Substituted indoles

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

 

The invention relates to new substituted the indoles, method of their production and their use as pharmaceuticals.

In the application WO 94/12478 amongst describes indole derivatives inhibiting platelet aggregation. In the application WO 94/08962 describes antagonists of the fibrinogen receptor, and which inhibit the binding of fibrinogen and platelet aggregation.

NFkB is the heterodimeric transcription factor that can activate a large number of genes, coding, among others, Pro-inflammatory cytokines, such as IL-1, IL-2, TNFα or IL-6. NFkB is located in the cytosol of cells, complexes with its naturally occurring inhibitor IkB. Stimulation of the cells, for example, by cytokines, leads to the phosphorylation and subsequent proteolytic cleavage of IkB. This proteolytic cleavage leads to the activation of NFkB, which then enters the cell nucleus and there activates a large number of proinflammatory genes.

Diseases, such as rheumatoid arthritis (inflammation), osteoarthritis, asthma, myocardial infarction, Alzheimer's disease or atherosclerosis, NFkB is activated in excess. Inhibition of NFkB is also useful in the treatment of cancer, as it is used there to enhance the treatment with cytostatics. It has been shown that drugs such as glucocortico the water, salicylates or gold salts that are used in the treatment of rheumatism, inhibiting, embedded in various position signal circuit that activates NFkB, or directly interfere with gene transcription.

The first step in these signaling cascades is the breakdown of IkB. This phosphorylation is regulated by specific IkB kinase. It is still not known inhibitors, inhibiting specific IkB-kinase.

With the aim of obtaining effective compounds for the treatment of rheumatoid arthritis (inflammation), osteoarthritis, asthma, myocardial infarction, Alzheimer's disease, cancer (potentiation of cytotoxic therapy) or atherosclerosis, it has been shown that indole derivatives according to the invention are strong and very specific inhibitors of IkB kinase.

Thus, the invention concerns the compounds of formula I

and/or stereoisomeric forms of the compounds of formula I and/or physiologically acceptable salts of the compounds of formula I, and one of the substituents R1, R2, R3and R4denotes a residue of formula II,

where D denotes-C(O)-, -S(O)- or-S(O)2-,

R7denotes a hydrogen atom or -(C1-C4)-alkyl,

R8means R9or characteristic statokinesigram,

R9means

1. aryl, where aryl is unsubstituted or substituted,

2. heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

3. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted, or

4. -(C1-C6)-alkyl, where alkyl is unbranched or branched and unsubstituted or, independently of one another, one, two or three times substituted

4.1 aryl, where aryl is unsubstituted or substituted,

4.2 heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

4.3 a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted,

4.4-O-R10,

4.5 =O,

4.6 halogen,

4.7-CN

4.8-CF3,

4.9-S(O)x-R10where x is the integer zero, 1 or 2,

4.10-C(O)-O-R10,

4.11-C(O)-N(R10)2,

4.12-N(R10)2,

4.13 -(C3-C6-cycloalkyl,

4.14 the remainder of the formula

or

4.15 balance formula

R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is nesnesinin or, independently of one another, from one - to three-fold substituted

1-aryl

2 heteroaryl with 5 to 14 members in the ring

3 heterocycle with 5 to 12 members in the ring,

4 halogen,

5-N-(C1-C6)n-alkyl, where n denotes the integer zero, 1 or 2, and alkyl unsubstituted or, independently of one another, one, two or three times substituted by halogen or-C(O)-or

6-C(O)-HE

c) aryl,

d) heteroaryl with 5 to 14 members in the ring,

e) a heterocycle with 5 to 12 members in the ring, and for the case (R10)2

R10matter, independently from each other, from a) to e),

Z denotes

1. aryl, where aryl is unsubstituted or substituted,

2. heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

3. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted, or

4. -C(O)-R11where

R11means

1. -O-R10or

2. -N(R10)2or

R7and R8form together with the nitrogen atom and carbon atom to which they are, if necessary, are connected, a heterocyclic ring of formula IIA,

where D, Z, and R11have the meanings as in formula II,

And denotes the nitrogen atom or the residue-CH2-,

In denotes an oxygen atom, a sulfur atom, a nitrogen atom or a residue -- CH2-,

X denotes an oxygen atom, a sulfur atom, a nitrogen atom or a residue -- CH2-,

Y denotes an oxygen atom is, a sulfur atom, a nitrogen atom or a residue -- CH2-or

X and Y together form the residue of a phenyl, 1,2-diazine, 1,3-diazine or 1,4-diazine,

moreover, the cyclic system formed by N, A, X, Y, b and the carbon atom that contains no more than one oxygen atom, X is an oxygen atom, a sulfur atom or a nitrogen atom, if a is a nitrogen atom, contains not more than one sulfur atom, contains 1, 2, 3 or 4 nitrogen atom at the same time does not present an oxygen atom and a sulfur atom, and a cyclic system formed by N, A, X, Y, b and the carbon atom is unsubstituted or independently from each other, from one - to three-fold substituted-(C1-C8)-alkyl, unsubstituted or one - to twofold substituted

1.1-HE,

1.2 -(C1-C8)-alkoxy group,

1.3 halogen,

1.4-NO2,

1.5-NH2,

1.6-CF3,

1.7 methylendioxy-group

1.8-C(O)-CH3,

1.9-CH(O),

1.10-CN

1.11-C(O)-HE,

1.12-C(O)-NH2,

1.13 -(C1-C4-alkoxycarbonyl,

1.14-phenyl,

1.15 phenoxy-group

1.16-benzyl,

1.17 benzyloxy group or

1.18 tetrazolium, or

1.19-HE

R8and Z form together with the carbon atoms to which they, if necessary, are bound, a heterocyclic ring of the formula IIC,

where D, R7 and R10have the meanings as in formula II,

T represents an oxygen atom, a sulfur atom, a nitrogen atom or a residue -- CH2-,

W represents an oxygen atom, a sulfur atom, a nitrogen atom or a residue -- CH2-,

V is absent or represents an oxygen atom, a sulfur atom, a nitrogen atom or a residue -- CH2-or

T and V or V and W together form a phenyl residue, the residue of 1,2-diazine, 1,3-diazine or 1,4-diazine, and cyclic system formed by N, T, V, W and two atoms of carbon contains no more than one oxygen atom, not more than one atom of sulfur, and 1, 2, 3 or 4 nitrogen atom, and simultaneously not present an oxygen atom and a sulfur atom, and a cyclic system formed by N, T, V, W and two carbon atoms that is unsubstituted or independently from each other, from one - to three-fold substituted by the substituents defined above under section 1.1 to 1.18 and, if necessary, other substituents R1, R2, R3and R4independently from each other, represent

1. a hydrogen atom,

2. halogen,

3. aryl, where aryl is unsubstituted or substituted,

4. heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

5. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted,

6. -(C1-C6)-alkyl,

7. -CN

8. -O-R10,

9. -N(R10)2,

10. -S(O)x-R10where x is the integer zero, 1, or 2, or

11. -CF3,

R5means

1. a hydrogen atom,

2. HE or

3. =O, and

R6means

1. aryl, where aryl is unsubstituted or substituted,

2. heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or from one - to three-times substituted, or

3. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or from one - to three-fold substituted.

Preferred is a compound of formula I, and one of the substituents R1, R2, R3and R4denotes a residue of formula II, where

D represents-C(O)-,

R7denotes a hydrogen atom or -(C1-C4)-alkyl,

R8means

1. -(C1-C4)-alkyl, where alkyl is unbranched or branched and are, independently of each other one - or twofold substituted

1.1 heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

1.2 a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted,

1.3-O-R10

1.4-S(O)x-R10where x is the integer zero, 1 or 2,

1.5-N(R10)2,

1.6 the remainder of the formula

or

.7 balance formula

or

2. typical amino acid residue,

R9means

1. R8,

2. -(C1-C4)-alkyl, where alkyl is unbranched or branched and, independently from each other, one-, two - or three-replaced

2.1 aryl, where aryl is unsubstituted or substituted,

2.2 halogen,

2.3-CN or

2.4-CF3or

3. aryl, where aryl is unsubstituted or substituted,

R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is nesnesinin or, independently of one another, from one - to three-fold substituted

1. the aryl

2. heteroaryl with 5 to 14 members in the ring,

3. a heterocycle with 5 to 12 members in the ring,

4. halogen,

5. -N-(C1-C6)n-alkyl, where n denotes the integer zero, 1 or 2, and alkyl unsubstituted or, independently of one another, one, two or three times substituted by halogen or-C(O) -, or

6. -C(O)-HE,

C) aryl,

d) heteroaryl with 5 to 14 members in the ring,

e) a heterocycle with 5 to 12 members in the ring, and for the case (R10)2

R10is set, independently from each other, from a) to e),

Z denotes

1. 1,3,4-oxadiazol where 1,3,4-oxadiazol is unsubstituted or from one - to three-fold substituted-NH2HE or -(C1-C4)-alkyl, or

2. -C(O)-R11where

R11hereafter the includes

1. -O-R10or

2. -N(R10)2,

R7and R8form together with the nitrogen atom and the carbon to which they are, if necessary, connected, loop formulas IIA from the group pyrrole, pyrrolin, indole, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazin, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, purine, isoxazol, 2-isoxazolidine, isoxazolidine, morpholine, isothiazol, thiazole, thiadiazole, benzimidazole, thiomorpholine, isothiazolin, indazole, quinoline, triazole, phthalazine, hinzelin, cinoxacin, pteridine, tetrahydroquinolin, isoquinoline, 1,2,3,5-oxadiazol-2-oxides, tetrazol, oxadiazoline, isoxazolone, triazolone, oxadiazolidine, triazole, which is substituted by F, -CN, -CF3or-C(O)-O-(C1-C4)-alkyl, 3-hydroxyprop-2,4-diones, 5-oxo-1,2,4-thiadiazole and tetrahydroisoquinoline, or

R8and Z form together with the carbon atoms to which they, if necessary, are connected, the loop formula IIC from the group pyrrole, pyrrolin, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazin, piperazine, pyrazole, imidazole, pyrazoline, 1,3,4-oxadiazol, imidazolin, pyrazolidine, imidazolidine, oxazole, isoxazol, 2-isoxazolidine, isoxazolidine, morpholine, isothiazol, thiazole, isothiazolin, tetrazol, thiomorpholine, indazole, thiadiazole, benzo is midazol, the quinoline, triazole, phthalazine, hinzelin, cinoxacin, purine, pteridine, indole, tetrahydroquinoline, triazolone, tetrahydroisoquinoline, 1,2,3,5-oxadiazol-2-oxides, oxadiazoline, isoxazolone, oxadiazolidine, triazole, which is substituted by F, -CN, -CF3or-C(O)-O-(C1-C4)-alkyl, 3-hydroxyprop-2,4-diones, 5-oxo-1,2,4-thiadiazole and isoquinoline, and, if necessary, other substituents R1, R2, R3and R4independently from each other, represent

1. a hydrogen atom,

2. halogen,

3. aryl, where aryl is unsubstituted or substituted,

4. heteroaryl with 5 to 14 members in the ring, where heteroaryl is unsubstituted or substituted,

5. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or substituted,

6. -(C1-C6)-alkyl,

7. -CN

8. -CF3,

9. -OR10,

10. -N(R10)2or

11. -S(O)x-R10where x is the integer zero, 1 or 2,

R5denotes a hydrogen atom, and

R6means

1. phenyl, independently of each other one - or twofold substituted

1.1-CN

1.2-CF3,

1.3 halogen,

1.4-O-R10,

1.5-N(R10)2,

1.6-NH-C(O)-R11,

1.7-S(O)x-R10where x is the integer zero, 1 or 2,

1.8 C(O)-R11or

1.9 -(C1-C4)-alkyl-NH2,

2. GE is Eroare with 5 to 14 members in the ring, where heteroaryl is unsubstituted or, independently of one another, one, two or three times substituted by the substituents defined above under section 1.1 to 1.9 or

3. a heterocycle with 5 to 12 members in the ring, where the heterocycle is unsubstituted or, independently of one another, one, two or three times substituted by the substituents defined above under section 1.1 to 1.9.

Particularly preferably the compound of formula I, and one of the substituents R1, R2, R3and R4denotes a residue of formula II, where

D represents-C(O)-,

R7denotes a hydrogen atom,

Z represents-C(O)-or-C(O)-NH2,

R8means

1. -(C1-C4)-alkyl, where alkyl is unbranched or branched and are, independently of each other one - or twofold substituted

1.1-S(O)-R10and R10has the above value,

1.2-N(R10)2and R10has the above value, or

1.3 pyrrole, or

2. typical amino acid residue, R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is unsubstituted or, independently of one another, from one - to three-fold substituted with halogen,

(C) phenyl, where phenyl is unsubstituted or, independently of one another, from one - to three-fold substituted with halogen or -(C1-C4)-alkyl, the La case (R 10)2has R10independently from each other, the value of (a) to (C)

if necessary, other substituents R1, R2, R3and R4represent a hydrogen atom,

R5denotes a hydrogen atom,

R6denotes phenyl or pyridine, and

R9means

1. the hydrogen atom

2. -(C1-C4)-alkyl, where alkyl is unbranched or branched and, independently from each other, one, two or three times substituted-C(O)-OH, -HE /

-C(O)-NH2or

3. phenyl, where phenyl is unsubstituted or, independently of one another, from one - to three-fold substituted with halogen or -(C1-C4)-alkyl.

The term “halogen” mean fluorine, chlorine, bromine or iodine.

Under the terms “-(C1-C8)-alkyl”, “-(C1-C6)-alkyl or-(C1-C4)-alkyl” mean hydrocarbon residues, carbon chain which are unbranched or branched and contain from 1 to 8, 1 to 6 or 1 to 4 carbon atoms. Cyclic alkyl residues are, for example, from 3 - to 6-membered monocycle as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Under the definition of “R7and R8form together with the nitrogen atom and carbon atom to which they, as necessary, related, a heterocyclic ring of formula IIA”mean residues, which are formed from pyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, isoxazol, tetrazole, isoxazoline, isoxazolidine, research, thiazole, isothiazole, isothiazoline, purine, isothiazolinone, thiomorpholine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine, indole, isoindole, indazole, benzimidazole, phthalazine, quinoline, isoquinoline, cinoxacin, heatline, cinnoline, pteridine, triazolone, tetrazole, 1,2,3,5-oxadiazol-2-oxides, oxadiazolones, isoxazolones, oxadiazolidine, triazoles, substituted by F, -CN, -CF3or-C(O)-O-(C1-C4)-alkyl, 3-hydroxyprop-2,4-diones, 5-oxo-1,2,4-thiadiazolo, imidazolidine, -carboline and benzanthracene derivatives of these heterocycles.

The term “aryl” is understood aromatic carbon residues with 6-14 carbon atoms in the ring. Aryl residues -(C6-C14) indicate, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl. Biphenylene residues, raftiline residues and, especially, phenyl residues are preferably aryl residues. Aryl residues, especially phenyl residues, one or more times, preferably once, twice or three times can be substituted by the same or different residues of the, preferably the remnants of the range: -(C1-C8)-alkyl, especially -(C1-C4)-alkyl, -(C1-C8)-alkoxy group, especially -(C1-C4)-alkoxy group, halogen, nitro group, amino group, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy group, Ethylenedioxy group, formyl, acetyl, cyano group, hydroxycarbonyl, aminocarbonyl, -(C1-C4-alkoxycarbonyl, phenyl, phenoxy group, benzyl, benzyloxy group, tetrazolyl. Accordingly, these include, for example, these residues, as arylalkyl or arylcarbamoyl. Arylalkyl remains indicate, especially benzyl, 1 - and 2-naphthylmethyl, 2-, 3 - and 4-biphenylyl and 9-fluorenylmethyl. Substituted arylalkyl remains indicate, for example, substituted in the aryl portion one or more -(C1-C8)-alkyl residues, especially -(C1-C4)-alkyl residues, benzyl residues and naphthylethylene residues, for example, 2-, 3 - and 4-methylbenzyl, 4-isobutylphenyl, 4-tert.-butylbenzyl, 4-octylbenzoic, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7 - and 8-methyl-1-naphthylmethyl, 1-, 3, 4-, 5-, 6-, 7 - and 8-methyl-2-naphthylmethyl, substituted in the aryl portion one or more -(C1-C8)-the remnants of the alkoxy group, especially -(C1-C4)-residues and is Coxe group, benzyl residues and naphthylethylene residues, for example, 4-methoxybenzyl, 4-neopentecostal, 3,5-dimethoxybenzyl, 3,4-methylene-dioxybenzene, 2,3,4-trimethoxybenzyl, nitroaniline residues, for example, 2-, 3 - and 4-nitrobenzyl, benzyl substituted with halogen residues, for example, 2-, 3 - and 4-chloro - and 2-, 3 - and 4-tormentil, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethyl-benzyl residues, for example, 3 - and 4-trifloromethyl or 3,5-bis(trifluoromethyl)benzyl.

In monosubstituted phenyl residues Deputy may be in position 2, position 3 or position 4. Doubly substituted phenyl may be substituted in position 2,3, position 2,4, position, 2,5, 2,6 position, position 3, 4, or in the position of 3.5. Three substituted phenyl residues, the substituents can be in position 2, 3 and 4, the position 2,3,5, position, 2,4,5 -, 2,4,6 position, position, 2,3,6 or position 3,4,5.

Notes to the aryl residues are, respectively, divalent Allenby residues, such as phenylenebis residues that may be present, for example, 1,4-phenylene or 1,3-phenylene.

Phenylene-(C1-C6)-alkyl is, in particular, phenylenedi (C6H4-CH2-and phenylenedi, (C1-C6-alkylen-phenyl represents, in particular, methylindenyl (-CH2-C6H4). Phenylene-(the 2-C6)-alkenyl represents, in particular, phenylanaline and phenylendiamine.

The concept of “heteroaryl with 5 to 14 members in the ring” denotes the residue of one monocyclic or polycyclic aromatic system with 5 to 14 members in the ring containing 1, 2, 3, 4 or 5 heteroatoms as members in the ring. Examples of heteroatoms are N, O and S. If there are several heteroatoms, they may be the same or different. Heteroaryl residues may also be substituted one or more times, preferably once, twice or three identical or different residues from the series: -(C1-C8)-alkyl, especially -(C1-C4)-alkyl, -(C1-C8)-alkoxy group, especially -(C1-C4)-alkoxy group, halogen, a nitro group, -N(R10)2group, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy group, formyl, acetyl, cyano group, hydroxycarbonyl, aminocarbonyl, -(C1-C4-alkoxycarbonyl, phenyl, phenoxy group, benzyl, benzyloxy group, tetrazolyl. Preferably heteroaryl with 5 to 14 members in the ring denotes a monocyclic or bicyclic aromatic residue, which contains 1, 2, 3 or 4, especially 1, 2 or 3 identical or different heteroatoms from the OC is and N, O and S, and which may be substituted by 1, 2, 3 or 4, especially from 1 to 3 identical or different substituents from the series: -(C1-C6)-alkyl, -(C1-C6)-alkoxy group, fluorine, chlorine, nitro group, -N(R10)2group, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, -(C1-C4-alkoxycarbonyl, phenyl, phenoxy group, benzyloxy group and benzyl. Especially preferably heteroaryl denotes a monocyclic or bicyclic aromatic residue with 5 to 10 members in the ring, especially a 5-membered or 6-membered monocyclic aromatic residue, which contains 1, 2 or 3, especially 1 or 2, identical or different heteroatoms from the series N, O and S, and which may be substituted by 1 or 2 identical or different substituents from the series: -(C1-C4)-alkyl, halogen, hydroxyl, -N(R10)2group, -(C1-C4)-alkoxy group, phenyl, phenoxy group, benzyloxy group and benzyl.

The term “heterocycle with 5 to 12 members in the ring” denotes a monocyclic or bicyclic 5-membered to 12-membered heterocycle, and a partially or fully saturated. Examples of heteroatoms are N, O and S. the Heterocycle is unsubstituted or substituted by one or more carbon atoms, or one or more heteroatoms, identical or different substituents. These deputies were determi is Elena higher for the remainder of heteroaryl. In particular, a heterocycle substituted one or more times, e.g. once, twice, three times or many times, carbon atoms, equal or different residues from the series: -(C1-C8)-alkyl, for example, -(C1-C4)-alkyl, -(C1-C8)-alkoxy group, for example, -(C1-C4)-alkoxy group, as a methoxy group, phenyl-(C1-C4)-alkoxy group, for example, benzyloxy group, hydroxyl, oxo group, halogen, nitro group, amino group, or trifluoromethyl, and/or substituted on the atom(s) of nitrogen in the heterocycle-(C1-C8)-alkyl, for example, -(C1-C4)-alkyl like methyl or ethyl, if necessary, substituted phenyl or phenyl-(C1-C4)-alkyl, for example benzyl.

Nitrogen-containing heterocycles can also be an N-oxide or a Quaternary salt.

Examples of concepts “heteroaryl with 5 to 14 members in the ring or a heterocycle with 5 to 12 members in the ring” are the remnants formed from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazole, tetrazole, 1,2,3,5-oxadiazol-2-oxides, triazolone, oxadiazolones, isoxazolones, oxadiazolidine, triazoles, which are substituted by F, CN, -CF3or-C(O)-O-(C1-C4)-alkyl, 3-hydroxyprop-2,4-diones, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, Piramide is a, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, cinoxacin, heatline, cinnoline, -carboline and benzenediamine, cyclopent-, cyclohexa or cyclohepta-analyoung derivatives of these heterocycles. Especially preferred residues: 2 - or 3-pyrrolyl, phenylpyrrole as 4 - or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, for example 1-methyl-2-, -4-or-5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3 - or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3 - or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl, 5-methoxy-, 5-benzyloxy-, 5-chloro - or 4,5-dimethyl-2-indolyl, 1-benzyl-2 - or-3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3 - or 4-chinolin, 1-, 3- or 4-ethanolic, 1-oxo-1,2-dihydro-3-ethanolic, 2-honokalani, 2-benzofuranyl, 2-benzothiazyl, 2-benzoxazolyl or benzothiazolyl, or dihydropyridines, pyrrolidinyl, for example 2 - or 3-(N-methylpyrrolidinyl), piperazinil, morpholinyl, thiomorpholine, tetrahydrothieno or benzodioxolyl.

The General structural formula α-amino acids is as follows:

α-Amino acids differ from each other in the residue R, which according to the invention is indicated as “typical balance of amino acids.

In the case when R8denotes the characteristic amino acid residue, PR is doctitle residuals are the following found in nature α -amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid. Especially preferred are histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid. Further, also preferred are characterized by amino acid residues that are used as residue R8not naturally occurring amino acids, such as 2-aminoadenosine acid, 2-aminobutyric acid, 2-aminoadamantane acid, 2,3-diaminopropionic acid, 2,4-diaminopentane acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminofilina acid, phenylglycine, 3-(2-thienyl)-alanine, 3-(3-thienyl)-alanine, 2-(2-thienyl)-glycine, 2-aminoheptanoic acid, pipecolinate acid, hydroxylysine, sarcosin N-methylisoleucine, 6-N-methyllysine, N-methylvaline, Norvaline, norleucine, ornithine, ALLO-isoleucine, ALLO-threonine, ALLO-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)-alanine, 3-(1-naphthyl-alanine), homophenylalanine, homocysteine, homocysteinemia acid, homotrimer, cysteine acid, 3-(2-pyridyl)-alanine, 3-(3-pyridyl)-alanine, 3-(4-pyridyl)Ala is in, 2-amino-3-phenylaminopropyl acid, 2-amino-3-phenylaminopropyl acid, phosphinotricin, 4-forfinally, 3-forfinally, 4-forfinally, 3-forfinally, 3-forfinally, 2-forfinally, 4-chlorophenylalanine, 4-nitrovanillin, 4-aminophenylalanine, cyclohexylamine, citrulline, 5-percription, 5-methoxytryptophol, methionine-sulfon, methionine-sulfoxide or-NH-NR10-C(O)N(R10)2that, if necessary, are also replaced. The natural and non-naturally occurring amino acids having such functional groups as amino group, hydroxyl group, carboxyl group, mercapto group, guanidyl, imidazolyl or indolyl, these groups can also be protected.

As suitable protective groups are preferably N-protective group used for this purpose in the chemistry of peptides, for example, protective groups, urethane type, benzyloxycarbonyl (Z), tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Aloc) or type of acid amides, especially formyl, acetyl or TRIFLUOROACETYL, and alkyl type, for example, benzyl. In the case of the imidazole residue in R8as a protective group is, for example, derived sulfonic acids of the formula IV used for education sulfonamida as a protective group is zhota imidazole, which, especially in the presence of bases as sodium hydroxide, once again it can be chipped off. Source substances for chemical interactions are known or can easily be described in the literature methods.

Further, the invention concerns a method of obtaining the compounds of formula I and/or stereoisomeric forms of the compounds of formula I and/or physiologically compatible salts of the compounds of formula I, wherein a) a compound of formula IV,

where Rd is a suitable protective group (for example, methyl ester), an amide group or a hydroxyl group, and Z, R7and R8have the meaning as in formula I, is subjected to the interaction with the acid chloride or activated complex ester compounds of the formula III,

moreover, D1 represents-COOH or sulfanilamide, and R5, R6and R9have the meanings as in the formula 1, in the presence of a base or, if necessary, means of dehydrating solution and after removal of the protective group is transferred to a compound of formula I, or

b) compound of formula IVa,

where R7and R8have the meanings as in formula I, and E is an N-amino-protective group, joins its carboxyl group through promezhutochnoe the circuit L to the polymer resin of General formula PS, this forms a connection fomula V,

which, after selective removal of the protective group E is subjected to interaction with the compound of the formula III, and R5, R6and R9have the meanings as in formula I, in the presence of a base or, if necessary, dehydrating means, to obtain the compounds of formula VI,

and the compound of formula VI after removal of the material of the carrier is transferred to a compound of formula I, or

(C) a compound of formula I is transferred in a physiologically compatible salt.

According to the variant of method (a) carboxyl group of compounds of formula IVa supply protective group of Rd, such selective preparation of derivatives of carboxylic acids is carried out by the methods described in Houben-Weyl ″Methods der Org. Chemie″, Band 15/1. In a variant of the method (b) the amino group of the parent compounds of formulas provide a protective group, such selective preparation of derivatives of the amino groups is carried out by the methods described in Houben-Weyl ″Methods der Org. Chemie″, Band 15/1. As a suitable protective group KMG preferably use the carboxy-protective group used for this purpose in the chemistry of peptides, for example, protective groups such as complex alilovic esters as methyl-, ethyl-, tert.-butyl, isopropyl-, benzyl-, fluorenylmethyl-, allyl-type complex is arolovich esters, as phenyl-, amide type, such as amide or benzhydrylamine. As a suitable protective group E is preferably used N-protective group used for this purpose in the chemistry of peptides, for example, protective groups, urethane type, as benzyloxycarbonyl (Z), tert-butyloxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc) or type of acid amides, especially formyl, acetyl or TRIFLUOROACETYL, alkyl type as benzyl. Particularly suitable for this purpose is also (trimethyl-silyl)ethoxycarbonyl (theos) group (.Kocienski, Protecting Groups, Thieme Verlag, 1994).

Deriving indolocarbazole acids is carried out by the methods described in Houben-Weyl "Methods der Org. Chemie", Band E6-2A or E6-2B. Thus, to obtain the derivatives indolocarbazole acids of the formula III preferably may be interaction hydrazinobenzene acid and aryl - or heteroarylboronic, in the presence of polyphosphoric acid as a solvent at 145°C. obtaining the necessary hydrazinobenzene acids is well-known specialist of ways, for example, from the corresponding anilines of benzoic acid, aryl - or heteroarylboronic also get available to a person skilled ways, for example, from the corresponding acid chlorides or NITRILES by reaction with, for example, ORGANOMETALLIC compounds.

For the condensation of compounds of the formula IV with compounds of formula III are used preferably in themselves well known to the expert methods of binding of peptide chemistry (see, for example, Houben-Weyl, Methods der Organischen Chemie, Band 15/1 and 15/2, Georg Thiem Verlag, Stuttgart, 1974). As a means of condensation or reagents binding mean such compounds as carbonyldiimidazole, carbodiimides as dicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC), O-((cyano(etoxycarbonyl)-methylene) amino)-N,N,N’,N’-tetramethyluronium-tetrafluoroborate (TOTU) or anhydride propylphosphonic acid (PPA).

The condensation can be carried out under standard conditions. When condensation is imperative that available not reactive amino groups were protected by reversible protective groups. This applies equally to not participating in the reaction of carboxyl groups, which during the condensation are preferably in the form -(C1-C6)-alilovic esters, benzyl esters or tert.-butyl esters. Protection of the amino groups is unnecessary, if the amino groups are in the form of a preliminary stage, as nitro or ceanography, and are formed only after condensation by hydrogenation. After condensation, the existing protective group otscheplaut suitable way. For example, NR2group (gua is adinova protection in amino acids), benzyloxycarbonyl group and benzyl group in the benzyl esters can be removed by hydrogenation. The protective group is tert.-Putilkovo type hatshepsuts in acidic conditions, while the remainder of the 9-fluorenylmethoxycarbonyl removed by secondary amines.

Polymeric media, indicated in formulas V and VI, “PS”, is a crosslinked polystyrene resin with a link labeled as intermediate circuit “L”. This link has a suitable functional group, such as an amine, it is known, for example, as an amide resin Rink, or IT band, and it is known, for example, as Wang resin or OXIMA resin Kaiser. An alternative can be used other polymeric carriers, such as glass, cotton or cellulose with various intermediate circuits L.

Intermediate circuit, denoted by L, covalently linked to a polymer carrier and allows reversible aminobutanol or ester bond with the compound of the formula IVa, in which for further interaction with the related compound of the formula IVa remains stable; however, under the action of the strongly acidic reaction conditions, for example, mixing with triperoxonane acid present in the connecting link group again released. The release of the desired compounds of General formula I from a bridge may be various upon the ozanian during the reaction.

A. General methods of linking protected aminocarbonyl acids of the formula IVa on solid media:

The synthesis was performed in the reactor with a reaction volume of 15 ml Each reactor was filled 0,179 g of Rink resin-Amid-AM (Fmoc-Rink-Amid AM/ Nova-Biochem; loading of 0.56 mmol/g; i.e., 0.1 mmol/reactor). For removal of Fmoc-protective group from the resin in each reactor was added a 30%solution of piperidine/DMF and the mixture was shaken for 45 minutes. Then filtered and the resin 3 times washed with dimethylformamide (DMF).

To link protected amino acids were added to the thus treated resin one a 0.5 molar solution of the corresponding Fmo-amino acids (0.3 mmol in DMF), a solution of HOBt (0.33 mmol in DMF) and a solution of DIC (0.33 mmol in DMF)and the mixture 16 hours was shaken at 35°C. Then the resin was repeatedly washed DMF).

To test the binding took some resin beads and subjected to the test according to the Kaiser; in all cases, the test was negative.

Cleavage Fmo-protective groups is carried out as above, 30%solution of piperidine/DMF.

To link indolocarbazole acid was added to 0.1 molar solution of the appropriate 4 - or 5-substituted acid (0.4 mmol in DMF), a 0.5 molar solution of the binding reagent TOTU (0.44 mmol in DMF) and 0.5 molar solution of ethyldiethanolamine (DIPEA) (0.6 mmol in DMF)and the mixture 16 hours was shaken at 40°C. Then the resin is repeatedly washed with DMF.

For control reactions took some resin beads and subjected to the test according to the Kaiser.

For removal of the desired substances from the solid carrier resin was repeatedly washed with dichloromethane. Then solution was added to off (50% dichloromethane and 50% mixture of 95% triperoxonane acid (TFA), 2% H2About 3% of triisopropylsilane) and the mixture was shaken for 1 hour at room temperature. The mixture was filtered and the filtrate was concentrated until dryness. The precipitate was besieged by diethyl ether and filtered.

Solid precipitation contained the desired products of the highest purity or fractionalise, for example, preparative liquid chromatography high-pressure reversed-phase (eluent: A: H2O/0.1% of TFA In acetonitrile/0.1% of TFA). Lyophilization of the resulting fractions gives the desired products.

Obtaining physiologically compatible salts of the compounds of the formula I is capable of salt formation, including their stereoisomeric forms, is carried out by known methods. Carboxylic acids form with basic reagents, as hydroxides, carbonates, bicarbonates, alcoholate, and ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine or triethanolamine, or basic amino acids as lysine, ornithine or arginine, stable alkali metal salts, alkaline earth metal sludge is, if necessary, substituted ammonium salts. Since the compounds of formula I have a basic group can be obtained with strong acids stable additive salts of acids. This is considered 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 applies to medicines, different effective content of at least one of the compounds of formula I and/or one physiologically acceptable salts of the compounds of formula I and/or, if necessary, one stereoisomeric forms of the compounds of formula I, together with a pharmaceutically suitable and physiologically compatible carrier, additive and/or other biologically active and auxiliary substances.

Due to the pharmacological properties of the compounds according to the invention are suitable for the prevention and treatment of all diseases, the occurrence of which is due to increased activity of IkB kinase. These include, for example, chronic diseases of the musculoskeletal system as inflammatory, immunological or metabolic activity due to acute and chronic arthritis, arthropathies, rheumatoid arthritis, or degenerative arthropathy as osteoarthritis, spondylosis, degenerative cartilage after joint injuries or long position of rest replacement after damage to the meniscus or kneecap, or torn ligaments or connective tissue disease, as collagenosis and periodontal disease, myalgias and disturbances of bone metabolism, or diseases caused by overexpression of the factor α tumor necrosis (TNFα) or high concentration of TNFαas exhaustion, diffuse sclerosis, traumatic brain injury, Crohn's disease and ulcers of the intestine, or disease as atherosclerosis, stenosis, ulcerate, Alzheimer's disease, muscle contraction, cancer (potentiation of cytotoxic therapy), myocardial infarction, gout, sepsis, septic shock, endotoxic shock, viral infections such as influenza, hepatitis, severe viral infection (HIV infection), AIDS, or diseases caused by adenoviruses or herpesviruses, parasitic infections such as malaria or leprosy, fungal or yeast infections, inflammation of the meninges, chronic inflammatory pulmonary diseases such as chronic bronchitis or asthma, acute respiratory distresse syndromes, acute synovitis, tuberculosis, psoriasis, diabetes, treatment acute or chronic rejection reactions of the body d is ipient against the transplanted organ, chronic disease graft versus host disease and inflammatory diseases of blood vessels.

Medicinal product according to the invention take on the whole oral or parenteral. It is also possible rectal or transdermal application.

The invention concerns also a method of producing a medicinal product, characterized in that at least one compound of formula I lead with a pharmaceutically suitable and physiologically acceptable carrier and, if necessary, other suitable biologically active substances, additives or auxiliary substances to a suitable form of administration.

Suitable solid or galenovye preparative forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and drugs with a slow release of biologically active substances, to obtain using conventional excipients such as carriers, sprays, binders, chemicals for coatings, swelling agents, substances imparting slipperiness or lubricants, flavorings, sweeteners and agents of dissolution. As commonly used auxiliary substances called magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, Thal is, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, like cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and the solvent, as, for example, sterile water, and one - or polyhydric alcohols as glycerol. Preferably, the pharmaceutical preparations are made and taken in single doses, each dose contains as an active integral part of a specific dose of a compound of formula I according to the invention. Solid single doses 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 for injection solutions in the form of ampoules approximately up to 300 mg, preferably from about 10 mg to 100 mg For the treatment of adult patients weighing about 70 kg, depending on the effectiveness of the compounds according to formula I, shown daily dose of from about 20 mg to 1000 mg of biologically active substances, preferably from about 100 mg to 500 mg Under certain conditions, however, also can be used with larger or smaller daily doses. Receiving the daily dose can be carried out by a single dose in the form of a separate single dose or several smaller doses, or by repeated administration of divided doses, particularly in the th interval.

Target products, as a rule, determined by mass spectrometric methods (FAB-, ESI-MS). The mean temperature in degrees Celsius, CT (RT) refers to room temperature (22°to 26°). Used abbreviations or explained or correspond to the standard agreements.

Examples

Getting substituted indolocarbazole acids

Variant A) method

2,3-diphenyl-1H-indole-5-carboxylic acid

a 1.96 g (10 mmol) of deoxybenzoin and 1.52 g of 4-hydrazinobenzene acid was finely ground in a mortar and then floated in an open flask for 15 minutes at 160°C. the Cooled melt was mixed with 100 ml of acetic acid and 30 ml of concentrated hydrochloric acid and heated for 3 hours under reflux. When mixing the cooled solution with water precipitated product 1,3-diphenyl-1H-indole-5-carboxylic acid. Was aspirated and then washed the precipitate with water and dried. For cleaning, the crude product is stirred with warm toluene was aspirated and re-dried. Received 2,3-diphenyl-1H-indole-5-carboxylic acid.

Variant B) method

2-pyridin-4-yl-1H-indole-5-carboxylic acid

Mixed 20 g of P2O5with 12.5 ml of N3RHO4(85%), and the reaction mixture was very hot. Accordingly, the reaction mixture was cooled to 60°and added 8.90 g (65,84 mmol) of 4-propenylidene and 4,20 g (27,60 mmol) 4-hydrazine what sainoi acid. Then was stirred 45 min at 145°C. the Reaction mixture was poured into water, and then precipitated yellow product 2-pyridin-4-yl-1H-indole-5-carboxylic acid. This precipitate was aspirated and washed with water until neutral. 2-pyridin-4-yl-1H-indole-5-carboxylic acid thus obtained with a quantitative yield, was used without further purification for binding derivatives of amino acids.

The binding of amino acid derivatives with substituted derivatives indolocarbazole acids.

Option (C) method

Example 1

(1-carbarnoyl-3-phenyl-propyl)-amide 2,3-diphenyl-1H-indole-5-carboxylic acid:

0.16 g (0.5 mmol) of 2,3-diphenyl-1H-indole-5-carboxylic acid (see variant A) method) was dissolved at room temperature in 10 ml drained of dimethylformamide (DMF), and one after another was added 0.11 g (0.5 mmol) of the hydrochloride of L-homophenylalanine, 0.16 g TOTU (O-[(cyano(etoxycarbonyl)methylidene)amino)-1,1,3,3-tetramethyl]uranium-tetrafluoroborate) and 0.14 ml (1 mmol) Diisopropylamine. Was stirred 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl ether, acetic acid. The organic phase is then washed with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered is concentrated under reduced pressure. Received (1-carbarnoyl-3-phenyl-propyl)-amide 2,3-diphenyl-1H-indole-5-carboxylic acid with a melting point of 120°s-125°C.

Example 7:

(1-carbarnoyl-3-pyrrol-1-yl-propyl)-amide 3-methyl-2-pyridin-4-yl-1H-indole-5-carboxylic acid

of 0.13 g (0.5 mmol) 3-methyl-2-pyridin-4-yl-1H-indole-5-carboxylic acid (see variant A) method) was dissolved at room temperature in 10 ml drained of dimethylformamide (DMF), and one after another was added 0.083 g (0.5 mmol) of amide 4-(1-pyrrolyl)-L-2-benzyloxycarbonylamino-butyric acid, 0.16 g (0.5 mmol) of TOTU (O-[(cyano-(etoxycarbonyl)methylidene)amino)-1,1,3,3-tetramethyl]uranium-tetrafluoroborate) and 0.14 ml (1 mmol) ethyldiethanolamine. Was stirred 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl ether, acetic acid. The organic phase is then washed with water, saturated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (HPLC).

a: 4-(1-pyrrolyl)-L-2-benzyloxycarbonylamino acid

To purged with argon to a solution of 1.25 g (5.0 mmol) of Nα-Z-L-2,4-diaminoalkanes acid in 60 ml of water was added 0.66 g (5.0 mmol) of 2,5-dimethoxytetrahydrofuran after 1.7 m is glacial acetic acid and stirred for 12 hours at 20° C. the Reaction mixture was repeatedly extracted with ethyl acetate, the combined organic phases were dried with sodium sulfate and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on kieselgel (CH2CL2/CH3HE/CH3COOH : 100/5/1). After separation of the eluent was obtained 1.3 g (87%) of 4-(1-pyrrolyl)-L-2-benzyloxycarbonylamino-butyric acid.

b: Amide 4-(1-pyrrolyl)-L-2-benzyloxycarbonylamino-butyric acid 1.2 g (4.0 mmol) of 4-(1-pyrrolyl)-L-2-benzyloxycarbonylamino-butyric acid and 0.61 g (4.0 mmol) of ammonium salt of N-hydroxybenzotriazole were dissolved together in 10 ml of DMF at 0°mixed with 0,82 g (4.0 mmol) of N,N’-dicyclohexylcarbodiimide and 0.68 ml (4.0 mmol) of N-ethyl-Diisopropylamine, stirred 30 min at 0°and 3 hours at 20°C. the Precipitated urea was aspirated and the filtrate evaporated to dryness. The crude product was purified by chromatography on kieselgel (CH2Cl2/CH3HE/CH3COOH: 100/5/1). The output of 0.89 g (74%).

from: Amide 4-(1-pyrrolyl)-L-2-amino-butyric acid

0,80 g (to 2.65 mmol) of amide 4-(1-pyrrolyl)-L-2-benzyloxycarbonyl-amino-butyric acid, dissolved in 20 ml of methanol, mixed in the atmosphere of inert gas with 80 mg of catalyst (10% Pd-C), then up to the complete removal of the Z-protective group were injected hydrogen. After filtering off katalizatori evaporation of the filtrate was obtained 0.4 g (90,5%) of amide 4-(1-pyrrolyl)-L-2-amino-butyric acid.

2. Option D) method

Example 3:

(1-carbarnoyl-2-phenylsulfanyl-ethyl)-amide 2-pyridin-4-yl-1H-indole-5-carboxylic acid

To 0.20 g (0.84 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid was added 0.21 g (1.07 mmol) of 2-amino-Z-phenylsulfanyl-propionic acid in 40 ml of DMF and, at 0°With added 0.66 g (1,27 mmol) benzotriazol-1 iloxi-triprolidine-phosphonium-hexaphosphate and 0.37 ml (2,12 mmol) N-ethyl-N,N-Diisopropylamine and stirred 2 hours at 20°C. the Solution was concentrated under reduced pressure and purified by column chromatography medium pressure (CH2Cl2/CH3IT is like 9:1). Thus received to 0.19 g (54%) (1-carbarnoyl-2-phenylsulfanyl-ethyl)-amide 2-pyridin-4-yl-1H-indole-5-carboxylic acid.

Example 9

Amide 3-phenyliminomethyl-2-[(2-pyridin-4-yl-1H-indole-5-carbonyl)-amino]-propionic acid

a) L-2-amino-Z-phenylaminopropyl acid

of 54.8 g (0,209 mol) of triphenylphosphine suspended in 600 ml of acetonitrile and cooled with the exclusion of moisture to -35°C-45°C. Then, at this temperature was added over 50 minutes dropwise of 36.4 g (0,209 mol) diethyl ester of azodicarboxylic acid. Was stirred for another 15 min at -35°C. To this mixture was bury a solution of 50 g (0,209 mol) N-benzyloxycarbonyl-L-serine in 500 ml of acetonitrile, it does not allow the temperature the temperature above -35° C. Then continued the reaction for 12 hours at 5°and was heated to room temperature. The reaction solution was freed from solvent under reduced pressure, and the crude product was purified by chromatography (medium pressure kieselgel (dichloromethane (DHM) (DCM)/acetonitrile: 25/1). After separation of the solvent was received of 20.8 g (yield 45%) of pure N-benzyloxy-carbonyl-L-serine-β-lactone (see also Org. Synth. 1991 (70) 1ff.) in the form of thin needles. Total formula C11H11NO4; the molecular mass (MM) (M.W.)=221,2; MS (M+H) 222,1.

To 7.3 ml (57,36 mmol) of N-ethylaniline in 250 ml of acetonitrile was added in a protective atmosphere of argon of 15.5 ml (63,51 mmol) N,O-bis(trimethylsilyl)ndimethylacetamide and stirred 3 hours at 50°C. were Then added at 20°With the solution of the above lactone (10.7 g, 48,37 mmol), dissolved in 250 ml of acetonitrile, and 17 h was heated under reflux. After separation of the solvent the residue was mixed with saturated sodium carbonate solution, and the pH value of the solution did not exceed 9. The aqueous suspension was washed with a small amount of diethyl ether and then acidified with concentrated hydrochloric acid to pH 6 to 7, and the buffer NaHPO4brought the pH value to 5. Then the aqueous solution was repeatedly extracted with ethyl ether acetic acid. After evaporation of the solvent was obtained the desired product the yield 45% (7,4 g). Total formula C19H22N2O4; M.M.=342,4; MS (M+H) 343,2.

To 75 ml of methanol was bury at -10°With 6.5 ml (89,1 mmol) of thionyl chloride and was stirred 30 min. Then was added 8.6 g (25,12 mmol) dissolved in 75 ml of methanol L-2-amino-ethyl-3-phenylaminopropyl acid, stirred for 30 minutes at -10°With a further 3 hours at room temperature. After evaporation of the solvent the residue was absorbed ethyl ester, acetic acid and washed with sodium carbonate solution. After evaporation of the solvent and purification by flash chromatography (n-heptane/ethyl ester acetic acid 7:3) was obtained 4,43 g (50% yield) of the methyl ester of L-2-amino-ethyl-3-phenylaminopropyl acid. Total formula C20H24N2O4; M.M.=356,4; MS (M+H) 357,3.

For removal of the protective group 4.4 g (12,35 mmol) derivative, protected by Z-group, was dissolved in 500 ml of methanol, was added in an atmosphere of inert gas 100 mg of catalyst (10% Pd(OH)2-C), and, until the complete removal of the Z-protective group, were injected hydrogen. After filtering off the catalyst and evaporating the filtrate was obtained 2.8 g of L-2-amino-ethyl-3-phenylamino-propionic acid (quantitatively). Total formula C12H18N2O2; M.M.=223,3; MS (M+H) 223,1.

Stage b) of the method

0,63 g (of 2.64 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid, obtained as in variantes) method, suspended in 150 ml of DMF and consistently added 1.01 g (is 3.08 mmol) of TOTU and 0.63 ml (3,71 mmol) ethyldiethanolamine. Was stirred 20 min at room temperature and was added to the resulting transparent solution of 0.73 g (or 3.28 mmol) of methyl ester of (S)-2-amino-3-phenylaminopropyl acid obtained according to a). After 15 hours stirring was concentrated under reduced pressure and separated the methyl ester of the compound by flash chromatography on kieselgel (DHM: Meon=19:1). The yield of 0.44 g, total formula C26H26N4O3; MM=442,2; MS (M+H) 443,3.

0,22 g (0,497 mmol) thus obtained methyl ester was dissolved in 100 ml of methanol, cooled to 0°and then 1.5 hours was injected ammonia. The solution was left overnight at room temperature and then evaporated methanol. The crude product was purified by flash chromatography on kieselgel (DHM: Meon=19:1). Output 0,096 g (45.2 percent). C25H25N5O2; M.M.=427,2; MS (M+H) 428,3.

In table 1 compounds were obtained analogously to the methods a)to D).

Pharmacological examples:

The activity of IkB kinase were determined using ELISA, consisting of one Biotin the new substrate peptide, which contains the amino acid sequence of the protein IkB from serine 32 and 36, and one specific poly - or monoclonal antibodies (e.g., from New England Biolabs, Beverly, MA, USA, cat.: 9240), which is associated only with the phosphorylated form of the peptide IkB. This complex immobilizovana on binding antibody 96-well plate (with layered protein (A) and determined with one conjugate of bytesmessage protein and horseradish peroxidase (HRP) (e.g., streptavidin-HRP). The activity can be quantitatively determined in accordance with a standard curve with substrate phosphopeptide.

Holding:

For more complex kinase 10 ml HeLa S3-extract S 100 cells were diluted with 40 ml of 50 mm HEPES, pH 7.5, were placed in a 40% ammonium sulfate and incubated on ice for 30 minutes. Besieged granulate was dissolved in 5 ml of SEC buffer (50 mm HEPES, pH 7.5, 1 mm dithiothreitol DTT, 0.5 mm EDTA ethylenediaminetetraacetate (EDTA), 10 mm 2-glycerol), was centrifuged at 20.000 x g for 15 minutes and filtered through a filter with pores of 0.22 μm. The sample was applied in 320 ml Superose-6 column HPLC (Amersham Pharmacia Biotech AB, Uppsala, Schweden), which was balanced by the SEC-buffer and operated by 4°With a flow rate of 2 ml/min Fraction, the running time which coincided with the running time of the standard molecular weight of 670 kDa, connected for activation. Activation was achieved by 45 minutes of the incubation with 100 nm MECKΔ , 250 μm Mgatp, 10 mm gl2, 5 mm dithiothreitol (DTT), 10 mm 2-glycerol, 2.5 μm microcystin-LR at 37°C. the Activated enzyme was stored at -80°C.

The test substance (2 ml), dissolved in DMSO, incubated for 30 minutes at 25°With 43 μl of activated enzyme (diluted 1:25 in the reaction buffer: 50 mm HEPES, pH 7.5, 10 mm MgCl2, 5 mm DTT, 10 mm β-glycerol, 2.5 μm microcystin-LR). Then added 5 μl of substrate peptide (Biotin-(CH2)6-DRHDSGLDSMKD-CONH2) (200 μm), incubated for one hour and stopped the process by 150 μl of 50 mm HEPES, pH 7.5, with 0.1% bovine serum albumin BSA (BSA), 50 mm EDTA, antibody [1:200]. 100 µl of the inhibited reaction mixture or the standard series, including phosphopeptide, (Biotin-(CH2)6-DRHDS[RHO3]GLDSMKD-CONH2) were then transferred to 96-well plate with protein A (Pierce Chemical Co., Rockford, IL, USA) and 2 hours and incubated with shaking. After 3-stage rinsing the substrate binding protein (PBS), was added 100 μl of 0.5 μg/l streptavidin-HRP (horseradish peroxidase) (diluted in 50 mm HEPES/ 0.1% BSA) for 30 minutes. After a 5-stage washing PBS was added 100 μl of TMB substrate (Kirkegaard &Perry Laboratories, Gaithersburg, MD, USA) and stop the color development by adding 100 μl of 0.18 M sulfuric acid. Adsorption was measured at 450 nm. A standard curve was obtained by linear reg is ASCII, the corresponding 4-parameter dependence of the dose - activity. Based on this standard curve quantify the enzyme activity or its inhibition by the tested substances.

Methods RCA, SW, SC II.

(camp cycle. the monophosphate) - dependent protein kinase (PKA), protein kinase C (CSWs) and caseinline II (ck II) with the appropriate set of tests from Upstate Biotechnologie according to the instructions of the manufacturer were determined at concentrations of ATP (ATP) 50 µm. Instead phosphocellulose filter to launder used multi-layer tablets (Multi-Screen-Platten) (Millipore; phosphocellulose MS-PH, Kat. MAPHNOB 10) with an appropriate exhaust system. Then the tablets were measured in acquired scintillation counter Wallac MicroBeta. As needed used 100 μm test substance.

Each substance was tested twice. From the average values (the enzyme with substances and no substances) subtracted the average value of pure experience (without enzyme), and calculated % inhibition. Determine the IC50conducted with the software package GraFit 3.0. The results are shown in table 2.

Table 2

Inhibition of the kinase at a concentration of substance 100 μm or ICso in microns.
Number exampleIkB-kinase IC50RKA % inhibition RKS % inhibitionSK II% inhibition
132The concentration isThe concentration isN.D.
20,61241535
30,55353937
40,50423347
51,855827
6a 4.9605839
73,0N.D.N.D.18
91,00230
100,5021,0042,0015,00
111,40-16,0073,0061,00
120,810,001,00-9,00
130,1521,0067,0043,00
140,1521,0029,00-19,00
150,3611,0028,00-24,00
N.O. - value does not determine the O.

Table 2A

Inhibition of the kinase at a concentration of 1 mm ATP and

50 µm ATP.
Number exampleIkB-kinase IC501 mm ATPIkB-kinase IC5050 µm ATP
1693 
1723 
18 a 3.9
19 0,62
20 10
21 0,575
22 0,75
23 0,8633
24 19,1
2536,23 
260,2248 
2731,09 
280,7273 
29 0,047

1. Substituted indoles of formula I

and/or a stereoisomeric form of the compounds of formula I and/or physiologically acceptable salt of the compounds of formula I, and R3denotes a residue of formula I,

where D denotes-C(O)-,

R7denotes a hydrogen atom or -(C1-C4)-alkyl,

R8means (a) the characteristic amino acid residue from the group of:

phenylalanine or homophenylalanine, and phenyl residue

unsubstituted or substituted with halogen, or

b) -(C1-C4)-alkyl, where alkyl is unbranched or branched and

b) 1) independently from each other one - or twofold substituted pyrrole residue, and the residue is unsubstituted or substituted with halogen,

b) 2) independently from each other one - or twofold substituted by a residue-S(O)x-R10where x is the integer zero, 1, or 2, or

b) 3) independently of one another one - or twofold substituted by a residue-N(R10)2,

R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is unsubstituted or from one - to three-fold substituted with halogen,

c) phenyl, where phenyl is unsubstituted or from one - to three-fold substituted with halogen,

if (R10)2the remains of R10independently of one another have the meanings (a), (b) or (C),

Z represents (a) a residue from the group of heterocycles, including benzothiadiazin, pyrrole, pyridine, pyrimidine, pirate is, the imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazol, tetrazol, oxadiazole and triazole, and heterocycles are unsubstituted or from one - to three-fold substituted-NH2,=O, alkoxycarbonyl or aminocarbonyl or

b) -C(O)-R11where

R11means 1. -O-R10or 2. -N(R10)2,

R9represents a) a hydrogen atom,

(b) (C1-C6)-alkyl, where alkyl is unbranched or branched and, independently from each other, one-, two - or three-fold substituted by phenyl or =O,

(C) phenyl, and phenyl is unsubstituted or substituted with halogen,

R1, R2and R4represent a hydrogen atom,

R5denotes a hydrogen atom,

R6represents (a) phenyl, and phenyl is unsubstituted or substituted by-NH2,

b) pyridine, or

c) pyrimidine,

moreover, the pyridine or pyrimidine are unsubstituted or substituted by-NH2or-NH-CH3.

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

D represents-C(O)-,

R7denotes a hydrogen atom or -(C1-C4)-alkyl,

R8means (a) the characteristic amino acid residue from the group of phenylalanine or homophenylalanine, and the phenyl residue is unsubstituted or substituted with halogen, or

b) -(C1-C4)-alkyl, where alkyl is unbranched or branched and

b) 1) independently from each other one - or twofold substituted residue pyrrole and pyrrole is unsubstituted or substituted by fluorine,

b) 2) independently from each other one - or twofold substituted by a residue-S(O)x-R10where x is the integer zero, 1, or 2, or

b) 3) independently of one another one - or twofold substituted by a residue-N(R10)2,

R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is unsubstituted or from one - to three-fold substituted with halogen,

(C) phenyl, where phenyl is unsubstituted or from one - to three-fold substituted with halogen, if (R10)2the remains of R10independently of one another have the meanings (a), (b) or (C),

Z represents (a) 1,3,4-oxadiazol, and 1,3,4-oxadiazol is unsubstituted or from one - to three-fold substituted-NH2or

b) -C(O)-R11where

R11means

1. -O-R10or

2. -N(R10)2,

R9represents a) a hydrogen atom,

(b) (C1-C4)-alkyl, where alkyl is unbranched or branched and, independently from each other, one-, two - or three-fold substituted by phenyl,

c) phenyl, precompany is unsubstituted or substituted with halogen,

R1, R2and R4represent a hydrogen atom,

R5denotes a hydrogen atom,

R6represents (a)phenyl, and phenyl is unsubstituted or substituted by-NH2,

b) pyridine, or

c) pyrimidine,

moreover, the pyridine or pyrimidine are unsubstituted or substituted by-NH2or-NH-CH3.

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

D represents-C(O)-, R7denotes a hydrogen atom,

R8means (a) the characteristic amino acid residue from the group of phenylalanine or homophenylalanine, and the phenyl residue is unsubstituted or substituted with halogen, or

b) -(C1-C4)-alkyl, where alkyl is unbranched or branched and

b) 1) independently from each other one - or twofold substituted residue pyrrol,

b) 2) independently from each other one - or twofold substituted by a residue-S(O)x-R10where x is the integer zero, 1, or 2, or

b) 3) independently of one another one - or twofold substituted by a residue-N(R10)2,

R10represents a) a hydrogen atom,

b) -(C1-C6)-alkyl, where alkyl is unsubstituted or from one - to three-fold substituted with halogen,

c) phenyl, where phenyl is unsubstituted or from one who is up to three times substituted by halogen, if (R10)2remains

R10independently of one another have the meanings (a), (b) or (C),

Z represents C(O)-or C(O)-NH2,

R9represents a) a hydrogen atom,

(b) (C1-C4)-alkyl, where alkyl is unbranched or branched and, independently from each other, one-, two - or three-fold substituted by phenyl,

c) phenyl, and phenyl is unsubstituted or substituted with halogen,

R1, R2and R4represent a hydrogen atom,

R5denotes a hydrogen atom,

R6represents (a) phenyl or (b) pyridine.



 

Same patents:

FIELD: organic chemistry, medicine.

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

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

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

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EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new hydroxyindole General formula

< / BR>
where R1- C1-C12-alkyl, linear or branched, if necessary monosubstituted monocyclic saturated or polyunsaturated carbocycles with 6 ring members, WITH6-aryl group and closed carbocyclic substituents on its part, if necessary, can be mono - or polyamidine R4; R5- monocyclic polyunsaturated carbocycles with 6 ring members, mono - or politeley atoms, halogen or a monocyclic polyunsaturated heterocycles with 6 ring members, one of which is N as heteroatom, mono - or politeley atoms of halogen; R2and R3can be hydrogen or HE, and at least one or both of the Deputy should be-HE; R4means-H, -OH, -F, -Cl, -J, -Br, -O-C1-C6-alkyl, -NO2; A -, or a bond, or -(CHOZ)m-(C= 0)-, and m= 0

The invention relates to new indole derivative of the formula I

< / BR>
where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new heterocyclic derivatives of the formula I, where one of R1, R2, R5are carboxy, C2-C5-alkoxycarbonyl, C1-C8by alkyl, substituted hydroxy, carboxy, C2-C5-alkoxycarbonyl or a group of the formula - NR9R10where R9, R10each independently is C1-C6the alkyl, and the other two are each independently is a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R3or R4group - NHCOR7where R7-C1-C20alkyl, C1-6alkoxy, - C1-C6alkyl, C1-C6alkylthio - C1-C6alkyl, C3-C8- cycloalkyl, C3-C8cycloalkyl-C1-C3alkyl, phenyl, phenyl-C1-C4alkyl group-other8where R8-C1-C20alkyl, and the others are a hydrogen atom, a C1-C6the alkyl or C1-C6alkoxy; R6-C1-C20alkyl, C3-C12alkenyl, C1-C6alkoxy, C1-C6alkyl, C1-C6alkylthio C1-C6alkyl, C3-C8cycloalkyl, C3-C8cycloalkyl, C3-C8cycloalkyl-C1-CLIGN="ABSMIDDLE">and is a bridging group to the nitrogen atom, provided that when one of R1, R2, R5is carboxy or C2-C5alkoxycarbonyl, Z is a group of

The invention relates to 1H-indol-3-acetamide General formula I where X is oxygen; R1selected from groups (i), (iii), where (i)6-C20-alkyl, C4-C12-cycloalkyl; (iii) - (CH2)n-(R80), where n is 1-8 and R80is the group specified in (i); R2is hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy; R3each independently is hydrogen or methyl; R4- R7each independently - C1-C10-alkyl, C2-C10alkenyl,3-C8-cycloalkyl,1-C10-alkoxy,

WITH4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -C(O)O(C1-C10-alkyl), hydrazide, hydrazino, NH2, NO2, -C(O)NR82R83where R82and R83independently is hydrogen, C1-C10-alkyl or a group of formula (a), where R84and R85independently is hydrogen, C1-C10-alkyl; p= 1 to 5; z is a bond, -O-, -NH-; Q is-CON(R82R83), -SO3H, phenyl, a group of formula b), C), (d), where R86independently selected from hydrogen, C1-C10-alkyl, and their pharmaceutically acceptable salts or their esters, or Amida

The invention relates to new chemical compounds having valuable biological properties, in particular indole derivative of General formula (I)

< / BR>
and their tautomers,

where R1is hydrogen, halogen, lower alkyl, hydroxyl, nitro, trifluoromethyl, OCOR group and OR where R is lower alkyl, and the remainder R1can replace one methine group rings of Aza-atom;

R2group (CH2)nCOOH, (CH2)nCONH2, (CH2)nCOOR, (CH2)nCONHR, (CH2)nCONRR, (CH2)nCONHCH2Ph, CONHR, CONRR, CONHPh, COPhCOOH, COPhCOOR, (CH2)nCONHPh or (CH2)nCONHPhR, in which R has the above meaning, Ph means phenyl, and n is the number 1 - 4, group COY and SO2Y, in which Y represents phenyl, unsubstituted or substituted lower alkyl, carboxyla or group OCOR, where R has the above meaning;

R3is hydrogen, lower alkyl, benzyl;

R4- group SH, S0X, S0Q and Se0Q', which means the number 1, 2 or 3, X is hydrogen, lower alkyl, benzyl, Q - further 2-diindolyl General formula (I), Q' - further 2-solenoidal General formula (I) provided that if R4lcil, -CONHR6where R6means lower alkyl or (CH2)2N-lower dialkyl, or a group-CH2CH(R'2), C(O)NHCH2Ph, where R'2means amino, and Ph is phenyl,

the following compounds are excluded from the claims: 2-(2-thioxo-3-indolinyl)acetic acid, 2-(1-methyl-2-thioxo-3 - indolinyl)acetic acid, methyl ester 2-(2-thioxo-3 - indolinyl)acetate complex ethyl ester 2-(1-methyl-2-thioxo-3 - indolinyl)acetate, disulfide bis[methylindolin-3-acetate-(2)] , the disulfide bis[indolyl-3-acetic acid-(2)] , the trisulfide bis[methylindole-3-acetate-(2)] disulfide bis[1-methylindole-3 - acetic acid-(2)] , methyl ester of 2,3-dihydro-2 - thioxo-1H-indole-3-acetic acid and methyl ester of 2- (methylthio)-1H-indole-3-acetic acid,

mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts

The invention relates to inhibitors of glycogen phosphorylase, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals

Derived indole // 2137759

The invention relates to medicine, namely to the use of Tris(2-hydroxyethyl) ammonium salt of 3-IntelliTouch acid having the following formula

< / BR>
as a highly effective protective means in cardiogenic shock and toxic stress

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

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