(15);

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

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3or phenyl, unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(13) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or CF3;

R(2) denotes hydrogen, alkyl with 1, 2, 3 or 4 C-atoms or CF3;

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

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

and y cannot be 0 if R(16) denotes OR(17) or SO2Me;

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, C is cloacal 3, 4, 5, 6, 7, 8, 9 C-atoms, CF3, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic cycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

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

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

or

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

R(18) denotes hydrogen or CzH2z-R(16)and R(16) is defined as above;

z is 0, 1, 2 or 3;

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

R(20) denotes hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2 -CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

R(21) denotes hydrogen or alkyl with 1, 2, 3, 4 or 5 C-atoms;

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

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

R(5) denotes, independently of one another, F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group or methylsulfonylamino,

R(30) R(31) denote, independently of one another, hydrogen or alkyl with 1, 2 or 3 C-atoms;

or

R(30) R(31) denote a chain of 2 methylene groups,

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I in which A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen, CH or CR(5), and at least one and at most two of these groups represent nitrogen and the edge is her least 4 groups represent CH.

The most preferred compounds of formula I, in which

A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen, CH or CR(5), and at least one and at most two of these groups represent nitrogen, and at least 4 groups represent CH;

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

R(9)R(10)R(11) R(12) denote CxH2x-R(14);

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

moreover, x cannot be 0 if R(14) denotes OR(15);

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

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(15) denotes alkyl with 1, 2, 3, 4 or 5 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3or phenyl, unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, al the sludge with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(13) denotes hydrogen, R(2) denotes hydrogen or alkyl with 1, 2 or 3 C-atoms;

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

R(18) denotes hydrogen or CzH2z-R(16)and R(16) is defined as above;

z is 0, 1, 2 or 3;

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

R(20) denotes hydrogen, alkyl with 1, 2, 3, 4 or 5 C-atoms, CvH2v-CF3or CwH2w-phenyl,

moreover, the phenyl ring is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

v is 0, 1, 2 or 3;

w is 0, 1, 2 or 3;

R(21) denotes hydrogen or alkyl with 1, 2, 3, 4 or 5 C-atoms;

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

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

R(5) denotes, independently of one another, F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sylphs who ilen group, methylsulfonyl group or methylsulfonylamino,

R(30) R(31) denote, independently of one another, hydrogen or methyl; and their pharmaceutically acceptable salts.

Also most preferred are the compounds of formula I, in which

A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen, CH or CR(5), and at least one and at most two of these groups represent nitrogen, and at least 4 groups represent CH;

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

R(9)R(10)R(11) R(12) independently of one another denote CxH2x-R(14);

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

R(14) denotes alkyl with 1, 2, 3 or 4 C-atoms, with cycloalkyl 3, 4, 5, 6, 7, 8 or 9 C atoms, CF3, phenyl, naphthyl, biphenylyl, furyl, thienyl or N-containing heteroaromatic cycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms,

moreover, phenyl, naphthyl, biphenylyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

R(13) denotes hydrogen,

R(2) denotes hydrogen or methyl;

R(3) represents Cy H2y-R(16);

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

and y cannot be 0 if R(16) denotes OR(17);

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, with cycloalkyl 3, 4, 5, 6, 7, 8, 9 C-atoms, CF3, OR(17), SO2Me, phenyl, naphthyl, furyl, thienyl or N-containing heteroaromatic cycle with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms,

moreover, phenyl, naphthyl, furyl, thienyl and N-containing heteroaromatic cycle is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

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

moreover, phenyl or 2-, 3 - or 4-pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group and methylsulfonylamino;

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

R(5) denotes, independently of one another, F, Cl, Br, I, CF3, NO2, CN, COOMe,CONH 2, COMe, NH2, OH, alkyl with 1, 2, 3 or 4 C-atoms, alkoxygroup with 1, 2, 3 or 4 C-atoms, dimethylaminopropyl, sulfamoyl group, methylsulfonyl group or methylsulfonylamino;

R(30) R(31) denote, independently of one another, hydrogen or methyl;

and their pharmaceutically acceptable salts.

Specifically preferred compounds of formula I, in which A4 represents nitrogen, and A1, A2, A3, A5, A6, A7 and A8 independently from each other represent CH or CR(5), with at least 5 groups represent CH;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula I in which:

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

R(9)R(10)R(11) R(12) denote CxH2x-R(14);

x is 0, 1, 2 or 3;

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

moreover, the phenyl and pyridyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms, or alkoxygroup with 1 or 2 C-atoms;

R(13) denotes hydrogen;

R(2) denotes hydrogen;

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

y is 0, 1 or 2;

R(16) denotes alkyl with 1, 2, 3 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, CF3, phenyl or pyridyl,

and phenyl, and PI is ideal not substituted or is substituted by 1 or 2 substituents, selected from the group consisting of F, Cl, CF3, OCF3, alkyl with 1, 2 or 3 C-atoms or alkoxygroup with 1 or 2 C-atoms;

R(4) denotes hydrogen;

R(5) denotes, independently of one another, F, Cl, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl with 1, 2 or 3 C-atoms or alkoxygroup with 1 or 2 C-atoms;

R(30) R(31) denote, independently of one another, hydrogen or methyl;

and their pharmaceutically acceptable salts.

Particularly preferred compounds of formula I in which:

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

R(9) and R(11) independently of one another denote CxH2x-R(14);

x is 0, 1, 2 or 3;

R(14) denotes cycloalkyl with 5 or 6 C-atoms or phenyl,

moreover, the phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, OH, alkyl with 1, 2 or 3 C-atoms, or alkoxygroup with 1 or 2 C-atoms;

R(2) denotes hydrogen;

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

y is 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms, phenyl or pyridyl,

moreover, the phenyl and pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, alkyl with 1, 2, 3 C-atoms and alkoxygroup with 1 or 2 C-atoms;

R(4) denotes hydrogen;

R(5) denotes, independently from each other is a, F, Cl, alkyl with 1, 2, 3 C-atoms or alkoxygroup with 1 or 2 C-atoms;

R(30) R(31) denote hydrogen;

and their pharmaceutically acceptable salts.

The invention concerns compounds is still unknown.

They operate on the so-called v1.5 potassium channel and inhibit the flow of potassium, referred to as "sverhbystro activating delayed cleaner" in the atrium of the person. Therefore, the compounds are particularly suitable as antiarrhythmic biologically active substances of a new type, particularly for the treatment and prevention of atrial arrhythmias, such as atrial fibrillation (trialno flicker, AF) or atrial flutter (trialno flutter).

Atrial fibrillation (AF) and atrial flutter are the increase of prolonged cardiac arrhythmias. Their occurrence increases with increasing age and often leads to fatal consequences, such as bleeding in the brain. AF affects about 1 million Americans annually and results each year in the United States to more than 80,000 hemorrhages in the brain. Antiarrhythmic agent of class I and III used in the present time, reduce the probability of re-occurrence of AF, but because of their potential prioritiesin side effects are only of limited use. Therefore, in medicine there is a great need in time is abode improved medicines for the treatment of trialing arrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094 -1106; "Newer developments in the management of atrial fibrillation").

It was shown that most supraventricular arrhythmias due to the so-called "circulation" waves of excitation. Such circulation occur when the tissue of the heart has a slow conductivity and at the same time is very short refractory phases. Increased myocardial refractory time by lengthening of the action potential is a known mechanism in order to terminate the arrhythmia or to prevent its occurrence (Colatsky TJ et al, Drug Dev. Res. 19, 1990, 129-140; "Potassium channels as targets for antiarrhythmic drug action"). The duration of the action potential depends largely on the size repolarizing To+stream, which through different+-channels arises from the cells. It is particularly great importance is attributed to the so-called "slow purifier IKthat consists of 3 different components: IKrIKsand IKur.

The most well-known antiarrhythmic agent of class III (e.g., dofetilide, E and d-sotalol) block, predominantly, or exclusively, rapidly activating potassium channel IKrthat is how in the cells of the ventricle of the human heart, and in the atrium. However, it was shown that these compounds at low or normal pulse characterize the SJ high prioritiesin risk and especially was observed arrhythmia, called piruetas tachycardia (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B; "Current status of class III antiarrhythmic drug therapy"). In addition, high, partly the risk of death at low frequency, reduces the efficiency IKr-blocker in the conditions of tachycardia, which requires exactly the opposite effect.

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

"Especially rapidly activating and slowly inactivating components delayed purifier IKurthat match Kv1.5 channel, play a particularly important role for the duration of the depolarization in the atrium of the person. Inhibition of IKur-outdoor flow of potassium is thus compared with the inhibition of IKror IKsa particularly effective way to extend trialing action potential and, thereby, to stop or prevent trialing arrhythmias. A mathematical model of action potential person closely correspond to the fact that the positive effect of the blockade of IKurshould be especially pronounced when pathological conditions khron the ical trialing atrial fibrillation (M. Courtemanche, R. J. Ramirez, and S. Nattel, Cardiovascular Research 1999, 42, 477-489: "Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model").

In contrast IKrand IKsthat take place in the ventricle of the human heart, IKurthough plays a significant role in the atrium of the person, but not in the ventricle. Based on this, when the inhibition of IKurstream, in contrast to the blockade of IKror IKsfrom the very beginning , avoid the risk proaritmicheskimi steps in the ventricle (Z. Wang et al, Circ. Res. 73, 1993, 1061-1076: "Sustained Depolarisation-Induced Outward Current in Human Atrial Myocites"; G.-R. Li et al, Circ. Res. 78, 1996, 689-696: "Evidence for Two Components of Delayed Rectifier K+-Current in Human Ventricular Myocytes"; G. J. Amos et al, J. Physiol. 491, 1996, 31-50: "Differences between outward currents of human atrial and subepicardial ventricular myocytes").

Antiarrhythmic agent, acting through the selective blockade of IKurstream or Kv1.5 channel, still not available for sale. Although many pharmaceutical biologically active substances (for example, tedisamil, bupivacaine or sertindole) described a blocking effect against Kv1.5 channel, still Kv1.5-blockade is here only side effect along with others, the main action of the substances.

In WO 98 04 521 and WO 9937607 as blockers potassium channel describes aminoindane and aminotetrahydrofuran that block Kv1.5 channel. Also the quality is TBE Kv1.5-blockers in WO 0012077 considered structurally related aminopropane. In the application WO 9992891 described thiazolidinone, which also block the potassium channel. In applications WO 9818475 and WO 9818476 described the use of various pyridazinones and phosphine oxides as antiarrhythmic drugs, which must act through blockade of IKur. However, these compounds were originally described as immunosuppressive funds (WO 9625936). The compounds described in these applications are completely different structure from the compounds according to the invention of this application. For all compounds described in the aforementioned applications, is not known clinical data.

Unexpectedly, it was found that described in this application is ortho, ortho-substituted nitrogen-containing bizarrerie compounds are potential inhibitors Kv1.5 channel man. Therefore they can be used as an antiarrhythmic agent of a new type with a particularly preferred security profile. In particular, the compound suitable for the treatment of supraventricular arrhythmias, such as atrial fibrillation or atrial flutter.

Connections can be used at the final stage of the existing scintillation fibrillation or same ones fibrillation to sinus rhythm (cardioversion). In addition, substances reduce exposure to the emergence of new phenomena scintillation (maintenance of sinus is ITMA, prevention).

Compounds according to the invention is still not known.

Alkyl residues and alkylene residues can be unbranched or branched. This also applies to alkilinity the remnants of the formula CxH2xCyH2y,CzH2zCvH2vand CwH2w. Alkyl residues and alkylene residues can also be unbranched 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. Examples alkilinity residues are divalent residues formed from these residues, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentile, 2,2-dimethyl-1,3-propylene, 1,6-hexylen and so on.

Cycloalkyl residues can also be branched. Examples cycloalkyl residues with 3 to 11 C-atoms are cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl, methylcyclobutane, 3-methylcyclobutene, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, mental, cycloheptyl, cyclooctyl and so on.

As N-containing heterocycles with 1, 2, 3, 4, 5, 6, 7, 8 or 9 C atoms are used, 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-yl or-5-yl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 1,3,4-thiadiazole-2 - or -5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-indazole, 2-, 3-, 4-, 5-, 6-, 7 - or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 2-, 4-, 5-, 6-, 7 - or 8-hintline, 3-, 4-, 5-, 6-, 7 - or 8-chinoline, 2-, 3-, 5-, 6-, 7 - or 8-honokalani, 1-, 4-, 5-, 6-, 7 - or 8-phthalazine. Next, the appropriate N-oxides of these compounds, for example, 1-hydroxy-2-, 3 - or 4-pyridyl.

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

Pyridyl refers to as a 2-, 3-, and 4-pyridyl. Thienyl refers to as 2-and 3-thienyl. Furyl refers to as 2-and 3-furyl.

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

If R(3) and R(4) together denote a chain of 4 or 5 methylene groups, of which one methylene group may be replaced by-O-, -S-, -NH -, and so on, this residue forms together with the nitrogen atom in the formula I 5 - or 6-membered nitrogen-containing heterocycle, such as, for example, pyrrolidine, piperidine, morpholine, thiomorpholine and so on.

If the compounds of formula I contain one or more acidic or basic groups or one or more basic compounds, the invention also includes the corresponding physiologically or toxicologically compatible salts, especially pharmaceutically acceptable salts. Thus, the compounds of formula I, which have acid groups, for example one or more COOH groups, can be used, for example, in the form of alkali metal salts, preferably sodium salts or potassium, or alkaline earth salts of metals, for example salts of calcium or magnesium, or ammonium salts, such as salts of accession of ammonia or the body of the ical amines, or amino acids. The compounds of formula I which have one or more primary, i.e. protonium groups, or one or more of the basic heterocyclic rings can also be applied in the form of their physiologically compatible acid additive salts with inorganic or organic acids, for example, in the form of hydrochloride, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malatov, gluconate, and so forth. If the compounds of formula I contain in the molecule at the same time acidic and basic groups, the invention are described along with forms salts also internal salts, the so-called betaines. Salts can be obtained from compounds of the formula I by conventional means, for example a compound with acid or base in a solvent or dispersing agent, or by anion exchange from other salts.

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

The compounds of formula I can be obtained by various chemical methods, which are also included within this invention. Some typical path synthesis is depicted in schemes 1-4. Residues A1-A8, and the remains of R(1)-R(4), R(30) R(31) have the above values, if not otherwise indicated.

For example, the compound of formula I get according to scheme 1 (method A) or scheme 2 (method B).

Bizarely formula IV in which at least one atom in the ring And1-A8is nitrogen, can be obtained by catalyzed by palladium combination Suzuki (which may be conducted in the presence of Pd[(PPh3)]4as a catalyst, sodium carbonate as a base and 1,2-dimethoxyethane as solvent) Aro is adicheskogo of halide of the formula III with an aromatic Bronevoy acid of formula II. If R(9) denotes easily ottsepleny the rest, as, for example, tert.-butyl or benzyl, can be obtained the compounds of formula V, which can then be converted into compounds of the formula I by reaction with a reagent R(1)-X and/or R(2)-Y.

The interaction of compounds of the formula V with compounds of formula R(1)-X corresponds to the well-known conversion of amine to amide derivative of carboxylic acid, amide sulfonic acids, carbamate, urea or thiourea. The residue X is thus suitable nucleophilic delete the group, such as F, Cl, Br, imidazole, o-succinimide and so on.

To obtain compounds of the formula I, in which R(1) denotes C(O)OR(9), i.e. carbamates, using, for example, the compounds of formula R(1)-X, in which X denotes chlorine or o-succinimide, i.e. chloroformiate or succinimidylester.

To obtain compounds of the formula I, in which R(1) denotes SO2R(10), i.e. sulfonamides, using, as a rule, the compounds of formula R(1)-X, in which X denotes chlorine, i.e. sulfochloride.

To obtain compounds of the formula I, in which R(1) denotes COR(11), i.e. amides of carboxylic acids, are used, for example, the compounds of formula R(1)-X, in which X denotes chlorine, imidazole or acetochlor, i.e. the carboxylic acid anhydrides, imidazolides carboxylic acids or mixed anhydrides. N which can also be used acid in the free form of the formula R(1)-HE is in the presence of a suitable condensing means, as carbodiimide or TFFH.

To obtain compounds of the formula I, in which R(1) denotes CONR(12)R(13) or C(S)NR(12)R(13), that is, ureas or thioureas, instead of the compounds of the formula R(1)-X can be used as compounds of the formula R(12)N(=C=O) or R(12)N(=C=S), i.e. isocyanates or thioisocyanate.

Bizarely formula VIII, in which at least one atom in the ring And is a nitrogen, can be obtained by catalyzed by palladium combination Suzuki aromatic bromide or iodide of the formula VII with an aromatic Bronevoy acid of formula II. By hydrolysis of ester LiOH get a free acid of formula IX, which through a combination with other amines(3)R(4) can be translated into bizarely formula IV. As shown in scheme I, the separation of labile group R(9) leads to the formation of compounds of formula V, which can then be subjected to conversion to the formation of compounds of formula I.

The above-mentioned interaction of compounds of the formula IX 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 carrying out these reactions in the literature describes numerous ways. Especially preferably, they can be carried out by activation of the carboxylic acid, for example, dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-(3-d is methylaminopropyl)carbodykitstore.com (EDC), if necessary, the addition of hydroxybenzotriazole (HOBt) or dimethylaminopyridine (DMAP). Also reactive derivatives of acids can be synthesized primarily by known methods, for example, the anhydrides of the acids by reaction of carboxylic acids of formula IX with inorganic acid halides, such as SOCl2or imidazoline acids by reaction with carbonyl diimidazol, which are then, if necessary, adding a secondary basis subject to interaction with amines of the formula HNR(3)R(4).

Aromatic boranova acid of the formula II required in the methods a and b, can be synthesized from aromatic cycles or aromatic halides of formula VI by the introduction of lithium in the ortho-position or the exchange of the metal - halogen, subsequent interactions with trimethylamin ester of boric acid (or other treeframe boric acid) and subsequent acidic hydrolysis.

The halides of formula VII used in the method, synthesized according to the literature methods or easily get conventional methods of esterification known from the literature acids of formula X. Aromatic ortho-halogenated formula III used in the method And get the according to the scheme 4 from esters of formula VII after hydrolysis prior to the formation of acids X through a combination with other amines(3)R(4). Linking amide bond can occur similar to that described above for the conversion of compounds of formula IX IV.

For all methods may be appropriate at certain stages of the reaction temporarily protected functional groups in the molecule. Such protecting groups are known to the specialist. The choice of protective groups for functional groups in question, and the manner of its introduction and removal are described in the literature and can, if necessary, easily be used in each case.

The compounds of formula I according to the invention and their physiologically compatible salts can be used as medicines for animals, preferably mammals, especially for humans individually, in mixtures with one another or in the form of pharmaceutical compositions. The object of the present invention are also the compounds of formula I and their physiologically compatible salts for use as pharmaceuticals, their use for the treatment and prevention of paintings called disease and their application to obtain medication for this and medicines with blocking To+-channel effect. Further, an object of the present invention are pharmaceutical compositions which contain as an active component an effective dose of at least one compounds the Oia formula I and/or one of its physiologically compatible salts along with the usual pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions usually contain from 0.1 to 90 weight percent of compounds of formula I and/or their physiologically compatible salts. Obtaining pharmaceutical compositions can be accomplished by known methods. In addition, the compounds of formula I and/or their physiologically compatible salts are used together with one or more solid or liquid galenovye carriers and/or excipients and, if desired, in combination with other medicinal biologically active substances in a suitable form of introduction or dosage form which can then be used as medicinal products in human medicine or veterinary medicine.

Drugs containing the compounds of formula I according to the invention and/or their physiologically compatible salts can be used orally, parenterally, for example intravenously, rectally, by inhalation, or locally, preferably the application depends on the individual case, for example, appropriate clinical treatable diseases.

The specialist on the basis of his special knowledge to know what excipients suitable for the desired pharmaceutical formulations prepared forms. In addition to solvents, geleobrazovanie, suppositories, auxiliary substances for tabletki other carriers of biologically active substances can be used, for example, antioxidants, dispersing funds, emulsifiers, defoamers, substances that enhance the taste of medicines, preservatives, substances that contribute to the dissolution means to achieve the effect, buffer substances or dyes.

The compounds of formula I to achieve the preferred therapeutic effects can also be combined with other medicinal biologically active substances. So, for the treatment of diseases of the circulatory heart is possible preferred combination of substances, the active circulation of the heart. As components of these combinations, preferred in diseases of the blood circulation of the heart, using, for example, other antiarrhythmic agent, such antiarrhythmic agent of class I, class II or class III, as, for example, blockers IKsor IKrchannel, for example, dofetilide, or, further, the substance that lowers blood pressure like ACE inhibitors (eg, enalapril, captopril, ramipril), antagonists of angiotensin, activators To+channel as alpha - and beta-receptor blockers, and adrenergic and adrenergichesky active compounds and inhibitors of Na+/H+exchange, calcium channel antagonists, phosphodiesterase inhibitors and other positive inotrope active substances which, as, for example, digitalis glycosides or diuretics.

For oral forms of application of the active compounds are mixed with suitable additives, as carriers, stabilizers or inert diluents and the conventional methods are translated into suitable forms of applications, such as tablets, pills, detachable capsules, aqueous, alcoholic or oily solutions. As inert carriers may be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Thus the composition may be in the form of dry and wet granulate. As oily carriers or solvents 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 a mixture of them. Other auxiliary substances, also suitable for other forms of application are, for example, glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active compounds are mixed, if desired, with the usual substances, like alcohol, emulsifiers or other auxiliaries, and brought into solution, suspension or EMU is SIU. The compounds of formula I and their physiologically compatible salts can also be liofilizovane, and containing lyophilisate used, for example, for injection or infusion preparations. As the solvent used, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerin, along with this also solutions of sugars, as glucose or mannitol, or a mixture of various of the aforementioned solvents.

As pharmaceutical preparative ready-made forms for administration in the form of aerosols or sprays are suitable, for example, solutions, suspensions or emulsions of biologically active substances of the formula I or their physiologically compatible salts in one pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or in mixtures of such solvents. Preparative ready form may also contain, as needed, other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as a blowing gas. One such composition typically contains biologically active substance in a concentration of from about 0.1 to 10, especially from about 0.3 to 3 weight percent.

Dosage introduce biologically active substances of formula I or its physiologically compatible salt depends on the individual case and is chosen typically to achieve an optimal in this case. So naturally, it depends on the frequency and receive on the strength and duration of action of the compounds used, depending on the circumstances, for the treatment or prevention, but also on the type and severity of the disease being treated, and gender, age, weight and individual predisposition of a human or animal being treated, and the treated whether the acute form of the disease or prevents. The daily dose of the compounds of formula I when administered to a patient weighing about 75 kg is from 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. The dose may be administered as a single dose or divided into several, for example two, three or four single doses. In particular in the treatment of acute cases of cardiac arrhythmias, for example, ambulance, can also be preferably parenteral administration by injection or infusion, for example, by prolonged intravenous infusion.

The experimental part.

The list of abbreviations.

Boc - trebuetsyasistemnye

CDI - carbonyldiimidazole

DCC - dicyclohexylcarbodiimide

DMAP - 4-dimethylaminopyridine

DMF - N,N-dimethylformamide (DMF)

DME - 1,2-dimethoxyethan

EDC - N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide

HOBt is 1-hydroxy-1H-benzotriazol Me - methyl

MeLi - IU illite (in hexane)

BuLi - utility (pentane)

RP-HPLC (HPLC PF) is a high - performance liquid chromatography with reversed phase

THF is tetrahydrofuran (THF)

TFFH - tetraethyldiamidophosphorous

TFA - triperoxonane acid (TFUC)

Synthesis Baranovich acids of the formula II.

Boranova acid were synthesized according to scheme 3 synthesis is demonstrated on the example of several compounds.

2-(tert.-butoxycarbonylamino)-phenylboronic acid (compound 1)

N-Boc-2-bromobenzylamine (5,72 g, 20 mmol) was dissolved in THF in a stream of argon, was cooled to -78°C, mixed with of 13.75 ml of MeLi (1.6 M in hexane, 22 mmol), after one hour was added 28 ml (1.5 M in pentane, 42 mmol) of tert.-BuLi, and after another hour at -78°C were added and trimethylol ester of boric acid (9.0 ml, 80 mmol). After heating to room temperature, was added dilute hydrochloric acid to pH 6, was extracted with dichloromethane, the organic phase is washed with saturated NaCl solution and dried. Received of 5.1 g (100%) light yellow solid foam. MS (FAB, the sample is mixed with glycerol): MEAs./the calc.=308 (M+57), 252 (M+1).

(R)-2-(tert.-butoxycarbonylamino)phenylboronic acid (compound 2)

2.2 g (10 mmol) N-Boc-(R)-phenethylamine was dissolved in 50 ml of anhydrous THF, cooled to -78°C and bury 14 ml (1.5 M of rastvor-pentane, 21 mmol) of tert. utility. Within 2 hours was heated to -20°C, then added to 4.5 ml (40 mmol) trimethylol ester of boric acid and heated to room temperature. The solution was cooled to 0°C, acidified 10%hydrochloric acid to pH 6, the aqueous phase was extracted with dichloromethane, the combined organic phase was washed with saturated solution of NaCl, dried and concentrated. Received 2.0 g (75%) light yellow solid foam used without further purification. MS (FAB, the sample is mixed with glycerol): MEAs./the calc.=322 (M+57), 266 (M+1).

3-(tert.-butoxycarbonylamino)pyridine-4-baronova acid (compound 3)

5.5 g (26,4 mmol) N-Boc-3-aminomethylpyridine was dissolved in THF, cooled to -78°C, mixed with 37 ml of tert.-BuLi (1.5 M in pentane, to 55.5 mmol)and the mixture is a deep green color was slowly warmed to -20°C. After adding trimethylboron ester of boric acid (12.0 ml, is 105.6 mmol) was heated to room temperature and was stirred overnight. After adding diluted hydrochloric acid to pH 6 solution was concentrated on a rotary evaporator and extracted with a mixture of chloroform/isopropanol (3/1). The organic phase was dried and concentrated. Received 4.3 g (65%) orange solid, used without further purification. MS (FAB, the sample is mixed with glycerol): MEAs./the calc.=309 (M+57).

Synthesis of ar the case of the halides of the formulae III and VII.

General working procedure for the synthesis of compounds of formula VII with thionyl chloride:

2.5 mmol of the acid of formula X is heated with 3 ml of thionyl chloride for 4 hours under reflux and then concentrated. The crude reaction product is evaporated twice together with toluene, absorb 12.5 ml dichloromethane and mixed with 3 mmol amine other(3)R(4) and 5.5 mmol of triethylamine. The mixture is stirred overnight, washed with a solution of NaHCO3, dried and concentrated. Get 1.5 to 2.5 mmol of the desired amide III, which can be used without further purification.

Amides III according to General working method.

Esters VII were synthesized according to known literature methods, partly acids X through the esterification of the usual laboratory methods.

Halides esters VII

Synthesis bizarely compounds through a combination of Suzuki catalyzed by palladium, to compounds of the formula IV (scheme 1) and VIII (scheme 2).

A General method.

It was saturated with argon 1,2-dimethoxyethane (10 ml/mmol of bromide III or VII) was added to 0.05 EQ. tetrakis-triphenylphosphine and 1 EQ. the corresponding bromide III or VII. After 10 min was added 1.5 EQ. the corresponding Bronevoy acid and finally 2 EQ. 2 molar process is and sodium carbonate. Within 18 hours the mixture was heated in a stream of argon under reflux, cooled and diluted with methylene chloride. The mixture was washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated and chromatographically purified. When cleaning by HPLC OFFICE has identified the main connection in the form of trifurcation.

Bizarrerie the compounds of formula VIII

Methyl ester of 3-[2-(tert.-butoxycarbonylamino)phenyl]pyrazin-2-carboxylic acid (compound 15)

107 ml of 1,2-dimethoxyethane saturated with argon, was added 597 mg (0.51 mmol) of Pd(PPh3)42.24 g (10.3 mmol) of methyl ester of 3-bromopyrazine-2-carboxylic acid. After 10 min was added to 3.9 g (15,45 mmol) of 2-(tert.-butoxycarbonylamino)phenylboronic acid and finally to 10.7 ml of 2 M sodium carbonate solution. The mixture for 18 hours, heated in a stream of argon to reflux and after cooling was diluted with dichloromethane and washed with water. The organic phase was dried, concentrated and purified by chromatography on kieselgel. Received 661 mg (19%) of viscous oil. MS (ES+): MEAs./the calc.=344 (M+1), 288 (M-55).1H-NMR (CDCl3): δ=8,78 (1H, d, J=2.4 Hz), 8,67 (1H, d, J=2.4 Hz), 7,54-7,14 (4H, m), 5,11 (1H, ush. C), 4,22 (2H, d, J=5,9 Hz), with 3.79 (3H, s)to 1.38 (9H, s).

Ethyl ester of 3-[2-(tert.-butoxycarbonylamino)phenyl]pyridine-2-carboxylic acid (Obedinenie 16)

150 ml of 1,2-dimethoxyethane saturated with argon, was added 874 mg (0.75 mmol) of Pd(PPh3)4and 3.45 g (15 mmol) of ethyl ester of 3-bromopyridin-2-carboxylic acid. After 10 min was added 5.53 g (to 22.5 mmol) of 2-(tert.-butoxycarbonylamino) phenylboronic acid and finally 15 ml of 2 M sodium carbonate solution. The mixture for 18 hours, heated in a stream of argon to reflux and after cooling was diluted with dichloromethane and washed with water. The organic phase was dried, concentrated and chromatographically purified on kieselgel.

Received 3.4 g (66 %) of a viscous oil. MS (ES+): MEAs./the calc.=357 (M+1).

Methyl ester 2-[3-(tert.-butoxycarbonylamino)pyridine-4-yl] benzoic acid (compound 17)

20 ml of 1,2-dimethoxyethane saturated with argon, was added 230 mg (0.2 mmol) of Pd(PPh3)4and 0,86 g (4 mmol) of methyl ester of 2-bromobenzoyl acid. After 10 min was added 1.51 g (6 mmol) of 3-(tert.-butoxycarbonylamino)pyridine-4-Bronevoy acid and finally 4 ml of 2 M sodium carbonate solution. The mixture for 13 hours was heated in a stream of argon to reflux and after cooling was diluted with dichloromethane and washed with water. The organic phase was dried, concentrated and chromatographically purified on kieselgel.

Got to 1.15 g (84%) of a viscous light yellow is the asle.

MS (ES+): MEAs./the calc.=343 (M+1).

1H-NMR (CDCl3): δ=8,65 (1H, s), 8,54 (1H, d, J=4,8 Hz), with 8.05 (1H, d, J=7,7 Hz), 7,70-the 7.43 (2H, m), 7,20 (1H, d, J=7,7 Hz), 7,02 (1H, d, J=4,8 Hz), to 4.81 (1H, ush. s, NH), 4,20 (1H, DD, J=14,7, 5,5 Hz), of 4.05 (1H, DD, J=14,7, 5,5 Hz), of 3.69 (3H, s, Me)to 1.38 (9H, s).

Bizarrerie the compounds of formula IV (method A)

According to the above General method were synthesized following connections:

Hydrolysis bizarely compounds VIII to acids of formula IX (scheme 2)

A General method.

1 EQ. of ester VIII was dissolved in methanol/THF (3/1,5 ml/mmol) was mixed with 2 EQ. 1 molar solution of lithium hydroxide and stirred overnight at room temperature. Then the solution was diluted with water and made a solution of KHSO4to pH 3. Was repeatedly extracted with dichloromethane, the organic phase was dried and concentrated.

In accordance with this method was presented a few examples:

Synthesis of amides IV through amide combination with acids IX (scheme 2)

General methodology for amide combinations.

1 EQ. acid IX was dissolved in dichloromethane (20 ml/mmol) was mixed with 2 EQ. of triethylamine, 1.2 EQ. EDC, 0.2 EQ. DMAP and 1.2 EQ. the corresponding amine NH(R3)(R4), and was stirred over night at room temperature. The reaction is ionic solution was washed with water and purified by HPLC OF. The main compounds were identified as trifurcation.

In accordance with this method were synthesized following examples:

Cleavage of the protective group "Boc" before the formation of amines V (scheme 1 and 2).

A General method.

1 EQ. N-Boc-compound was dissolved in a mixture of dichloromethane/triperoxonane acid (3/1, 10 ml/mmol) and 3 hours and stirred at room temperature. Then concentrated in a rotary evaporator and evaporated with toluene. Amines V without further purification was used for further transformations. All compounds were characterized using mass spectrometry.

The interaction of the amine V with various reagents to the formation of the target compounds I.

A General method of conversion prior to the formation of carbamates of formula I.

1 EQ. Amin V was dissolved in dichloromethane (about 10 ml/mmol), was mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) of triethylamine and 1.2 EQ. succinimidylester (or, optionally, the corresponding chloroformate) and stirred over night. Was diluted with dichloromethane and washed with a solution of NaHCO3. The organic phase was dried, concentrated and, if necessary, purified by HPLC OF.

Example 18: benzyl ether {2-[2-(3-methylbutanoyl)pyridine-3-yl]benzyl} carbenoxolone.

46 mg (0.15 mmol) (3-methylbutyl)amide 3-(2-aminomethylphenol)pyridine-2-carboxylic acid was dissolved in 3 ml of dried dichloromethane, mixed with 17 mg (0,17 mmol) of triethylamine and 41 mg (0,17 mmol) of benzyloxycarbonylglycine. After 18 hours after start of the reaction mixture was diluted with 20 ml dichloromethane, washed with saturated solution of NaHCO3, the organic phase was dried and concentrated. After purification by HPLC OF received 60 mg (73%) of colorless substances in the form of his trifenatate.

MS (ES+): MEAs./the calc.=432 (M+1).

1H-NMR (CDCl3): δ=to 8.57 (1H, DD, J=4,8, 1.5 Hz), of 7.96 (1H, ush. C), 7,60 (1H, d, J=7,7 Hz), 7,47-7,26 (9H, m), 7,02 (1H, m), 5,73 (1H, ush. C)to 4.98 (2H, s), 4,27 (1H, DD, J=14,0, 6,6), 3,98 (1H, DD, J=14,0, and 3.7 Hz), with 3.27 (2H, m), 1,58 (1H, m)of 1.40 (1H, m)0,86 (6H, d, J=6,6 Hz).

The following examples in accordance with the methods:

A General method of conversion to the formation of the amides of formula I

A) 1 EQ. Amin V dissolved in dichloromethane (about 10 ml/mmol), mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) diisopropylethylamine and 1.2 EQ. the carboxylic acid and stirred over night. Diluted with dichloromethane and washed with a solution of NaHCO3. The organic phase is dried, conc the Ute and, if necessary, purified by HPLC OF.

In) 1 EQ. Amin V dissolved in dichloromethane (about 10 ml/mmol), mixed with 1.2 EQ. (2.2 EQ. when using trifenatate) diisopropylethylamine, 1,2 EQ. acid and 1,2 EQ. TFFH and stirred over night. Diluted with dichloromethane and washed with a solution of NaHCO3. The organic phase is dried, concentrated and, if necessary, purified by HPLC OF.

Example 35: cyclopropylmethyl 3-{2-(R)-[(3-phenylbutyramide)methyl]phenyl}pyridine-2-carboxylic acid

100 mg (0.35 mmol) of cyclopropanemethylamine 3-(2-aminomethylphenol)pyridine-2-carboxylic acid was dissolved in 4 ml of dichloromethane, mixed with 44 mg (0.43 mmol) of diisopropylethylamine, 70 mg (0.43 mmol) of (R)-3-phenylalkanoic acid and 114 mg (0.43 mmol) and TFFH was stirred over night. Was diluted with 20 ml dichloromethane and washed with a solution of NaHCO3. The organic phase was dried, concentrated and purified by HPLC OF. Has been allocated 150 mg (77%) of the compound in the form of his trifenatate.

MS (ES+): MEAs./the calc.=428 (M+1).

The following examples are given according to the General method a or b:

Pharmacological studies.

Kv1.5 channels of a person expressed in Xenopus oocytes. DL the first oocytes were isolated from Xenopus Iaevis and depolymerase. Then in these oocytes in vitro were injected synthesized Kv1.5-coding RNA. After 1-7 days Kv1.5-protein expression in oocytes was measured Kv1.5 threads by fixing the voltage with two microelectrodes. In this case, as a rule, Kv1.5 channels activated by power surges with a duration of 500 MS to 0 mV and 40 mV. The bath was washed with a solution of the following composition: NaCl 96 mm, KCl 2 mm, CaCl21.8 mm, MgCl21 mm, 5 mm HEPES (titrated with NaOH to a pH of 7.4). These experiments were performed at room temperature. To retrieve the data and analysis used: Geneclamp amplifier (Axon Instruments, Foster City, USA) and MacLab D/A Converter and software (ADInstruments, Castle Hill, Australia). The substances according to the invention was tested by adding to the electrolyte solution in different concentrations. The effectiveness of the substances was calculated as percentage of inhibition of Kv1.5-control thread, which was obtained when the solution was not added substances. The data is then extrapolated using the hill equation (Hille) to determine the concentration braking IC50for the relevant substances.

This method for the compounds determined the following values IC50:

Example IC50[Ám]Example IC50[Ám]Example IC 50[Ám]Example IC50[Ám]
1102103<1004<100
5<1006<1007<1008<100
9<10010inactive11inactive12<100
182.6190.6201.2212
220.6230.4242.5252.5
26<100279289297.6
301031<1003210331.7
344.7350.436<10037<100
385.639<10040<10041<100
42<100/td> 43<100446.7450.5
462.7473.1482.4490.9
501051<100521053inactive
54<100553.8566.15710
580.7593.2603.1611.7
621.8631.8640.965<100
66<10067<100

1. The compounds of formula 1

in which

A1, A2, A3, A4, A5, A6, A7 and A8 independently from each other represent nitrogen or CH, and at least one or at most two of these groups represent nitrogen;

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

R(9) and R(11) independently of one another denote CxH2x-R(14);

x is 0, 1, 2, 3 is whether 4,

R(14) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, phenyl or isoxazolyl, and phenyl and isoxazolyl not substituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, alkyl with 1, 2, 3 or 4 C-atoms and alkoxygroup with 1, 2, 3 or 4 C-atoms;

R(2) denotes hydrogen;

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

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

R(16) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms, cycloalkyl 3, C-atoms, OR(17), phenyl or pyridyl, and phenyl and pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, and alkoxygroup with 1, 2, 3 or 4 C-atoms;

R(17) denotes hydrogen;

or

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

R(18) denotes alkyl with 1, 2, 3, 4, 5 or 6 C-atoms;

R(19) represents CONH2;

R(4) denotes hydrogen;

R(30) R(31) denote hydrogen;

and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, characterized in that

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

R(9) and R(11) independently of one another denote WithxH2-R(14);

x is 0, 1, 2 or 3;

R(14) represents phenyl, whereby phenyl is not substituted or is substituted by 1 or 2 substituents selected from the group, with the standing of F, Cl, Br, I, CF3, OCF3, alkyl with 1, 2 or 3 C-atoms or alkoxygroup with 1 or 2 C-atoms;

R(2) denotes hydrogen;

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

y is 0, 1 or 2;

R(16) denotes alkyl with 1, 2 or 3 C-atoms, cycloalkyl to 3 C-atoms, phenyl or pyridyl, and phenyl and pyridyl is not substituted or is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl or alkoxygroup with 1 or 2 C-atoms;

R(4) denotes hydrogen;

R(30) R(31) denote hydrogen.

3. The compounds of formula I according to claim 1 or 2, and their pharmaceutically acceptable salts, useful as pharmaceuticals.

4. Pharmaceutical composition with blocking To+-channel effect, containing an effective amount of at least one of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt as biologically active substances, together with pharmaceutically acceptable carriers and additives.

5. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt for a drug with a blocking K+channel action for the treatment and prevention of disease due To+channel.

6. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt to obtain medication for the treatment of isopropylacetate cardiac arrhythmias, which can be eliminated by lengthening of the action potential.

7. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt for a drug for treatment or prevention of circulation of arrhythmias due to recurrent excitation.

8. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt for a drug for the treatment or prophylaxis of supraventricular arrhythmias.

9. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt for a drug for treatment or prevention trialing flicker or trialing utter.

10. The use of the compounds of formula I according to claim 1 or 2, and/or its pharmaceutically acceptable salt for a drug to limit trialing flicker or trialing utter (cardioversion).



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula (1):

wherein R1 means (C1-C6)-alkyl that can be substituted once or multiply with phenyl; R2 and R3 means independently of one another hydrogen atom, (C6-C10)-aryl, (C3-C8)-cycloalkyl, (C6-C10)-aryloxymethyl, O-benzyl can be substituted once or multiply with halogen atom, -CF3,, O-(C6-C10)-aryl or O-(C3-C8)-cycloalkyl, O-(C1-C6)-alkyl, that can be substituted once or multiply with fluorine atom or amino-group wherein amino-group, in turn, can be substituted once or multiply with (C1-C4)-alkyl; SO2-NH-(C1-C6)-alkyl substituted possibly with group N-[(C1-C6)-alkyl]2; SO2-NH-(2,2,6,6-tetramethylpiperidin-4-yl); SO2-NH-(C3-C8)-cycloalkyl substituted possible once or multiply with (C1-C4)-alkyl; SO2-N-[(C1-C6)-alkyl]2 or COX wherein X means N-[(C1-C6)-alkyl]2; and N-[(C1-C6)-alkyl-alkyl]2 can mean also pyrrolidine, piperidine, morpholine or piperizine group that if necessary can be substituted with (C1-C4)-alkyl; under condition that R2 and R3 don't mean hydrogen atom simultaneously, and to their physiologically acceptable salts and optical isomers. Compounds show inhibitory effect on activity of hormone-sensitivity lipase (HSL). Also, invention describes a method for preparing these compounds.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

SUBSTANCE: invention describes substituted azadioxocycloalkenes of the general formula (I): wherein A means unsubstituted or methyl-substituted dimethylene; Ar means unsubstituted or fluorine-substituted ortho-phenylene, thiophendiyl or pyridindiyl; E means group of the formula: wherein G means oxygen atom, groups -O-CH2-, -CH2-O- or -C(CH3)=N-O-CH2-; Z means unsubstituted or substituted phenyl, pyrimidinyl or thiadiazolyl, or naphthyl. Invention describes 4 methods for preparing compounds of the formula (I), 5 species of intermediate compounds used for preparing compounds of the formula (I), fungicide agents comprising compound of the formula (I) as an active substance, a method for preparing fungicide agents, method for control of harmful fungi using compound of the formula (I). Compounds of the formula (I) show fungicide properties and therefore they can be used in agriculture.

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

New ketoenamine // 2190599
The invention relates to new ketoenamine formula (1), where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, which may be unsubstituted or substituted, R2means hydrogen or alkyl, R3means alkyl, which may carry phenyl ring, X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)0-, -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH=CH-, -(CH2)m-NHCO-(CH2)0-, -(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-; R4means group OR6, NR7R8; n is a number from 0 to 2

The invention relates to new heterocyclic tetracarbonyl General formula I

< / BR>
where X =communications,

< / BR>
Connections can be used to obtain polyhexamethylene - fluorophores, bifluorophors besed, trifluoroprop

Imidazopyridine // 2092487
The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors

The invention relates to a new series of tetracyclic compounds having two or three nitrogen atoms included in the ring, which have significant anti-allergic and anti-asthma activity, provides methods and compositions for their use, as well as technologies of their production

The invention relates to the field of organic chemistry, to the class of heterocyclic compounds - derivatives of 1,2,3,4-tetrahydroquinoxaline, namely to a new way to obtain previously unknown connections - 2,3-bis-koimeterion - 1,2,3,4-tetrahydroquinoxaline formula

< / BR>
(Ia, b) where R = Br(a), NO2(b) that may find application in medicine as drugs with antimicrobial action

FIELD: organic chemistry, agriculture, insecticides.

SUBSTANCE: invention relates to a substituted anilide derivative of the formula (I): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2; Z represents oxygen atom; Q means a substitute represented by any of the following formulae: Q1-Q3, Q6, Q8-Q12, Q14-Q19, Q21 and Q23 (wherein each among Y1 that can be similar or different represents halogen atom, (C1-C6)-alkyl group, and so on); Y2 represents (C1-C6)-alkyl group or halogen-(C1-C6)-alkyl group; Y3 represents (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl group or substituted phenyl group; p represents a whole number from 1 to 2; q represents a whole number from 0 or 2; r represents a whole number from 0 to 2. Also, invention proposes a chemical for control of pests of agricultural and fruit crops. The chemical comprises substituted anilide derivative of the formula (I) as an active component and represents insecticide, fungicide or acaricide. Also, invention proposes a method for addition of the chemical for control of pests of agricultural and fruits crops. Also, invention proposes aniline derivative represented by the general formula (II): wherein R1 represents hydrogen atom, (C1-C6)-alkyl group; R2 represents hydrogen atom, halogen atom or halogen-(C1-C6)-alkyl group; R3 represents hydrogen atom, halogen atom, (C1-C6)-alkyl group, hydroxyl group or (C1-C6)-alkoxy-group; t = 1; m = 0; each among X that can be similar or different represents (C2-C8)-alkyl group, hydroxy-(C1-C6)-alkyl group or (C3-C6)-cycloalkyl-(C1-C6)-alkyl group; n = 1 or 2. Invention provides the development of anilide derivative as insecticide, fungicide and acaricide against pests of agricultural and fruit crops.

EFFECT: valuable properties of compound.

5 cl, 6 tbl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc
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