Substituted beta-carbolines, method for their preparing

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to derivatives of carboline of the general formula (I): wherein R3 means hydrogen atom (H), hydroxyl (OH), -O-(C1-C6)-alkyl; R4 means -N(R17)2 wherein R17 means hydrogen atom (H), (C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -S(O)y-R14 wherein y = 0, 1 or 2; R14 means (C1-C6)-alkyl, phenyl substituted with halogen atom; or R means amino-group (-NH2), -NH-C(O)-R15 wherein R15 means pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxaline, thiophene possibly substituted with -CF3 or (C1-C6)-alkyl; (C3-C7)-cycloalkyl, -N(R13)2 wherein R12 means hydrogen atom (H) or phenyl under condition that -N(R13)2 doesn't mean -NH2; phenyl possibly substituted with (C1-C6)-alkyl, -CF3 if two substituted at phenyl form dioxalane ring; R5 means hydrogen atom (H), or R and R5 in common with nitrogen atom (N) form a heterocycle. Also, invention describes a method for their preparing. Compounds of the formula (I) are suitable for preparing medicinal agents used in prophylaxis and treatment of diseases wherein the enhanced activity of 1 κB is involves.

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

6 cl, 2 tbl, 83 ex

 

The invention relates to new substituted beta-carbolines, method of their production and their use as pharmaceuticals.

In U.S. patent 4631149 described beta-carboline that can be used as antiviral, antibacterial and anticancer agents. In U.S. patent 5604236 described derivatives of beta-carbolines, which containing acid group, used as inhibitors of the synthesis of thromboxane. In German patent 19807993 A1 describes derivatives of beta-carbolines, which used for the treatment of TNFα dependent diseases.

NFkB is a heterodimeric transcription factor that can activate a large number of genes, coding, inter alia, proinflammatory cytokines, such as IL-1, IL-2, TNFα or IL-6. NFkB is present in the cytosol of cells, creating complex with its existing in nature inhibitor lkB. Stimulation of cells, such as cytokines leads to proliferation and subsequent proteolytic degradation of the lkB. Such proteolytic degradation leads to activation of NFkB, which subsequently migrates into the cell nucleus and there activates a large number of proinflammatory genes.

Diseases, such as rheumatoid arthritis (in the case of inflammation, osteoarthritis, asthma, myocardial infarction, Alzheimer's disease or atherosclerosis, NFkB is activated at a level that exceed the statutory normal degree. Inhibition of NFkB successfully in the treatment of cancer, because here it is used to enhance the cytostatic therapy. It was possible to demonstrate that drugs, such as glucocorticoids, salicylates, or gold salts, which are used in rheumatoid therapy, come inhibiting image in different points in NFkB-activating signal circuit or directly interfere with the transcription of genes. Degradation lkB is the first stage in the specified signaling cascade. This phosphorylation is regulated by specific kinase lkB. To date, no known inhibitors that specifically inhibit kinase lkB.

When trying to get active compounds for the treatment of rheumatoid arthritis (in the case of inflammation, osteoarthritis, asthma, myocardial infarction, Alzheimer's disease, cancer (increased cytotoxic effect) or atherosclerosis, it was found that benzimidazole according to the invention are strong and highly selective inhibitors of kinase lkB.

Thus, the invention relates to compounds of formula I

and/or stereoisomeric forms of the compounds of the formula I and/or physiologically acceptable salts of the compounds of formula I, where B6B7B8and In9independently selected from the group consisting whom her from the carbon atom and nitrogen atom, where B6B7In8and In9together represent no more than two nitrogen atoms at the same time; where

in case (a)

the substituents R1, R2and R3, independently of one another, represent

1.1 hydrogen atom,

1.2 halogen

1.3-CN

1.4-COOH,

1.5-NO2,

1.6-NH2,

1.7-O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another,

1.7.1-phenyl, which is unsubstituted or mono-to Penta-substituted, by halogen or-O-(C1-C4)-alkyl,

1.7.2 halogen,

1.7.3-NH2,

1.7.4-HE,

1.7.5-COOR16where R16represents a hydrogen atom or - (C1-C10)-alkyl,

1.7.6-NO2,

1.7.7-S(O)y-R14where y is zero, 1 or 2, R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or

-N(R13)2,

where R13independently of one another represent a hydrogen atom, phenyl, -(C1-C10)-alkyl, -C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-NH-(C1-C7)-alkyl, -C(O)-O-phenyl, -C(O)-NH-phenyl, -C(O)-O-(C1-C7)-alkyl, -S(O)y-R14where R14and y are as defined above, and where the alkyl or phenyl in each of the case are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

1.7.8-O-phenyl, where phenyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

1.7.9 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

1.7.10 -(C3-C7-cycloalkyl or

1.7.11 =O,

1.8-N(R13)2where R13is as defined above in 1.7.7,

1.9-NH-C(O)-R15where R15represents a

1.9.1 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

where the specified radicals is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, CF3, benzyl or -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another as defined above in 1.7.1-1.7.11,

1.9.2 -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or-O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

1.9.3 - (C3-C7-cycloalkyl,

1.9.4-N(R13)2where R13is as defined above in 1.7.7,

1.9.5 phenyl, where phenyl is unsubstituted or mono-to Penta-substituted independently of one another, as defined above in 1.7.1-1.7.11, -O-(C1-C10)-alkyl, CN, CF3- (C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or two substituent of the phenyl radical to form a dioxolane ring,

1.10 S(O)y-R14where R14and u are as defined in 1.7.7 above,

1.11-C(O)-R12where R12represents phenyl or -(C1-C7)alkyl, where the alkyl or phenyl are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

1.12-C(O)-O-R12where R12is the same as defined in 1.11 above,

1.13 -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined by the United use in 1.7.1-1.7.11,

1.14-O-(C1-C6)-alkyl-O-(C1-C6)-alkyl,

1.15-O-(C0-C4)-alkyl-(C3-C7-cycloalkyl,

1.16 -(C1-C4)-alkyl-N(R13)2where R13is as defined above in 1.7.7

1.17-CF3or

1.18-CF2-CF3,

R4represents a

1. -(C1-C4)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

2. -CF3,

3. -CF2-CF3,

4. -CN

5. -S(O)y-R14where R14and u are as defined in 1.7.7 above,

6. -NH2,

7. -O-(C1-C10)-alkyl, where alkyl is mono-to Penta-substituted, independently of one another,

7.1-phenyl, which is unsubstituted or mono-to Penta-substituted by halogen or-O-(C1-C4)-alkyl,

7.2 halogen,

7.3-NH2,

7.4-HE,

7.5-COOR16where R16represents a hydrogen atom or -(C1-C10)-alkyl,

7.6-NO2,

7.7-S(O)y-R14where y is zero, 1 or 2, R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or-N(R13)2,

where R13, independently of one another, represents a hydrogen atom, Anil, -(C1-C10)-alkyl, -C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-NH-(C1-C7)-alkyl, -C(O)-O-phenyl, -C(O)-NH-phenyl, -C(O)-O-(C1-C7)-alkyl, -S(O)y-R14where R14and y are as defined above,

and where the alkyl or phenyl in each case are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or

R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

7.8-O-phenyl, where phenyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

7.9 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, thiophene, 2-isoxazoline, isothiazoline, 2-isothiazoline or thiomorpholine,

7.10 -(C3-C7-cycloalkyl or

7.11 =O,

8. -N(R17)2where R17, independently of one another, represents a hydrogen atom, phenyl, -(C1-C10)-alkyl, -C(O)-phenyl, -C(O)-NH-(C1-C7)alkyl, -C(O)-(C1-C10)-alkyl, -C(O)-O-phenyl, -C(O)-NH-phenyl, -C(O)-O-(C1-C7)-alkyl, -S(O)y-R14where R14and y are as defined above,

and RG is alkyl or phenyl in each case are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or

R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

9. -NH-C(O)-R15where R15represents a

9.1 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

where the specified radicals is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, -CF3, benzyl or -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

9.2 -(C1-C10)-alkyl, where alkyl is mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or-O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

9.3 -(C3-C7-cycloalkyl,

9.4-N(R13)2where R13is as defined above in 1.7.7, provided that-N(R13)2is not-NH2or

9.5 phenyl, where phenyl is unsubstituted or MES is-Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, -O-(C1-C10)-alkyl, -CN, -CF3, - (C1-C10) -alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or two substituent of the phenyl radical to form a dioxolane ring,

10. -C(O)-R12where R12represents phenyl or -(C1-C7)alkyl, where the alkyl or phenyl is mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

11. -C(O)-O-R12where R12is the same as defined in 10. above,

12. -O-(C1-C6)-alkyl-O-(C1-C6)-alkyl,

13. -O-(C0-C4)-alkyl-(C3-C7-cycloalkyl, or

14. -(C1-C4)-alkyl-N(R13)2where R13is as defined above in 1.7.7,

R5represents a

1. a hydrogen atom,

2. -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.4,

3. -C(O)-R9where R9represents a

-NH2, -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.4, or-N(R13)2where R13is as defined above in 1.7.7, or

4. -S(O) 2-R9where R9is as defined in 3 above,

or

R4and R5together with the atom to which they are attached, form a heterocycle, or

R3and R5together with the atom to which they are attached, form a heterocycle containing an additional oxygen atom in the ring, and

R6, R7and R8independently of one another represent a hydrogen atom or methyl, or in the case of (b)

the substituents R1, R2and R4independently of one another are as defined above in 1.1-1.18 in the case (a)

R3represents a

1. -CF3

2. -CF2-CF3,

3. -CN

4. -COOH,

5. -NO2,

6. -NH2,

7. -O-(C1-C10)-alkyl, where alkyl is mono-to Penta-substituted, independently of one another,

7.1-phenyl, which is unsubstituted or mono-to Penta-substituted by halogen or-O-(C1-C4)-alkyl,

7.2 halogen,

7.3-NH2,

7.4-HE,

7.5-COOR16where R16represents a hydrogen atom or

-(C1-C10)-alkyl,

7.6-NO2,

7.7-S(O)y-R14where y is zero, 1 or 2, R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1.-1.7.11, amino or-N(R13)2,

where R13, independently of one another represents hydrogen atom, phenyl, -(C1-C10)-alkyl, -C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-NH-(C1-C7)-alkyl, -C(O)-O-phenyl, -C(O)-NH-phenyl, -C(O)-O-(C1-C7)-alkyl,

-S(O)y-R14where R14and y are as defined above,

and where the alkyl or phenyl in each case are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11

or

R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

7.8-O-phenyl, where phenyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

7.9 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

7.10 -(C3-C7-cycloalkyl or

7.11 =O,

8. -N(R13)2where R13is the same as defined in 1.7.7 above,

9. -NH-C(O)-R15where R15represents a

9.1 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, the truck is and, the research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

where the specified radicals is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, -CF3, benzyl or -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 1.7.1-1.7.11

9.2 -(C1-C10)-alkyl, where alkyl is mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or-O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11

9.3 -(C3-C7-cycloalkyl,

9.4-N(R13)2where R13is as defined above in 1.7.7, or

9.5 phenyl, where phenyl is unsubstituted or mono-to Penta-elementnum, independently of one another, as defined above in 1.7.1-1.7.11, -O-(C1-C10)-alkyl, -CN, -CF3, -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 1.7.1-1.7.11, or two substituent of the phenyl radical to form a dioxolane ring,

10. -S(O)y-R14where R14and u are as defined in 1.7.7 above,

11. C(O)-R 12where R12represents phenyl or -(C1-C7) alkyl, where the alkyl or phenyl are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

12. -C(O)-O-R12where R12is the same as defined above 11,

13. -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11,

14. -O-(C1-C6)-alkyl-O-(C1-C6)-alkyl,

15. -O-(C0-C4)-alkyl-(C3-C7-cycloalkyl, or

16. -(C1-C4)-alkyl-N(R13)2where R13is as defined above in 1.7.7,

R5is the same as R5in case a) above,

R6, R7and R8independently of one another represent a hydrogen atom or methyl.

Preferred are the compounds of formula I, where in the case (a)

each of the B6B7B8and In9represents a carbon atom,

R1, R2and R3independently of one another represent hydrogen atom, halogen, cyano, nitro, amino, -O-(C1-C7)-alkyl, where alkyl is unsubstituted or substituted by phenyl,

-CF2-CF3, -CF3, -N(R18)2,

where R18, independently of one another, represents the ATO is hydrogen, -(C1-C7)-alkyl, phenyl, -C(O)-phenyl, -C(O)- pyridyl, -C(O)-NH-phenyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-alkyl or-C(O)-(C1-C7)-alkyl, where alkyl, pyridyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1.-1.7.11, or R18together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

S(O)y-R14,

where y is zero, 1 or 2, and R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or-N(R18)2where R18is the same as defined above, where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

-C(O)-O-R12where R12is the same as defined above,

R4represents cyano, amino, -O-(C1-C7)-alkyl, where the alkyl is substituted by phenyl; -CF2-CF3, -CF3, -N(R18)2,

where R18, independently of one another represents hydrogen atom, -(C1-C7)-alkyl, phenyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-NH-phenyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-alkyl or-C(O)-(C1-C7)-alkyl, where alkyl, pyridyl or phenyl are unsubstituted, ikimono-tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or R18together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

S(O)y-R14,

where y is zero, 1 or 2, and R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or-N(R18)2where R18is the same as defined above,

where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

-C(O)-O-R12where R12is the same as defined above,

R6, R7and R8independently of one another represent a hydrogen atom or methyl,

R5is as defined in paragraph 1 of the claims,

or in the case of (b)

the substituents R1, R2and R4independently of one another represent hydrogen atom, halogen, cyano, nitro, amino, -O-(C1-C7)-alkyl, where alkyl is unsubstituted or substituted by phenyl,

-CF2-CF3, -CF3, -N(R18)2,

where R18, independently of one another, represents a hydrogen atom, -(C1-C7)-alkyl, phenyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-NH-phenyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-al is silt or-C(O)-(C 1-C7)-alkyl, where alkyl, pyridyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or R18together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

S(O)y-R14,

where y is zero, 1 or 2, and R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or-N(R18)2where R18is the same as defined above,

where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

-C(O)-O-R12where R12is the same as defined above, R3represents a cyano, nitro, amino, -O-(C1-C7)-alkyl, where the alkyl is substituted by phenyl;

-CF2-CF3, -CF3, -N(R18)2,

where R18, independently of one another, represents a hydrogen atom, - (C1-C7)-alkyl, phenyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-NH-phenyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-alkyl or-C(O)-(C1-C7)-alkyl, where alkyl, pyridyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or R18together with the nitrogen atom, is which it is attached, form a heterocycle having 5 to 7 ring atoms,

S(O)y-R14,

where y is zero, 1 or 2, and R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in 1.7.1-1.7.11, amino or-N(R18)2where R18is the same as defined above,

where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

-C(O)-O-R12where R12is the same as defined above,

R6, R7and R8independently of one another. represent a hydrogen atom or methyl, and

R5is the same as defined above.

Even more preferred are the compounds of formula (II)

and/or a stereoisomeric form of the compounds of formula II, and/or a physiologically acceptable salt of the compounds of formula II, where

R1and R2, independently of one another, represent a hydrogen atom, halogen, cyano, amino, -O-(C1-C4)-alkyl, nitro, -CF3, -CF2-CF3, S(O)y-R14where y is 1 or 2, R14represents amino, -(C1-C7)-alkyl or phenyl, which is unsubstituted or mono-to tri-substituted as defined above for substituents in 1.7.1-1.7.11,

-N(R18)sub> 2where R18, independently of one another, represents a hydrogen atom, - (C1-C7)-alkyl-C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-NH-(C1-C4)-alkyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-alkyl or -(C1-C10)-alkyl, where pyridyl, alkyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

R18together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

R3represents cyano, amino, -O-(C1-C4)-alkyl, nitro, -CF3, -CF2-CF3, S(O)y-R14where y is 1 or 2, R14represents amino, -(C1-C7)-alkyl or phenyl, which is unsubstituted or mono-to tri-substituted as defined above for substituents in 1.7.1-1.7.11,

-N(R18)2where R18, independently of one another, represents a hydrogen atom, -(C1-C7)-alkyl-C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-O-phenyl, -C(O)-NH-(C1-C4)-alkyl, -C(O)-O-(C1-C4)-alkyl or -(C1-C10)-alkyl, where pyridyl, alkyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.11, or

R18together with the nitrogen atom to which it is connected is inen, form a heterocycle having 5 to 7 ring atoms,

R5isone hydrogen atom, -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.4,

-C(O)-R9or-S(O)2-R9where

R9represents -(C1-C10)-alkyl, -O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 1.7.1-1.7.4, or phenyl, which is unsubstituted or mono-to tri-substituted as defined in 1.7.1-1.7.11, or-N(R18)2where R18is the same as defined above.

Most preferred are the compounds of formula (II), where

R1represents bromine, -CF3or chlorine,

R2represents a hydrogen atom or-O-(C1-C2) alkyl,

R3represents-N(R18)2where R18, independently of one another, represents a hydrogen atom, -N-C(O)-pyridyl, -C(O)-phenyl, (C1-C7)-alkyl, -C(O)-(C1-C4)-alkyl or-C(O)-O-(C1-C4)-alkyl, where the alkyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another by halogen or-O-(C1-C2) alkyl, and

R5represents a hydrogen atom, methyl or-S(O2)-CH3.

The con is specific preferred compounds and their pharmaceutically acceptable salts, representing illustration of the compounds of the invention include the following:

Especially preferred are compounds

N-(6-Chloro-N-β-carbolin-8-yl)nicotinamide, and bismesylate salt, bestreferat.ru salt and bishydroxamic salt of N-(6-chloro-N-β-carbolin-8-yl)nicotinamide, N-(6-chloro-N-β-carbolin-8-yl)-3,4-diflorasone and cleaners containing hydrochloride salt of N-(6-chloro-N-β-carbolin-8-yl)-3,4-differentated, N-(6-chloro-7-methoxy-N-β-carbolin-8-yl)nicotinamide, and bestreferat.ru salt and bishydroxamic salt of N-(6-chloro-7-methoxy-N-β-carbolin-8-yl)nicotinamide and 6-chloro-N-(6-chloro-N-β-carbolin-8-yl)nicotinamide.

The term "alkyl" by itself or as part of another substituent, unless otherwise stated, means linear or branched hydrocarbon radical having from 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, pentyl, hexyl, heptyl, nonyl, octyl, decanol, or cycloalkyl having from 3 to 7 atoms, such as cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl.

The term "alkoxy" by itself or as part of another substituent, unless otherwise stated, means-O-alkyl or O-substituted alkyl.

The term "heterocycle having 5 to 7 ring atoms" snakedriver monocyclic saturated system, having from 5 to 7 ring members, which contains 1, 2 or 3 heteroatoms as ring members. Examples of heteroatoms are N, O and S. Examples of the term "heterocycle having 5 to 7 ring atoms are pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazin, oxolan, imidazolin, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazolin, thiophene or thiomorpholine.

The term "aryl" by itself or as part of another substituent, unless otherwise stated, refers to an organic radical derived from an aromatic molecule by removing one atom, such as phenyl, pyridyl, thiazolyl, morpholinyl and naphthyl.

The term "substituted alkyl" means an alkyl radical substituted in one or more positions by one or more radicals from the group comprising halogen, nitro, sulfo, amino, substituted amino, carboxyl, alkoxy, -O-aryl, -O-substituted aryl, and hydroxyl.

The term "substituted aryl" means aryl radical substituted in one or more positions by one or more radicals from the group comprising halogen, alkyl, substituted alkyl, nitro, sulfo, amino, alkoxy, aryl, substituted aryl, or hydroxyl groups, preferred is an aryl radical substituted in 1-3 positions 1-3 gr is pami.

The term "substituted amino" refers to-N(R13)2where R13, independently of one another represents hydrogen atom, sulfo, alkyl, aryl, -C(O)-alkyl, -C(O)-NH-aryl, -C(O)-O-aryl, -C(O)-O-alkyl or-C(O)-O-aryl, where each alkyl or aryl may be independently substituted.

The term "sulfo" refers to-S(O)y-R14where R14represents alkyl, aryl, substituted aryl, substituted alkyl, amino or substituted amino and y is zero, one, or two.

The term "halogen" is to be understood as meaning fluorine, chlorine, bromine or iodine.

The term "-(C1-C4)-alkyl" is to be understood as meaning hydrocarbon radicals, the carbon chain which is linear or branched and contains from 1 to 4 carbon atoms.

The invention also relates to a method for producing compounds of the formula I and/or stereoisomeric forms of the compounds of the formula I and/or physiologically acceptable salts of the compounds of formula I, which includes

a) interaction of the compounds of formula III

where each of R1, R2, R3, R4B6In7B8and In9is the same as defined in formula I, with a compound of formula IV

in the presence of acid, converting the compound of formula V

and its interaction with hydrazinehydrate and then with formaldehyde (R6represents N or R6CHO, obtaining the compounds of formula VI

and its oxidation to obtain the compounds of formula VII

where R1-R4and In6In9are as defined in formula I, and R5represents a hydrogen atom, or

b) interaction of the compounds of formula VII with the compound of the formula VIII

where Y is halogen or-HE, and R5is as defined for formula I, or

c) separation obtained by methods a) or b) compounds of the formula I, which on the basis of their chemical structures exist in enantiomeric forms, the pure enantiomers by salt with enantiomerically pure acids or bases, and chromatography on chiral stationary phases, or a derivation with a chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers and the removal of the chiral auxiliary groups, or

d) isolation of the compounds of formula I, obtained by methods a), b) or C) or in free form or in the presence of acidic or basic groups, converting in a physiologically PR is acceptable salt.

Obtaining physiologically acceptable salts of the compounds of the formula I is capable of salt formation, including their stereoisomeric forms, carried out in a known manner. With basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides, and ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine or triethanolamine or, alternatively, the basic amino acids, for example lysine, ornithine or arginine, carboxylic acids form stable alkali metal salts, alkaline earth metal or optionally substituted ammonium salts. If the compounds of formula I contain basic groups, when using strong acids can also be obtained a stable acid salt additive. To do this, are suitable as inorganic and organic acids, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, benzolsulfonat, p-toluensulfonate, 4-bromobenzophenone, cyclohexanesulfonyl, triftormetilfullerenov, acetic, oxalic, tartaric, succinic or triperoxonane acid.

The invention also relates to medicines, which include an effective amount of at least one of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, and/or neoba is consequently stereoisomeric forms of the compounds of the formula I together with a pharmaceutically suitable and physiologically acceptable excipients, additive and/or other active compounds and auxiliaries.

On the basis of their pharmacological properties the compounds according to the invention are suitable for the prevention and treatment of all these diseases, which included increased activity of kinase lkB. They include, for example, asthma, rheumatoid arthritis (in the case of inflammation, osteoarthritis, Alzheimer's disease, cancer (enhanced activity cytotoxic therapy) myocardial infarction or atherosclerosis.

Medicinal product according to the invention are usually administered orally, parenterally or rectally, by inhalation or percutaneous injection.

The invention also relates to the use of compounds of formula I

and/or stereoisomeric forms of the compounds of the formula I and/or physiologically acceptable salts of the compounds of the formula I, to obtain drugs for the prevention and treatment of diseases, which included increased activity of kinase lkB, where B6In7In8and In9independently selected from the group consisting of carbon atom and nitrogen atom, and where B6In7In8and In9together represent no more than two nitrogen atoms simultaneously; where the substituents R1, R2, R3, R4and R8regardless od the n from each other, are

1. a hydrogen atom,

2. halogen,

3. HE

4. -CN

5. sulfo,

6. -NO2,

7. -NH2,

8. alkoxy,

9. substituted amino,

10. -NH-C(O)-R15where R15represents a heterocycle having 5 to 7 ring atoms, alkyl, aryl, substituted aryl or substituted alkyl,

11. -COOH,

12. -O-R10where R10represents alkyl, substituted alkyl or aryl,

13. -C(O)-R12where R12represents alkyl, substituted alkyl or aryl,

14. -C(O)-O-R12where R12is the same as defined above,

15. aryl,

16. -O-aryl,

17. substituted aryl,

18. -O-substituted aryl,

19. alkyl,

20. substituted alkyl,

21. -CF3or

22. -CF2-CF3,

provided that at least one of R1, R2, R3, R4and R8is not a hydrogen atom,

R5represents a

1. a hydrogen atom,

2. alkyl,

3. alkyl radical substituted in one or more positions by one or more radicals, halogen, amino or hydroxyl,

4. -C(O)-R9or

5. -S(O)2-R9where

R9is

a) alkyl,

b) alkyl radical substituted in one or more positions by one or more radicals, halogen, amino or hydroxyl,

c) aryl,

d) aryl Radik is l, substituted in one or more positions by one or more radicals, halogen, amino or hydroxyl,

e) -NH2,

f) alkoxy or

d) substituted amino, and

R6and R7independently of one another represent

1. a hydrogen atom,

2. halogen,

3. HE

4. methyl,

5. -O(C1-C10) alkyl, where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another

5.1. the aryl,

5.2. halogen,

5.3. -NO2,

5.4. sulfo,

5.5. -COOH,

5.6. -NH2,

5.7. -O-(C1-C4) alkyl, or

5.8. HE or

6. -N(R13)2where R13independently of one another represents hydrogen atom, aryl, -C(O)-(C1-C4)alkyl or substituted aryl or alkyl, where alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 5.1-5.8, or R13together with the nitrogen atom to which it is attached, a heterocycle having 5 to 7 ring atoms.

It is preferable to use compounds of the formula I, where

each of the B6In7B8and In9represents a carbon atom, R1, R2, R3, R4and R8, independently of one another, is a

1. a hydrogen atom,

2. halogen

3. -CN

4. -COOH,

5. -NO2,

6. -NH2,

7. -O-(C1-C10-alkyl, where the alkyl is unsubstituted or mono-to Penta-substituted, independently of one another

7.1-phenyl, which is unsubstituted or mono-to Penta-substituted by halogen or-O-(C1-C4)-alkyl,

7.2 halogen,

7.3-NH2,

7.4-HE,

7.5-COOR16where R16represents a hydrogen atom or -(C1-C10)-alkyl,

7.6-NO2,

7.7-S(O)y-R14where y is zero, 1 or 2, R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in the 7.1-7.11, amino or-N(R13)2,

where R13independently of one another represents hydrogen atom, phenyl, -(C1-C10)-alkyl, -C(O)-(C1-C7)-alkyl, -C(O)-phenyl, -C(O)-NH-(C1-C7)-alkyl, -C(O)-O-phenyl, -C(O)-NH-phenyl, -C(O)-O-(C1-C7)-alkyl, -S(O)y-R14where R14and y are as defined above, and where the alkyl or phenyl in each case are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11, or R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

7.8-O-phenyl, where phenyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 1.7.1-1.7.11

7.10 -(C3-C7-cycloalkyl or

7.11 =O,

8. -N(R13)2where R13is the same as defined in 7.7,

9. -NH-C(O)-R15where R15represents a

9.1 radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, research, pyridine, pyridazine, pyrazine, oxolane, imidazoline, isoxazolidine, 2-isoxazoline, isothiazoline, 2-isothiazoline, thiophene or thiomorpholine,

where the specified radicals is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11, -CF3, benzyl or -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 7.1-7.11

9.2. -(C1-C10)-alkyl, where alkyl is mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11 or-O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11

9.3. -(C3-C7)-cyclea the Kil,

9.4. -N(R13)2where R13is as defined above in 7.7, or

9.5. phenyl, where phenyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11, -O-(C1-C10)-alkyl, -CN, -CF3, -(C1-C10)-alkyl, where alkyl is mono-to tri-substituted, independently of one another, as defined above in 7.1-7.11, or two substituent of the phenyl radical to form a dioxolane ring,

10. -S(O)y-R14where R14and u are as defined in 7.7 above,

11. -C(O)-R12where R12represents phenyl or -(C1-C7)alkyl, where the alkyl or phenyl are unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11

12. -C(O)-O-R12where R12is the same as defined above 11,

13. -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.11,

14. -O-(C1-C6)-alkyl-O-(C1-C6)-alkyl,

15. -O-(C0-C4)-alkyl-(C3-C7-cycloalkyl,

16. -(C1-C4)-alkyl-N(R13)2where R13is as defined above in 7.7,

17. -CF3or

18. -CF2-CF3,

provided that at least one of R1, R2,R 3, R4and R8is not a hydrogen atom,

R5represents a

1. a hydrogen atom,

2. -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined above in 7.1-7.4,

3. -C(O)-R9where R9represents a

-NH2, -(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to Penta-substituted, independently of one another, as defined in 7.1-7.4, or-N(R13)2where R13is as defined above in 7.7, or

4. -S(O)2-R9where R9is as defined above in paragraph 3;

or

R4and R5together with the atom to which they are bound, form a heterocycle, or

R3and R15together with the atom to which they are bound, form a heterocycle containing a ring extra atom of oxygen, and

R6and R7independently of one another represent a hydrogen atom or methyl.

It is preferable to use compounds of the formula I to obtain drugs for the prevention and treatment of diseases for which involved increased activity of kinase lkB, where each of the B6In7B8and In9represents a carbon atom,

R1, R2, R3and R4independently of one another represent the keys of a hydrogen atom, halogen, cyano, nitro, amino, -O-(C1-C7)-alkyl, phenyl, -O-phenyl, -CF2-CF3, -CF3, -N(R13)2,

where R13independently of one another represent a hydrogen atom, -(C1-C7)-alkyl, phenyl, -C(O)-phenyl, -C(O)-pyridyl, -C(O)-NH-phenyl, -C(O)-O-phenyl, -C(O)-O-(C1-C4)-alkyl, -C(O)-(C1-C7)-alkyl or -(C1-C10)-alkyl, where alkyl, pyridyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 7.1-7.11, or R13together with the nitrogen atom to which it is attached, form a heterocycle having 5 to 7 ring atoms,

S(O)y-R14,

where y is zero, 1 or 2, and R14represents -(C1-C10)-alkyl, phenyl, which is unsubstituted or mono-to Penta-substituted, as defined for the substituents in the 7.1-7.11, amino or-N(R13)2where R13is the same as defined above,

where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 7.1-7.11, or

-C(O)-O-R12where R12is the same as defined above,

R6, R7and R8independently of one another represent a hydrogen atom or methyl, amino, -N(R13)2where R13is the same as defined above, provided that at least one of the Rsup> 1, R2, R3, R4and R8is not a hydrogen atom, and R5is the same as defined above.

Even more preferably the use of compounds of formula II

and/or stereoisomeric forms of the compounds of the formula II and/or physiologically acceptable salts of the compounds of formula II to obtain drugs for the prevention and treatment of diseases for which involved increased activity of kinase lkB, where

R1, R2and R3independently of one another represent hydrogen atom, halogen, cyano, amino, -O-(C1-C4)-alkyl, nitro, -CF3, -CF2-CF3, -S(O)y-R14where y is 1 or 2, R14represents amino, -(C1-C7)-alkyl, phenyl, which is unsubstituted or mono-to tri-substituted as defined above for substituents in 7.1-7.9, or-N(R13)2where

R13independently of one another represent-C(O)-pyridyl, hydrogen atom, -(C1-C7)-alkyl-C(O)-(C1-C7)-alkyl, C(O)-phenyl, -(C1-C10)-alkyl, -C(O)-NH-(C1-C4)-alkyl, -C(O)-O-phenyl or-C (O)-O-(C1-C4)-alkyl, where

pyridyl, alkyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another, as defined in 7.1-7.11, or

R13together with the atom is the monk, to which it is attached, form a heterocycle having 5 to 7 ring atoms, provided that at least one of R1, R2and R3is not a hydrogen atom, and

R5represents a hydrogen atom, -(C1-C10)-alkyl,

where the alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 7.1-7.4, -C(O)-R9or-S(O)2-R9where

R9is -(C1-C10)-alkyl, -O-(C1-C10)-alkyl, where alkyl is unsubstituted or mono-to tri-substituted, independently of one another, as defined in 7.1-7.4, phenyl, which is unsubstituted or mono-to tri-substituted as defined in 7.1-7.11, or-N(R13)2,

where R13is the same as defined above.

Most preferably the use of compounds of formula II to obtain drugs for the prevention and treatment of diseases for which involved increased activity of kinase lkB, where

R1, R2and R3independently of one another represent hydrogen atom, halogen, cyano, amino, -O-(C1-C4)-alkyl, nitro, -CF3or-N(R13)2where

R13independently of one another represent a hydrogen atom, -(C1-C7)-alkyl, -C(O)-(C1-C7)-alkyl, -C(O)-pyridyl, -C(O)-phenyl or-C(O)-O-(C -C4)-alkyl, where the alkyl or phenyl are unsubstituted or mono-to tri-substituted independently of one another by halogen or-O-(C1-C4)-alkyl, and

R5represents a hydrogen atom, -C(O)-CH3, methyl, -S(O)2-CH3-C(O)-morpholinyl, -CH2-CH2-HE or-CH2-C(O)-NH2provided that not more than two of R1, R2, R3and R5represent a hydrogen atom.

Even more preferably the use of compounds of formula II to obtain drugs for the prevention and treatment of diseases for which involved increased activity of kinase lkB, where

R1represents bromine, -CF3or chlorine, R2represents a hydrogen atom or-O-(C1-C2) alkyl, R3represents a hydrogen atom, bromine, chlorine, or-N(R13)2,

where R13independently of one another represents hydrogen atom, -C(O)-phenyl, (C1-C7)-alkyl, -C(O)-(C1-C4)-alkyl or-C(O)-O-(C1-C4)-alkyl, where the alkyl or phenyl are unsubstituted or mono-to tri-substituted, independently of one another by halogen or-O-(C1-C2) alkyl, and

R5represents a hydrogen atom, -C(O)-CH3, methyl or-S(O2)-CH3,

provided that not more than two of R1, R2, R3 and R5represent a hydrogen atom.

In particular, it is preferable to use compounds of formula II to obtain drugs for the prevention and treatment of diseases for which involved increased activity of kinase lkB, where

R1represents chlorine, each of R2and R3represents a hydrogen atom, and R5represents-C(O)-CH3or

R1represents bromine, each of R2and R3represents a hydrogen atom, and R5represents-C(O)-CH3or

R1represents chlorine, R3represents a-N-C(O)- CH2-O-CH3and each of R2and R5represents a hydrogen atom, or

R1represents chlorine, R3represents a-N-C(O)-para-fluoro-phenyl and each R2and R5represents a hydrogen atom, or each of R1and R3represents chlorine, R2represents-C(O)-CH3and R5represents a hydrogen atom, or

each of R1and R3represents chlorine, R5represents a hydrogen atom, and R2represents-C(O)-CH2-CH3.

From the point of view of the pharmacological properties of the compounds according to the invention are suitable for the prevention and L. the treatment of all those diseases, in the course of which involved increased activity of kinase lkB. Diseases for which involved increased activity lkB kinases include, for example, the treatment of General inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, arthritis rubella, psoriatic arthritis and osteoarthritis. In addition, the compounds can be used in the treatment of acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia (wasting), Reiter syndrome, endotoxemia (the presence in the blood endotoxin), sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, toxic shock syndrome, chronic inflammatory lung diseases, including asthma and respiratory distress syndrome in adults, silicosis, sarcoidosis lung syndrome, bone resorption, reperfusion lesions, carinosa, leukemia, sarcoma, tumors of the lymph nodes, carinosa skin, lymphoma, apoptosis, reactions, graft-against the host, transplant rejection and leprosy. In addition, the compounds useful in the treatment of infections such as viral infections, such as HIV (human immunodeficiency virus), cytomegalovirus (CMV), influenza, adenovirus and the viruses of herpes group, parasitic infections, such as malaria and, such as cerebral malaria, and yeast and fungal infections, such as fungal meningitis; fever and myalgia (muscle pain) due to infection; acquired immune deficiency syndrome (AIDS); related to AIDS; secondary cachexia due to infection or malignant neoplastic disease; secondary cachexia due to acquired immunodeficiency syndrome (AIDS) or cancer; the formation of keloid and healed tissues; high temperature; diabetes and inflammatory bowel disease such as Crohn's disease and ulcerative colitis. Compounds of the invention are also useful in the treatment of diseases or lesions of the brain are involved, the over-expression of TNFαsuch as multiple sclerosis and head injury. Compounds according to the invention are also useful in the treatment of psoriasis, Alzheimer's disease, carcinomatosis violations (enhanced activity of cytotoxic therapy), heart attack, chronic obstructive pulmonary disease (COPD) and acute respiratory distress sintrom (ARDS).

The invention also relates to a method for obtaining a medicinal product, which comprises bringing at least one compound of formula I in a suitable mould, injection using a pharmaceutically suitable and physiologically acceptable excipient and, if is is suitable additional suitable active compounds, additives or auxiliaries.

Suitable solid or pharmaceutical preparative forms are, for example, granules, powders, tablets with sheath, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and drugs with prolonged release of the active compound, such drugs are used conventional auxiliaries, such as excipients, dezintegriruetsja agents, binders, coating agents, swelling agents, glidant or lubricants, flavorings, sweeteners and soljubilizatory. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols, such as glycerin.

The pharmaceutical preparations are preferably receive and impose a single preparative drug, form, each unit dosage form contains as active component is definitely the dose of the compounds of formula I according to the invention. In the case of a solid single preparative dosage forms such as tablets, capsules, coated tablets or suppositories, this dose can be approximately up to 1000 mg, preferably from about 50 mg to 300 mg, and in the case of injection solutions in the form of capsules up to about 300 mg, preferably from about 10 mg to 100 mg

For the treatment of an adult patient weighing approximately 70 kg, depending on the effectiveness of the compounds according to formula I shows daily dose of from about 20 mg to 1000 mg of active compound, preferably from about 100 mg to 500 mg However, certain circumstances may be appropriate even higher or lower doses. The introduction of the daily dose can be in the form of a single administration in the form of individual preparative dosage form or, otherwise, in the form of a series of smaller single preparative dosage forms or by multiple injection subdivided dosage forms at regular intervals.

Typically, the final products were determined by mass-spectroscopic methods (FAB (fast atom bombardment), ESI-MS (electron impact - mass spectra). Temperatures are given in degrees Celsius, CT means room temperature (22°to 26°). Used reduced the I or explained, or in accordance with the conventional rules.

Example 1. 7-Bromo-β-carbolin

The solution norharmane (600 mg, of 3.57 mmol) in tetrahydrofuran (THF; 50 ml) was treated with bromine (0,40 ml, 7,80 mmol) at room temperature under stirring. After stirring for 18 hours at room temperature the reaction mixture was concentrated under reduced pressure and the obtained residue was treated with ultrasound in 10%aqueous Na2CO3(100 ml). The product was filtered and washed with water, getting 905 mg of crude (crude) product. The crude product was led from the xylenes, getting 580 mg of 7-bromo-β-carboline in two portions.

Example 2. 1-Acetyl-7-bromo-β-carbolin

A solution of the product of example 1 (25 mg, 0.1 mmol) in dimethylformamide (DMF; 2 ml) was treated with 0.10 ml of aqueous NaOH (0.10 mmol). After stirring at room temperature for 30 minutes was added acetic anhydride (0,010 ml, 0,095 mmol) and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was distributed in EtOAc and 5%citric acid and the organic layer was washed with water, dried (saturated salt solution; MgSO4) and concentrated, gaining 23 mg of crude product. The crude product was chromatographically (7:3 hexane-acetone) on silica gel to give 10 mg of 1-acetyl-7-bromo-β-carboline.

Example 3. 7-Fluoro-β-carbolin

p> A mixture of the hydrochloride of 5-fortitudine (200 mg, of 0.93 mmol) in EtOAc (4 ml) and water (2 ml) was treated with hydrate glyoxalase acid (90 mg, 0.98 mmol), pH of the aqueous layer was brought to 5 (with 5%NaHCO3then 1M HCl) and the mixture was intensively stirred at room temperature for 18 hours. The mixture then was diluted with hexane (4 ml) and the product was filtered and washed with water and a mixture (1:1) hexane-ethyl acetate. The result of the above crude product in the 6N. HCl (3 ml) was treated 3 times with concentrated HCl (0,050 ml) every 15 minutes at the boil under reflux. After heating at boiling under reflux just for 45 minutes the reaction mixture was concentrated, obtaining the remainder. The above residue is suspended in xylenes with triethylamine (and 0.40 ml, 2.9 mmol) and 10% Pd/C (200 mg). The mixture was heated at the boil under reflux for 1 hour and then filtered hot through celite. The filtrate was concentrated and the residue was chromatographically (5:95 methanol-chloroform) on silica gel, receiving 25 mg of 7-fluoro-β-carboline.

Example 4. Hydrochloride 7-isopropyl-β-carboline

A mixture of the hydrochloride of 4-isopropylpiperazine (660 mg, 3,55 mmol) and diethylacetal 4-phthalimidobutyl (1,15 g, 3.95 mmol) in ethanol (EtOH; 30 ml) was heated at a temperature of from 60°to 65°C for 1 hour with water (0,050 ml). Then the mixture was treated with concentrated HCl (0,50 ml) and was heated at the boil under reflux for 14 hours. After concentrating the reaction mixture, the residue was distributed between methylene chloride and saturated aqueous NaHCO3. The aqueous solution was extracted with methylene chloride (3 times) and the combined organic solutions were dried (MgSO4) and concentrated, after receiving chromatography (4:1 hexane-ethyl acetate) on silica gel 146 mg of the product.

The above product was treated with hydrazine hydrate (1 ml) in EtOH (4 ml) and water (1 ml) and stirred at room temperature overnight. After concentration of the reaction to water mixture, the product was extracted with methylene chloride (3 times). The combined organic solution was dried (MgSO4) and concentrated. The residue was re-dissolved in methylene chloride and was treated with 1M HCl in simple ether. The precipitate was collected and washed by a simple ether and hexane and dried, receiving 102 mg cleaners containing hydrochloride salt of 6-isopropylnaphthalene. Obtained above tryptamine were converted into 7-isopropyl-β-carbolin in accordance with the method used in example 3. Cleaners containing hydrochloride salt was obtained by processing a solution of 7-isopropyl-β-carboline in methylene chloride 1M HCl in ether and concentrating, the residue triturated with a mixture (1:1) methylene chloride-hexane, receiving 15 mg of the hydrochloride of 7-isopropyl-β-carboline.

Example 5. 7-Cyano-β-carbolin

The dark solution of the product of example 1 190 mg, of 0.62 mmol) and CuCN (110 mg, 1,22 mmol)in N-methyl-2-pyrrolidone(1.5 ml) was heated in a sealed reaction tube at 200°C for 48 hours. The mixture was filtered and the filtrate was diluted with water (50 ml). Precipitated precipitated brown solid was filtered, washed with water, saturated aqueous NaHCO3and then with methanol. This substance was dissolved in DMSO and diluted aqueous HCl. This homogeneous dark solution was decolorized with activated charcoal, filtered and concentrated, obtaining a concentrated solution in DMSO. This solution in DMSO was distributed between a mixture (1:1) EtOAc-THF and saturated aqueous NaHCO3. The organic solution was dried (MgSO4) and concentrated, receiving 8 mg of 7-cyano-β-carboline.

Example 6. The hydrochloride of 7-nitro-β-carboline

Norharman (100 mg, of 0.60 mmol) was treated with concentrated nitric acid (1.0 ml) and the resulting suspension was heated at 65°until then, until the mixture became homogeneous (3 to 4 minutes). The solution was carefully poured into water (20 ml), the precipitate was filtered and washed with water, then with methanol. The solid is re-suspended in a saturated aqueous solution of NaHCO3and intensively stirred before filtering and washing with water. The solid was placed in hot methanol and the solution was treated with 1M HCl in simple ether (5 ml The solution was concentrated and the residue triturated with simple ether, receiving 58 mg of a mixture of 7:3 of the hydrochloride of 7-nitro-β-carboline and hydrochloride of 9-nitro-β-carboline.

Example 7. Triptorelin 7-carboxy-β-carboline

The crude product from example 5 (out of 210 mg of the product of example 1 of 0.085 mmol) was treated with 6M HCl in a sealed reaction tube for 15 hours at 110°C. the Reaction mixture was evaporated, obtaining a concentrated solution of the product in N-methyl-2-pyrrolidone. A portion (half) was purified preparative HPLC using a Packed column C18and elwira using a gradient from 5:95 to 50:50) mixture of water-acetonitrile (0.1%triperoxonane acid). Pure fractions were combined and hydrolyzed, receiving 11 mg trifenatate 7-carboxy-β-carboline

Example 8. Hydrochloride 7,9-dibromo-β-carboline

A solution of the product from example 1 (140 mg, of 0.58 mmol) in THF (2 ml) was treated with bromine (0,50 ml). After 10 minutes at room temperature, the reaction mixture was diluted with chloroform and the product was filtered. The filtered product was placed in methanol and treated with 1M HCl in simple ether and concentrated. The residue is triturated with simple ether, receiving 160 mg hydrochloride 7,9-dibromo-β-carboline.

Example 9. 7,9-Dichloro-β-carbolin

To a suspension of norharmane (84 mg, 0.50 mmol) in water (3 ml) at room temperature until alali 1M aqueous HCl (1.1 ml, 1.1 mmol). To this homogeneous solution was added in portions N-chlorosuccinimide (747 mg, to 5.58 mmol) and the resulting solution was stirred at 60°S-70°C for 3 hours. The reaction mixture was distributed between EtOAc and saturated aqueous NaHCO3and the organic layer was dried (saturated salt solution; MgSO4) and then concentrated. The residue was chromatographically (2:3 THF-hexane) on silica gel, receiving 24 mg 7,9-dichloro-β-carboline after trituration with a mixture of methylene chloride-hexane (1:1)and then with hexane.

Example 10. 1-Acetyl-7-bromo-β-carbolin

To a suspension of NaH (95%, 14 mg of 0.60 mmol) in DMF (1.0 ml) at 5°C-10°C was added the product of example 1 (74 mg, 0.30 mmol). The resulting mixture was stirred for 15 minutes at 5°C-10°before adding methanesulfonanilide (0,030 ml, 0.38 mmol). The reaction mixture was left to warm to room temperature and stirred for 2 hours, then was distributed between saturated aqueous NaHCO3and EtOAc. After stirring the mixture overnight the organic layer was washed with water, dried (saturated salt solution; MgSO4) and concentrated. The residue was purified by chromatography (1:1 hexane-ethyl acetate) on silica gel, receiving 23 mg of 1-acetyl-7-bromo-β-carboline.

Example 11. 7-Bromo-1-methyl-β-carbolin

To a suspension of NaH (95%, 6 mg, 0.24 mmol) in DMF (2.0 ml) at 5°C-10°EXT is ulali the product of example 1 (50 mg, 0.20 mmol). The resulting mixture was stirred for 15 minutes at 5°C-10°before adding iodotope bromide (0,030 ml, 0.20 mmol) at 0°-5°C. the Reaction mixture was stirred 12 hours at 0°-5°With, then distributed between water and EtOAc. The organic layer was washed with water, dried (saturated salt solution; MgSO4) and concentrated. The residue was purified by chromatography (gradient elution from 1:3 hexane-ethyl acetate to ethyl acetate) on silica gel to give 10 mg of 7-bromo-1-methyl-β-carboline.

Example 12. 7-Chloro-β-carbolin

To a solution of norharmane (2.0 g, to 11.9 mmol) in water (89 ml) and 1M aqueous HCl (29,8 ml, to 29.8 mmol) was added in portions N-chlorosuccinimide (3,17 g of 23.8 mmol). The resulting solution was stirred at room temperature for 6 hours and then at 0°-5°C for 12 hours. The reaction mixture was diluted with water (100 ml) and carefully podslushivaet hard To2CO3(4.3 g). After stirring at room temperature for 1 hour the product was collected and washed with water. The crude product was heated at boiling under reflux in chloroform for 1 hour and was filtered after cooling to 15°receiving 2,05 g of 7-chloro-β-carboline.

Example 13. 1-Acetyl-7-chloro-β-carbolin

To a solution of the product of example 12 (104 mg, 0.50 mmol) in DMF (2.0 ml) at 3°-5°C was added NaH (95%, 15 mg of 0.625 mmol who). The resulting mixture was stirred for 15 minutes before addition of acetic anhydride (0,083 ml, 0,875 mmol). The reaction mixture was left to warm to room temperature and was stirred for 3 hours, then poured into water (25 ml). The suspension was stirred for 12 hours and the product was collected, after receiving chromatography (1:3 hexane-ethyl acetate) on silica gel 82 mg of 1-acetyl-7-chloro-β-carboline.

Example 14. 7-Chloro-9-nitro-β-carbolin

A mixture of the product of example 12 (500 mg, 2.48 mmol) in concentrated nitric acid (20 ml) was stirred at room temperature for 22 hours. The reaction mixture was carefully poured into cold (3°-5° (C) water (50 ml) and after stirring for 2 hours collecting the precipitate. The solid is suspended in a saturated aqueous NaHCO3(50 ml) and stirred at room temperature for 12 hours. The product was filtered and washed with water, getting 550 mg of 7-chloro-9-nitro-β-carboline.

Example 15. 9-Amino-7-chloro-β-carbolin

To a suspension of the product of example 14 (548 mg, 2.22 mmol)in EtOH (14 ml) at 65°S-70°With added chloride dihydrate tin (2.5 g, 11.1 mmol). After this was added dropwise 6M aqueous HCl (14 ml). The mixture was stirred at 70°S-80°C for 3.5 hours and then slowly distributed in a mixture of saturated aqueous NaHCO3(150 ml) and EtOAc (100 ml). Aq is th phase was extracted (2 times) and the combined organic solutions were dried (saturated salt solution; Na2SO4and focused, getting 484 mg of 9-amino-7-chloro-β-carboline.

Example 16. Triptorelin 9-amino-7-chloro-β-carboline

To a solution of the product of example 15 (35 mg, 0.16 mmol) in pyridine (0,80 ml) was added acetic anhydride (0,018 ml to 0.19 mmol). The resulting mixture was left at room temperature for 12 hours, then poured into water (15 ml). The crude product was filtered and was purified preparative HPLC using a C18-filled column and elwira using a gradient from 5:95 to 60:40) mixture of water-acetonitrile (0.1% triperoxonane acid). Pure fractions were combined and liofilizovane, receiving 18 mg trifenatate 9-amino-7-chloro-β-carboline.

Example 17. 7-Bromo-1-carbonyl-(4'-morpholine)-β-carbolin

A solution of the product of example 1 (125 mg, 0.51 mmol) in DMF (2 ml) was treated with 0.55 ml of a 1M aqueous solution of NaOH (0,mol). After stirring at room temperature for 30 minutes was added 4-morpholinylcarbonyl (to 0.060 ml, 0.51 mmol) and the reaction mixture was stirred 18 hours at room temperature. The reaction mixture was distributed between EtOAc and 5%citric acid and the organic layer was washed with water, dried (saturated salt solution; MgSO4) and concentrated. The residue was chromatographically (7:3 hexane-acetone) on silica gel, getting 105 mg of 7-bromo-1-carbonyl-(4'-morpholine)-β-carboline.

Example 1. 1-(2'-Acetate)-7-chloro-β-carbolin

To a suspension of NaH (95%, 28 mg, 1.15 mmol) in DMF (1.0 ml) at 5°C-10°C was added the product of example 12 (202 mg, 1.0 mmol) in DMF (3 ml). The resulting mixture was stirred for 30 minutes at 5°C-10°before adding ethylbromoacetate (0,116 ml, 1.05 mmol). The reaction mixture was left to mix for 1.5 hours and then the reaction mixture was diluted with saturated aqueous NaHCO3(30 ml). The product was extracted with EtOAc (30 ml 2 x 15 ml each) and the combined organic extracts were dried (saturated salt solution; MgSO4) and concentrated. The residue was purified by chromatography (1:3 hexane-ethyl acetate) on silica gel, getting 270 mg of 1-(2'-acetate)-7-chloro-β-carbolin.

Example 19. 1-(2'-Ethanoyl)-7-chloro-β-carbolin

To a solution of the product of example 18 (50 mg, 0,17 mmol) in THF (1.7 ml) at 5°C-10°With added 1M LAH in THF (0.17 ml, 0,17 mmol). The resulting mixture was stirred for 2 hours at 5°C-10°C, after which was added EtOAc (0.10 ml). Then the mixture was diluted with EtOAc (5 ml) and slowly treated with saturated aqueous NaHCO3(5 ml). After dilution with water (10 ml) and saturated salt solution (10 ml) the mixture was extracted with EtOAc. The organic solution was dried (saturated salt solution; MgSO4), then concentrated, receiving 42 mg of 1-(2'-ethanoyl)-7-chloro-β-carboline.

Example 20. 1-(2'-Acetyl)-chlor-β -carbolin

To a solution of the product of example 18 (107 mg, and 0.37 mmol) in Meon (3,7 ml) at room temperature was added water (3,7 ml) followed by treatment of 1M aqueous solution of NaOH (of 0.41 ml, 0.41 mmol). The resulting mixture was stirred for 2 hours and the volatile components were removed under reduced pressure. Then the mixture was diluted with water (5 ml) and the pH brought up to 5-6. The precipitate was filtered and washed with water, receiving 96 mg of 1-(2'-acetyl)-7-chloro-β-carboline.

Example 21. 8-Methoxy-β-carbolin

Was obtained from 6-methoxytryptamine using the methods of example 3.

Example 22. Structure, see table 1

To a solution of the product of example 20 (59 mg, 0.23 mmol) in DMF (2.8 ml) at room temperature was added p-NITROPHENOL (40 mg, 0.29 mmol), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48 ml, 0.25 mmol). The resulting mixture was stirred for 1.5 hours at room temperature and then was added ammonium bicarbonate (55 mg, 0.69 mmol). The reaction mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). The aqueous mixture was podslushivaet To2CO3to a pH of about 10. The precipitate was filtered and washed with water, receiving 47 mg specified in the connection header.

Example 23. 8-Methoxy-2-methyl-β-carbolin

The solution harmina (616 mg, 2.9 mmol) in dichloroethane (20 ml) was treated with 2.0 ml, 1M BBr3(4 mmol) of dihl is retune. The reaction mixture was stirred at 60°C for 48 hours and then was cooled to 0°With, then extinguished the Meon (5 ml). The reaction mixture was concentrated and the residue triturated with methanol, getting 413 mg of 8-methoxy-2-methyl-β-carboline.

Example 24. 6,8-Dibromo-7-methoxy-β-carbolin

A solution of the product of example 30 (90 mg, 0.45 mmol) in acetic acid (8 ml) was treated with bromine (0,025 ml, 0.48 mmol). The reaction mixture was stirred at room temperature for 18 hours, then concentrated. The residue was distributed in a mixture of EtOAc and aqueous NaHCO3. The organic layer was dried (saturated salt solution; MgSO4) and concentrated. The residue was purified by chromatography (5:4 hexane-acetone) on silica gel, receiving 3 mg of 6,8-dibromo-7-methoxy-β-carboline.

Example 25. Structure, see table 1

A solution of the product of example 23 (60 mg, 0.30 mmol) in DMF (3 ml) was treated with K2CO3(100 mg) and tert-butyl-bromoacetate (0,040 ml, 0.27 mmol). After stirring at room temperature for 18 hours the reaction mixture was distributed in EtOAc and water. The organic layer was dried (saturated salt solution; MgSO4) and then concentrated. The residue was chromatographically (1:1 hexane-EtOAc) on silica gel, receiving 20 mg specified in the connection header.

Example 26. Structure, see table 1

A solution of the product of example 23 (50 mg, 0.25 mmol) in DMF (3 ml) of relatively To 2CO3(100 mg) and methyl-benzyl (0,030 ml, 0.25 mmol). After stirring at room temperature for 18 hours the reaction mixture was distributed in EtOAc and water. The organic layer was dried (saturated salt solution; MgSO4) and then concentrated. The residue was chromatographically (1:1 hexane-EtOAc) on silica gel, receiving 12 mg specified in the connection header.

Example 27. 7 Ethoxy-2-methyl-β-carbolin

A solution of the product of example 23 (60 mg, 0.30 mmol) in DMF (3 ml) was treated with K2CO3(100 mg) and idestam the ethyl (0,029 ml, 0.36 mmol). After stirring at room temperature for 18 hours the reaction mixture was distributed in EtOAc and water. The organic layer was dried (saturated salt solution; MgSO4) and then concentrated. The residue was chromatographically (1:1 hexane-EtOAc) on silica gel, receiving 20 mg of 7-ethoxy-2-methyl-β-carboline

Example 28. 7-Bromo-2-methyl-β-carbolin

Received from Harman, using the same method as in example 1.

Example 29. Structure, see table 1

A solution of the product of example 23 (60 mg, 0.30 mmol) in DMF (3 ml) was treated with K2CO3(100 mg) and acetic anhydride (0,034 ml, 0.36 mmol). After stirring at room temperature for 18 hours the reaction mixture was distributed in EtOAc and water. The organic layer was dried (saturated salt solution; MgSO4) and then concentrated, the Residue was chromatographically (1:1 hexane-EtOAc) on silica gel, receiving 18 mg specified in the connection header.

Example 30. 7-Methoxy-β-carbolin

Was obtained from 5-methoxytryptamine using the method of example 3.

Example 31. 8-Fluoro-β-carbolin

Was obtained from 6-percription using the same method as in example 3.

Example 32. 7-Bromo-2-methyl-8-methoxy-β-carbolin

Received from Harman, using the same method as in example 1.

Example 33. 7-Hydroxy-β-carbolin

Received from the product of example 30 using the method of example 23.

Example 34. 7-Chloro-8-fluoro-β-carbolin

Received from the product of example 31 using the method of example 12.

Example 35. 7-Methoxy-1-methyl-β-carbolin

Received from the product of example 30 using the method of example 11.

Example 36. Triptorelin 9-chloro-8-methoxy-β-carboline and

Example 37 Triptorelin 7,9-dichloro-8-methoxy-β-carboline

A solution of the product of example 21 (195 mg, 1.0 mmol) in 1M HCl (3 ml) was treated with portions of N-chlorosuccinimide (270 mg, 2 mmol) and the resulting solution was stirred at a temperature of 60°S-70°C for 3 hours. The reaction mixture was evaporated and the crude product was purified HPLC using a C18-Packed column and a gradient elution from 5:95 to 50:50) mixture of water-acetonitrile (0.1% triperoxonane acid). Pure fractions of each product were combined and were liofilizovane getting 78 m is trifenatate 9-chloro-8-methoxy-β -carboline and 51 mg of triptoreline 7,9-dichloro-8-methoxy-β-carboline.

Example 38. 7,9-Dichloro-8-hydroxy-β-carbolin

A mixture of the product of example 37 (590 mg, 2.21 mmol) in methylene chloride (25 ml) at 35°was treated with a solution of BBr3in methylene chloride (1M, 6 ml, 6 mmol). After heating at boiling under reflux for 3 hours, the reaction mixture was extinguished with methanol (5 ml) and then concentrated. The residue is suspended in 60%solution of NaHCO3the product was filtered and washed with water, receiving 500 mg 7,9-dichloro-8-hydroxy-β-carboline.

Example 39. 7,9-Dichloro-8-ethoxy-β-carbolin

A mixture of the product of example 38 (35 mg, 0.14 mmol), K2CO3(100 mg) and iodine ethyl (of 0.014 ml, 0,17 mmol) in acetone (5 ml) was stirred in a sealed reaction vial at room temperature for 3 days. After concentrating the reaction mixture, the residue was distributed in ethyl acetate and water, the organic layer was dried (MgSO4) and concentrated give crude product. The crude product was chromatographically (5% methanol in chloroform) on silica gel, receiving 8 mg 7,9-dichloro-8-ethoxy-β-carboline.

Example 40. Triptorelin 7-chloro-8-fluoro-β-carboline

A solution of the product of example 31 (78 mg, 0.42 mmol) in 1M HCl (1 ml) was treated with portions of N-chlorosuccinimide (115 mg, 0.9 mmol) and the resulting mixture was stirred at 60°S-70&#HWS for 3 hours. The reaction mixture was evaporated and the crude product was purified preparative HPLC using C18-Packed column and a gradient elution from 5:95 to 50:50) mixture of water-acetonitrile (0.1% triperoxonane acid). Pure fractions containing the product were combined and were liofilizovane, receiving 33 mg specified in the connection header.

Example 41. 1-Hydroxy-7-trifluoromethyl-β-carbolin and

Example 42. 7-Trifluoromethyl-β-carbolin

A solution of 3-hydroxy-2-piperidone (96 mg, 0.83 mmol) in methylene chloride (5 ml) was treated with reagent dess-Martin (Dess Martin) (352 mg, 0.85 mmol) at room temperature and the resulting mixture was stirred for 1 hour. After filtering off the salts from the reaction mixture ketone in the solution was treated with 4-trifluoromethyl-phenylhydrazine (145 mg, 0.83 mmol). After 15 minutes, was added hexane (20 ml) and the hydrazone was collected by filtration. This crude hydrazone was heated at 95°in formic acid (70%, 10 ml) for 1 hour. The reaction mixture was evaporated and the residue was chromatographically (ethyl acetate) on silica gel, receiving 60 mg dihydro-1-hydroxy-7-trifluoromethyl-β-carboline.

Portion dihydro-1-hydroxy-7-trifluoromethyl-β-carboline (6 mg) in xylene (1 ml) was treated with Pd/C (10%, 7 mg) and the mixture was heated at 50°C for one week. The reaction mixture was concentrated after filtration through celite and the OS is atok was chromatographically (1:1 hexane-ethyl acetate) on silica gel, receiving 1 mg 1-hydroxy-7-trifluoromethyl-β-carboline.

Portion dihydro-1-hydroxy-7-trifluoromethyl-β-carboline (25 mg) in THF (1 ml) was treated with a solution of sociallyengaged in THF (1M, 0.5 ml). The reaction mixture was stirred at 60°C for 6 hours, then extinguished with water (5 ml) and was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were dried (MgSO4) and concentrated, obtaining tetrahydro-7-trifluoromethyl-β-carbolin. This substance was placed in xylenes (5 ml) and was treated with Pd/C (10%, 15 mg). The mixture was stirred at 150°C for 48 hours, then filtered through celite and concentrated. The residue was chromatographically (ethyl acetate) on silica gel, receiving 5 mg of 7-trifluoromethyl-β-carboline.

Example 43. Triptorelin 7-chloro-9-(methylamino)-β-carboline

A solution of the product of example 15 (50 mg, 0.23 mmol) in a mixture of Asón/methanol (1%, 3 ml) was treated with cyanoborohydride sodium (30 mg, 0.46 mmol), followed by formaldehyde (37%, of 0.017 ml, 0.23 mmol). The reaction mixture was stirred at room temperature for 36 hours and then was diluted with saturated solution of NaHCO3(9 ml). After stirring for 15 minutes of raw (untreated) the product was filtered and washed with water. The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 13 mg indicated what about in the connection header.

Example 44. Triptorelin 7-chloro-9-(dimethylamino)-β-carboline

A solution of the product of example 15 (50 mg, 0.23 mmol) in a mixture of Asón/methanol (1%, 3 ml) was treated with cyanoborohydride sodium (30 mg, 0.46 mmol), followed by formaldehyde (37%, to 0.060 ml, 0.69 mmol). The reaction mixture was stirred at room temperature for 36 hours and then was diluted with saturated solution of NaHCO3(9 ml). After stirring for 15 minutes the crude product was filtered and washed with water. The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 40 mg specified in the connection header.

Example 45. Triptorelin 7-chloro-9-(methylsulfonylamino)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (0.5 ml) was treated with methanesulfonamide (0,024 ml, 0.30 mmol) in two portions over 30 hours. The reaction mixture was diluted with water (5 ml) and the crude product was collected and washed with water (several times). The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 16 mg specified in the connection header.

Example 46. Triptorelin 7-chloro-9-(propionamido)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with propionylcarnitine (0,015 ml of 0.17 mmol). After stirring at anatoy temperature for 4 hours, the reaction mixture was diluted with water (9 ml) and a saturated solution of NaHCO 3(1 ml). The crude product was collected and washed with water (several times). The crude product was purified preparative HPLC using a C18-Packed column and a gradient elution from 5:95 to 50:50) mixture of water-acetonitrile (0.1% triperoxonane acid). Pure fractions containing the product were combined and were liofilizovane, receiving 21 mg specified in the connection header.

Example 47. Triptorelin 7-chloro-9-(benzoylamine)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with benzoyl chloride (0,020 ml of 0.17 mmol). After stirring at room temperature for 4 hours, the reaction mixture was diluted with water (9 ml) and a saturated solution of NaHCO3(1 ml). The crude product was collected and washed with water (several times). The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 12 mg trifenatate 7-chloro-9-(benzoylamine)-β-carboline.

Example 48. Triptorelin 7-chloro-9-(acetylecholine)-β-carboline

A solution of the product of example 43 (19 mg, 0,082 mmol) in pyridine (0,40 ml) was treated with acetic anhydride (0.037 ml, 0.36 mmol) in two portions over 48 hours. The reaction mixture is subsequently concentrated to dryness and the residue was co-evaporated with Asón under reduced pressure. The crude product was purified as described in example 46. Net is racchi, containing the product were combined and were liofilizovane, receiving 9 mg specified in the connection header.

Example 49. Triptorelin 7-chloro-9-(perbenzoate)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with 4-tormentilla (0,018 ml of 0.17 mmol). After stirring at room temperature for 18 hours the reaction mixture was diluted with water (10 ml). The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 13 mg specified in the connection header.

Example 50.

Chilled (from 3°to 5° (C) a solution of the product of example 15 (30 mg, 0.14 mmol) and pyridine (of 0.014 ml, 0,17 mmol) in THF (0.7 ml) was treated with phenylcarbamate (0,018 ml, 0,145 mmol). After stirring at room temperature for 2 hours the reaction mixture was distributed in ethyl acetate and buffer (pH 7.2). The organic layer was dried (saturated solution of salt, Na2SO4) and concentrated, gaining 43 mg phenylcarbamate. To a solution of phenylcarbamate (30 mg, 0,089 mmol) in DMSO (0.5 ml) was added 2-methoxyethylamine (0,010 ml, 0/10 mmol). After stirring at room temperature for 30 minutes, the crude reaction mixture was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 21 mg specified in the connection header

Example 51. Triptorelin 7-chloro-9-(methoxyethylamine)-β-carboline

A solution of the product of example 15 (35 mg, 0.16 mmol) in pyridine (1.0 ml) was treated with methoxyacetanilide (0,016 ml, 0.18 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10 ml). The crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 32 mg specified in the connection header.

Example 52. Triptorelin 7-chloro-9-β-methoxy-benzoxanthene)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with m-antillarum (0,027 ml to 0.19 mmol) in two portions over 6 hours. The reaction mixture was subsequently diluted with water (10 ml) and the crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 33 mg specified in the connection header.

Example 53. Triptorelin 7-chloro-9-(4-methoxy-benzoxanthene)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with p-antillarum (37 mg, 0.22 mmol) in two portions within 24 hours. The reaction mixture was subsequently diluted with water (10 ml) and the crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 24 mg specified the header connection.

Example 54. Triptorelin 7-chloro-9-(methylcobalamin)-β-carboline

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine (1.0 ml) was treated with p-antillarum (0,017 ml, 0.21 mmol) in two portions over 4 hours. The reaction mixture was subsequently diluted with water (10 ml) and the crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 35 mg specified in the connection header.

Example 55. Triptorelin 7-chloro-9-(isovaleramide)-β-carboline

A solution of the product of example 15 (35 mg, 0.16 mmol) in pyridine (1.0 ml) was treated with isovaleraldehyde (0,033 ml, 0.28 mmol) in two portions within 24 hours. The reaction mixture was subsequently diluted with water (10 ml) and the crude product was purified as described in example 46. Pure fractions containing the product were combined and were liofilizovane, receiving 52 mg specified in the connection header.

Example 60. N-(6-Chloro-N-β-carbolin-8-yl)nicotinamide

To a solution of norharmane (2.0 g, to 11.9 mmol) in water (89 ml) and 1M aqueous HCl (29,8 ml, to 29.8 mmol) was added in portions N-chlorosuccinimide (3,17 g of 23.8 mmol). The resulting solution was stirred at room temperature for 6 hours and then at 0°-5°C for 12 hours. The reaction mixture was diluted with water (100 ml) and carefully podslushivaet hard To2CO3(4.3 g). After stirring at room is the temperature for 1 hour the product was collected and washed with water. The crude product was heated at boiling under reflux in chloroform for 1 hour and was filtered after cooling to 15°receiving 2,05 g of 7-chloro-β-carboline.

A mixture of 7-chloro-β-carboline (500 mg, 2.48 mmol) in concentrated nitric acid (20 ml) was stirred at room temperature for 22 hours. The reaction mixture was carefully poured into cold (3°-5° (C) water (50 ml) and after stirring for 2 hours collecting the precipitate. The solid is suspended in a saturated aqueous solution of NaHCO3(50 ml) and stirred at room temperature for 12 hours. The product was filtered and washed with water, getting 550 mg of 7-chloro-9-nitro-β-carboline.

To a suspension of 7-chloro-9-nitro-β-carboline (548 mg, 2.22 mmol) in EtOH (14 ml) at 65°S-70°With added chloride dihydrate tin (2.5 g, 11.1 mmol). After this was added dropwise 6M aqueous HCl (14 ml). The mixture was stirred at 70°S-80°C for 3.5 hours and then slowly distributed in a saturated aqueous solution of NaHCO3(150 ml) and EtOAc (100 ml). The aqueous phase was extracted (2 times) and the combined organic solutions were dried (saturated salt solution; Na2SO4and focused, getting 484 mg of 9-amino-7-chloro-β-carboline.

To a chilled (3°-5° (C) to a solution of 9-amino-7-chloro-β-carboline (2,75 g, 12.7 mmol) in pyridine (150 ml) was added Ki is rochloride of nicotinanilide (2,82 g, 15.8 mmol). The reaction mixture was left to warm to room temperature and was stirred for 20 hours before diluting the reaction mixture with water (100 ml) and 1M NaOH (25 ml). After stirring for 1 hour at room temperature the reaction mixture was poured into water (200 ml). The mixture was left for 1 hour and the product was filtered, getting 3.80 g specified in the connection header after washing with water and drying under reduced pressure at room temperature.

Example 68. N-(6-Chloro-7-methoxy-N-β-carbolin-8-yl)-nicotinamide

A mixture of 6-methoxytryptamine (9,10 g of 47.8 mmol) in EtOAc (40 ml) and NaOAc buffer pH 4.5 (40 ml) was treated with hydrate glyoxalase acid (5.30 g, 57.6 mmol). The mixture was intensively stirred for 2 days and then was diluted with hexane (40 ml). The product was filtered and washed with water and a mixture (1:1) hexane-ethyl acetate. The crude product was led from methanol after filtration of the hot methanolic solution.

The result of the above crude product (11.5 g) in 6N. HCl (100 ml) was treated 3 times with concentrated HCl (5.0 ml) every 15 minutes at the boil under reflux. After heating at boiling under reflux in General, within 1 hour, the reaction mixture was concentrated, obtaining the remainder. The residue is suspended and were treated by ultrasound with a 10%solution of Na2CO3(300 ml)and filtered, getting free amine (7.20 g). The above amine was heated at boiling under reflux in xylene (200 ml) and pyridine (100 ml) with 10%Pd/C (3 g) for 5 hours. The hot reaction mixture was filtered through celite and the filtrate was concentrated, receiving 6,38 g of 8-methoxy-β-carboline.

To a mixture of 8-methoxy-β-carboline (1.0 g, 5 mmol) in THF (100 ml) was added N-chlorosuccinimide (0,70 g, 5.2 mmol). The reaction mixture was stirred at room temperature for 4 hours, then concentrated and washed the residue with a mixture of 1:1:1 10% Na2CO3, hexane and EtOAc (400 ml). The obtained residue was washed with xylenes, getting 677 mg of 7-chloro-8-methoxy-β-carboline.

A solution of 7-chloro-8-methoxy-β-carboline (677 mg, 2.9 mmol) in triperoxonane acid (10 ml) was treated with NaNO3(260 mg, a 3.06 mmol). The reaction mixture was stirred for 3 hours at room temperature and then concentrated. The crude product was chromatographically on silica gel, gradient elwira from 5% to 10% methanol in chloroform, getting 463 mg of 7-chloro-8-methoxy-9-nitro-β-carboline.

A solution of 7-chloro-8-methoxy-9-nitro-β-carboline (460 mg, of 1.66 mmol) in EtOH(25 ml) was treated with SnCl2-2H2O (450 mg, 2.00 mmol). The reaction mixture was stirred for 5 hours at 60°and then concentrated. The crude product was chromatographically on silica gel, gradient elwira from 5% to 10% is the ethanol in chloroform, getting 410 mg of 7-chloro-8-methoxy-9-nitro-β-carboline.

A solution of 7-chloro-8-methoxy-9-nitro-β-carboline (21 mg, of 0.085 mmol) in pyridine (1 ml) was treated with the hydrochloride nicotinamide (54 mg, 0.30 mmol) and 4-dimethylaminopyridine (5 mg). After stirring at 95°S-100°C for 7 hours, the reaction mixture was concentrated, the residue is suspended with 10%Na2CO3and then chromatographically on silica, gradient elwira from 5% to 10% methanol in chloroform, getting to 4.7 mg specified in the connection header.

Example 82. N-(6-Chloro-N-β-carbolin-8-yl)-3,4-diflorasone To a chilled (3°-5° (C) to a solution of 9-amino-7-chloro-β-carboline (2.50 g, 11.5 mmol, obtained above in example 60) in pyridine (130 ml) was added 3,4-differentiald (1,67 ml, 13,25 mmol). The reaction mixture was left to warm to room temperature and was stirred for 20 hours before diluting the reaction mixture with water (60 ml) and 1M NaOH (15 ml). After stirring for 3 hours at room temperature the pH of the mixture was brought to 8-9 1M HCl and then poured into water (250 ml). The mixture was left for 30 minutes and the product was filtered, getting 3,95 g specified in the connection header after washing with water and drying under reduced pressure at 55°S-60°C.

Example 83. 6-Chloro-N-(6-chloro-N-β-carbolin-8-yl)nicotinamide

To a chilled (3° (C-5#x000B0; C) a solution of 9-amino-7-chloro-β-carboline (1.40 g, of 6.45 mmol, obtained above in example 60) in pyridine (72 ml) was added 6-chloro-nicotinoid (1.30 grams, 7,42 mmol). The reaction mixture was left to warm to room temperature and was stirred for 16 hours before diluting the reaction mixture with water (60 ml) and 1M NaOH (8 ml). After stirring for 40 minutes at room temperature the mixture was poured into water (200 ml). The mixture was left for 30 minutes and the product was filtered, getting 2.20 g specified in the connection header after washing with water and drying under reduced pressure at room temperature.

The examples in table 1 shows the structures of the obtained compounds, which were obtained in accordance with the preceding examples.

Table 1
ExampleStructureEmpirical formulaMass spectrum (M+H)
1C11H7BrN2248
2C13H9BrN2O290
3C11H7FN2187
4 C14H15CIN2211
5G12H7N3194

ExampleStructureEmpirical formulaMass spectrum (M+H)
6With11H8CIN3O2214
7With14H9F3N2O4213
8C11H7Br2CIN2327
9C11H6CI2N2238
10C12H9BrN2O2S326
11C12H9BrN2262
12C11H7CIN2204
13 C13H9CIN2O246

ExampleStructureEmpirical formulaMass spectrum (M+H)
14With11H6CIN3O2249
15C11H8CIN3219
16C15H11CIF3N3O3261
17C16H14BrN3O2361
18C15H13CIN2O2290
19C13H11CIN2O248
20C13H9CIN2O2262
21C12H10N2O199

ExampleStructureEmpirical formulaMass spectrum (M+H)
22With13H10CIN3About261
23C12H10N2O199
24C12H8Br2N2O257
25With18H20N2O3313
26C19H16N2O289
27C14H14N2O227
28C12H9BrN2262

ExampleStructureEmpirical formulaMass spectrum (M+H)
29C14H12N2O2214
30 C12H10N2O199
31C11H7FN2187
32C13H11BrN2O292
33C11H8N2O185
34C11H6CIFN2222
35C13H12N2O213
36348

ExampleStructureEmpirical formulaMass spectrum (M+H)
37382
38254
39282
40222
41253
42237
43347
44361
45411

ExampleStructureEmpirical formulaMass spectrum (M+H)
46389
47437
48388
49454
50448
51404
52 467
53467
54391

ExampleStructureEmpirical formulaMass spectrum (M+H)
55416
56With19H12CIF3N4O3323
57With18H17CIF3N3About3302
58With16H14CI2N2About2338
59With16H13CI2N3About3367
60C19H12CIF3N4O3323
61 20H12CIF4N3About3340
62C20H12CIF4N3O3340

ExampleStructureEmpirical formulaMass spectrum (M+H)
63With12H9N3About3244
64C15H12CI2N2O308
65C15H13CI3N2O
66C12H9CIN2O234
67C12H10CIN3O249
68C18H13CIN4O2353
69C21H14CIF3N4O3349
70 C13H10CI2N2O2298

ExampleStructureEmpirical formulaMass spectrum (M+H)
71With20H16CIN3About3383
72C19H11CIN4O348
73C19H11CIN4O348
74C19H11CIF3N3O391
75With16H10CIN3O2313
76With16H10CIF3OS329
77C18H11CIF3N3O2395
78C20H20CIN5O383

ExampleStructureEmpirical formulaMass spectrum (M+H)
79C15H9CIN4O2314
80C16H11CIN4O2328
81C18H12CI2N2O344
82With18H10CIF2N3About359
83C17H10CI2N4O358
84C14H12CI2N2O296
85C15H14CI2N2O310
86C17H12CIN3OS343

ExampleStructureEmpirical formulaMass spectrum (M+)
87C17H11CIN4O323
88C16H10CIN5O323
89C19H12CIN3O3367
90With20H16CIN3O2366
91With13H8CIN3O2274
92C16H14CI2N2O322
93C17H19CI2N3O353
94With12H8CIN3About3279
95C12H10CIN3O248

ExampleStructureEmpirical formulaMass is the range of (M+H)
96C18H18CI2N2O350
97C18H15CI3N4O337
98C15H17CI3N4O290
99C16H13CIN4O2330
100C19H14CIN3O2353
101C13H8CI2N2O2296
102C15H10CI2N2O3338
103C16H13CIN4O2330

ExampleStructureEmpirical formulaMass spectrum (M+H)
104C7 H11CIN4O2340
105C20H20CIN5O383
106C17H14CIN5O341
107C26H24CIN5O359
108C18H13CIN4O338
109C17H11CIN4O2340
110C17H13CIN4O2342

ExampleStructureEmpirical formulaMass spectrum (M+H)
111With16H12CIN3About3331
112C17H11CIFN3O2S377
113 18H11BrCIN3About401
114With19H13CIF3About2371
115C17H13CI3N4O2339
116C18H11CI2N3O357
117C17H16CIN3O314

ExampleStructureEmpirical formulaMass spectrum (M+H)
118C18H12CI2N4O2388
119C18H11CIN4O3343
120C19H12CIF2N3O2390
121C17H12CIN5O339

Pharmacological examples/p>

lkB-kinase ELISA (enzyme-linked immunosorbent assay)

In in vitro assays for the detection and measurement of inhibitory activity alleged pharmacological agents against lkBα-kinase complex using biotinylated polypeptide binding as Ser32and Ser36in lkBα and specific binding of antibodies only with the phosphorylated form of the polypeptide, which is either monoclonal or polyclonal (such as commercially available antibodies anti-phospho-serine32lkBα from New England Biolabs, Beverly, MA, USA, catalog No. 9240). After the formation of a complex of antibody-phospho-polypeptide complex can be detected using a variety of analytical methods using radioactivity, luminescence, fluorescence or optical absorption. For the application of the ELISA method, the complex can be immobilized either on the Biotin-binding tablet (such as a tablet, coated neutravidin (Neutravidin), and detected using a secondary antibody conjugated with horseradish peroxidase (HRP)or antibody-binding tablet (such as a tablet, with Protein-a) and detected using a Biotin-binding protein conjugated to horseradish peroxidase (such as streptavidin-HRP). The level of activity can be correlated from the standard curve using SR is synthetic polypeptides, corresponding to the polypeptide substrate.

Experimental part

lkBα-kinase complex received an initial dilution of 10 ml S100 fractions of cell extracts of HeLa S3 40 ml of 50 mm HEPES with pH 7.5. Then was added a 40% ammonium sulfate and incubated on ice for 30 minutes. Loose sediment after centrifugation, re-dissolved in 5 ml of SEC buffer (50 mm HEPES with pH 7.5, 1 mm DTT, 0.5 mm EDTA, 10 mm 2-glycerol), was purified by centrifugation at 20000g for 15 minutes and filtered through the filter unit 0.22 μm. The sample was loaded onto a column of Superose-6. FPLC capacity of 320 ml (Amersham Pharmacia Biotech AB, Uppsala, Sweden), equilibrated SEC buffer and functioning at a flow rate of 2 ml/min at 4°C. Fraction, binding the marker with molecular weight of 670 kDa, were United for activation. Then the kinase-containing pool was activated by incubation with 100 nm MECKΔ, 250 μm Mgatp, 10 mm MgCl2, 5 mm DTT, 10 mm 2-glycerol, 2.5 μm Microcystin-LR for 45 minutes at 37°C. the Activated enzyme was stored at -80°C until further use. In the wells of 96-hole tablet compounds in different concentrations in 2 μl DMSO pre-incubated for 30 minutes at 25°With 43 μl of activated enzyme, diluted [1:25] buffer for analysis (50 mm HEPES with pH 7.5, 5 mm DTT, 10 mm MgCl2, 10 mm 2-glycerol, 2.5 μm Microcystin-LR). Five micro is itrow peptide substrate (Biotin-(CH 2)6-DRHDSGLDSMKD-CONH2) 200 µm initial solution was added to each well and incubated for 1 hour before blocking with 150 μl of 50 mm ARE with pH 7.5, 0.1% BSA, 50 mm EDTA plus [1:200] the antibody. Blocked samples kinase reaction and phosphopeptide calibration standards (Biotin-(CH2)6-DRHDS [RHO3] GLDSMKD-CONH2, serially diluted in buffer for analysis) at the rate of 100 μl per well was transferred to the Protein And the tablet (Pierce Chemical Co., Rockford, IL, USA) and incubated for 2 hours with shaking. After 3 washes with PBS (phosphate buffered saline) was added for 30 minutes, 100 μl of 0.5 μg/ml of streptavidin conjugated with HRP (horseradish peroxidase)diluted in 50 mm HEPES/0.1% BSA. After 5 washes with PBS was added 100 μl of TMB substrate (Kirkegaard &Perry Laboratories, Gaithersburg, MD, USA) and the development of the staining was stopped by adding 100 μl of 0,18M H2SO4. The absorption signals were recorded at 450 nm. Standards calibration curve was fitted by linear regression using a 4-parameter equation of the dose-response. Based on this standard curve was calculated levels of kinase activity to determine the inhibitory activity of the alleged pharmacological agents.

The results are presented below in table 2.

The compound of example 121 showed IC50equal to 1.7.

18
Table 2

Inhibition of the kinase at a concentration of substances for IC50in mcm
Number examplelkB-kinase IC50Number examplelkB-kinase IC50Number examplelkB-kinase IC50Number examplelkB-kinase IC50
10,4313,3610,94912,3
20,4324,6620,38920,4
31331,5631,3931,3
42,5341640,11940,64
51353,5650,10951,0
63361,4660,7961,3
765370,15670,5970,69
80,23811680,16980,9
90,2390,1693,0990,09
100,4402700,361001,5
110,7412,2713,01011,8
120,4420,8720,581020,8
130,5431730,41030,31
14444274the 3.81041,0
150,8458,3750,291050,4
160,3460,3760,91060,6
175470,6774,41070,4
23484782,31082,1
193490,22790,181092,1
20145010800,311100,3
211,8510,6810,251110,54
2215520,6820,151120,93
2322531,4830,061130,64
244,6540,7840,11142,1
2531550,8850,21154,6
2612560,27860,71161,8
274,5574,3870,751170,67
28 11580,33880,281180,12
2940593,2890,571190,6
305,2600,052901,41200,4

Murine heterotopic model of a heart transplant

In murine heterotopic model of a heart transplant over hurdles full histocompatibility (BALB/c->C57BL/6 or B6/129) the durability of the graft is usually limited to 7.3±0.4 days (mean ± standard deviation, n0 allograft) (see, for example, Hancock WW, Sayegh MH, Zheng XG, Peach R, Linsley PS, Turka LA. Costimulatory function and expression of CD40-ligand, CD80 and CD86 or in vascularized murine cardiac allograft rejection (Co-stimulatory function and expression of CD40 ligand, CD80 and CD86 or vascular rejection in cardiac allograft in mice). Proc. Natl.Acad. Sci (USA), 93, 1996, 13967-13972; and Hancock W.W., Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arterosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes (Prevention of antibody-induced transplant atherosclerosis by expression transplant anti-oxidant and anti-apoptotic genes). Nature Med., 4, 1998, 1392-1396).

On the specified animal models have examined the effect of oral administration with the of dinani in examples 49 and 60 using 25 mg/kg/day for 14 days since the transplant.

Despite the fact that the grafts in animals that received only the carrier - methylcellulose, were rejected within 7 days (6,7±0,8), grafts in mice treated with compound 49, survived 15 days (15,3±0,6), and grafts in animals that were given the compound 60 was maintained for 20 days (20±1). Currently used in transplantation immunosuppressive therapy has limited efficacy and/or significant toxicity. Target action on lkB-kinase data agents significantly increases the duration of preservation of allograft in the absence of associated toxicity.

1. Substituted beta-carboline General formula I

or stereoisomers, or a physiologically acceptable salt,

where R2denotes halogen, R3independently represents

1.1 hydrogen atom,

1.2 is IT or

1.3-O-(C1-C6)-alkyl,

R4means 1. -N(R17)2where R17independently represents a hydrogen atom, -(C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C10)-alkyl, -C(O)-O-(C1-C6)-alkyl, -S(O)y-R14where y is zero, 1 or 2,

R14denotes -(C1-C6)-alkyl, phenyl, substituted by halogen atom,

2. -NH2,

3. -NH-C(O)-R15where R15you are the wounds of pyrrolidine, pyrazolidine, furan, pyridine, pyrazine, imidazoline, isoxazolidine, 2-isoxazoline or thiophene, where the specified radicals is unsubstituted or substituted-CF3or -(C1-C6)-alkyl, or

R15means 3.2 -(C3-C7-cycloalkyl,

3.4-N(R13)2where R13independently denotes a hydrogen atom or phenyl, provided that N(R13)2not means-NH2or

3.5 phenyl, possibly substituted -(C1-C6)-alkyl, -CF3or two substituent at the phenyl form a dioxolane ring,

R5represents a hydrogen atom or

R4and R5together with the nitrogen atom that is attached to R5form a heterocyclic radical.

2. The compound of formula I, where R2denotes halogen,

R3independently represents a hydrogen atom, -O-(C1-C4)-alkyl,

R4represents-N(R17)2where R17independently represents a hydrogen atom, -(C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C7)-alkyl, -C(O)- O-(C1-C4)-alkyl, -S(O)y-R14where y is zero, 1 or 2, R14denotes -(C1-C6)-alkyl, phenyl, substituted by halogen atom, R5represents a hydrogen atom.

3. The compound according to claim 1 of the formula, or its stereoisomers, or a physiologically the ski acceptable salt, where R2denotes halogen,

R3independently represents a hydrogen atom, -O-(C1-C4)-alkyl,

R4represents-N(R17), where R17independently represents a hydrogen atom, -(C1-C6)-alkyl, -C(O)-phenyl, -C(O)-O-(C1-C4)-alkyl, R5denotes a hydrogen atom.

4. The compound according to claim 3, where R2is bromine or chlorine, R3represents a hydrogen atom or-O-(C1-C2)-alkyl,

R4represents-N(R17)2where R17independently represents a hydrogen atom, -(C1-C6)-alkyl, -C(O)-phenyl, -C(O)-(C1-C4)-alkyl, -C(O)-O-(C1-C4)-alkyl, R5represents a hydrogen atom.

5. The compound of formula II according to claim 3 or 4, where

R2represents chlorine,

R4is-NH-C(O)-pyridyl,

R3and R5represent a hydrogen atom, or

R2is chlorine, R4is-NH-C(O)-phenyl,

R3and R5represent a hydrogen atom.

6. The method of obtaining compounds of formula I as defined in any one of claims 1 to 5, including

a) interaction of the compounds of formula III

where each of R1, R2, R3, R4In6In7B8and B9is the same as defined in the formula I, and R5means a hydrogen atom,

with the compound of the formula IV

in the presence of acid to obtain the compounds of formula V

and interaction with hydrazinehydrate and then with formaldehyde to obtain the compounds of formula VI

and oxidation with obtaining the compounds of formula VII

where R1-R4and In6In9are as defined in formula I, and R5represents a hydrogen atom, or

b) interaction of the compounds of formula VII with the compound of the formula VIII

where Y is halogen or-HE, and R5is a hydrogen atom, or

c) separation obtained by methods a) or b) compounds of the formula I, which on the basis of their chemical structures exist in enantiomeric forms, the pure enantiomers by salt with enantiomerically pure acids or bases, chromatography on chiral stationary phases or a derivation with a chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers and the removal of the chiral auxiliary groups, or/p>

d) isolation of the compounds of formula I, obtained by methods a), b) or C) or in free form or in the presence of acidic or basic groups, converting into a physiologically acceptable salt.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydropyridine of the formula (I): wherein (a) means unsubstituted phenyl group or phenyl group substituted with 1, 2 or 3 substitutes chosen independently among (C1-C4)-alkoxy-group, or (b) means unsubstituted indolyl group; R1 and R2 are similar or different and mean hydrogen atom, (C1-C4)-alkyl or phenyl group; X means alkylene group with a direct chain comprising 5, 6, 7 carbon atoms, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to HDAC based on these compounds. Invention provides new compounds and pharmaceutical composition based on thereof for aims the stimulation of anti-proliferative effect in warm-blooded animals, such as humans.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 1 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing substituted imidazopyridine of the general formula (1): wherein R1 means (C1-C6)-alkoxy-group or -NH2. Method involves interaction of compound of the formula (2): with 3-halogen-2-butanone in cyclohexanone medium at temperature 80-100°C. Using cyclohexanone as a solvent allows reducing the process period and to enhance the yield of the end product.

EFFECT: improved preparing method.

9 cl, 19 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to a method for preparing a pharmaceutically active compound 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (risperidone) of the formula (I): that possesses the neuroleptic properties. Method involves the condensation reaction of (2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-yl)acetaldehyde of the formula (II): with (6-fluoro-3-piperidinyl)-1,2-benzisoxazole of the formula (IV): to yield intermediate enamine representing 3-{2-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidine-1-yl]vinyl}-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidine-4-one of the formula (III): and the following reduction of this enamine in the presence of hydride. Also, invention claims intermediate compounds of the formula (II) and formula (III) and describes a method for preparing compound of the formula (II) comprising oxidation of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one of the formula (X): Method is characterized by high reproducibility in large-scale manufacturing and represents the unique combination of the synthesis simplicity, decreased cost, safety and protection of the environment.

EFFECT: improved preparing method.

9 cl, 3 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

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

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

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

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

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

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

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

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

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

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

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

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

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

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: medicine, neurology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition as a solid medicinal formulation possessing cerebrovasodilating and nootropic activity and comprising vinpocetin and piracetam as active components. The composition possesses high effectiveness in more low doses due to synergetic effect and possesses high bioavailability.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

3 cl, 9 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new azaheterocycles comprising fragment of piperidin-2-yl- of the general formula (1):

as separate enantiomers or mixture of enantiomers, or their pharmaceutically acceptable salts, oxides or hydrates. In compounds of the formula (1) R1 represents hydrogen atom, inert substitute or NH-protecting substitute; W represents optionally substituted azaheterocycle, such as: pyridin-3-yl, pyrazolo[1,5-a]pyridin-6-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-8-yl or [1,8]naphthyridin-3-yl. Compounds elicit activity with respect to nicotine receptors and can be used in pharmaceutical industry. Also, invention relates to the focused library for search of physiologically active compound-leaders, and to pharmaceutical compositions based on new compounds of the formula (1).

EFFECT: valuable medicinal and pharmacological properties of compounds.

9 cl, 1 tbl, 15 sch, 22 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

The invention relates to new highly efficient ligands (agonists, antagonists, modulators, etc.) nicotinic receptors - new substituted 1,2-dihydro[2,7]naphthirydines General formula 1 in the form of single stereoisomers, racemic or additive mixtures, or their pharmaceutically acceptable salts, N-oxides or hydrates

in which: R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, or R1and R2together represent polymethene chain, including 2-5 optionally substituted methylene group; R3and R4independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, optionally substituted C1-6allyloxycarbonyl group, optionally substituted karbamoilnuyu group; R5located at the carbon atoms of the pyridine fragment represents: a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl is the function group; or R5if it is at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy

The invention relates to medicine, namely to liquid pharmaceutical compositions of a wide spectrum of action on the basis of alkaloids aberamentho stimulants and vitamins, which can be used to improve blood circulation of the brain, in particular in the treatment of the effects of traumatic brain injury, as well as for the prevention and treatment of ischemic lesions of the brain, stimulate brain activity, for the adaptation of the vestibular apparatus to the overload

The invention relates to the field of pharmaceutical industry and relates to a pharmaceutical composition for improving cerebral circulation and method of its production

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to the field of pharmaceutical industry and relates to a medicinal product of Vinpocetine

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

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