Anthranilic acid amides with by-side heteroarylsulfonyl chain and pharmaceutical composition containing thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

 

The invention relates to compounds of formula (I):

where R(1), R(2), R(3), R(4), R(5), R(6) R(7) have the following values:

R(1) means

And means-CnH2n-;

n means 0, 1, 2, 3, 4 or 5;

D is a bond or-O-;

E. means-CmH2m-;

m means 0, 1, 2, 3, 4 or 5;

R(8) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CpH2p-R(14);

p denotes 0, 1, 2, 3, 4 or 5;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, 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(9) means a hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, NO2CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxyl 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(11) means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl,, Br, I, CF3, OCF3, NO2CN, 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(12) denotes alkyl with 1, 2, 3 or 4 carbon atoms, quinil with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, 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 is;

R(13) implies CpH2p-R(14);

p denotes 0, 1, 2, 3, 4 or 5;

R(15) means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms;

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

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, OCF3, 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(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, Br, I, CF3, OCF3, 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 and methylsulfonylamino;

and their pharmaceutically acceptable salts; and their use, particularly in medicines.

Preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0, 1, 2 or 3;

E. means-CmH2n-;

m means 0, 1, 2 or 3;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

Dr. oz is achet 0, 1, 2 or 3;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(9) means a hydrogen atom or alkyl with 1, 2, 3 or 4 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(11) means phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, thienyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted 1, 2 is 3 substituents, selected from the group consisting of F, Cl, CF3, OCF3CN, 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(2) means a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0 or 1;

E. means-CmH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

p> R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3,of alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, Dima is laminography, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(2) means a hydrogen atom, methyl or ethyl;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Highly preferred compounds of formula (I), where:

And means-CnH2n;

n means 0 or 1;

E. means-FrommH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfa is Oila or methylsulfonyl;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl or methylsulfonyl;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl or methylsulfonyl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl or methylsulfonyl;

R(4) means a hydrogen atom, F, Cl, CF3, methyl or methoxy group;

R(5) means the volume of hydrogen, F, Cl, CF3, methyl, methoxy group, PINES3, OCF3CN or HE;

R(6) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group or IT;

R(7) means a hydrogen atom, F, Cl, CF3,methyl, ethyl, methoxy group or IT;

and their pharmaceutically acceptable salts.

Also preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-; n is 0, 1, 2 or 3;

D is a bond or-O-;

E. means-CmH2m-; m is 0, 1, 2 or 3;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(9) means a hydrogen atom or alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, Pirim dinil, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(12) denotes alkyl with 1, 2 or 3 carbon atoms, quinil with 1, 2 or 3 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(2) means a hydrogen atom or alkyl with 1, 2 or 2 carbon atoms;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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 IU is isalphanumeric;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmacologically acceptable salts.

Also especially preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-CmH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(9) means a hydrogen atom, methyl or ethyl;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, Indus is alil, chenail, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(12) denotes alkyl with 1, 2 or 3 carbon atoms, ethinyl, cyclopropyl, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(2) means a hydrogen atom, methyl or ethyl;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl,methylsulphonyl and methylsulfonylamino;

and their pharmacologically acceptable salts.

Also highly preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-CmH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(9) means a hydrogen atom, ethyl or methyl;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl and ethylsulfonyl;

R(12) denotes alkyl with 1, 2 or 3 carbon atoms, ethinyl, cyclopropyl, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl and methylsulfonyl;

R(4) means a hydrogen atom, F, Cl, CF3,methyl or methoxy group;

R(5) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group, PINES3, OCF3CN or HE;

R(6) means a hydrogen atom, F, Cl, CF3, methyl or methoxy group or IT;

R(7) means a hydrogen atom, F, Cl, CF3, methyl, ethyl, methoxy group or IT;

and their pharmacologically acceptable salts.

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

R(1) means

And means-CnH2n-;

n means 0, 1, 2 or 3;

D is a bond or-O-;

E. means-CmH2m-;

m means 0, 1, 2 or 3;

R(9) means the atom ogorodili alkyl with 1, 2, 3 or 4 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, COOCHF3, 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(11) means phenyl, naphthyl, thienyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, thienyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(13) implies CpH2p-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 mandated what teli, selected from the group consisting of F, Cl, CF3, OCF3CN, 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(2) means a hydrogen atom or alkyl with 1, 2 or 3 carbon atoms;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Especially preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-CmH2m-;

m denotes 0 or 1;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) Osnach is no hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, NH2HE metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(13) implies CpH2p-R( 14) ;

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dim is filamentgroup, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(2) means a hydrogen atom, methyl or ethyl;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Highly preferred compounds of formula (I),

And means-CnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-CmH2m-;

m denotes 0 or 1;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, is sulfamoyl, methylsulfonyl, methylsulfonylamino;

R(11) means phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline, and phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline or cinnoline unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl;

R(13) implies CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl;

R(4) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group;

R(5) means and what Ohm hydrogen, F, Cl, CF3, methyl, methoxy group, PINES3, OCF3CN, HE;

R(6) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group, HE;

R(7) means a hydrogen atom, F, Cl, CF3, methyl, ethyl, methoxy group, HE;

and their pharmaceutically acceptable salts.

Also preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0, 1, 2 or 3;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, 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) means cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms;

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

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, SOON3, CONH2The PINES3, NH2HE, alkyl with 1, 2, 3 or 4 carbon atoms, alcox the La 1, 2, 3 or 4 carbon atoms, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Also especially preferred compounds of formula (I), where:

R(1) means

And means-CnH2n-;

n means 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(15) means cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms;

R(2) means a hydrogen atom, methyl or ethyl;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3that is Lila 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulfonyl and methylsulfonylamino;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, CF3, OCF3CN, PINES3HE, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan, dimethylaminopropyl, sulfamoyl, methylsulphonyl and methylsulfonylamino;

and their pharmaceutically acceptable salts.

Also highly preferred compounds of formula (I), where:

R(1) means

And means-FromnH2n-;

n means 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, ethoxypropan, dimethylaminopropyl, sulfamoyl and methylsulfonyl;

R(15) means cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3CN, PINES3, methyl, metoxygroup, taksigrup is, dimethylaminopropyl, sulfamoyl or methylsulfonyl;

R(4) means a hydrogen atom, F, Cl, CF3, methyl or methoxy group;

R(5) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group, PINES3, OCF3CN or HE;

R(6) means a hydrogen atom, F, Cl, CF3, methyl, methoxy group or IT;

R(7) means a hydrogen atom, F, Cl, CF3, methyl, ethyl, methoxy group or IT;

and their pharmaceutically acceptable salts.

The term "heteroaryl" see in particular the remains of the phenyl or naphthyl, in which at least two adjacent CH groups are replaced by N and/or in which at least two adjacent CH groups (in the formation of five-membered aromatic cycle) replaced by S, NH or O. Further, one or both of the atom in place of the condensation of a bicyclic residues (as in indolizinyl) can be nitrogen atoms.

As heteroaryl have value in particular furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazoles, hinely, ethanolic, phthalazine, honokalani, hintline, cinnolines.

Alkyl and alkylene residues may be linear or branched. This also applies to alkilinity the remnants of the formula CmH2mCnH2nand CpH2P . Alkyl and alkylene residues can also be linear or branched, if they substituted or contained in other residues, for example, in the 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 residues divalent 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 etc. are examples alkilinity residues.

If the compounds of formula (I) contain one or more acidic or basic groups, respectively, one or more main or heterocycles heterocycles acid character, the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts. Thus, the compounds of formula (I)comprising acidic groups, for example, one or more COOH groups, can be used, for example, in the form of alkali metal salts, preferably as sodium or kalavacherla, or in the form of salts of alkali-earth metals such as calcium or magnesium salts, or as ammonium salts, such as salts with ammonia or organic amines or amino acids. The compounds of formula (I)comprising one or more primary, i.e. protonium, groups, or one or more basic heterocycles, can also be used 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 in the molecule at the same time acidic and basic groups, the invention includes, in addition to these salt forms are also internal salts, the so-called betaines. Salts of compounds of formula (I) can be obtained by conventional means, for example, by combining with acid or, respectively, a base in a solvent or dispersant, or by anion exchange from other salts.

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 centers of asymmetry, they may have, independently from each other, S - or R-configuration. The invention includes all possible stereozoom the market, for example, the enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, for example, enantiomers and/or diastereomers, in all ratios. Enantiomers, for example, relate to the invention in the individual enantiomeric form, in the form of left-, and programada antipodes, as well as in the form of mixtures of both enantiomers in different ratios or in the form of racemates. Obtaining individual stereoisomers can be done in a desirable way, by separating the mixture by conventional means, for example, or by stereoselective synthesis. In the presence of mobile hydrogen atoms present invention also includes all tautomeric forms of the compounds of formula (I).

Proposed according to the invention the compounds of formula (I) and their physiologically acceptable salts can be used in the case of an animal, preferably a mammal, and in particular in the case of man, as the drugs 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 acceptable salts for use as pharmaceuticals, their use in the case of therapy and prophylaxis of these paintings diseases and their application to obtain drugs for these purposes and drugs is the R means from the blocking To the +-channel effect. Further, an object of the present invention are pharmaceutical compositions, which, as active components 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 be obtained in itself known. For this purpose the compounds of formula (I) and/or their physiologically acceptable salts together with one or more solid or liquid galenovye carriers and/or excipients and, if desired, in combination with other biologically active substances of medicines transferred to a suitable form of administration, respectively, dosage form, which can then be used in human medicine or animal as a medicine.

Drugs, containing proposed according to the invention the compounds of formula (I) and/or their physiologically acceptable salts can be entered orally, parenterally, for example intravenously, rectally, by inhalation, or locally, preferably the introduction depends on the specific case, voltage is emer, the corresponding picture of the symptoms of treatable diseases.

What excipients suitable for the desired pharmaceutical form, the specialist is known on the basis of his expert knowledge. Along with solvents, geleobrazovanie, the basics of suppositories, excipients for tablets and other carriers of biologically active substances can be applied, for example, antioxidants, dispersants, emulsifiers, antispyware, improves the taste of the ingredients, preservatives, promote dissolving agents, agents for achieving a depot effect, buffer substances or dyes.

To achieve a beneficial 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 in relation to cardiovascular disease component combinations are used, for example, other antiarrhythmic agent, namely, antiarrhythmic agent of class I, class II or class III, as, for example, channel blockers IKsor IKrfor example, dofetilide, or, further, blood pressure-lowering substances, such as ACE inhibitors (e.g. enalapril, Capto the reel, ramipril), antagonists of angiotensin, activators To+channel, as well as blockers alpha - and beta-receptors, as well as sympathomimetic and adrenergichesky active compounds, inhibitors of Na+/N+exchange, calcium channel antagonists, phosphodiesterase inhibitors, and others acting positively inotrope substances, as, for example, digitalis glycosides or diuretics.

In the case of oral use, the active compounds are mixed with suitable additives, as carriers, stabilizers or inert diluents, and the usual ways to bring 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, magnesia, 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 DL the other forms of application, are, for example, glycols and polypropylenglycol.

For subcutaneous or intravenous administration, the active compounds in the desired normal for this kind of introduction of substances such as contributing to the dissolved substances, emulsifiers or other auxiliaries, are dissolved, suspended or emuleret. 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 them also solutions of sugars, as glucose or mannitol, or a mixture of these solvents.

As a pharmaceutical preparation 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 drug can also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as prop lent. 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) or its physiologically acceptable salts, depending on the individual case and, as usual, must be adapted to the optimal action in a particular case. So, it depends, of course, on the frequency of administration and on the intensity and duration of steps used in each case for the treatment or prevention of compounds, and also on the nature and intensity of treatable disease, gender, age, weight and individual sensitivity of the treated human or animal, and from that, do you treat acute cases of disease or prophylactically. Daily dose of the compounds of formula (I) when administered to a patient weighing approximately 75 kg is usually from 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 can be useful also parenteral administration by injection or infusion, e.g. the R, by continuous intravenous infusion.

Proposed according to the invention the compounds of formula (I) affect the so-called Kvl.5 potassium channel and inhibit referred to as "sverhbystro activated the purifier delayed action" potassium tray in the human atrium. Connections are therefore highly suitable as a new type 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 fibrillation).

Atrial fibrillation (AF) and atrial flutter are often long-term atrial fibrillation. Their appearance increases with increasing age and often leads to fatal consequences, such as bleeding in the brain. AF affects approximately 1 million Americans each year and leads to more than 80,000 strokes each year in the United States. The currently adopted antiarrhythmic agent of class I and class III reduce the speed of recurrence of AF, however, because of their potential prioritiesin side effects are only of limited use. Consequently, in medicine there is a great need to create the best medicines for the treatment of atrial arithm the th (S. Nattel "Newer developments in the management of atrial fibrillation", Am. Heart. J., 130, 1094-1106 (1995)).

Found that most of supraventricular arrhythmias obliged so-called "reflexive" waves of excitation. Such returns occur when cardiac tissue has a slow conductivity and at the same time is very short refractory periods. The increase in myocardial refractory time by lengthening the action potential is a recognized mechanism to terminate arrhythmias, respectively, prevent their occurrence (Colatsky TJ and others, "Potassium channels as targets for antiarrhythmic drug action. Drug Dev. Res., 19, 129-140 (1990)). The duration of the action potential is essentially determined by the amount repolarizes To+streams that flow from the cells via different To+-channels. It is particularly of great importance attributed to the so-called "cleaner delayed action" Ito, which consists of three different components: IKrIKsand Ikur.

Most of the known antiarrhythmic drugs class III (e.g. dofetilide, E and d-sotalol) predominantly or exclusively block quickly activated potassium channel IKr, which can be detected in cells of the human ventricle, and also in the atrium. However, we discovered that these compounds in small or normal cardiac frequency with which krasheny have increased prioritiesin risk factor, and see especially arrhythmia, denoted as pirueta tachycardia (D.M. Roden "Current status of class III antiarrhythmic drug therapy", Am. J. Cardiol., 72, 44B-49B (1993)). Along with this high, partly as a deadly risk factor at low frequency, for IKr-blockers found to reduce the effectiveness in terms of tachycardia, which should impact (negative dependence on use").

While some of these drawbacks can be overcome by blockers slow motion-activated component (IKs), their effectiveness is still not proven as unknown clinical research blockers IKschannel.

"Especially quickly activated and very slowly inactiveusers component purifier delayed action 1Kur(=sverhbystro activated the purifier slow-action), which corresponds to the Kvl.5 channel, plays a particularly important role in relation to the duration of repolarization in the human atrium. Inhibition facing potassium flow IKurcompared to the inhibition of IKsaccordingly, IKsrepresents, therefore, a particularly effective way of lengthening the atrial action potential and, together with the termination, respectively, prevent atrial arrhythmias. Matematiche the Kai model of human action potential allows to understand the positive effects of the blockade of IKurespecially should appear exactly in the pathological conditions of chronic atrial fibrillation (M. Courtemanche, R.J. Ramirez, and S. Nattel,"Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model. Cardiovascular Research, 42, 477-489 (1999)).

In contrast IKrand IKsthat also exist in the human ventricle, IKur, however, plays a significant role in the human atrium, but not in the ventricle. On this basis, when the inhibition of IKurstream, in contrast to the blockade of IKror IKsfrom the beginning eliminates the risk proaritmicheskimi effects on the heart (2. Wang et Al., "Sustained depolarisation-induced outward current in Human atrial myocytes", Circ. Res., 73, 1061-1076 (1993)); G.-R. Li and others, "Evidence for two components of delayed rectifier K+-current in human ventricular myocytes", Circ. Res., 78, 689-696 (1996); G.J. Amos and others, "Differences between outward currents of human atrial and subepicardial ventricular myocytes", J. Physiol., 491, 31-50 (1996)).

Antiarrhythmic agent that act by selective blockade of IKurstream, respectively, Kvl.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 Kvl-5-channel, however, the blockade of Kvl.5 here represents the only side effects along with other key action is s substances.

In the application WO 98/04521 described aminoindane as potassium channel blockers, which block v1.5 channel. In applications WO 98/18475 and WO 98/18476 described the use of various pyridazinones and phosphine oxides as antiarrhythmic drugs, which must act through the blockade of IKur. Also described is similar to the connection initially, but as immunosuppressants (application WO 96/25936). Described in these applications, the compounds have the structure of a completely different kind than proposed in the invention compounds according to the present application.

Unexpectedly, it was shown that described in this application amides heteroarylboronic acids are potent blockers of human Kvl.5 channel. Therefore, they can be used as a new kind of antiarrhythmic drugs with a particularly useful security profile. Compounds particularly suitable for the treatment of supraventricular arrhythmias, such as flicker or atrial flutter.

Proposed according to the invention the connection is still not known. Some structurally related compounds are described in the application WO 00/02851, applications EP 0686625-A1 and EP 0947500-A1. For the derivatives of Anthranilic acid, however, is unknown blocking potassium channel activity.

According to the scheme 1 proposed according to the image is the shadow of your connection you can get, for example, the fact that the first aminocarbonyl acid of formula (VI) in a solvent, such as water, pyridine or a simple ester, in the presence of a base enter into interaction with sulphonylchloride formula R(3)-SO2-Cl or a sulfonic anhydride. As grounds use inorganic bases, such as sodium carbonate, or organic bases, such as pyridine or triethylamine. Received sulphonilecarbomide acid of the formula (VII) then, for example, by introducing into interaction with gloriouse agent, as, for example, pentachloride phosphorus, phosphorus oxychloride or thionyl chloride, in an inert solvent can be activated to obtain a carboxylic acid of formula (VIII) and then to enter into interaction with the amine of the formula H-R(l), obtaining the target compound of formula (I). Activating the carboxyl group in the compound of formula (VII), however, can be made in other ways, for example, one of the numerous, well-known specialist methods, which are used in the chemistry of peptides for the formation of amide bonds, for example, by transferring into a mixed anhydride or activated ester, or by using carbodiimide as dicyclohexylcarbodiimide.

Reaction of the activated sulfonilmocevinnah acid with an amine of the formula H-R(l) is carried out preferably in inert the m solvent, as, for example, pyridine, tetrahydrofuran or toluene, without additives or with the addition of an inert auxiliary base, for example, tertiary amine or pyridine.

List of abbreviations:

BuLi - utility;

CDI - carbonyldiimidazole;

DIC - diisopropylcarbodiimide;

DIP - diisopropyl ether;

DIPEA - diisopropylethylamine;

DMAP - 4-dimethylaminopyridine;

DMF - N,N-dimethylformamide;

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

HER - ethyl acetate;

TPL - melting temperature (unless nothing else, shows the melting temperature of the crude raw foods; the melting temperature of the respective pure substances may be explicitly above) ;

NAVT - 1-hydroxy-1H-benzotriazole;

MTB - tert-butyl methyl ether;

THF - tetrahydrofuran;

TOTU - O-[(cyano(etoxycarbonyl)methylene)amino]-1,1,3,3-tetramethylpropylenediamine;

MS - mass spectrum;

ES, ESI - ionization electron spray.

General method 1

The interaction of Anthranilic acids with sulphonylchloride with the formation of o-sulfonilmocevinnah acids (analogous Organic Syntheses, 32, 8 (1952)).

To a solution of 260 g (2.4 mol) of sodium carbonate and 1 mol of the corresponding Anthranilic acid in 1.5 l of water at a temperature of 60 °With portions add 1.2 mol appropriate harangued the IDA sulfonic acids. The reaction mixture is heated until complete conversion (approximately 1-6 hours) at a temperature of 60-80°and, if necessary, impose additional future the number of the sulfonic acid chloride. After cooling, the reaction mixture is poured into 500 ml of 6 M hydrochloric acid, the precipitated precipitate is filtered under vacuum and dried in a drying Cabinet at a temperature of 45°C. If the product is not crystalline precipitates, select by extraction with ethyl acetate.

Predecessor 1A: 4-fluoro-2-(quinoline-8-sulfonylamino)benzoic

According to the General method 1 from 5.0 g of 2-amino-4-fermenting acid and 8.8 g of 8-chinaincorporated obtain 7.6 g of target compound in a solid white color.

TPL: 248°C; MS (ES): 347 (M+1).

Predecessor 1b: 6-chloro-2-(quinoline-8-sulfonylamino)benzoic acid

(C)

According to the General method 1 from 5.0 g of 2-amino-6-chlorbenzoyl acid and 8.0 g of 8-chinaincorporated gain of 8.3 g of target compound in the form of solids.

TPL: 88°C; MS (ES): 363 (M+1).

Predecessor 1C: 3-chloro-2-(quinoline-8-sulfonylamino)benzoic

According to the General method 1 from 5.0 g of 2-amino-6-chlorbenzoyl acid and 8.0 g of 8-chinaincorporated obtain 4.1 g of C is a left join.

MS (ES): 363 (M+1).

According to the General method 1 synthesize, in particular, the following precursors (smfbl):

Table 1

General method 2

Turning sulfonilmocevinnah acids into the corresponding acid chlorides of the acids (A) using pentachloride phosphorus:

8 mmol of sulfoaluminate acid are suspended in 15 ml of anhydrous toluene and, at room temperature slowly bring 9.6 mmol of pentachloride phosphorus. The mixture is stirred for 3 hours at a temperature of 50°C, cooled to a temperature of 0°With the acid chloride of the acid is filtered under vacuum, washed with a small amount of toluene and dried in a vacuum drying Cabinet at a temperature of 45°C.

C) using thionyl chloride:

8 mmol of sulfoaluminate acid in 6 ml of thionyl chloride are heated for 3 hours at a temperature of 60°, concentrated and the residue evaporated twice together with toluene.

A General method 3A Obtain secondary amines by reductive amination

0.18 mol of the primary amine are dissolved in 200 ml of methanol, mixed with 0.09 mol of aldehyde, 0.18 mol cyanoborohydride sodium, and 0.18 mole of glacial acetic acid and stirred at room temperature for 6 hours.

The solution is concentrated and education is anywayt with ethyl acetate and washed twice with a solution of NaHCO 3. The organic phase is concentrated and the residue is distilled in high vacuum. In the case of secondary amines volatile ingredients evaporated volatile components, the residue is dissolved in diethyl ether/tetrahydrofuran, mixed with a solution of HCl in diethyl ether and precipitated precipitated hydrochloride is filtered under vacuum, washed with diethyl ether and dried. The resulting secondary amines without further purification used in reactions with sulfonamidophenylhydrazine or sulfonylbisbenzenamine acids.

Predecessor 3A: benzyl-(1-methyl-1H-imidazol-2-ylmethyl)Amin

According to the General technology 3A, and 19.4 g of benzylamine and 10 g of 2-formyl-1-methylimidazole gain of 20.5 g of the hydrochloride.

MS (ES+): m/z=202 (M+1).

Predecessor 3b: benzylpyridine-3-ylmethylamino

According to the General technology 3A, 4,32 g 3-pyridylmethylamine and 2.12 g of benzaldehyde, after distillation in the tube with ball extension at pressures of 0.1 mbar and a temperature of 130°receive 2.8 g secondary amine.

MS (ES+): m/z=199 (M+1).

Predecessor 3C: benzyl-(3-imidazol-1-ylpropyl)Amin

According to the General technology 3A, 12.5 g of 3-imidazol-1-iproplatin and 5.3 g of benzaldehyde, after distillation in the tube with ball extension at pressures of 0.1 mbar and temp is the temperature 130° To get 3.5 g secondary amine.

MS (ES+): m/z=216 (M+1).

According to the General method of operation FOR receive, inter alia, the following precursors (smfbl).

Table 2

The General procedure 3B Obtaining α-branched amines from ketones

To a solution of 200 mmol of hydroxylaminopurine and 200 ml of sodium acetate in 120 ml of water at a temperature of 30 °With added dropwise a solution of 67 mmol of the appropriate ketone in 120 ml of ethanol and heated until complete conversion (1-3 hours) at a temperature of 60°C. After cooling, the reaction mixture is diluted with water and dropped the oxime precipitates is filtered off under vacuum or, if necessary, isolated by extraction. The obtained product is dissolved in 100 ml of methanol, 100 ml of tetrahydrofuran and 10 ml of concentrated ammonia solution and in the presence of Raney Nickel at room temperature and normal pressure hydronaut until the cessation of hydrogen absorption. After filtering off the catalyst and concentrating the reaction mixture will receive the corresponding amine, which, if necessary, purified by chromatography.

Predecessor 31: 1-benzoylpropionic

According to the General method 3V, 10 g of 1-phenyl-2-butanone obtain 4.5 g of the target compound.

Predshestvennik: 1-pyridine-4-ylpropionic

According to the General method 3 from 10 g of 4-propenylidene obtain 10.2 g of the target compound.

Predecessor 3n: 1-pyridine-3-ylpropionic

According to the General method 3B of 1 g of 1-pyridine-3-improper-1-she get 0.9 g of the target compound.

Predecessor 3O: 1-cyclopropyl-1-phenylethylamine hydrochloride

a) N-(Cyclopropylmethyl)formamid

14.8 g (0.1 mol) of cyclopropylacetylene, 11,4 ml (0.3 mol) of formic acid and 20 ml (0.5 mol) of formamide are heated for 18 hours at a temperature of 160°C. After cooling, mixed with 100 ml of water and extracted twice with 50 ml diethyl ether. The ether phase is washed with 50 ml of 10%sodium carbonate solution, dried over sodium sulfate and concentrated. Get to 13.6 g (77.4 mmol) of a yellow oil.

b) 1-Cyclopropyl-1-phenylethylamine hydrochloride

of 13.6 g (77.4 mmol) of N-(Cyclopropylmethyl)formamide (see (a) in 100 ml of 2 N. hydrochloric acid is refluxed for 18 hours. After cooling, extracted with 2 times 50 ml of dichloromethane and the aqueous phase is concentrated. The residue is treated with 30 ml of 2-propanol, heated to boiling and during the night cooled in the refrigerator. Phase precipitate crystals of 1-cyclopropyl-1-phenylethylamine hydrochloride inthe number of 3.85 g (21 mmol) is filtered under vacuum and dried in a vacuum drying Cabinet.

Predecessor 3P: cyclopropylidene-2-ylmethylamino hydrochloride

a) Cyclopropylidene-2-ylmethylene

To 100 ml (160 mmol) of a solution of n-BuLi in 300 ml of diethyl ether at -70°C for 20 minutes was added dropwise a solution of 25 g (157,5 mmol) of 2-bromopyridine in 100 ml of diethyl ether. The solution is dark red is stirred for 5 hours and then mixed with 8.8 g (131 mmol) of the nitrile cyclopropanecarbonyl acid in 100 ml of diethyl ether. The mixture is stirred at -70°C for 30 minutes, warmed to room temperature and stirred for 30 minutes. Then add 15 g of Na2SO4×H2O and continue stirring for 1 hour. Red color solution is mixed with Na2SO4, filtered and concentrated. The product is distilled in the tube with ball expansion at a temperature of 75 to 120°and a pressure of 0.3 mbar in the form of a light yellow oil (18.6 g, 127 mmol) and stored at -18°C.

b) Cyclopropylidene-2-ylmethylamino hydrochloride

2,72 g (to 18.6 mmol) cyclopropylidene-2-ylmethylamino (see a) is dissolved in 35 ml of anhydrous methanol. At a temperature of 0°With portions add to 0.69 g (to 18.6 mmol) NaBH4. After keeping for 30 minutes at a temperature of 0°stirred for 2 hours at room tempera is ur, using 1 M HCl establish a pH value of 3, the methanol is removed in a rotary evaporator and the residue is dried by freezing. Obtain 8.8 g of cyclopropylmethyl-2-ylmethylamino hydrochloride, which is mixed with inorganic salts and boric acid.

Predecessor 3q: cyclopropylidene-3-ylmethylamino hydrochloride

a) Cyclopropylidene-3-ylmethylene

Accordingly, the method of obtaining predecessor 3P, 8.8 g (131 mmol) of the nitrile cyclopropanecarbonyl acid, 25 g (157,5 mmol) 3-bromopyridine and 173 mmol of n-BuLi in the form of a solution, after distillation in the tube with ball extension (temperature 130°C, a pressure of 0.2 mbar), allocate 7.5 g (51 mmol) of the imine in the form of a yellow oil.

b) Cyclopropylidene-3-ylmethylamino hydrochloride

Accordingly, the method of obtaining predecessor 3P, 7.5 g (51,5 mmol) imine (see a) and 1.9 g (51,4 mmol) NaBH4get 16,6 g cyclopropylmethyl-3-ylmethylamino hydrochloride, which is mixed with inorganic salts and boric acid.

Predecessor 3r:1-(5-methylfuran-2-yl)Propylamine

To 5 g (36 mmol) of 2-methyl-5-propiertary and 28.2 g (366 mmol) of ammonium acetate in 300 ml of methanol under stirring portions add 11,35 g (180 mmol) of cyanoborohydride sodium and subjected to interaction within 18 hours at room tempera is ur. The mixture was further concentrated, mixed with 200 ml of dichloromethane and the organic phase is washed with 3 times 50 ml of a solution of sodium bicarbonate, dried over Na2SO4and concentrate. Gain of 3.9 g (28 mmol) of amine in the form of oil is light yellow in color.

Predecessor 3s: 1-phenylprop-2-ynylamine hydrochloride

Connection receive, respectively, the method Bjorn M. Nilsson and others, J. Heterocycl. Chem., 26 (2), 269-275 (1989), on the basis of 1-phenyl-2-propionovogo spirit by means of Ritter reaction and subsequent hydrolysis under the action of hydrochloric acid.

Predecessor 3t:-cyclopropyl-C-(6-methoxypyridine-2-yl)methylamine

a) Cyclopropanecarboxaldehyde-O-benzyloxy

6.7 g (95,6 mmol) cyclopropanecarboxaldehyde together from 15.3 g (95,6 mmol) O-benzylhydroxylamine and 15.7 g (191,2 mmol) of sodium acetate in 250 ml of ethanol is stirred for 18 hours at room temperature, concentrated and mixed with Na2SO4. The residue is extracted with 3 times 50 ml of dichloromethane, the organic phase is concentrated and the crude product is purified by chromatography on silica gel. Get 5 g (28.6 mmol) of colorless liquid.

b) O-Benzyl-N-[cyclopropyl(6-methoxypyridine-2-yl)methyl]hydroxylamine

3,76 g (20 mmol) of 2-bromo-6-methoxypyridine in 20 ml of tetrahydrofuran at a temperature of -78°mixed with 8.8 ml (22 mmol) is-BuLi (2.5 M in toluene). After 30 minutes, this solution is dark red are added to a solution of 1.4 g (8 mmol) cyclopropanecarboxaldehyde-O-benzyloxy (see a) and 2.52 ml (20 mmol) of epirate of boron TRIFLUORIDE in 40 ml of toluene, which was stirred at a temperature of -78°C for 15 minutes. Stirred for 4 hours at a temperature of -78°slowly warmed to room temperature, mixed with water and then alkalinized with a saturated solution of Na2CO3. The organic phase is separated, the aqueous phase is extracted with toluene and the combined organic phases are dried over sodium sulfate and concentrated. The crude product is treated with 12 ml of acetonitrile, separating insoluble components and allocate product using preparative high performance liquid chromatography (HPLC) in the amount of 650 mg of oil red.

C)-cyclopropyl-C-(6-methoxypyridine-2-yl)methylamine

650 mg (2.3 mmol) of O-benzyl-N-[cyclopropyl-(6-methoxypyridine-2-yl)methyl]hydroxylamine (see b) is dissolved in 18 ml of glacial acetic acid and diluted with 18 ml of water. To this solution was added 3.3 grams of zinc dust and the suspension is subjected to interaction within 24 hours in an ultrasonic bath. The mixture is filtered through kieselguhr, optionally washed policecontributing acetic acid, the filtrate is partially concentrated and with us the seal of the sodium carbonate solution is brought to pH 11. Extracted with 3 times 100 ml of dichloromethane, dried over sodium sulfate and concentrated. Obtain 0.4 g (2.2 mmol) of product in the form of oil deep red color.

A General method 4A

Obtaining the amides of 2-aminobenzoic acid 2-nitrobenzoic acids

The corresponding 2-nitrobenzoic acid first, similarly to General methods 2 and 5, enter into interaction with the corresponding amine with getting amide 2-nitrobenzoic acid. Then 4 mmol of amide 2-nitrobenzoic acid in 50 ml of tetrahydrofuran and 50 ml of methanol in the presence of the number at the tip of the spatula 10%palladium-on-coal hydronaut at room temperature and normal pressure. Is sucked off from the catalyst, the reaction mixture was concentrated and receive the corresponding amide 2-aminobenzoic acid.

Thus synthesize, in particular, the following predecessor (see table 3).

Table 3

The General procedure 4B obtaining the amides of 2-aminoaniline acid of the anhydride

Stanovoy acid

A solution of 20 mmol of anhydride Stanovoy acid and 22 mmol of the corresponding amine in 75 ml of dimethylformamide is heated at a temperature of 60°With up to a full transformation. The reaction mixture is mixed with 100 ml of water and the product is filtered under vacuum or allocate by extraction.

Before estwanik 4b: (S)-2-amino-N-(1-phenylpropyl)benzamide

According to the General method 4B, 3 g of (S)-1-phenylpropylamine and

3.2 g of anhydride Stanovoy acid, after keeping within

2 hours at a temperature of 60°receive 3.4 g of the target compound.

General method 5

The interaction of sulfonamidophenylhydrazine with amines

To a solution of 0.66 mmol of the corresponding amine and 0.9 mmol of triethylamine in 3 ml of dichloromethane added 0.6 mmol of the corresponding sulfonamidophenylhydrazine and the mixture is stirred over night at room temperature. The reaction mixture was diluted with 5 ml water and 10 ml of dichloromethane and the organic phase is washed sequentially with 1 M hydrochloric acid and saturated solution of sodium bicarbonate. After drying over magnesium sulfate the solution was concentrated in vacuo and the product, if necessary, purified by preparative HPLC or column chromatography.

General method 6

Interaction sulfonilmocevinnah acids with amines

To a solution of 0.42 mmol appropriate sulfoaluminate 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 Rabba is by hydrochloric acid and a solution of sodium bicarbonate. After drying over magnesium sulfate and concentration in vacuo receive the corresponding amide, which, if necessary, purified by preparative HPLC.

General method 7 the Interaction of amides of 2-aminobenzoic acid with sulphonylchloride

To a solution of 0.2 mmol of the corresponding amide 2-aminobenzoic acid (precursor 4) and 0.6 mmol of pyridine in 5 ml of dichloromethane at a temperature of 0°With added dropwise a solution of 0.3 mmol of the corresponding sulphonylchloride in 2 ml of dichloromethane, and stirred overnight at room temperature. The organic phase is washed with water, diluted hydrochloric acid and a solution of sodium bicarbonate and the resulting crude product, if necessary, purified by preparative HPLC.

Example 1

(S)-N-(1-Phenylpropyl)-2-(quinoline-8-sulfonylamino)benzamid

a) 2-(Quinoline-8-sulfonylamino)benzoic acid

To a solution of 1.32 g of Na2CO3in 10 ml of water at a temperature of 60°With portions added 690 mg of Anthranilic acid. Stirred for 10 minutes at this temperature, then at a temperature of 70° With portions added to 1.25 g of 8-chinaincorporated. Stirred for 5 hours at a temperature of 70°With, then add the following 230 mg 8-chinaincorporated. Stirred for 2 hours PR is a temperature of 70° C, then the reaction mixture is cooled to room temperature. Using a 2H. aqueous HCl establish pH 1 and the suspension is stirred for one hour at room temperature. After that, the precipitate is filtered off, dried in high vacuum at a temperature of 60°and gain of 1.57 g of colorless amorphous solid.

MS (ESI): 329 (M+H)+.

b) 2-(Quinoline-8-sulfonylamino)benzoyl chloride

100 mg of 2-(quinoline-8-sulfonylamino)benzoic acid dissolved in 1 ml of SOCI2and refluxed for 4.5 hours. Volatile components are then removed under vacuum, the residue is treated with 10 ml of toluene and then the volatile components removed in vacuo. Receive 120 mg of the carboxylic acid, which without treatment is injected into the interaction further.

C) (S)-N-(1-Phenylpropyl)-2-(quinoline-8-sulfonylamino)benzamid

120 mg of 2-(quinoline-8-sulfonylamino)of benzoyl chloride are suspended in 4 ml of dichloromethane and at room temperature add 85 l of triethylamine. Then add a solution of 41 mg of (S)-1-phenylpropylamine in 2 ml dichloromethane and stirred for 18 hours at room temperature. The reaction mixture is diluted with 50 ml dichloromethane and washed 2 times with 20 ml of a saturated aqueous solution of sodium carbonate. The aqueous phase is then extracted with 20 ml dichloromethane, the combined body of the economic phase is dried over sodium sulfate and solvents removed under vacuum. By chromatography of the residue on silica gel using a mixture of tert-butyl methyl ether and diisopropyl ether in a ratio of 1:1 to obtain 77 mg of an amorphous solid.

Rf(MTB/DIP=1:1)=0,31; MS (ES): 446 (M+N)+.

The target compounds of examples 2-11 were synthesized analogously to the compound of example 1:

Example 2 (R)-N-(1-Phenylpropyl)-2-(quinoline-8-sulfonylamino)benzamid

Rf(MTB/DIP=1:1)=0,31; MS (ES): 446 (M+H)+.

Example 3 (R)-N-(1-Phenylethyl)-2-(quinoline-8-sulfonylamino)benzamid

Rf (MTB/DIP=1:1)=0,25; MS (ES): 432 (M+N)+.

Example 4 (S)-N-(1-Phenylethyl)-2-(quinoline-8-sulfonylamino)benzamid

Rf (MTB/DIP=1:1)=0,25; MS (ES): 432 (M+H)+.

Example 5 (S)-N-[1-(4-Chlorophenyl)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

Rf (MTB/DIP=1:1)=0,23; MS (ES): 466 (M+N)+

Example 6 (R)-N-[1-(4-Chlorophenyl)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

Rf (MTB/DIP=1:1)=0,23; MS (ES): 466 (M+N)+

Example 7 4-Chloro-N-pyrazin-2-ylmethyl-2-(quinoline-8-sulfonylamino)benzamid

Rf(ethyl acetate)=0,10; MS (ES): 454 (M+N)+.

Example 8 N-(2-Benzyloxyethyl)-5-fluoro-2-(quinoline-8-sulfonylamino)benzamid

Rf(MTB/DIP=1:1)=0,24; MS (ES): 480 (M+H)+

Example 9 N-(2-Benzyloxyethyl)-2-(quinoline-8-sulfonylamino)benemid

Rf(MTB)=0,36; MS (ES): 462 (M+H)+

Example 10

N- (2-Benzyloxyethyl)-5-methoxy-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 492 (M+N)+.

Example 115-fluoro-N-(2-phenoxyethyl)-2-(quinoline-8-sulfonylamino) benzamid

Rf(MTB/DIP=1:1)=0,29; MS (ES): 466 (M+H)+

Example 12

N-Benzyl-5-methoxy-N-(1-methyl-1H-imidazol-2-ylmethyl)-2-(quinoline-8-sulfonylamino) benzamid

a) Benzyl-(1-methyl-1H-imidazol-2-ylmethyl)Amin

of 19.4 g (0.18 mol) of benzylamine dissolved in 200 ml of methanol, mixed with 10 g (0.09 mol) of 2-formyl-1-methylimidazole, 11.4 g (0.18 mol) of cyanoborohydride sodium, as well as of 10.9 g (0.18 mol) of glacial acetic acid and stirred for 16 hours at room temperature. The solution is concentrated and treated with ethyl acetate and washed twice with a solution of sodium bicarbonate. The organic phase is dried, concentrated and still present benzylamine distilled off in high vacuum. The residue is dissolved in a mixture of diethyl ether and tetrahydrofuran in the ratio of 1:1 and mixed with a saturated solution of HCl in diethyl ether. Precipitated precipitated hydrochloride (20.5 g) is filtered under vacuum, washed with diethyl ether the m and dried in vacuum.

MS (ES): 202 (M+N)+

b) N-Benzyl-5-methoxy-N-(1-methyl-1H-imidazol-2-ylmethyl)-2-(quinoline-8-sulfonylamino)benzamid

66 mg of benzyl-(1-methyl-1H-imidazol-2-ylmethyl)amine is injected into the interaction as described in 1C) methodology and obtain 78 mg of the target compound as amorphous solid.

Rf(ethyl acetate)=0,09; MS (ES): 542 (M+N)+.

Example 13 N-(Phenylpyridine-3-ylmethyl)-2-(quinoline-8-sulfonylamino)benzamid

Similarly to the method of example 1, 120 mg vinylpyridin-3-ylmethylamino (Synthesis, 593 (1976)) enter into an interaction with 450 mg of 2-(quinoline-8-sulfonylamino)of benzoyl chloride and obtain 130 mg of an amorphous solid.

Rf(eteltetet)=0,29; MS (ES): 495 (M+N)+.

Example 14

N-Benzyl-N-pyridin-3-ylmethyl-2- (quinoline-8-sulfonylamino)benzamid

Similarly to the method of example 1, 99 mg of N-benzyl-N-(3-pyridylmethyl)amine (predecessor 3b) enter into interaction with 87 mg of 2-(quinoline-8-sulfonylamino)of benzoyl chloride and obtain 66 mg of an amorphous solid white color.

MS (ES): 509 (M+H)+

Example 15

N-Cyclohexyl-2-(quinoline-8-sulfonylamino)benzamid

Similarly to the method of example 1, 50 mg cyclohexylamine enter into interaction with 87 mg of 2-(quinoline-8-sulfonylamino)of benzoyl chloride and obtain 59 mg and Ortega solid white color.

MS (ES): 410 (M+N)+.

The target compounds of examples 16 to 44 was synthesized similarly to the method of example 1.

Example 16

N-(1-Benzylbutyl)-2-(quinoline-8-sulfonylamino)benzamid

The target compound is obtained from 2-(quinoline-8-sulfonylamino)of benzoyl chloride (example 1b) and 1-benzylpiperazine (predecessor to 31).

MS (ES): 460 (M+H)+

Example 17

(S)-5-Chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 469 (M+N)+

Example 18 N-(1-Pyridine-3-ylpropyl)-2-(quinoline-8-sulfonylamino)benzamid

The target compound is obtained from 2-(quinoline-8-sulfonylamino)of benzoyl chloride (example 1b) and 1-pyridin-3-iproplatin (predecessor 3n).

MS (ES): 447 (M+N)+.

Example 19

N-Benzyl-N-(1-methyl-1H-imidazol-2-ylmethyl)-2- (quinoline-8-sulfonylamino)benzamid

MS (ES): 512 (M+N)+

Example 20 N-Benzyl-1N-furan-2-ylmethyl--2- (quinoline-8-sulfonylamino) benzamid

MS (ES): 498 (M+N)+

Example 21

N-Cyclopropyl-N-pyridin-3-ylmethyl-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 459 (M+N)+.

Example 22 N-Benzyl-N-cyclopropyl-2-(quinoline-8-sulfonylamino)benzamid

M (ES): 458 (M+N) +.

Example 23

N-Benzyl-N-pyridine-2-ylmethyl-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 509 (M+N)+

Example 24 (R)-2-(Quinoline-8-sulfonylamino)-N-(1-p-triletal)benzamid

MS (ES): 446 (M+H)+

Example 25 N-[1-(4-Forfinal)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

F

MS (ES): 450 (M+H)+

Example 26

(R)-N-[1-(4-Methoxyphenyl)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 462 (M+N)+.

Example 27 N-(1-Methyl-1-phenylethyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 446 (M+N)+.

Example 28 N-[-Indan-1-yl-2- (quinoline-8-sulfonylamino) benzamid

MS (ES): 444 (M+N)

Example 29

[2-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)phenyl]amide of the quinoline-8-sulfonic

MS (ES): 444 (M+N)+.

Example 30

N-[2-(4-Forfinal)-1,1-dimethylethyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 478 (M+N)+.

Example 31 N-(1-Phenylbutyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 460 (M+N)+

Example 32 (S)-2-(Quinoline-8-sulfonylamino)-N-(1-p-triletal)benzamid

MS (ES): 46 (M+H) +

Example 33

(S)-N-[1-(4-Methoxyphenyl)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 462 (M+N)+.

Example 34

(S)-N-[1-(3-Methoxyphenyl)ethyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 462 (M+H)+

Example 35

(R)-N-(2-Hydroxy-1-phenylethyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 448 (M+N)+

Example 36

(S)-N-(1-(4-Cyclohexylethyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 438 (M+N)+.

Example 37 N-(2-Vinylcyclopropyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 444 (M+N)+

Example 38 N-[1-(2-Forfinal)propyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 464 (M+N)+

Example 39 N-(2-Methoxy-1-phenylethyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 462 (M+N)+

Example 40

N-[1-(4-Chlorophenyl)propyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 480 (M+N)+

Example 41

N-Cyclopropyl-N-phenyl-2-(quinoline-8-sulfonylamino) benzamid

MS (ES): 444 (M+N)+.

Example 42

N-(2-Isopropyl-5-methylcyclohexyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 466 (M+N)+.

Example 43 N-(Cyclopropylmethyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 458 (M+N)+.

Example 44 N-[1-(4-Forfinal)propyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 464 (M+N)+..

The target compounds of examples 45-51 was obtained from (S)-2-amino-N-(1-phenylpropyl)benzamide (predecessor 4b) according to the General method 7:

Example 45 (S)-N-(1-Phenylpropyl)-2-(thiophene-2-sulfonylamino)benzamid

MS (ES): 401 (M+N)+.

Example 46

2-(3,5-Dimethylisoxazol-4-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 414 (M+N)+.

Example 47 (S)-2-(Isoquinoline-5-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 446 (M+N)+.

Example 48

2-(Benzo[1,2,5]oxadiazol-4-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 437 (M+N)+..

Example 49

2-(5-Chlorothiophene-2-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 435 (M+N)+.

Example 50

2-(2-Methylinosine-8 sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 460 (M+N)+.

Example 51

(S)-2-(4-Chlorhydrin-8 sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 480 (M+N)+..

Example 52

(S)-5-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

a) 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid

The reaction mixture of 10.0 g (64 mmol) of 5-fluoro-2-aminobenzoic acid, 16.3 g (193 mmol) of sodium bicarbonate and 16.3 g of 8-chinaincorporated in 325 ml of water and 325 ml of ethyl acetate is stirred over night at room temperature. The aqueous phase is separated and extracted 1 time with 50 ml of ethyl acetate. Then the aqueous phase is acidified with concentrated hydrochloric acid and stirred for 2 hours. The precipitation is filtered under vacuum, dried in vacuum and obtain 19.5 g of 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid.

b) 5-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

Of 5.5 g (15.9 mmol) of 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid and 2.3 g (of 16.7 mmol) of (S)-phenylpropylamine, according to the General method 6, obtain 5.7 g of the target compound.

TPL: 163°C; MS (ES): 464 (M+N)+..

Sodium salt of (S)-5-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-

phenylpropyl)benzamide

To a solution of 5 g of compound of example 52 in 120 ml of ethyl acetate is added 2 ml of 30%aqueous solution of sodium methylate. Precipitated precipitated sodium salt is filtered off under vacuum and recrystallized from 25 ml of ethanol and gain of 3.3 g of the spruce connection.

The target compounds of examples 53-58 received from the corresponding precursors 1 and (S)-phenylpropylamine according to General method 6:

Example 53

(S)-5-Methoxy-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 476 (M+N)+.

Example 54

(S)-4-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 464 (M+N)+.

Example 55

(S)-6-Chloro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 480 (M+N)+..

Example 56

(S)-6-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 464 (M+N)+.

Example 57

(S)-3-Chloro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 480 (M+N)+..

Example 58

(S)-5-Chloro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

MS (ES): 480 (M+N)+.

The target compounds of examples 59-60 received from the corresponding precursors 1 and a*-cyclopropylbenzene (predecessor 3O) according to General method 6:

Example 59

N-(Cyclopropylmethyl)-5-fluoro-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 476 (M+N)+..

Example 60

N-(Cyclopropylmethyl)-5-methods the si-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 488 (M+H)+.

Example 61

(R)-5-fluoro-2-(quinoline-8-sulfonylamino)-N-(1-phenylpropyl)benzamide

The target compound was obtained analogously to example 52 (R)-phenylpropylamine.

MS (ES): 464 (M+N)+..

The target compounds of examples 62-63 received from the corresponding precursors 1 and 1-(5-methylfuran-2-yl)Propylamine (predecessor 3r) according to General method 5.

Example 62

N-[1-(5-Methylfuran-2-yl)propyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 450 (M+H)+.

Example 63

5-fluoro-N-[1-(5-methylfuran-2-yl)propyl]-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 468 (M+N)+..

The target compounds of examples 64-66 received from the corresponding precursors 1 and 1-phenylprop-2-ynylamine (predecessor 3s) according to General method 5.

Example 64 N-(1-Phenylprop-2-inyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 442 (M+N)+.

Example 65

5-fluoro-N-(1-phenylprop-2-inyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 460 (M+N)+..

Example 66

5-Methoxy-N-(1-phenylprop-2-inyl)-2-(quinoline-8-sulfonylamino)benzamid

MS (ES): 472 (M+N)+.

Example 67 N-(1-Phenylprop is)-2-(pyridine-2-sulfonylamino)benzamid

a) the acid chloride pyridine-2-sulfonic acids (similar to J. Org. Chem. 54, 2, 389-393 (1989))

60,4 mmol 2-mercaptopyridine dissolved in 100 ml of 20%hydrochloric acid and cooled to a temperature of 2-5°C. Then through the solution for 30 minutes pass chlorine gas so that the temperature does not exceed 5°C. Then add a further 50 ml of water. The aqueous phase is extracted with 3 times 100 ml of diethyl ether, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated. Output: 4.52 g (42%).

b) According to the General method 7, 100 mg (3) -2-amino-N- (1-phenylpropyl)benzamide and 70 mg of the acid chloride pyridine-2-sulfonic get 11 mg of N-(1-phenylpropyl)-2-(pyridine-2-sulfonylamino)benzamide in the form of a solid white color.

MS (ES): 396 (M+N)+..

Example 68

5-Methoxy-N-(1-phenylpropyl)-2-(pyridine-2-sulfonylamino)benzamid

According to the General method 1, from 100 mg of (S)-2-amino-5-methoxy-N-(1-phenylpropyl)benzamide and 62 mg of the acid chloride pyridine-2-sulfonic receive 30 mg of target compound in a solid white color.

MS (ES): 426 (M+N)+.

Example 69

5-Methoxy-2-(6-methylpyridin-3-sulfonylamino)-N-(1-phenylpropyl)benzamide

a) 6-Methylpyridin-3-acid (similar to J. Airier. Chem. Soc., 6, 2233-2236 (1943))

To 0,408 mol of oleum (20% free sulfur trioxide) under cooling with ice for 10 minutes, added dropwise to 0.1 mole of 2-picoline. Then add 0,843 mmol sulfate mercury and stirred for 24 hours at a temperature of 230°C. After that sulfuric acid is distilled off in vacuum. Adding 200 ml of acetonitrile, the product precipitates. It is filtered off under vacuum, optionally washed with a small amount of acetonitrile and dried at a temperature of 100°C. Output: 8,16 g (48%).

b) the acid chloride 6-methylpyridin-3-sulfonic acids (similar to J. Org. Sing., 54, 2, 389-393 (1989))

The mixture was 47.1 mmol 6-methylpyridin-3-sulfonic acids and of 56.5 mmol of pentachloride phosphorus suspended in 80 ml of phosphorus oxychloride and stirred for 24 hours at a temperature of 120°C. the Solution was concentrated in vacuo and cooled, carefully add water. The aqueous phase is then extracted with 3 times 100 ml of diethyl ether, dried over sodium sulfate and concentrated. Yield: 0.6 g (7%).

C) According to the General method 7 of 445 mg of (S)-2-amino-5-methoxy-N-(1-phenylpropyl)benzamide and 300 mg of the acid chloride 6-methylpyridin-3-sulfonic obtain 67 mg of 5-methoxy-2-(6-methylpyridin-3-sulfonylamino)-N-(1-phenylpropyl)benzamide in the form of a solid white color.

MS (ES): 440 (M+H)+.

Example 70

5-Methyl-N-[1-(5-methylfuran-yl)propyl]-2-(pyridine-2-sulfonylamino)benzamid

a) 5-Methyl-N-[1-(5-methylfuran-2-yl)propyl]-2-nitrobenzamide

2 g (10 mmol) of acid chloride of 2-nitro-5-methylbenzoic acid and 1.39 g (10 mmol) of 1-(5-methylfuran-2-yl)Propylamine (=predecessor 3r) with 1.3 ml DIPEA in 20 ml of dichloromethane is injected into the interaction at room temperature for 18 hours. The mixture is diluted with dichloromethane, washed, dried over sodium sulfate and purified by chromatography on silica gel. Get 1,14 g (3.8 mmol) of solid light yellow color.

b) 2-Amino-5-methyl-N-[1-(5-methylfuran-2-yl)propyl]benzamide

1,14 g (3.8 mmol) of 5-methyl-N-[1-(5-methylfuran-2-yl) propyl] -2-nitrobenzamide (see a) was dissolved in 20 ml of methanol, hydronaut when using 1 g of 10%palladium-on-coal at room temperature and normal pressure. After filtering and concentrating obtain 0.9 g (3.3 mmol) of solid substances.

C) 5-Methyl-N-[1-(5-methylfuran-2-yl)propyl]-2-(pyridine-2-sulfonylamino)benzamid

100 mg (from 0.37 mmol) 2-Amino-5-methyl-N-[1-(5-methylfuran-2-yl) propyl] benzamide (see b) and 117 mg (0.66 mmol) of 2-pyridinesulfonamide hydrochloride are dissolved in 1 ml of pyridine and allowed to interact for 18 hours at room temperature. The reaction mixture was concentrated and by preparative HPLC allocate, after freeze-drying, the compound of example 70 in the amount of 61 mg (0,12 IMO the ) in the form of triptoreline.

Similarly, the above examples also receive the following compounds (see table 4).

Table 4

1. The compounds of formula (I):

where

R(1) means

or

And means-CnH2n-;

n means 0, 1, 2, 3, 4 or 5;

D is a bond or-O-;

E. means-CmH2m-;

m means 0, 1, 2, 3, 4 or 5;

R(8) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or CpH2p-R(14);

p denotes 0, 1, 2, 3, 4 or 5;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms;

R(9) means a hydrogen atom or alkyl with 1, 2, 3,4, 5 or 6 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl, and phenyl, furyl, pyridyl, pyrazinyl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms;

R(12) denotes alkyl with 1, 2, 3 or 4 carbon atoms, quinil with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl;

R(13) meanspH2P-R(14);

p denotes 0, 1, 2, 3, 4 or 5;

R(15) means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms;

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

and their pharmaceutically acceptable salts.

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

R(1) means

And means-FromnH2n-;

n means 0, 1, 2 or 3;

E. means-FrommH2m-;

m means 0, 1, 2 or 3;

R(8) sachetto hydrogen, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(9) means a hydrogen atom or alkyl with 1, 2, 3 or 4 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, furyl, pyridyl, pyrazinyl, and phenyl, furyl, pyridyl, pyrazinyl, unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmaceutically acceptable salts.

3. The compounds of formula (I) p. or 2, where

R(1) means

And means-CnH2n-;

n means O or 1;

E means WithmH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms or CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of the other is, means a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmaceutically acceptable salts.

4. The compounds of formula (I) according to claims 1-3, where

R(1) means

And means-CnH2n-;

n means 0 or 1;

E. means-FrommH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl, metoxygroup, ethoxypropan;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group, with the standing of F, Cl, methyl;

R(4), R(5), R(6) denote a hydrogen atom, F, Cl, methyl or methoxy group;

R(7) means a hydrogen atom, F, Cl, methyl, ethyl or methoxy group;

and their pharmaceutically acceptable salts.

5. The compounds of formula (I) according to claim 1, where:

R(1) means

And means-CnH2n-;

n means 0, 1, 2 or 3;

D is a bond or-O-;

E. means-FrommH2m-;

m means 0, 1, 2 or 3;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(9) means a hydrogen atom or alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms;

R(12) denotes alkyl with 1, 2 or 3 carbon atoms, quinil with 1, 2 or 3 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmacologically acceptable salts.

6. The compounds of formula (I) according to claims 1 and/or 5, where

R(1) means

And means-FromnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-FrommH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(9) means a hydrogen atom, methyl or ethyl;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan;

R(12) denotes alkyl with 1, 2 or 3 carbon atoms, ethinyl, cyclopropyl, the dryer is l or heteroaryl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmacologically acceptable salts.

7. The compounds of formula (I) according to claims 1, 5 and/or 6, where

R(1) means

And means-FromnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-FrommH2m-;

m denotes 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(9) means a hydrogen atom, ethyl or methyl;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, metoxygroup, ethoxypropan;

R(12) denotes alkyl with 1, 2 or 3 carbon atoms, ethinyl, cyclopropyl, phenyl or heteroaryl

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, methyl or methoxy group;

and their pharmacologically acceptable salts.

8. The compounds of formula (I) according to claim 1, where

R(1) means

And means-CnH2n-;

n means 0, 1, 2 or 3;

D is a bond or-O-;

E. means-FrommH2m-;

m means 0, 1, 2 or 3;

R(9) means a hydrogen atom or alkyl with 1, 2, 3 or 4 carbon atoms;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, furanyl, pyridyl, pyrazinyl, and phenyl, furanyl, pyridyl, pyrazinyl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy with 1, 2, 3 or 4 carbon atoms;

R(13) implies CpH2p-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl or heteroa is l, moreover, the phenyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmaceutically acceptable salts.

9. The compounds of formula (I) according to claims 1 and/or 8, where

R(1) means

And means-CnH2n-;

n means 0 or 1;

D is a bond or-O-;

E means WithmH2m-;

m denotes 0 or 1;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(11) means phenyl, pyridyl, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl is from 1, 2, 3 or 4 carbon atoms, metoxygroup, ethoxypropan;

R(13) implies CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

and their pharmaceutically acceptable salts.

10. The compounds of formula (I) according to claims 1, 8 and/or 9, where

R(1) means

And means-FromnH2n-;

n means 0 or 1;

D is a bond or-O-;

E. means-FrommH2m;

m denotes 0 or 1;

R(9) means a hydrogen atom, methyl or ethyl;

R(10) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms, phenyl, naphthyl or heteroaryl, and phenyl, naphthyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(11) means phenyl, p is Ridel, pyrazinyl, and phenyl, pyridyl, pyrazinyl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl, metoxygroup, ethoxypropan;

R(13) implies CpH2p-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl;

R(4), R(5), R(6) independently of one another mean a hydrogen atom, F, Cl, methyl or methoxy group;

R(7) means a hydrogen atom, F, Cl, methyl, ethyl, methoxy group;

and their pharmaceutically acceptable salts.

11. The compounds of formula (I) according to claim 1, where

R(1) means

And means-CnH2n-;

n means 0, 1, 2, or C;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0, 1, 2 or 3;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(2) denotes the atom of water is ode;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted 1, 2 or 3 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

R(15) means cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms;

and their pharmaceutically acceptable salts.

12. The compounds of formula (I) according to claims 1 and/or 11, where

R(1) means

And means-FromnH2n-;

n means 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms;

R(4), R(5), R(6) R(7)independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

R(15) means cycloalkyl is 3, 4, 5, 6 or 7 carbon atoms;

and their pharmaceutically acceptable salts.

13. The compounds of formula (I) according to claims 1, 11 and/or 12, where

R(1) means

And means-FromnH2n-;

n means 0 or 1;

R(8) means a hydrogen atom, alkyl with 1, 2 or 3 carbon atoms orpH2P-R(14);

p denotes 0 or 1;

R(14) means phenyl or heteroaryl, and phenyl and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(2) means a hydrogen atom;

R(3) means heteroaryl, and heteroaryl unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, methyl;

R(4), R(5), R(6) independently of one another, mean a hydrogen atom, F, Cl, alkyl with 1, 2, 3 or 4 carbon atoms, a methoxy group, ethoxypropan;

R(7) means a hydrogen atom, F, Cl, methyl, ethyl or methoxy group;

R(15) means cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms;

and their pharmaceutically acceptable salts.

14. Pharmaceutical composition with blocking Kv1.5 channel effect, containing an effective amount of at least one of the compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts as biologically Akti the aqueous substances together with pharmaceutically acceptable carriers and additives, and if necessary, one or more other pharmacologically active substances.

15. The compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts, suitable for medicinal products with a blocking K+channel action for the treatment and prevention of mediated+channel diseases.

16. The compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts, suitable for medicinal products for treatment or prevention of cardiac arrhythmias, which can be eliminated by lengthening of the action potential.

17. The compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts, suitable for medicinal products for treatment or prevention of recurrent arrhythmias.

18. The compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts, suitable for medicinal product for the treatment or prophylaxis of supraventricular arrhythmias.

19. The compounds of formula (I) according to one or more of claims 1 to 13 and/or its physiologically acceptable salts, suitable for medicinal product for the treatment or prophylaxis of atrial fibrillation or atrial utter.

20. The pharmaceutical is Skye the composition according to 14, characterized in that it further comprises a beta-blocker as biologically active substances.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: chemistry of polymers, chemical technology.

SUBSTANCE: invention relates to sulfoxides or sulfones grafted on polymers, polymeric compositions, a method for grafting and method for stabilization of polymers. Invention describes polymers comprising a grafted compound of the formula (I): [R1-SOm]n-R-SOp-R2 (I) wherein total symbols have values given in cl. 1 of the invention claim and represents a composition comprising thereof, a method for grafting compound of the formula (I) on polymers and a method for stabilization of polymers. Polymers comprising grafted sulfoxides or sulfones possess high stability against oxidative, thermal, dynamic destruction caused by the light effect and/or destruction caused by ozone effect.

EFFECT: improved preparing method, improved and valuable properties of polymers.

14 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane of the formula (I): and its salts. Method involves direct reaction of 5-(4-fluorophenyl)pyridine-3-carbaldehyde of the formula (II): with 2-aminomethylchromane or its salts under reductive conditions resulting to formation of compound of the formula (I). Synthesized compound of the formula (I) is converted to one of its salts by treatment with acid. Method provides simplifying process based on decreasing amount of by-side products formed.

EFFECT: improved method of synthesis.

8 cl, 2 dwg, 4 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of 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.

32 cl, 1 tbl, 132 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

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

15 cl, 14 tbl, 118 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyridylcyanoguanidines of the general formula (I):

or their pharmaceutically acceptable salts wherein 1 means hydrogen atom; X means hydrocarbon (C1-C12)-biradical; Y means a bond or oxygen atom (O); Z means 5-10-membered aromatic heterocyclic radical optionally substituted with hydroxy-group under condition that R1 is not bound to nitrogen atom in pyridyl ring. Compounds of the formula (I) and their salts possess antiproliferative activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 1 tbl, 7 ex

FIELD: organic chemistry, polymers, chemical technology, catalysts.

SUBSTANCE: invention relates to ligands, different precursors of catalysts and catalytic systems prepared from these ligands and designated for the oligomerization reaction of ethylene to synthesize linear alpha-olefins with high yield and selectivity. Also, invention relates to a method for synthesis of indicated alpha-olefins, namely, to mixed bis-iminepyridine ligands of the formula (II) given in the invention description wherein indicated atoms form cyclopentadienyl or aryl moiety of π-coordinated metal complex, to mixed complexes of bis-iminepyridine-MXn comprising ligand of the formula (II) wherein M represents metal atom chosen from Fe or Co; n = 2 or 3; X represents halide atom, (C1-C30)-hydrocarbon radical optionally comprising one or more functional inert groups comprising heteroatom and chosen from fluoride, chloride, silanes, stannans, ethers and amines, alkoxides, amides or hydrides, to mixed complexes [bis-iminepyridine MYp . Ln+][NC-]q comprising ligand of the formula (II) wherein Y represents ligand that is able to incorporation of olefin; M represents metal atom chosen from Fe or Co; NC- represents non-coordinated anion; p + q = 2 or 3 in accordance of formal degree of oxidation of indicated metal atom; L represents the Lewis neutral donor molecule; n = 0, 1 or 2, and to a method for synthesis of alpha-olefins from ethylene with using indicated complexes.

EFFECT: valuable properties of ligands and systems.

6 cl, 2 tbl, 4 dwg, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formulas (1) , (2) , (3) or (4) , or isomers of compounds of formulas (2) and (3) wherein symbol values are determined in the invention claim. Also, invention relates to their pharmaceutically acceptable salts showing the improved solubility in aqueous media and improved bioavailability wherein indicated compounds possess the inhibitory activity with respect to secretion of gastric acid.

EFFECT: valuable medicinal properties of compounds.

35 cl, 44 sch, 4 tbl, 165 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

28 cl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1):

and their salts wherein ring A comprises optionally heteroatom oxygen (O); dotted lines represent the optional unsaturation; R1 represents (C1-C4)-alkoxy-group; R2 and R3 represent independently hydrogen atom (H), optionally halogenated (C1-C4)-alkyl, optionally substituted aromatic group, or R2 and R3 in common can form substituted or unsubstituted 5-7-membered ring condensed with ring E; k = 0-4; L1 represents a covalent bond or (C1-C6)-alkyl optionally comprising nitrogen atom (N); X represents unsubstituted or substituted carbon © atom or N, or represents O or sulfur (S) atom; Ar represents phenylene; each n = 0-2 independently; each R represents independently H or (C1-C6)-alkyl; Y represents optionally substituted aromatic or heteroaromatic group or 5-11-membered heterocyclic group comprising 1-4 heteroatoms cgosen from N, O and S that are bound with chemokine receptors comprising CXCR4 and CCR5, and elicit the protective affect against damage of host-cells by human immunodeficiency virus (HIV).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein X means -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO, -SO2; m = 1; A represents a direct bond; R1 means hydrogen atom (H); R2 and R3 are chosen independently from H, (C1-C6)-alkyl, heterocycloalkyl, phenyl, heteroaryl, phenylalkyl, phenylheteroalkyl, heteroarylalkyl, heterocycloalkylalkyl; R4 represents H; R5 represents monocyclic, bicyclic or tricyclic group. Also, invention describes a pharmaceutical composition and using compounds in preparing a medicinal agent for using in treatment of diseases or states mediated by one ore more enzymes representing metalloproteinase. Compounds of the formula (I) are useful as inhibitors of metalloproteinases being especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

14 cl, 16 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

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

15 cl, 1 tbl, 9 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

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