Substituted benzimidazoles and medicinal agent based on thereof

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

 

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

In the international application WO-94/12478 describes, in particular, derivatives of benzimidazole, which inhibit platelet aggregation.

NFkB is a heterodimeric transcription factor that can activate many genes encoding, in particular, Pro-inflammatory cytokines as IL-1, IL-2, TNFα or IL-6. NFkB is in cytosole cells in the form of a complex with its naturally occurring inhibitor IkB. Stimulation of the cells, for example, using cytokines leads to the phosphorylation and subsequent proteolytic cleavage of IkB. This proteolytic cleavage leads to the activation of NFkB, which then migrates into the cell nucleus and there activates many proinflammatory genes.

When diseases such as rheumatoid arthritis (inflammation), osteoarthritis, asthma, heart attack, 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 to enhance the cytostatic therapy. Discovered that drugs like glucocorticoids, salicylates, or gold salts that are used in the treatment of rheumatism, ingibiruet affect different parts of the activating NFkB signal is real chain or directly interfere with gene transcription.

The first stage in the specified signaling cascade is the breakdown of IkB. This phosphorylation is regulated by specific IkB-kinase. It is still not known inhibitors that specifically inhibit IkB-kinase.

In the desire to obtain an effective compound for the treatment of rheumatoid arthritis (inflammation), osteoarthritis, asthma, heart attack, Alzheimer's disease, cancer (increased cytotoxic therapies) or atherosclerosis is shown that the proposed according to the invention, the benzimidazole are strong and highly specific inhibitors of IkB kinase.

The invention, therefore, relates to the compound of formula (I):

and/or a stereoisomeric form 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 R4means the residue of formula (II):

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

R8means a hydrogen atom or a (C1-C4)-alkyl;

R9means:

1. typical amino acid residue;

2. aryl, where aryl unsubstituted or substituted;

3. 5-14-membered heteroaryl where heteroaryl unsubstituted or substituted;

4. 5-12-membered heterocycle, where the heterocycle unsubstituted or substituted;

5. (C1-C6)-and the keel, where the alkyl is linear or branched and unsubstituted or one-, two -, or three times, independently of one another, replaced with:

5.1-aryl, where aryl unsubstituted or substituted;

5.2 5-14-membered heteroaryl where heteroaryl unsubstituted or substituted;

5.3 5-12-membered heterocycle, where the heterocycle unsubstituted or substituted;

5.4-O-R11;

5.5 =On;

5.6 halogen;

5.7-CM;

5.8-CF3;

5.9 -3(O)x-R11where x is the integer zero, 1

or 2;

5.10-C(O)-O-R11;

5.11-C(O)-N(R11)2;

5.12-C(R11)2;

5.13 (C3-C6-cycloalkyl;

5.14 the remainder of the formula:

or

5.15 residue of the formula:

where R11means:

(a) a hydrogen atom;

b), (C1-C6)-alkyl, where alkyl unsubstituted or one-, two - or three-replaced

1. the aryl, where aryl unsubstituted or substituted;

2. 5-14-membered heteroaryl;

3. 5-12-membered heterocycle;

4. halogen;

5. -N-(C1-C6) n-alkyl where n stands for the integer zero, 1 or 2 and the alkyl unsubstituted or one-, two -, or three times, independently of each other, substituted with halogen, or-COOH;

6. -O-(C1-C6)-alkyl or

7. the group-COOH;

c) aryl, where aryl unsubstituted or substituted;

d) 5-14-membered heteroaryl or

e) 5 to 12-membered heterocycle; and

in case the (R 11)2the remains of R11independently from each other have the meaning of (a) to (e);

Z means:

1. aryl, where aryl unsubstituted or substituted;

2. 5-14-membered heteroaryl where heteroaryl unsubstituted or substituted;

3. 5-12-membered heterocycle, where the heterocycle unsubstituted or substituted;

4. -(C1-C6)-alkyl, where alkyl substituted or unsubstituted; or

5. -C(O)-R10where R10means:

1. -O-R11or

2. -N(R11)2;

or R8and R9together with the nitrogen atom and carbon atom, which

they, respectively, are connected, form a heterocycle of formula (IIa):

where D, Z, and R10are specified in the formula (II) value;

A represents a nitrogen atom or a residue -- CH2-;

In a means an oxygen atom, a sulfur atom, a nitrogen atom, or

the rest-CH2-;

X means an oxygen atom, a sulfur atom, a nitrogen atom, or

the rest-CH3-;

Y is absent or denotes an oxygen atom, a sulfur atom,

the nitrogen atom or the residue-CH2-; or

X and Y together form a phenyl; 1,2-, 1,3-or 1,4 - casinoby balance;

moreover, educated N, A, X, Y, b and the carbon atom of the cyclic system contains no more than one oxygen atom; X denotes an oxygen atom, a sulfur atom or nitrogen atom when a represents a nitrogen atom; contains not more than one sulfur atom; contains 1, 2, 3 or 4 atoms which zhota, and at the same time does not present an oxygen atom and a sulfur atom;

moreover, educated N, A, X, Y, b and the carbon atom of the cyclic system is unsubstituted or one, two or three times, independently of each other, substituted (C1-C8)-alkyl, where alkyl unsubstituted or one - or twofold substituted

1.1 group-HE;

1.2 (C1-C8-alkoxyl;

1.3 halogen;

1.4 NO2;

1.5-NH2;

1.6-CF3;

1.7 methylendioxyphenyl;

1.8-C(O)-CH3;

1.9-CH(O);

1.10-CN;

1.11-COOH;

1.12-C(O)-NH2;

1.13 (C1-C4-alkoxycarbonyl;

1.14-phenyl;

1.15 phenoxypropane;

1.16 the benzyl;

1.17 benzyloxypropionic or

1.18 tetrazolium;

or

R9and Z together with the carbon atoms to which they, respectively, are connected, form a heterocycle of formula (IIc):

where D, R8and R11are specified in the formula (II) value;

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

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

V is absent or denotes 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; 1,2-, 1,3 - or 1,4-casinoby balance;

moreover, formed by N, T, V, W and two carbon atoms of the cyclic system content is t not more than one oxygen atom, not more than one atom of sulfur, and 1, 2, 3 or 4 nitrogen atom at the same time does not present an oxygen atom and a sulfur atom; and being educated N, T, V, W and two carbon atoms of the cyclic system is unsubstituted or one-, two -, or three times, independently of each other, substituted specified above in paragraph 1.1 - 1.18 substituents,

and, accordingly, the other substituents R1, R2, R3and R4,

independently from each other, means:

1. a hydrogen atom;

2. halogen;

3. (C1-C4)-alkyl;

4. 5-14-membered heteroaryl where heteroaryl unsubstituted or substituted;

5. 5-12-membered heterocycle, where the heterocycle unsubstituted or substituted;

6. (C1-C4) -alkyl;

7. -CN;

8. -O-(C0-C4-alkylaryl;

9. -O-(C1-C4)-alkyl;

10. OR11;

11. -OR11;

12. S(O)x-R11where x is the integer zero, 1 or 2;

13. -NO2; or

14. -CF3;

R5means:

1. a hydrogen atom;

2. -HE; or

3. =On;

and

R6means:

1. aryl, where aryl unsubstituted or substituted;

2. phenyl, one - or twofold substituted;

2.1-CN;

2.2-NO2;

2.3-O-(C1-C4)-alkyl;

2.4-N(R11)2;

2.5-NH-C(O)-R11;

2.6-S(O)x-R11where x is the integer zero, 1 or 2;

2.7-C(O)-R11; or

2.8 (C1-C4)-alkyl-NH2;

3 5-12-membered heterocycle, where the heterocycle unsubstituted or one-, two - or three-fold substituted.

Preferred is a compound of formula (I), and one of the substituents R1, R2, R3and R4means the residue of formula (II), where:

R8means a hydrogen atom;

R9means:

1. typical amino acid residue;

2. (C1-C6)-alkyl, where alkyl is linear or branched and unsubstituted or one - or twofold substituted by a residue from the group consisting of pyrrole, one - or twofold substituted (C1-C4)-alkyl pyrrole, pyrazole, phenyl, imidazole, triazole, thiophene, thiazole, oxazole, isoxazol, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole, benzothiazole, azetidine, pyrroline, pyrrolidine, piperidine, isothiazole, diazepine, thiomorpholine, -CN, research, azepine, pyrazine, 1,3,4-oxadiazole, -N(R13)-phenyl, where R13has the following value (C3-C6) -cycloalkyl, -OR11; -NH(R11), where R11therefore has the above meaning; -S(O)x-R12where x is zero, 1 or 2 and R12means naphthyl, pyrimidinyl, morpholinyl or phenyl, which is unsubstituted or one - or twofold substituted by a group- (C1-C4)-alkyl, -CF3, halogen, -O-(C1-C4)-alkyl, -COOH, -C(O)-(C1-C4)alkyl, -NH2or-NH-C(O)-(C1-C4) -alkyl, or C(O)-R12where R12has the above meaning;

Z denotes-C(O)-R10tetrazol, (C1-C6)-alkyl, where alkyl is linear or branched and unsubstituted or one - or twofold substituted by phenyl or by a group-HE or 1,3,4-oxadiazol where 1,3,4-oxadiazol unsubstituted or once substituted by a group-NH2, -NH(C1-C4)-alkyl, -N[(C1-C4)-alkyl]2, -NH-C (O) (C1-C4)-alkyl, -NH-C(O)-NH-(C1-C4)-alkyl, -NH-C(O)-NH-(C3-C7-cycloalkyl, -NH-C(O)-NH-aryl, -NH-C(O)-NH-phenyl, -NH-SO2-aryl, -NH-SO2-(C1-C4)-alkyl, a group-HE or (C1-C4) -alkyl, where

R10means-O-R11, phenyl, pyrimidinyl, HE, morpholinyl, -N(R11)2or-NH2;

R11means:

1. (C1-C4) -alkyl;

2. R13or

3. -N(R13)2,

where R13independently from each other, means:

(a) a hydrogen atom;

b) - (C1-C6)-alkyl;

c) - (C1-C4) -alkyl-O(C1-C4) -alkyl;

d) - (C1-C6)-alkyl-NH2;

e) halogen or

f) -(C0-C4)-alkyl, one - or twofold substituted aryl, imidazolyl, morpholinyl or phenyl;

or

R8and R9together with the nitrogen atom and carbon atom, to which they shall respectively, are bound, form a loop of the formula (IIa) from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazol, 2-isoxazolidine, isoxazolidine, research, isothiazole, thiazole, tetrazole; 1,2,3,5-oxadiazol-2-oxides, oxadiazolones, isoxazolones, triazolone, oxadiazolidine, triazoles, which are substituted by F, CN, CF3or COO-(C1-C4)-alkyl; 3-hydroximino-2,4-diones, 5-oxo-1,2,4-thiadiazole, 1,3,4-oxadiazole, isothiazolinone, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, heatline, cinoxacin, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline and isoquinoline;

or

R9and Z together with the carbon atoms to which they, respectively, are connected, form a loop of the formula (IIc) from the group consisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazol, 2-isoxazolidine, isoxazolidine, research, isothiazole, thiazole, isothiazolinone, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, chinasol is on, finokalia, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline, isoquinoline, tetrazole; 1,2,3,5-oxadiazol-2-oxides, oxadiazolones, isoxazolones, triazolone, oxadiazolidine, triazoles, which are substituted by F, CN, CF3or COO-(C1-C4)-alkyl; 3-hydroximino-2,4-diones, 1,3,4-oxadiazole and 5-oxo-1,2,4-thiadiazole; and, accordingly, the other substituents R1, R2, R3and R4independently from each other, means:

1. a hydrogen atom;

2. halogen;

3. (C1-C4)-alkyl;

4. CN;

5. -NO2;

6. -O(C0-C4-alkylaryl;

7. -O-(C1-C4)-alkyl;

8. -N-(C0-C4-alkylaryl;

9. -N-(C1-C4)-alkyl; or

10. -CF3;

R5means:

1. a hydrogen atom;

2. -HE; or

3. =O; and

R6means:

1. phenyl, one - or twofold substituted

1.1. -CN;

1.2-NO2;

1.3-O-(C1-C4)-alkyl;

1.4-NH2; or

1.5 (C1-C4)-alkyl N2; or

2. 5-14-membered heteroaryl, unsubstituted or once substituted up to three times the group-N-R14where R14means (C1-C6)-alkyl, (C3-C4-cycloalkyl or phenyl; halogen, the group-HE or -(C1-C4)-alkyl; or

3. 5-12-membered heterocycle, unsubstituted or once to three times samisen the nd group-N-R 14where R14means (C1-C6)-alkyl, (C3-C6-cycloalkyl or phenyl; halogen, the group-HE or -(C1-C4)-alkyl.

Under the term "halogen" refers to fluorine, chlorine, bromine or iodine. Under ≪(C1-C6)-alkyl≫ understand hydrocarbon residues, carbon chain which is linear or branched and contains 1 to 6 carbon atoms. Under "C0-alkyl" is understood covalent bond. Cyclic alkyl residues are, for example, 3-6-membered monocycle as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Under the definition of "R8and R9together with the nitrogen atom and carbon atom, to which they are bound, form a heterocycle of formula (IIa)" understand residues, which are formed from pyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, tetrazole; 1,2,3,5-oxadiazol-2-oxides, triazolone, oxadiazolones, isoxazolones, 1,3,4-oxadiazole, oxadiazolidine, triazoles, which are substituted by F, CN, CF3or COO-(C1-C4)-alkyl; 3-hydroximino-2,4-diones, 5-oxo-1,2,4-thiadiazolo, isoxazol, indole, isoxazoline, isoxazolidine, research, thiazole, isothiazole, isothiazoline, purine, isothiazolinone, thiomorpholine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine, isoindole, indazole, benzimidazole, f is Alesina, quinoline, isoquinoline, cinoxacin, heatline, cinnoline, pteridine, imidazolidine, carboline and benzenediboronic derivatives of these heterocycles.

Under the definition of "aryl" is understood aromatic hydrocarbon residue with 6 to 14 carbon atoms in the cycle. (C6-C14) -aryl residues are, 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 in particular phenyl residues are preferred aryl residues. Aryl residues, in particular phenyl residues may be one or more times, preferably once, twice or three times, replaced by identical or different residues, preferably residues from the series: (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8-alkoxy, in particular (C1-C4-alkoxy; halogen, the nitro-group, amino group, trifluoromethyl, hydroxyl; hydroxy-(C6-C14)-alkyl, as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl; methylendioxy, atlantoxerus, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, fenoxaprop, benzyl, benzyloxy, tetrazolyl. Accordingly, it is relative to the Xia, for example, such residues, as arylalkyl or arylcarbamoyl. Arylalkylamine residues are, in particular benzyl, 1-and 2-naphthylmethyl; 2-, 3-or 4-biphenylyl and 9-fluorenylmethyl. Substituted arylalkylamine residues are, for example, substituted in the aryl part by one or more (C1-C8)-alkyl residues, in particular (C1-C4)-alkyl residues, benzyl residues and naphthylethylene residues, such as 2-, 3-and 4-methylbenzyl, 4-isobutylphenyl, 4-tert-butylbenzyl, 4-octylbenzoic, 3,5-dimethylbenzyl, pentamethyl-benzyl; 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 part one or more (C1-C8)-CNS residues, in particular (C1-C4)-CNS remains, benzyl residues and naphthylethylene residues, such as, for example, 4-methoxybenzyl, 4-neopentecostal, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl; nitroaniline residues, such as 2-, 3-and 4-nitrobenzyl; halogenosilanes residues, such as 2-, 3-and 4-chloro - and 2-, 3-and 4-tormentil, 3,4-dichlorobenzyl, pentafluorobenzyl; triptoreline residues, such as 3 - and 4-trifloromethyl or 3.5 bis(trifluoromethyl)benzyl.

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

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

Phenylene-(C1-C6)-alkyl, represents in particular phenylenedi (C6H4-CH2-and phenylenedi; (C1-C6-alkylester is a particularly methylindenyl (-CH2-C6H4-). Phenylene-(C2-C6-alkenyl is particularly phenylanaline and phenylendiamine.

The definition of "5-14-membered heteroaryl" means the residue 5-14-membered monocyclic or polycyclic aromatic system, which contains 1, 2, 3, 4 or 5 heteroatoms as members of the cycle. 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 one or more times, preferably once, twice or three times, replaced by the same or different is the action of a series: (C 1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8-alkoxy, in particular (C1-C4-alkoxy; halogen, the nitro-group, -N(R11)2, trifluoromethyl, hydroxyl; hydroxy (C1-C4) -alkyl, as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl; methylendioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4-alkoxycarbonyl, phenyl, fenoxaprop, benzyl, benzyloxy, tetrazolyl. Preferably 5-14-membered heteroaryl means a monocyclic or bicyclic aromatic residue, which contains 1, 2, 3 or 4, in particular 1, 2 or 3 identical or different heteroatoms from the series N, O and 3 and which may be substituted by 1, 2, 3 or 4, in particular 1 to 3 identical or different substituents from the series: (C1-C6)-alkyl, (C1-C6-alkoxy, fluorine, chlorine, nitro-group, -N(R11)2trifluoromethyl, hydroxyl, hydroxy (C1-C4) -alkyl, (C1-C4-alkoxycarbonyl, phenyl, fenoxaprop, benzyloxy and benzyl. Especially preferably heteroaryl means a 5-10 membered monocyclic or bicyclic aromatic residue, in particular a five-membered or six-membered monocyclic aromatic residue, which contains 1, 2 or 3, especially 1 or 2, identical or different heteroatoms from the OC is and N, O and S and may be substituted by one or two identical or different substituents from the series: (C1-C4)-alkyl, halogen, hydroxyl, -N(R11)2(C1-C4-alkoxyl, phenyl, fenoxaprop, benzyloxy and benzyl.

The definition of "5-12-membered heterocycle" means a 5-membered to 12-membered monomaterial or bilaterial, which is partially or fully saturated. Examples of heteroatoms are N, O and S. the Heterocycle unsubstituted or have one or more carbon atoms or one or more heteroatoms substituted by identical or different substituents. These substituents mentioned above in the case of heteroaryl residue. In particular, a heterocycle one or more times, e.g. once, twice, three times or four, carbon atoms substituted by identical or different residues from the series: (C1-C8)-alkyl, for example (C1-C4)-alkyl, (C1-C8-alkoxy, for example (C1-C4-alkoxy as methoxy group; phenyl-(C1-C4-alkoxyl, such as benzyloxy; hydroxyl, oxoprop, halogen, the nitro-group, amino group or trifluoromethyl; and/or atom (atoms) of nitrogen in the cycle he substituted C1-C8)-alkyl, for example (C1-C4)-alkyl, like methyl or ethyl; it may be substituted by phenyl or phenyl-(C1-C4)and the kilometres, such as benzyl. Nitrogen-containing heterocycles can also be present as N-oxides or as Quaternary salts.

Examples of the "5 to 14-membered heteroaryl or 5-12-membered heterocycles are the remains of which are formed from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazole, tetrazole; 1,3,4-oxadiazole, 1,2,3,5-oxadiazol-2-oxides, triazolone, oxadiazolones, isoxazolones, oxadiazolidine, triazoles, which are substituted by F, CN, CF3or COO-(C1-C4)-alkyl; 3-hydroximino-2,4-diones, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, cinoxacin, heatline, cinnoline, carboline and benzeneamine, cyclopent-, cyclohexa or cycloheptanone derivatives of these heterocycles. Particularly preferred are the following balances: 2 or 3-pyrrolyl; phenylpyrrole as 4 - or 5-phenyl-2-pyrrolyl; 2-furyl, 2-thienyl, 4-imidazolyl; methylimidazole, 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-INAIL; 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 in the residue R, which according to the invention is denoted as "typical balance of amino acids. In the case when R9means a characteristic amino acid residue, preferably using characteristic remains of the following, occurring 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. Particularly preferred histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid. Hereinafter, preferred characteristic residues of amino acids that are used as residue R9are also the remains are not naturally occurring amino acids, such as 2-aminoadenosine acid, 2-aminobutanoic acid-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutane 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, sarcosine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolinate acid, hydroxylysine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, Norvaline, norleucine, ornithine, alliteration, 4-hydroxyproline, allowedactions, allochrony, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthyl)-alanine, homophenylalanine, homocysteine, 2-amino-3-phenylamino-ethylpropylamine acid, homocysteinemia acid, homotrimer, cysteine acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)-alanine, 3-(4-pyridyl)alanine, phosphinotricin, 4-forfinally, 3-forfinally, 3-forfinally, 2-forfinally, 4-chlorophenylalanine, 4-nitrovanillin, 4-aminophenylalanine, cyclohexylamine, citrulline, 5-percription, 5-methoxytryptophol, 2-amino-3-phenylaminopropyl acid, methionine-sulfon, methanesulfonic or-NHNR11-CON(R11)2, which can also be substituted. In the case of occurring or not naturally occurring amino acids, which contain functional groups as amino, hydroxyl, carboxyl, mercaptopropyl, guanidyl, imidazolyl or indolyl, this group can also be protected.

As a suitable protective group, preferably using conventional in the chemistry of peptides N-protective group, for example a protective group of the urethane type, as benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Aloc), or aminokislotnogo type, in particular formyl, acetyl or TRIFLUOROACETYL, and alkyl type, as, for example, benzyl. In the case of the imidazole residue in R9this is, for example, used for education sulfonamida derived sulfonic acids of the formula (IV) as a protective group of the imidazole nitrogen, which again can be chipped off especially in the presence of bases like sodium hydroxide solution.

Source substances for chemical transformations known or they can get well-known from the literature methods.

The invention relates further to a method for obtaining 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), characterized in that:

a) compound of formula (IV):

where Pg denotes a suitable protective group (for example, methyl residue), an amide group, or hydroxyl, and Z, R8and R9are specified in the formula (II) is, subject to the interaction with the acid chloride of the acid or activated the private complex ester compounds of the formula (III):

and D1means-COOH or halogenmethyl and R5and R6are specified in the formula (I) is, in the presence of a base or, if necessary, drying means, in solution, and after removal of the protective group is transferred to the compound of formula (I); or

b) compound of formula (IVa):

where R8and R9are specified in the formula (II) is and E protective means for N amino group, through its carboxyl group via an intermediate circuit L is connected with the polymer resin of General formula PS, forming a compound of formula (V):

which, after selective removal of the protective group E is subjected to interaction with the compound of the formula (III), and R5and R6are specified in the formula (I) is, in the presence of a base or, if necessary, drying the means of obtaining the compounds of formula (VI):

and the compound of formula (VI) after removal from the material of the carrier is transferred to a compound of formula (I); or

(C) a compound of the formula (V) after selective removal of the protective group E is subjected to interaction with the compound of the formula (VII):

and D1means-COOH or halogenmethyl and RX denotes halogen and RY means the rest-NO 2or-NH-E and E denotes a protective group, to obtain compounds of formula (VIII):

and then the compound of formula (VIII) is subjected to interaction with the compound of the formula (IX):

NH2-R6(IX)

where R6is specified in the formula (I) value, to obtain the intermediate compounds of formula (VIa):

then the intermediate compound of formula (VIa) or after removal from the material of the carrier is transferred to a compound of formula (I), or, for example, using tributylphosphine reduced to the compounds of formula (VI) and after removal from the material of the carrier is transferred to a compound of formula (I); or

d) compound of formula (I) is transferred to a physiologically acceptable salt.

According to a variant of the method a), the acid functional group of compounds of the formula (IVa) is provided with a protective group, Rgthis selective derivatization of carboxylic acids is performed by the methods described in the book Houben-Weil "Methods of organic chemistry", volume 15/1. According to a variant of the method b, the amino group of the parent compounds of formula (IVa) is provided with a protective group E, this selective derivatization of amino groups carry out the methods described in the book Houben-Weil "Methods of organic chemistry", volume 15/1.

As a suitable protective group Pdpredpochtitel is but use conventional in the chemistry of peptides protective for carboxyl group, for example, protective groups such as ester alkyl groups as methyl, ethyl, tert-butyl, isopropyl, benzyl, fluorenylmethyl, allyl; type ester of aryl groups as phenyl; amide type, such as amide or benzhydrylamine. As a suitable protective group for this purpose, preferably using conventional in the chemistry of peptides N-protective group, for example, protective groups, urethane type, as benzyloxycarbonyl (Z), tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc), or aminokislotnogo type, in particular formyl, acetyl or TRIFLUOROACETYL; and alkyl type as benzyl.

Especially suitable for this purpose was also (trimethylsilyl)ethoxycarbonyl group (theos) (R.Protecting Groups, ed. Thieme, 1994).

As the original products to obtain the benzimidazole derivatives of the formula (III), preferred are 2,3 and 3,4-diaminobenzoic acid and aryl - or heterokedasticity, which is injected into the interaction in the presence of nitrobenzene as a solvent at a temperature of 145°C. Further, the above acid is injected into the interaction with methyl - or ethylenically who will receive the Pinner reaction of the corresponding arylnitrenes or heterogenisation.

For the condensation reaction of compounds of formula (IV) with compounds of the formula (III), PR is doctitle use in itself well known to the expert combination of methods of peptide chemistry (see, for example, Houben-Weil, Methods of organic chemistry, volume 15/1 and 15/2, ed. Georg Thieme, Stuttgart, 1974). As the condensing medium or binding agents are used such compounds as carbonyldiimidazole, carbodiimides as dicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC), O-((cyano(etoxycarbonyl)methylene)amino)-N,N,N',N' -tetramethylethylenediamine (TOTU) or anhydride papapostolou acid (PPA).

The condensation can be performed under standard conditions. During condensation, as a rule, you need to existing, not reactive amino groups were protected by reversible protective groups. The same applies for not participating in the reaction of carboxyl groups, which during the condensation reaction are preferably in the form of a complex (C1-C6)-alilovic esters, complex benzyl ethers or complex tert-butyl esters. Protection of the amino groups is unnecessary, when the amino groups are in the form of precursors, as nitro or ceanography, and are formed only after the condensation reaction by hydrogenation. After the condensation reaction of the available protective group suitable way otscheplaut. For example, NO2group (guanidine protecting the amino acids), benzyloxycarbonyl groups and benzyl groups in complex benzyl ester is removed by gidrirovanie is. The protective group is tert-Putilkovo type otscheplaut in acidic conditions, while the 9-fluorenylmethoxycarbonyl the residue is removed by secondary amines.

Specified in formulas (V) and (VI), denoted as PS polymer carrier is a cross crosslinked polystyrene resin referred to as intermediate circuit L linker. The linker includes a suitable functional group such as amino group, known, for example, as an amide resin Rinca, or IT band, is known, for example, as Wang resin, or OXIMA resin Kaiser. Alternative you can use other polymeric carriers, such as glass, cotton or cellulose, with various intermediate circuits L.

Denoted as L intermediate chain covalently linked to a polymer carrier and allows reversible amidoamine type or ester linking with the compound of the formula (IVa), which during the further transformation remains stable on a linked compound of formula (IVa), however, in strongly acidic reaction conditions, for example, in the case of mixtures with triperoxonane acid located on the linker group again released. The release of the desired compounds of General formula (I) from the linker can occur at different stages of the reaction.

A. General method of linking protected aminocarbonyl the slot of the formula (IVa) with a solid carrier according to a variant of the method b:

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

To link protected amino acid to the thus prepared resin was added in each case 0.5 M solution of the appropriate Fmoc-amino acid (0.3 mmol in dimethylformamide), a solution of HOBt (0.33 mmol in dimethylformamide) and a solution of DIC (0.33 mmol in dimethylformamide) and the mixture was shaken for 16 hours at a temperature of 35°C. Then the resin was repeatedly washed with dimethylformamide.

To control binding was extracted several balls of resin and subjected to the test KAISER; in all cases, the test was negative.

The removal of Fmoc protection group was carried out as described above, using a 30%solution of piperidine in dimethylformamide.

To link benzimidazolecarbamic acid was added a 0.1 M solution of the appropriate 4 - or 5-substituted acid (0.4 mmol in dimethylformamide); 0.5 M solution of the binding reagent TOTU (0.44 mmol in dimethylformamide) and 0.5 M solution of DIPEA (0.6 mmol who in dimethylformamide) and the mixture was shaken for 16 hours at a temperature of 40° C. Then repeatedly washed with dimethylformamide.

To control the reaction was again extracted several balls of resin and subjected to the test 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, 2% H2O, 3% of triisopropylsilane) and the mixture was shaken for 1 hour at room temperature. The mixture was filtered and the filtrate was concentrated to dryness. The residue was besieged from diethyl ether and was filtered.

Solid residues contained the desired products are often of high purity or they were fractionally, for example, by using preparative high performance liquid chromatography (HPLC) with reversed phase (eluent: A: H2O/0.1% of triperoxonane acid; b: acetonitrile/0.1% of triperoxonane acid). By freeze-drying the obtained fractions were obtained desirable products.

Physiologically acceptable salts capable of salt formation of compounds of formula (I), including their stereoisomeric forms, get itself known. Carboxylic acids with basic reagents, as hydroxides, carbonates, bicarbonates, alcoholate, and ammonia or organic bases, such as trimethyl - or triethylamine, is tanolin or triethanolamine, or with basic amino acids, such as lysine, ornithine or arginine, form stable alkali metal salts, alkaline earth metal or, if necessary, substituted ammonium salt. If the compounds of formula (I) contain basic groups, using strong acids it is also possible to obtain a stable additive salts of acids. For this are used as inorganic and organic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonate, benzosulfimide, p-toluensulfonate, 4-bromobenzonitrile, cyclohexanedicarboxylate, triftormetilfullerenov, acetic acid, oxalic acid, tartaric acid, succinic acid or triperoxonane acid.

The invention relates also to medicines, different 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, if necessary, stereoisomeric forms of the compounds of formula (I), together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other biologically active and auxiliary substances.

Thanks pharmacological properties proposed according to the invention compounds suitable for prophylact the key and cure all those diseases, in the course of which involved increased activity of IkB kinase. These include, for example, asthma, rheumatoid arthritis (inflammation), osteoarthritis, Alzheimer's disease, cancer (increased cytotoxic therapies), heart attack, heart failure, acute coronary syndrome (unstable angina), septic shock, acute and chronic renal failure, stroke or atherosclerosis.

Proposed according to the invention the drug is injected mainly oral or parenteral. It is also possible rectal, inhalation or percutaneous introduction.

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

Suitable solid or galenovye forms of the composition are, for example, granules, powders, coated tablets, tablets, (micro)capsules with the medication, suppositories, syrups, juices, suspensions, emulsions, drops or solutions for injection, and preparations with prolonged release of biologically active substances, in the preparation of which use isout conventional auxiliary means, as carriers, extenders, binders, coatings, contributing to the swelling means, antiadhesive or lubricants, flavorings, sweeteners and agents of dissolution. As commonly used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oil, as fish oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols as glycerol.

The pharmaceutical preparations are preferably prepared and administered in single doses, each dose as an active ingredient contains a number of proposed according to the invention the compounds of formula (I). In the case of a solid single doses as tablets, capsules, coated tablets or suppositories, this quantity may be up to about 1000 mg, preferably from about 50 mg to 300 mg, and in the case of solutions for injections in ampoules it could be 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 a daily dose of from about 20 mg to 100 mg of biologically active substances, preferably from about 100 mg to 500 mg Under certain conditions, however, can be higher or lower daily doses. The introduction of the daily dose can be carried out both by single dose in the form of a separate single dose or as multiple smaller doses, as well as by repeated administration of divided doses at certain intervals of time.

Target products, usually determined using methods of mass spectrometry (fast atom bombardment (FAB-MS)ionization electron spray (ESI-MS)). The temperature data are in degrees Celsius; RT means room temperature (22-26°). Abbreviations are either explained or correspond to the usual conventional abbreviations.

Examples according to the variant of method (b) was carried out according to the General method; high-performance liquid chromatography (HPLC) (RP 18; UV 210 nm); gradient 0-15 minutes,=5-70% (=100% H2O/0.1% of triperoxonane acid; B=100% acetonitrile/0.1% of triperoxonane acid).

Connections as shown in the following table 1 examples get the same version of method b according to the General method.

Example 91

Methyl ether (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl, L)-leucine (1)

Ammonium salt of amide 3-nitrophthalic acid (1A)

Placed in a flask, 100 g (518 mmol) of anhydride 3-nitrophthalic acid at room temperature and under stirring rapidly mixed with 170 ml of concentrated ammonium hydroxide solution. Additionally stirred for 1 hour at room temperature. The precipitate is filtered off and dried in a desiccator. Output: 95,6 g (88%). 2-Amino-3-nitrobenzoic acid (1b)

22 g (of 105.2 mmol) Ammonium salt of amide 3-nitrophthalic acid (1A) with stirring, mixed with 165 ml of sodium hypochlorite solution. After 5 minutes, add a solution of 8.8 g of sodium hydroxide dissolved in 22 ml of water and then stirred for 1 hour at a temperature of 70°C. the Suspension with stirring, poured into 500 ml of water. The resulting clear solution is acidified with concentrated HCl. The precipitate is filtered off and dried in a desiccator. Output: 9,68 g (51%).

2,3-Diamine sauna acid (1C)

2-Amino-3-nitrobenzoic acid (1b) in an amount of 14 g (76.9 mmol) was dissolved in 500 ml of methanol, mixed with Pd/C and hydronaut using hydrogen. After 4 hours the catalyst is filtered off and the solution concentrated. Get a solid dark brown color. Output: 11,67 g (99%).

2(Pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d)

700 mg (4.6 mmol) of 2,3-Diaminobenzoic acid (1C) and 0.47 ml (of 4.95 mmol) of 4-peredelanaya dissolved in 40 ml of nitrobenzene and heated with stirring for two hours at a temperature of 145°C. Then cooled and the precipitate filtered off. The precipitate is washed with ethyl acetate and dried in a desiccator. Yield: 800 mg (73%).

Methyl ether (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl)-(L)-leucine (1)

120 mg (0.5 mmol) 2(pyrid-4-yl)-1H-benzimidazol-4-carboxylic acid (1d) and 84 mg (0.5 mmol) of methyl ester of N-(L)-leucine was dissolved in 5 ml of dimethylformamide. Add 164 mg (0.5 mmol) of TOTU (O-[(cyano(etoxycarbonyl)-methylidene)amino-1,1,3,3-tetramethyl]uniterruptible) and 0,086 ml diisopropylethylamine and stirred for 3 hours at room temperature. The precipitate is filtered off and the filtrate concentrated. The residue is dissolved in ethyl acetate, washed with water, the organic phase is dried over anhydrous sodium sulfate and concentrated. Yield: 180 mg (98%).

Mass spectrum (chemical ionization+): (M+N)+=367,1

Example 92

Amide (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl)-(L)-valine (2)

120 mg (0.5 mmol) 2-(pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d) and 76.4 mg (0.5 mmol) of amide H-(L)-valine dissolved in 5 ml of dimethylformamide. Add 164 mg (0.5 mmol) of TOTU (O-[(cyano(etoxycarbonyl)methylidene)amino-1,1,3,3-tetramethyl]uniterruptible) and 0,086 ml diisopropylethylamine and stirred for 3 hours at room temperature. The precipitate is filtered off and the filtrate concentrated. The residue is dissolved in ethyl acetate, washed with saturated sodium chloride solution, the organic phase is dried over anhydrous sodium sulfate and concentrated. Yield: 168 mg (99%).

Mass spectrum (chemical ionization+)(M+H+)=338,2

Example 93

Methyl ether (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl)-

(S)-histidine (3)

Methyl ether (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl)-(L)-histidine (Trt) (3a) 120 mg (0.5 mmol) (2-(pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d) and 242 mg (0.5 mmol) of methyl ester of N-(L)-histidine (Trt) is dissolved in 5 ml of dimethylformamide. Add 164 mg (0.5 mmol) of TOTU and 0,172 ml diisopropylethylamine and stirred for 3 hours at room temperature. A clear solution concentrate. The residue is dissolved in ethyl acetate, washed with water, the organic phase is tub over anhydrous sodium sulfate and concentrated. Yield: 380 mg of crude product.

Mass spectrum (ei e spray+) (M+N)+=to 633.3.

Example 94

Amide (2-(pyrid-4-yl)-1H-benzimidazole-4-carbonyl)-(L)-methionine (4)

120 mg (0.5 mmol) 2-(pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d) and 74.2 mg (0.5 mmol) of amide H-(L)-methionine dissolved in 5 ml of dimethylformamide. Add 164 mg (0.5 mmol) of TOTU and 0,086 ml diisopropylethylamine and stirred for 3 hours at room temperature. A clear solution concentrate. The residue is dissolved in ethyl acetate, washed with saturated sodium chloride solution, the organic phase is dried over anhydrous sodium sulfate and concentrated. Output: 149 mg (81%).

Mass spectrum (ei e spray+) (M+N)+=370,2.

Connections as shown in the following table 2 examples get similar to the methods of examples 91-94.

Example 156

The following connections will receive a variant of the method a):

a) obtaining a 2-personication acid

to 5.00 g (45 mmol) of 2-fluoro-4-methylpyridine and 1.00 g (17 mmol) of KOH mixed with 50 ml of pyridine and refluxed. At this temperature for 30 minutes added in several portions of 20.00 g (127 mmol) of potassium permanganate and the following 1.5 hours refluxed. Then cooled in a bath with ice, mixed with 100 ml of water and concentrated hydrochloric acid is brought to a pH value equal to 1. After adding 100 ml of ethyl acetate is filtered off from the insoluble residue and the aqueous phase is extracted with twice 100 ml of ethyl acetate. United an ethyl acetate phase is dried over magnesium sulfate and concentrate under reduced pressure. Obtain 2.70 g of 2-personication acid. Yield: 42%.

b) Receiving (2-herperidin-4-yl)methanol

12,60 g (89 mmol) of 2-Personication acid together with 13.3 ml (95 mmol) of triethylamine bring in 300 ml of toluene and mixed with the remaining 9.08 ml (95 mmol) of the ethyl ether of Harborview acid and stirred for 1 hour at room temperature (20-23°). Then triethylammonium filtered off and the toluene phase is concentrated under reduced pressure. The residue is treated with 200 ml of absolute tetrahydrofuran and cooled to a temperature of -78°C. If this t is mperature added dropwise a suspension of 3.55 g (95 mmol) of sociallyengaged in tetrahydrofuran and stirred for 30 minutes. After that the reaction mixture is brought to room temperature and poured into 1 l of ice water. After performing extraction 4 times in 300 ml ethyl acetate, drying of the United an ethyl acetate phase over magnesium sulfate and evaporation of solvent to obtain the crude product, after purification by medium pressure chromatography (CH2Cl2:CH3HE is in the ratio of 9:1) to give 5.10 g (40 mmol) of the desired product. Yield: 45%.

c) Obtaining 2-herperidin-4-carbaldehyde

To a solution of 4.6 ml (54 mmol) of oxalicacid and 7.6 ml (106 mmol) of dimethyl sulfoxide (DMSO) in 450 ml dichloromethane at a temperature of -78°With added dropwise a solution of 5 g (39 mmol) (2-herperidin-4-yl)methanol in dichloromethane and stirred additionally for 15 minutes. Then add 24 ml (180 mmol) of triethylamine and the reaction solution is slowly heated to room temperature. Poured into 500 ml of water and washed once with 200 ml of 10%citric acid and with 10%sodium carbonate solution. The dichloromethane phase is dried over magnesium sulfate and concentrate under reduced pressure. Output: 4,60 g (37 mmol; 94%).

d) Obtaining 2-(2-herperidin-4-yl)-1H-benzimidazole-5-carboxylic acid

2.00 g (15 mmol) of 2-herperidin-4-carbaldehyde with 2,40 g (15 mmol) of 3,4-diaminobenzoic acid are suspended in 100 ml of nitrobenzene and paramesh who live within three hours at a temperature of 145° C. Then the reaction solution is cooled to a temperature of 0°and slowly the resulting crystals are filtered. Get 2,53 g (9.8 mmol) of the desired benzimidazole. Yield: 62%.

e) Obtaining 2-(2-methylaminomethyl-4-yl)-1H-benzimidazole-5-carboxylic acid 100 mg (0.38 mmol) of 2-(2-herperidin-4-yl)-1H-benzimidazole-5-carboxylic acid are dissolved in 5 ml of methanol. Then a methanol solution saturated with gaseous methylamine and the reaction mixture is stirred in an autoclave for 10 hours under its own pressure at a temperature of 120°C. By chromatography medium pressure (CH2Cl2:CH3HE=2:1) to obtain 56 mg (0.21 mmol) of product substitution. Yield: 55%.

f) Receiving trifenatate 2-(S)-{[2-(2-methylamino-pyridin-4-yl)-1H-benzimidazole-5-carbonyl]amino}-4-pyrrol-1-yl-butane acid

50 mg (0,186 mmol) of 2-(2-herperidin-4-yl)-1H-benzimidazole-5-carboxylic acid are dissolved in 3 ml of dimethylformamide and cooled to a temperature of 0°C. To the resulting solution was added 100 μl (of 0.58 mmol) diisopropylethylamine and 64 mg (of € 0.195 mmol) of TOTU. Then add 33 mg (0,196 mmol) of 2-(S)-amino-4-pyrrol-1-yl-butane acid and the reaction solution is brought to room temperature. Additionally stirred for 18 hours, then poured into 20 ml of 10%aqueous solution of sodium bicarbonate and extracted with 3 times 50 ml of n-butanol is. After evaporation of the butanol residue purified by preparative HPLC (acetonitrile, with 0.1%triperoxonane acid). So get 40 mg (0,075 mmol) of the associated product. Yield: 42%.

Connections as shown in the following table 3 examples get a similar way:

Example 163

The following connection receive regular way and,

a) obtaining the ethyl ester of 2-(S)-amino-3-phenylcarbonylamino acid

It dissolved in 10 ml of methanol and 1.00 g (5 mmol) of 2-(S)-amino-3-phenylcarbonylamino acid at a temperature of -10°With added dropwise 1.7 ml (23 mmol) of thionyl chloride. Then the reaction solution is brought to room temperature and add 5 ml of dimethylformamide. Then heated at a temperature of 70°C for 23 hours and after cooling to a temperature of -10°again add 1 ml (13.5 mmol) of thionyl chloride. Then stirred for 14 hours at a temperature of 70°C. After evaporation of the liquid phase residue is treated with water and alkalinized with concentrated aqueous ammonia solution and extracted 3 times with 75 ml ethyl acetate. After drying over magnesium sulfate and evaporation receive the product in the form of oil, which without further PTS the harsh conditions used for the reaction in combination with a carboxylic acid as a component. Output: 830 mg (3.7 mmol) (74%).

b) obtaining the ethyl ester of Z-phenylsulfanyl-2-(S) - [(2-(pyridin-4-yl)-1H-benzimidazole-5-carbonyl)amino]propionic acid

In this case, the reaction mix standard TOTU with 188 mg (0.83 mmol) of the ethyl ester of 2-(S)-amino-3-phenylcarbonylamino acid and 200 mg (0.83 mmol) of 2-pyridin-4-yl)-1H-benzimidazole-5-carboxylic acid leads to the production of the desired product. Yield: 43% (160 mg, 0.36 mmol).

Connections as indicated in table 4 examples get a similar way:

Example 168

The following connection receive regular way:

a) Obtaining [1(2-morpholine-4-yl-ethylcarbamate)-2-phenylsulfanyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

100 mg (0.24 mmol) of 3-Phenylsulfanyl-2-[(2-pyridin-4-yl-1H-benzimidazole-5-carbonyl)amino]propionic acid are dissolved in 10 ml of dimethylformamide. To the resulting solution at a temperature of 0°add 68 μl (0,39 mmol) diisopropylethylamine and 248 mg (0.48 mmol) benzotriazol-1-electropermeabilization. Then bring to room temperature and stirred for additional 24 hours. The solvent is removed under high vacuum at room temperature and the residue purified by medium pressure chromatography (CH2 Cl2:CH3IT=8:2). Yield: 73 mg (0,1376 mmol) (57%).

Connections as indicated in table 5 examples get a similar way:

Example 180

The following connection receive variant of method (a)

a) obtaining a Z-homophenylalanine

5 g (16 mmol) of Z-Homophenylalanine at room temperature, dissolved in 100 ml of methyl tert-butyl ether, is mixed with 3.3 g (16 mmol) of N,N'-dicyclohexylcarbodiimide and 50 mg dimethylaminopyridine and stirred for two hours at room temperature. Then the reaction mixture is filtered through a folded filter and the filtrate washed with 1M solution of potassium hydrosulfate, saturated solution of sodium bicarbonate and water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in 20 ml of anhydrous ethanol is mixed with 0,78 ml (16 mmol) of hydrazine hydrate is added and stirred for two hours at room temperature. Over the course of the reaction is monitored by thin layer chromatography (TLC), and upon termination of the reaction mixture is concentrated under reduced pressure. The remainder will recrystallized from a mixture of ethyl acetate with the-heptane in the ratio of 1:1 and get Z-homophenylalanine, therefore, subjected to further transformation.

b) Obtaining benzyl ester [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid

0.66 g of Z-Homophenylalanine at room temperature, suspended in 10 ml of water, mixed with 200 mg of potassium bicarbonate and then added dropwise 0.4 ml of a 5M solution of bromine cyan in acetonitrile. The mixture is stirred for 3 hours at room temperature and then repeatedly extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is stirred with methyl tert-butyl ether, filtered under vacuum and dried under reduced pressure. The thus obtained benzyl ester [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid without further purification used in the next stage.

c) Receiving 5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine

0.33 g of Benzyl ether [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid at room temperature is dissolved in 50 ml of anhydrous methanol in an atmosphere of argon mixed with a hydrogenation catalyst (10%palladium-on-coal) and hydronaut for three hours at room temperature. The reaction mixture is filtered h is through celite, the filtrate is concentrated under reduced pressure and the residue dried in high vacuum. Get a 5-(1-amino-3-phenylpropyl)[1,3,4] oxadiazol-2-ylamine, which without further purification used in the next stage.

d) Obtaining [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl] amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

0.18 g of 5-(1-Amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine at room temperature, dissolved in 10 ml of anhydrous dimethylformamide, mixed with 200 ml of 2-pyridine-4-yl-1H-benzimidazole-5-carboxylic acid, 270 mg TOTU and 0.12 ml of Diisopropylamine and stirred for 4 hours at room temperature. The reaction mixture was concentrated, the residue is treated with ethyl acetate and washed successively with water, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is stirred with methyl tert-butyl ether, filtered and dried in high vacuum. Get [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, which melts at a temperature of 160°With decomposition.

Example 181

The following connection receive regular way:

a) Z-Homophenylalanine receive is as described in example 180.

b) Obtaining benzyl ester (1-[1,3,4]oxadiazol-2-yl-3-phenylpropyl)carbamino acid

1 g Z-Homophenylalanine at room temperature, suspended in 8 ml of ethyl ether of orthomorphisms acid and refluxed for 4 hours. The cooled reaction mixture is mixed with methyl tert-butyl ether, the precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is subjected to chromatographicaliy on silica gel using mixtures of ethyl acetate with n-heptane in the ratio of 1:1 and get a benzyl ether (1-[1,3,4]oxadiazol-2-yl-3-phenylpropyl)carbamino acid, which is used in the next stage.

c) Obtaining 1-[1,3,4]oxadiazol-2-yl-3-phenylpropylamine perform similarly to obtain 5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-ylamine, as described in example 180.

d) Receiving (1[1,3,4]oxadiazol-2-yl-3-phenylpropyl)amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

220 mg of 1-[1,3,4]-Oxadiazol-2-yl-3-phenylpropylamine at room temperature, dissolved in 10 ml of anhydrous dimethylformamide, mixed with 260 mg of 2-pyridine-4-yl-1H-benzimidazole-5-carboxylic acid, 350 mg TOTU and 0.15 ml of Diisopropylamine and stirred for 4 hours at room temperature. The reaction mixture was concentrated, the residue is treated with ethyl acetate and washed successively with water, n is sasenum solution of sodium bicarbonate, water and a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatographicaliy on silica gel using mixtures of dichloromethane with methanol in the ratio of 8:1 and get (1-[1,3,4]oxadiazol-2-yl-C-phenylpropyl)amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, which melts at a temperature of 103°With decomposition.

Example 182

The following connection receive regular way:

a) Obtaining L-N-benzyloxycarbonyl-4-([1,3,4]oxadiazol-2-yl)-2-aminobutanoic acid

1 g γ-Hydrazide Z-glutamic acid with 30 mg of p-toluenesulfonic acid are suspended in 20 ml of methyl ether of orthomorphisms acid and stirred at room temperature. The suspension is clarified within 30 minutes, the formed due to this, the solution is filtered and diluted with 100 ml of water. After adding 20 ml of 2 N. hydrochloric acid and extracted 5 times with ethyl acetate and then the combined organic phases are dried over sodium sulfate. After filtration the solution is concentrated under reduced pressure and get opaque viscous mass.

b) Obtaining morpholide L-N-benzyloxycarbonyl-4-([1,3,4]oxa-diazol-2-yl)-2-aminobutanoic acid

300 mg L-M-benzyloxycarbonyl-4( [1, 3, 4 ] oxidiazol-2-yl) -2-aminobut the new acid and 200 mg of N-ethyl-N'-(3-dimethylamino-propyl)carbodiimides dissolved in 20 ml of dichloromethane and then mixed with 2 ml of the research. After stirring for two days at room temperature the solution is shaken 3 times with saturated sodium hydrogen carbonate solution, 3 times with aqueous citric acid solution and once with saturated sodium hydrogen carbonate solution. The organic phase is dried over sodium sulfate and after filtration, concentrated under reduced pressure. Get yellowish opaque residue.

c) Obtaining morpholide L-4-([1,3,4]oxadiazol-2-yl)-2-aminobutanoic acid

70 mg of Morpholine L-N-benzyloxycarbonyl-4-([1,3,4]oxadiazol-2-yl)-2-aminobutanoic acid was dissolved in 20 ml of methanol and mixed with made once at the tip of a spatula of 5%palladium-on-coal, and the suspension is stirred in a hydrogen atmosphere. After three hours the catalyst is filtered off on celite and the filtrate after filtration through 0.45 µm filter, concentrate under reduced pressure.

d) Obtaining [1-(morpholine-4-carbonyl)-3-[1,3,4]oxadiazol-2-ylpropyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

43 mg of 2-Pyridine-4-yl-1H-benzimidazole-5-carbonate acid, 75 mg of HATU and 51 mg of diisopropylethylamine dissolved in 1 ml N,N-dimethylformamide and after stirring for 10 minutes, mixed with 40 mg of morpholine L-4-([1,3,4]oxadiazol-2-yl)-2-aminobutanoic acid in 0.4 ml of N,N-dimethylformamide. After stirring for 7 hours at room temperature add the 200 mg aminomethylpyridine (1.37 mmol/g) and 20 ml of N,N-dimethylformamide. After 1 hour, filtered and distilled N,N-dimethylformamide under reduced pressure. The remainder insist with cold acetonitrile. The insoluble residue on the floor and the combined acetonitrile solution is subjected to a gradient filter through RP18 silica using mixtures of water with acetonitrile. Emit a yellowish glassy solid.

Example 183

Hydroheat 3 phenoxy-2-[(2-(pyridin-4-yl-1H-benzimidazole-5-carbonyl)amino]propionic acid

a) 2-Pyridin-4-yl-1H-benzimidazole-5-carboxylic acid (hereinafter referred to as compound 1)

15.2 g (0.1 mol) of 3,4-Diaminobenzoic acid are suspended in 1 l of nitrobenzene and mixed with 11.2 g (0.104 g mol) pyridine-4-aldehyde. Then the mixture under vigorous stirring heated for 8 hours at a temperature in the range from 145°155°C. After cooling, the solution is precipitated precipitated product is filtered under vacuum and washed thoroughly with ethyl acetate and dichloromethane. For purification the crude product in a mixture of 300 ml of methanol, 100 ml of dichloromethane and 10 ml of dimethylformamide is heated to boiling. After cooling nerastvorim the product is filtered and washed with dichloromethane. The resulting material is treated with about 200 ml of dimethylsulfoxide, and then the mixture is heated until the resulting homogeneous is astora, cooled to a temperature of about 50°and mixed with 200 ml of methanol; the product crystallizes after approximately 30 minutes at room temperature. The precipitate is filtered off and thoroughly washed with methanol. Output: 19,4,

(b) Hydrochloride (S)-2-amino-3-phenoxypropionic acid (MM 217,6)

2.8 g of Trt-Ser-OMe (Bachem), 0.75 g of phenol and 2.25 g of triphenylphosphine together dissolved in 60 ml of absolute tetrahydrofuran and at a temperature of 0°C for 30 minutes, dropwise mixed with 1,49 g diethyl ester of azodicarboxylic acid. The reaction mixture is additionally stirred for 30 minutes at a temperature of 0°C, warmed to room temperature (approximately 1 hour). Order processing to remove the solvent under reduced pressure and the crude product is purified by chromatography on silica gel (heptane:ethyl acetate=1,5:1). The thus obtained methyl ester (S)-2-trailmen-3-phenoxypropionic acid slowly crystallizes in long needles, and for removal of protective groups is refluxed for 1 hour in the 5M model HC1. The reaction solution is evaporated to dryness under reduced pressure by repeated joint evaporation with toluene and the residue will recrystallized from a small amount of tert-butanol.

Stage C)

239 mg of 2-Pyridine-4-yl-1H-benzimidazole-5-carboxylic acid of the stage is) suspended in 10 ml of dimethylformamide and mixed successively with 328 mg TOTU and 0.17 ml of ethyldiethanolamine. Stirred for 45 minutes at room temperature and to the resulting clear solution was added 217,6 mg hydrochloride (S)-2-amino-3-phenoxypropionic acid, obtained as described in stage b), and 0.34 ml of ethyldiethanolamine. After stirring for 4 hours, concentrated under reduced pressure and produce the target compound by flash chromatography on silica gel (dichloromethane:methanol:acetic acid:water=70:10:1:1). Received specified in the title compound has a molecular mass equal to 402,41; molar mass equal to 402; total formula of the compound: C22H18N4O4

Example 184

Hydroheat 3 phenylamino-2-[(2-pyridin-4-yl-1H-benzimidazole-5-carbonyl)amino]propionic acid

a) L-2-Amino-3-phenylaminopropyl acid

to 2.74 g of Triphenylphosphine are dissolved by heating in 30 ml of acetonitrile and cooled with the exclusion of moisture to a temperature in the range from -35°C to -45°With (this finely dispersed precipitates phosphine) and after that at this temperature for 40 minutes is added dropwise to 1.82 ml diethyl ester of azodicarboxylic acid. Stirred additionally for 15 minutes at a temperature of -35°C. To this mixture is added dropwise a solution of 2.5 g of N-benzyloxycarbonyl-L-serine in 5 ml of acetonitrile and 2 ml of t is trageriemen, the temperature should not exceed -35°C. Then leave to further react for 1 hour at -35°C and warmed to room temperature. From the reaction solution to remove the solvent under reduced pressure and the crude product was immediately purified by medium pressure chromatography on silica gel (dichloromethane/acetonitrile=20:1). After removal of the solvent to obtain 1.4 g of purified N-benzyloxy-carbonyl-L-serine-β-lactone (see also Org. Synth., 1991 (70), S. 1 and later) in the form of fine needles. 1.2 g of the Lactone is dissolved in 10 ml of acetonitrile and together with 0.51 g of aniline is refluxed for two hours. After removal of solvent the product produce by chromatography on silica gel (dichloromethane/methanol/acetic acid=100:5:1). Obtain 1.1 g (68%) of L-2-benzyl-oxycarbonyl-3-phenylaminopropyl acid.

For removal of the protective group Z-protected derivative is dissolved in methanol, in an atmosphere of inert gas added 80 mg of catalyst (10%palladium-on-coal) and miss hydrogen until complete removal of the Z-protective group. After filtering off the catalyst and evaporating the filtrate gain of 0.58 g (92%) of L-2-amino-3-phenylaminopropyl acid in the form of a yellowish soft, needle-like formations.

Stage b)

239 mg of 2-Pyridine-4-yl-1H-benzimidazole-5-carboxylic KIS is the notes, obtained as described in example 183, suspended in 10 ml of dimethylformamide and mixed successively with 328 mg TOTU and 0.17 ml of ethyldiethanolamine. Stirred for 45 minutes at room temperature and to the resulting clear solution was added 180,2 mg (S)-2-amino-3-phenylaminopropyl acid obtained according to a), and 0.34 ml of ethyldiethanolamine. After stirring for 4 hours, concentrated under reduced pressure and produce the target compound by flash chromatography on silica gel (dichloromethane:methanol:acetic acid:water=70:10:1:1). Received specified in the title compound has a molecular mass equal to 401,43; total formula of the compound: C22H19N5O3

Example 185

239,2 mg (1 mmol) of the Compound 1, obtained as described in example 183, approximately 8 ml of dimethylformamide sequentially mixed with 182,7 mg (1 mmol) of H-Leu-OMe.HC1, 328 mg (1 mmol) of TOTU and 0.34 ml (2 mmol) of ethyldiethanolamine. After incubation for 6 hours at room temperature the solvent is distilled off under reduced pressure, the residue is treated with ethyl acetate and washed 3 times with water and saturated NaCl solution. The organic phase is dried and evaporated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel (dichloro-what'étang/methanol=15:1). Output: approximately 200 mg

Example 186

239,2 mg (1 mmol) of the Compound 1, obtained as described in example 183, approximately 8 ml of dimethylformamide sequentially mixed with 166,6 mg (1 mmol) of H-Leu-NH2·HCl, 328 mg (1 mmol) of TOTU and 0.34 ml (2 mmol) of ethyldiethanolamine. After incubation for 6 hours at room temperature the solvent is distilled off under reduced pressure, the residue is treated with ethyl acetate and washed 1 time with water. The aqueous phase is then saturated with sodium chloride and extracted 2 times with a mixture of ethyl acetate with tetrahydrofuran in a ratio of 1:1. The combined organic phases are washed 1 time with saturated NaCl solution, dried and evaporated to dryness under reduced pressure. The residue is precipitated with dichloromethane and filtered. For purification the crude product is subjected to boiling with a mixture of dichloromethane and ethyl acetate in the ratio of 1:1, filtered off and thoroughly washed with a mixture of dichloromethane with diethyl ether. Output: approximately 200 mg

Example 187

239,2 mg (1 mmol) of the Compound 1, obtained as described in example 183, approximately 8 ml of dimethylformamide sequentially mixed with 152,6 mg (1 mmol) of H-Val-NH2·HCl, 328 mg (1 mmol) of TOTU and 0.34 ml (2 mmol) of ethyldiethanolamine. After incubation for 6 hours at room temperature the PE the solvent is distilled off under reduced pressure, the residue is treated with ethyl acetate and washed 1 time with water. The aqueous phase is then saturated with sodium chloride and extracted 2 times with a mixture of ethyl acetate with tetrahydrofuran in a ratio of 1:1. The combined organic phases are washed 1 time with saturated NaCl solution, dried and evaporated to dryness under reduced pressure. The residue is precipitated with dichloromethane and filtered. For purification the crude product is subjected to boiling with a mixture of dichloromethane and ethyl acetate in the ratio of 1:1, filtered off and thoroughly washed with a mixture of dichloromethane with diethyl ether. Output: approximately 200 mg

Example 188

239,2 mg (1 mmol) of the Compound 1, obtained as described in example 183, approximately 8 ml of dimethylformamide sequentially mixed with 247,7 mg (1 mmol) of H-Dopa-OMe·HCl, 328 mg (1 mmol) of TOTU and 0.34 ml (2 mmol) of ethyldiethanolamine. After incubation for 6 hours at room temperature the solvent is distilled off under reduced pressure, the residue is treated with ethyl acetate and washed 3 times with water and saturated NaCl solution. The organic phase is dried and evaporated to dryness under reduced pressure. The residue is precipitated with dichloromethane and filtered. For purification the crude product is subjected to boiling with a mixture of dichloromethane and ethyl acetate in the ratio of 1:1, filtered off and thoroughly washed the t with a mixture of dichloromethane with diethyl ether. Output: approximately 200 mg

Example 189

The following connection receive regular way):

2.0 g of the Resin of the polystyrene-AM, RAM, 160-200 microns (0.64 mmol/g, Rapp Polymere) placed in a plastic syringe, leave to swell for 20 minutes in dimethylformamide and then treated with a solution of dimethylformamide/piperidine (1:1) for 20 minutes. After washing with dimethylformamide, dichloromethane, dimethylformamide resin used in the next stage of the synthesis.

Stage a)

To a solution of 0.71 g (of 3.84 mmol) Fmoc-PheOH and 0.59 g (of 3.84 mmol), HOBt-hydrate in dimethylformamide type of 0.59 ml (3,84 mmol) DIC ((dimethylamino)isopropylpalmitate).

The resulting solution is injected in the above-mentioned syringe and the mixture is shaken for 16 hours at room temperature. The resin is washed 10 times in 15 ml of dimethylformamide, 4 times in 15 ml of dichloromethane and 2 times 15 ml of dimethylformamide and then stored at a temperature of 4°C. To monitor the reaction on a few resin beads carry out the test KAISER.

Stage b)

From the resin removes the protective group as described above, and washed. To a solution of 0.71 g (of 3.84 mmol) 4-fluoro-3-nitrobenzoic acid and 0.59 g (of 3.84 mmol), HOBt-hydrate (approximately 15 ml of dimethylformamide type of 0.59 ml (3,84 mmol) DIC. The resulting solution is injected into the syringe from under otoplenie resin and the mixture is shaken for 16 hours at room temperature. The resin is washed 10 times in 15 ml of dimethylformamide and stored at a temperature of 4°C. To monitor the reaction on a few resin beads carry out the test KAISER.

Stage C)

A solution of 1.4 ml (12.8 mmol) of 4-(aminomethyl)of pyridine in 10 ml of dimethylformamide is added to the prepared resin and the mixture is shaken for two days at room temperature. The resin is washed 8 times with 15 ml of dimethylformamide, 4 times in 15 ml of dichloromethane and 2 times 15 ml of dimethylformamide. Note: later found that simply including heating the resin mixture in dimethylacetamide (instead of dimethylformamide) for 16 hours leads to the desired hydroxybenzo-imidazole; thus, the synthesis can be accelerated.

Stage d)

The resin solution in dimethylacetamide are placed in a closed glass reactor and the reaction mixture is heated for 16 hours at a temperature of 125°With slightly shaking. Last cyclization can be confirmed using gas chromatography/mass spectrometry (after removal of an aliquot of the substance from the resin). After washing 5 times with 15 ml of dimethylacetamide thus obtained resin used in the synthesis step (e).

Stage e)

To a solution of 0.5 g of the resin from step d) in 5.0 ml of dimethylacetamide add 0.6 ml of tributylphosphine and the mixture was kept slightly stirring, for 6 hours PR is a temperature of 150° C. the Resin is then washed 20 times with 10 ml of dimethylformamide, 10 times in 10 ml methanol and 10 times in 10 ml of dichloromethane.

Stage f): Cleavage and purification

Obtained in stage e) resin for 3 hours at room temperature is treated with a mixture of triperoxonane acid/water (95:5). The mixture triperoxonane acid and water are removed under reduced pressure and get glassy solid brown color in the form of a crude product. The crude product chromatographic on silica gel (flash chromatography; solvent: dichloromethane/2.0 M NH3in methanol in the ratio 95:5; then dichloromethane/2.0 M NH3in methanol in the ratio of 92:8). The desired fractions are collected and the solvent is removed under reduced pressure. The product is obtained in the form of a solid white color.

Mass spectrum (ei e spray; M+N4=400)

1H-NMR spectrum consistent with the above structural formula

Example 190

The following connection receive regular way)

A) Synthesis of 3(R/S)-vinyl-2(S)-azido-3-phenylpropionic acid

a) To a solution of 0,129 mol ethyl ester 3-vinyl-4-phenylbutanoate acid in aqueous tetrahydrofuran (120 ml/20 ml of N2O) added 21 g (645 mmol) of lithium hydroxide in the form of a monohydrate. The reaction mixture is stirred during the night and then concentrated under reduced pressure. The residue is distributed between ethyl acetate and aqueous 0.1 M HCl solution, the phases are separated and the aqueous phase is washed 2 times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure. Obtain 15.6 g (yield 62%) acid, which is thus used in the next reaction.

b) To a cooled to a temperature of -78°With the solution of 1.74 g (9,16 mmol) of the above acid in 10 ml of anhydrous tetrahydrofuran type of 1.27 ml of triethylamine and after 15 minutes of 1.18 ml pualeilani. The mixture is stirred for 1 hour at a temperature of 0°and cooled to a temperature of -78°C. In a separate flask cooled to temperatures of -78°With a solution of 1.64 g S-phenyloxazolidine in 36 ml of tetrahydrofuran is added slowly to 5.7 ml of a 1.6 M solution of n-utility in hexane. The solution is stirred for 1 hour at a temperature of -78°C, warmed to 0°and the cannula is added dropwise to visaelectron solution. At the end of the addition the solution is stirred over night at room temperature. Add 20 ml of a saturated solution of NH4Cl and volume of the solution reduced to 1/3 under reduced pressure. The aqueous solution is extracted 3 times with dichloromethane, the combined organic phases are washed with aqueous solution of sodium hydroxide, su is at over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography (silica gel; 5-20% ethyl acetate/hexane). Get to 2.06 g (yield 67 %) of imide in the form of a mixture of both diastereomers.

(C) To a cooled to a temperature of -78°With a solution of 1.88 g (5,61 mmol) imide in 15 ml of anhydrous tetrahydrofuran is added dropwise to 14.6 ml of 0.5 M solution in toluene potassium salt 1,1,1,3,3,3-hexamethyldisilazane. After 40 minutes add the cooled (-78° (C) a solution of 2.51 g trimethylsilane in tetrahydrofuran. After following 35 minutes add 1,47 ml of acetic acid and the solution is stirred over night at room temperature. The reaction mixture was partitioned between dichloromethane and a saturated solution of sodium chloride, the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is subjected to flash chromatography on silica gel (eluent: (a) dichloromethane/methanol/aqueous ammonia = 95:5:1; b) dichloromethane; the original ratio a:b=1:10, up to pure dichloromethane). Obtain 2.5 g (yield 95%) of etidocaine.

d) To a cooled (0° (C) a solution of 2.5 g of the above etidocaine in 20 ml of tetrahydrofuran, 4 ml of water and 558 mg of the monohydrate of lithium hydroxide add 3 ml of hydrogen peroxide (30%). The mixture is stirred for 2 hours at room temperature and then add 19 ml of 10%aqueous solution of sodium sulfate. The volume of the solution reduced the t under reduced pressure to 1/10 of the initial volume, the resulting residue is extracted 3 times with ethyl acetate, the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified on silica gel (flash chromatography; eluent: 1-5% methanol in 1%aqueous solution of ammonia/99% dichloromethane). Get 912 mg of the desired acid (yield: 74%).

C) Synthesis of 2-pyridine-4-yl-1H-benzimidazole-5-carbonyl-3-R,S-benzyl-3-prolinamide

0.4 g of the Resin of the polystyrene-Knorr resin (0.61 mmol/g) was placed in a plastic syringe, leave to swell for 20 minutes in dimethylformamide and then treated with a solution of dimethylformamide/piperidine (1:1) for 20 minutes. After washing with dimethylformamide, dichloromethane, dimethylformamide resin used in the next stage of the synthesis.

Stage a)

To the above resin add a solution of 0.28 mmol 3(R/S)-vinyl-2(S)-azido-3-phenylpropionic acid (see also stages a-d)), 0.28 mmol Rumor and 0.32 mmol of DIPEA. The resulting mixture was shaken for 16 hours at room temperature. The resin is washed with 3 times 15 ml of methanol and 4 times in 15 ml of dichloromethane and dried under reduced pressure. To monitor the reaction on a few resin beads carry out the test KAISER.

Stage b)

In the atmosphere of inert gas 23 mmol of cyclohexene are added to a 2 M solution of the complex decollage is silburn/dimethyl sulfide (11.6 mmol) in anhydrous diethyl ether. One hour later formed a solid white color. The solvent is removed under reduced pressure and add the above resin and 10 ml dichloromethane. A heterogeneous mixture is gently stirred for 2.5 hours until the gas evolution stops. The resin is washed with methanol and dried under reduced pressure. Then for 1 hour it is stirred with a mixture in the ratio of 50:50 (vol/vol) of ethanolamine and dimethylformamide and then washed 3 times with methanol and dichloromethane, and then dried.

Stage C)

To a solution of 0.69 mmol 4-fluoro-3-nitrobenzoic acid and 0.69 mmol HOAt about 5 ml of dimethylformamide added 0.69 mmol DIC. This solution will contribute to the syringe with the prepared resin and the mixture is shaken for 16 hours at room temperature. The resin is washed 10 times in 15 ml of dimethylformamide and dried in vacuum. To monitor the reaction on a few resin beads carry out the test KAISER.

Stage d)

A solution of 4-(aminomethyl)pyridine (4.6 mmol) in 4 ml of dimethylformamide is added to the prepared resin and the mixture is shaken for 32 days at room temperature. The resin is washed with 3 times 15 ml of methanol and 3 times with 15 ml dichloromethane and dried.

Stage e)

The resin solution in dimethylacetamide are placed in a closed glass reactor and reacciona the mixture is heated for 16 hours at a temperature of 125° With slightly shaking. Last cyclization can be confirmed using gas chromatography/mass spectrometry (after removal of an aliquot of the substance from the resin). The resin is washed with 3 times 15 ml of methanol and 3 times with 15 ml dichloromethane and dried.

Stage f)

To a solution 0,021 mmol of resin from step e) in 3.0 ml of dimethylacetamide add 0.5 ml of tributylphosphine and the mixture was kept slightly, stirring, for 5 hours at a temperature of 125°C. the Resin is then washed with 2 times 10 ml of dimethylformamide, 2 times 10 ml of methanol and 3 times with 10 ml dichloromethane and dried under reduced pressure.

Stage g): Cleavage and purification

Obtained in stage f) resin for 1 hour at room temperature is treated with a mixture of triperoxonane acid/water (97:3). The mixture triperoxonane acid and water are removed under reduced pressure and get glassy solid brown color in the form of a crude product. The crude product chromatographic on silica gel (flash chromatography; solvent: dichloromethane/2,0 NH3in methanol in the ratio 95:5; then dichloromethane/2,0 NH3in methanol in the ratio of 92:8). The desired fractions are collected and the solvent is removed under reduced pressure. The product is obtained in the form of a solid white color.

Mass spectrum (ei e spray; M+N4=426) 1H-NMR spectrum consistent with the above structural formula.

Example 191

The following connection receive regular way):

1.5 g of Polystyrene Knorr resin (0.64 mmol/g) was placed in a plastic syringe, leave to swell for 20 minutes in dimethylformamide and then treated with a solution of dimethylformamide/piperidine (1:1) for 20 minutes. After washing with dimethylformamide, dichloromethane, dimethylformamide resin used in the next stage of the synthesis.

Stage a)

To the resin add a solution of 1.5 mmol Fmoc-3R,S-phenyl-3-Proline, 1.5 mmol Rumor and 2.1 mmol DIPEA in dichloromethane. The resulting mixture was shaken for 16 hours at room temperature. The resin is washed 4 times in 15 ml of dichloromethane, 2 times 15 ml of methanol and dichloromethane and dried under reduced pressure. To monitor the reaction on a few resin beads carry out the test KAISER.

Stage b)

The resin, as described in example 190 according to the method, then enter into interaction to obtain the desired connection.

Mass spectrum (ei e spray; M+N4=412)1H-NMR spectrum consistent with the above structural formula.

Example 192

The following connection receive regular way:

a) obtaining a Z-homophenylalanine

Z-Homophenylalanine receive as described in example 180°.

b) Obtaining benzyl ester [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid

Benzyl ether [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid get as described in example 180b.

C) Obtaining benzyl ester [1-(5-benzosulfimide-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid

0.35 g of the Compound according to example 192b at room temperature is dissolved in 5 ml of pyridine, mixed with 0,13 ml benzosulfimide and stirred for 4 hours at a temperature of 80°C. Add again 0,13 ml benzosulfimide and stirred for further 2 hours at a temperature of 80°C. the Reaction mixture was concentrated in vacuo and the residue treated with ethyl acetate, an ethyl acetate phase is washed twice with water and three times with saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. Get benaraby ether[1-(5-benzosulfimide-[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid, which without further purification enter into interaction further.

d) Obtaining N - [5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-yl]benzosulfimide

0.18 g of the Compound from example s at room temperature RAS is varaut in 30 ml of anhydrous methanol, in the atmosphere of argon mixed with Pd/C catalyst and hydronaut for 4 hours at room temperature. After filtration, washing of the residue with methanol and concentration of the filtrate receive N-[5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-yl]-benzosulfimide, which is used in the next stage.

e) Obtaining [1-(5-benzosulfimide[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

70 mg of the Compound according to example 192d at room temperature is dissolved in 5 ml of anhydrous dimethylformamide, mixed with 30 μl of Diisopropylamine, 48 mg of 2-pyridine-4-yl-1H-benzimidazole-5-carboxylic acid and 66 mg TOTU. After stirring for 4 hours at room temperature the reaction ends and the reaction mixture is concentrated. The residue is treated with ethyl acetate and water. The solvent is decanted; the oily residue is treated with warm acetone, cooled and the crystalline product is collected on a filter, washed with acetone and dried. Get [1-(5-benzosulfimide[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]-amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, which melts since temperature 220°With decomposition.

Example 193

The following connection receive regular way:

a) obtaining a Z-homogenital ingegrated

Z-Homophenylalanine receive as described in example 180°.

b) Obtaining benzyl ester [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid

Benzyl ether [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid get as described in example 180b.

c) Obtaining benzyl ether {1-[5-(3-methylurea)-[1,3,4]oxadiazol-2-yl]-3-phenylpropyl}carbamino acid

350 mg Benzyl ester [1-(5-amino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]carbamino acid are dissolved in 5 ml of anhydrous dimethyl sulfoxide, mixed with 140 mg of potassium carbonate and 140 mg of methyl isocyanate and stirred for 16 hours at a temperature of 80°C. the Reaction mixture is cooled, mixed with ethyl acetate, washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Get a benzyl ether {1-[5-(3-methylurea)-[1,3,4]oxadiazol-2-yl]-3-phenylpropyl}carbamino acid, which without further purification used in the next stage (hydrogenolysis).

d) Obtaining 1-[5-(1-amino-3-phenylpropyl)-[1,3,4]oxadiazol-2-yl]-3-metalmachine

120 mg Obtained in stage C) of the compounds at room temperature is dissolved in 20 ml of anhydrous methanol in an atmosphere of argon mixed with Pd/C catalyst and hydronaut for 4 hours at room Tempe is the atur. The reaction mixture is filtered, the residue is washed with methanol and the filtrate concentrated in vacuo. 1[5-(1-Amino-3-phenylpropyl)-[1,3,4] -oxadiazol-2-yl]-3-metalmachine without further purification used in the next stage.

e) Obtain {1-[5-(3-methylurea)-[1,3,4]oxadiazol-2-yl]-3-phenyl-propyl}amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

40 mg of the Preceding compound at room temperature is dissolved in 3 ml of anhydrous dimethylformamide and mixed successively with 33 mg of 2-pyridine-4-yl-1H-benzimidazole-5-carboxylic acid, 20 μl of Diisopropylamine and 40 mg TOTU and stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue is treated with a mixture of ethyl acetate/tetrahydrofuran 1/1, washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Get {1-[5-(3-methylurea) -[1,3,4]-oxadiazol-2-yl]-3-phenylpropyl}amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, which according to the mass spectrum is m/z=497,3(=MN+).

Example 194

The following connection receive regular way:

[1-(5-Acetylamino[1,3,4]oxadiazol-2-yl)-3-phenylpropyl]-amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid get in principle similar is cnym way however, with the difference that instead of methyl isocyanate is injected into the interaction with acetylchloride. The compound has a melting point 183-186°With decomposition.

Example 195

The following connection receive regular way:

a) Obtaining benzyl ester (1-cyano-3-phenylpropyl)-carbamino acid

2,78 g Benzyl ester (1-carbarnoyl-3-phenylpropyl)-carbamino acid derived from L-homophenylalanine and N-Cbz-succinimide, dissolved in 30 ml of anhydrous pyridine and mixed with 6 ml of acetanhydride. The reaction mixture is stirred for 24 hours at a temperature of 75°C. the Cooled solution was concentrated in vacuo, mixed with 100 ml of ethyl acetate and then shaken out three times with 50 ml of 5%citric acid solution and saturated solution of sodium chloride. The organic extract is dried over magnesium sulfate, concentrated in vacuo and chromatographic on silica gel using a mixture of n-heptane/ethyl acetate 1:1 ratio. Receive benzyl ester (1-cyano-3-phenylpropyl)carbamino acid, which without further purification used in the next stage.

b) Obtaining benzyl ester [3-phenyl-1-(1H-tetrazol-5-yl)-propyl]carbamino acid

0.15 g of the Compound obtained in example a, together with 0,115 g trimethylborazine suspender the Ute in 5 ml of anhydrous toluene and stirred for 6 hours while boiling under reflux. The cooled reaction mixture is acidified with a solution of hydrogen chloride in diethyl ether and incubated over night in the fridge. The next day, the mixture was concentrated in vacuo and chromatographic on silica gel using mixtures of dichloromethane/methanol in the ratio 9:1. The thus obtained benzyl ester [3-phenyl-1-(1H-tetrazol-5-yl)propyl]carbamino acid without further purification used in the next stage.

c) Obtaining 3-phenyl-1-(1H-tetrazol-5-yl)Propylamine

337 mg of the Compound obtained in example 195b, dissolved in 2 ml of acetonitrile, mixed with 0,477 ml of triethylsilane, one drop of triethylamine and with the amount on the tip of a spatula chloride palladium(II) and stirred for 3 hours at boiling under reflux. The cooled solution is filtered, concentrated in vacuo and the residue dried in high vacuum. The thus obtained 3-phenyl-1-(1H-tetrazol-5-yl)Propylamine enter into interaction further.

d) Obtaining [C-phenyl-1-(1H-tetrazol-5-yl)propyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid

0.9 mmol of the Compound obtained in example C, dissolved in 5 ml of anhydrous dimethylformamide and mixed with 0.9 mmol of 2-pyridine-4-yl-1H-benzimidazole-5-carboxylic acid, 0,365 ml Diisopropylamine and 415 mg TOTU, stirred for 20 hours at room temperature and in accordance with what their next 4 hours at a temperature of 50° C. the Reaction mixture was concentrated in vacuo, the residue is treated with ethyl acetate, an ethyl acetate phase is washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The thus obtained crude product chromatographic on silica gel using mixtures of dichloromethane/methanol/water/glacial acetic acid in the ratio of 60:10:1:1. Get [3-phenyl-1-(1H-tetrazol-5-yl)-propyl]amide 2-pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, starting with a temperature of 87°decomposes and has a molecular peak at m/z=425,2(M+).

Example 196

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

a) L-2-Amino-3-phenylaminopropyl acid

of 54.8 g (0,209 mol) of Triphenylphosphine are suspended in 600 ml of acetonitrile and with the exclusion of moisture is cooled to a temperature in the range from -35°C to -45°C. Then, at this temperature for 50 minutes is added dropwise of 36.4 g (0,209 mol) diethyl ester of azodicarboxylic acid. Additionally stirred for 15 minutes at a temperature of -35°C. To this mixture is added dropwise a solution of 50 g (0,209 mol) N-benzyloxycarbonyl-L-serine in 500 ml of acetonitrile, the temperature should not revisit -35° C. then leave to further react for 12 hours at a temperature of 5°C and warmed to room temperature. From the reaction solution to remove the solvent under reduced pressure and the crude product is purified by medium pressure chromatography on silica gel (dichloromethane/acetonitrile=25:1). After removal of the solvent gain of 20.8 g (yield 45%) of purified N-benzyloxycarbonyl-L-serine-β-lactone (see also Org. Synth. 1991 (70), S. 1 and later) in the form of fine needles. Total formula: C11H11NO4; molecular weight=221,2; mass spectrum (M+H):222,1.

To 7.3 ml (57,36 mmol) of N-ethylamine in 250 ml of acetonitrile in an argon atmosphere add to 15.5 ml (63,51 mmol) N,O-bis(trimethylsilyl)ndimethylacetamide and stirred for 3 hours at a temperature of 50°C. and Then at a temperature of 20°add a solution of 10.7 g (48,37 mmol) videolounge of lactone in 250 ml of acetonitrile and refluxed for 17 hours. After removal of solvent the residue is mixed with a saturated solution of sodium carbonate, and the pH value of the solution does not exceed 9. The aqueous suspension was washed with a small amount of diethyl ether and then with concentrated hydrochloric acid to establish a pH value of from 6 to 7 and using NaHPO4-buffer set pH value equal to 5. An aqueous solution repeatedly ek is tracerout with ethyl acetate. After evaporation of the solvent produces the desired product with a yield of 45% (7,4 g). Total formula: C19H22N2About4; molecular weight=342,4; mass spectrum (M+H):343,2.

To 75 ml of methanol at a temperature of -10°With added dropwise to 6.5 ml (89,1 mmol) of thionyl chloride and stirred for 30 minutes. Then add a solution of 8.6 g (25,12 mmol) of L-2-amino-ethyl-3-phenylaminopropyl acid in 75 ml of methanol, stirred for 30 minutes at a temperature of -10°and for a further three hours at room temperature. After evaporation of the solvent the residue is treated with ethyl acetate and an ethyl acetate phase is washed with sodium carbonate solution. After evaporation of the solvent and purification by flash chromatography (n-heptane/ethyl acetate=7:3) receive 4,43 g (yield 50%) of the methyl ester of L-2-amino-ethyl-3-phenylaminopropyl acid. Total formula: C20H24N2O4; molecular weight=356,4; mass spectrum (M+H):357,3.

For removal of the protective group 4.4 g (12,35 mmol) of Z-protected derivative is dissolved in 500 ml of methanol, in an atmosphere of inert gas was added 100 mg of catalyst (10% Pd(OH)2-C) and miss hydrogen until complete removal of the Z-protective group. After filtering off the catalyst and evaporating the filtrate obtain 2.8 g (yield quantitative) L-2-amino-ethyl-3-phenylaminopropyl the th acid. Total formula: C12H18N2O2; molecular weight=222,3; mass spectrum (M+H): 223,1.

Stage b)

2.4 g (there is a 10.03 mmol) of 2-Pyridin-4-yl-1H-benzimidazole-5-carboxylic acid, obtained as described in example 183, suspended in 350 ml of dimethylformamide and mixed successively with 4.2 g (12,80 mmol) of TOTU and 2.3 ml (13,52 mmol) ethyldiethanolamine. Stirred for 10 minutes at room temperature and to the resulting clear solution was added 2.8 g (12,60 mmol) of methyl ester of (S)-2-amino-3-phenylaminopropyl acid, obtained according to stage a). After stirring for two hours, concentrated under reduced pressure and produce methyl ester target compound by flash chromatography on silica gel (dichloromethane/methanol=9:1). Output: 4,36 g (98%); total formula: C25H25N5About3; molecular weight=443,5; mass spectrum (M+H):444,3.

4.3 g (9.7 mmol) of the Thus obtained complex methyl ester in 400 ml of methanol hydrolyzing for two hours at room temperature by adding 200 ml of 1 M sodium hydroxide solution. After evaporation of methanol to the resulting suspension with a solution of NaH2PO4set the value of pH=5. In addition, the product precipitates from solution. Purification using flash chromatography on silica gel (dichloromethane/methanol=4:1) and p is operativnoy HPLC (acetonitrile/0.1% of triperoxonane acid) gives of 2.92 g (yield 70%) of triptoreline 3-phenyliminomethyl-2-[(2-pyridin-4-yl-1H-benzimidazole-5-carbonyl)amino]propionic acid. Total formula: C24H23N5About3; molecular weight=of 429.5; mass spectrum (M+H):430,3; melting point is about 25°C (decomposition).

The drugs examples

Filter test against IkB-kinase

The activity of IkB kinase was determined using the system for the analysis of protein kinases "Signa TEST™(Promega; catalog 1998, S. 330; similarly, the statement "Signa TEST™" in relation to DNA-dependent protein kinase). The kinase was purified according Z.J. Chen(Cell, 84, 853-862 (1996)) from extracts of HeLa cells and incubated with 20 µmol of substrate peptide (Biotin-(CH2)6-DRHDSGLDSMKD-CONH2). The buffer for the reaction contains 50 mm HEPES, pH 7.5; 10 mm MgCl2; 5 mm dithiothreitol (DTT), 10 mm β-glycerol, 10 mm 4-nitrophenylphosphate; 1 μm microcystin-LR and 50 μm adenosine-5' -triphosphate (ATP) (containing 1 MCI γ-33P-ATP).

The method of the RCA, SW, SK II

camp (cyclic amp)-dependent protein kinase (PKA), protein kinase C (CSWs) and caseinline II (ck II) was determined using the test set Upstate Biotechnology accordance with manufacturer's instructions at a concentration of 50 µm ATP. In contrast, not used any phosphocellulose filters, and used tablets for multiscreening (firm Millipore; phosphocellulose Ms-PH-cat. MAPHNOB10) with the corresponding suction system. Tablets or membrane (IkB-kinase) is then measured in scinti the air counter Wallac MicroBeta. In each case used 100 µmol test substance.

Each substance was tested twice. From the average values (the enzyme with substances and no substances) subtracted the mean value of the control (without enzyme) and calculated the percentage of inhibition. Calculations IR50(inhibiting 50% concentration) was performed using the software package GraFit 3.0. The results are presented in table 6.

Examples 197-224, are shown in table 7, were performed in accordance with one of the above methods a), b) or C).

1. Substituted benzimidazole of the formula (I)

and/or their stereoisomeric forms and/or their physiologically acceptable salts, and one of the substituents R1, R2, R3and R4means the residue of formula (II)

where D denotes-C(O)-;

R8means a hydrogen atom or a (C1-C4)-alkyl;

R9means:

1. (C1-C6)-alkyl, where alkyl is a linear or did the run and unsubstituted or mono-, two or three times, independently from each other substituted:

1.1 phenyl, naphthyl, biphenyl, which is unsubstituted or one-, two - or three-fold substituted (C1-C4)-alkyl, (C1-C4-alkoxyl, a halogen, a nitro-group, amino, trifluoromethyl, hydroxyl, cyano, hydroxycarbonyl, fenoxaprop;

1.2 balance 5-14-membered aromatic system which contains 1 or 2 heteroatoms as members of the cycle are nitrogen, where the aromatic system is unsubstituted or substituted;

1.3 1,3,4-oxadiazol, which is unsubstituted or substituted;

1.4 5-12-membered heterocycle, which is fully or partially unsaturated and which contains 1 heteroatom, which is a sulfur, where the heterocycle unsubstituted or substituted;

1.5-O-R11;

1.6-CN;

1.7-S(O)x-R11where x is the integer zero, 1 or 2;

1.8-N(R11)2;

1.9 (C3-C6-cycloalkyl;

1.10 the remainder of the formula

or 1.11 the remainder of the formula ≡R11;

where R11means

(a) a hydrogen atom;

b), (C1-C6)-alkyl, where alkyl unsubstituted or one-, two - or three-fold substituted:

1. by phenyl, where the phenyl unsubstituted or substituted;

2. the remainder 5-14-membered aromatic system, which contains 1 Il is 2 heteroatoms as members of the cycle, which represent nitrogen;

3. 5-12-membered heterocycle, which is fully or partially unsaturated and which contains 1 or 2 heteroatoms, represents nitrogen and oxygen;

4. halogen;

5. -NH-(C1-C6)n-alkyl, where n denotes the integer zero, 1 or 2 and the alkyl unsubstituted;

6. -O-(C1-C6)-alkyl;

(C) phenyl, naphthyl, which are unsubstituted or substituted;

d) 5 to 12-membered heterocycle, which is unsaturated and which contains 1 or 2 heteroatoms, represents nitrogen and oxygen, and

e) 5 to 12-membered heterocycle, which is unsaturated and contains 2 heteroatoms, represents nitrogen and sulfur;

and if (R11)2the remains of R11independently of one another have the value from (a) to (e);

Z means:

1. the remainder 5-14-membered aromatic system containing from 1 to 4 heteroatoms as members of the cycle, which are nitrogen and oxygen, where the aromatic system is unsubstituted or substituted;

1.1 a heterocycle selected from the group of oxadiazole or oxadiazoline, which can be unsubstituted or substituted;

2. (C1-C6)-alkyl, where alkyl is linear or branched and substituted once by phenyl or by a group-HE, or

3. -C(O)-R10where R10means-O-R11, -N(R 11)2or morpholinyl;

or R8and R9together with the nitrogen atom and carbon atom to which they are respectively bound, form a heterocycle of formula (IIa)

where D, Z, and R10have indicated in the formula (II) value;

And means balance-CH2-;

In the mean rest-CH2-;

X means the residue-CH2-;

Y is absent or denotes a residue-CH2-; or

X and Y together form a phenyl;

moreover, educated N, A, X, Y, b and the carbon atom of the cyclic system is unsubstituted or once substituted (C1-C8)-alkyl, where alkyl substituted once by phenyl, and

accordingly, the other substituents R1, R2, R3and R4independently from each other mean a hydrogen atom;

R5means a hydrogen atom;

R6means heteroaromatic cyclic system with 5 to 14 members in the cycle that contains 1 or 2 nitrogen atom and is unsubstituted or substituted.

2. Substituted benzimidazole of the formula (I) according to claim 1, wherein one of the substituents R1, R2, R3and R4means the residue of formula (II), where

R8means a hydrogen atom;

R9means:

1. (C1-C6)-alkyl, where alkyl is linear the output or branched and nesnesinin or one - or twofold substituted:

1.1 phenyl, naphthyl, biphenyl, which is unsubstituted or one-, two - or three-fold substituted (C1-C4)-alkyl, (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, cyano, hydroxycarbonyl, fenoxaprop;

1.2 balance 5-14-membered aromatic system containing 1 or 2 heteroatoms, represents nitrogen, as members of a cycle selected from the group pyrrole, pyrrole, one - or twofold substituted - (C1-C4)-alkyl, imidazole, pyridine, pyrimidine, pyrazin, pyrazole, indole, indazole, indoline, benzimidazole, hinzelin, quinoline, cinoxacin, isoquinoline;

1.3 1,3,4-oxadiazol;

1.4 5-12-membered heterocycle, which is a partially or fully unsaturated and contains 1 heteroatom, representing sulfur selected from the group of thiophene, benzothiophene, which are unsubstituted or once substituted by halogen;

1.5-OR11;

1.6-CN;

1.7-S(Oh)x-(C1-C4)-alkyl, -S(O)x-naphthyl, -S(O)x-pyrimidinyl or-S(O)xis phenyl, which are unsubstituted or one - or twofold substituted- (C1-C4)-alkyl, CF3, halogen, O-(C1-C4)-alkyl, -COOH, C(O)-O-(C1-C4)-alkyl, -NH2or-NH-C(O)-(C1-C4)-alkyl, where x is zero, 1 or 2;

1.8-N(R11)-phenyl, -NH(R11);

19 (C 3-C6-cycloalkyl, or

1.10 styrene residue;

where R11means

(a) a hydrogen atom;

b), (C1-C6)-alkyl, where alkyl unsubstituted or one-, two - or three-fold substituted:

1. by phenyl;

2. the remainder 5-14-membered aromatic system which contains 1 or 2 heteroatoms as members of the cycle are nitrogen, selected from the group pyridine, pyrimidine, pyrrole, pyrazole, imidazole, pyrazin, indole, indazole, indoline, benzimidazole, hinzelin, quinoline, cinoxacin, isoquinoline;

3. 5-12-membered heterocycle, which is fully or partially unsaturated and which contains 1 or 2 heteroatoms, represents nitrogen and oxygen selected from the group of furan, oxazole, isoxazol;

4. halogen;

5. -NH-(C1-C6)n-alkyl, where n denotes the integer zero, 1 or 2 and alkyl is unsubstituted;

6. -O-(C1-C6)-alkyl;

c) phenyl, naphthyl, which are unsubstituted or once substituted by halogen;

d) 5 to 12-membered heterocycle, which is unsaturated and which contains 1 or 2 heteroatoms, represents nitrogen and oxygen selected from the group pyridine, pyrimidine, furan, oxazole, isoxazol, pyrrole, pyrazole, imidazole, pyrazin, indole, indazole, indoline, benzimidazole, hinzelin, quinoline, cinoxacin, skinoren;

e) 5 to 12-membered heterocycle, which is unsaturated and contains 2 heteroatoms, represents nitrogen and sulfur selected from the group of the thiazole, isothiazol, benzothiazole;

and if (R11)2the remains of R11independently from each other have the meaning of (a) to (e);

Z means:

1. tetrazol, oxadiazole, 1,3,4-oxadiazol where 1,3,4-oxadiazol is unsubstituted or once substituted by a group-NH2, -NH(C1-C4)-alkyl, -N[(C1-C4)-alkyl]2, -NH-C(O)-(C1-C4)-alkyl, -NH-C(O)-NH-(C1-C4)-alkyl, -NH-C(O)-NH-(C3-C7-cycloalkyl, -NH-C(O)-NH-aryl, -NH-C(O)-NH-phenyl, -NH-SO2-phenyl, -NH-SO2-(C1-C4)-alkyl, -HE or -(C1-C4)-alkyl,

2. (C1-C6)-alkyl, where alkyl is linear or branched and unsubstituted or one - or twofold substituted by phenyl or-IT;

3. -C(O)-R10where R10means-O-R13HE, morpholinyl, -N(R13)2or NH2;

R13independently from each other, means:

(a) a hydrogen atom;

b) -(C1-C6)-alkyl;

c) -(C1-C4)-alkyl-O-(C1-C4)-alkyl;

d) -(C1-C6)-alkyl-N((C1-C6)-alkyl)2;

e) halogen or

f) -(C0-C4)-alkyl, single or double is but replaced by imidazolium, morpholinyl or phenyl, or

R8and R9together with the nitrogen atom and the carbon atom with which they are linked, form a loop of the formula (IIa) from the group of pyrrolidine or piperidine which is unsubstituted or once substituted (C1-C8)-alkyl, where the alkyl is substituted once by phenyl;

and, accordingly, the other substituents R1, R2, R3and R4mean a hydrogen atom;

R5means a hydrogen atom;

R6means pyridine or pyrimidine, which is unsubstituted or once substituted by halogen, -OH, -(C1-C4)-alkyl, -NH2or-NH-R14, -N(R14)2where R14means -(C1-C6)-alkyl, -(C3-C6-cycloalkyl or phenyl.

3. Drug for inhibition of IkB kinase, characterized in that it contains an effective amount of at least one of the compounds of formula (I) according to claim 1 or 2 together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other biologically active and auxiliary substances.

4. The method of obtaining drugs for inhibition of IkB kinase, characterized in that at least one compound of formula (I) according to claim 1 or 2 are mixed together with a pharmaceutically suitable and physio is logicheskie acceptable carrier and, if necessary, other suitable biologically active substances, additives or auxiliary substances.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives if azaindole of the formula (I)

or its pharmaceutically acceptable salts wherein the formula is taken among the group consisting of , , and and wherein each among R1, R2, R3 and R4 is taken independently among the group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, halogen atom, cyano-group (CN), phenyl, nitro-group, -OC(O)R15, -C(O)R15, -C(O)OR16, -OR19, -SR20 and NR21R22 wherein R15 is taken independently among the group including hydrogen atom (H),(C1-C6)-alkyl and (C2-C6)-alkenyl; each among R16, R19 and R0 is taken independently among the group including hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-alkyl substituted with from 1 to 3 halogen atoms; each among R21 and R22 is taken among the group including hydrogen atom(H), hydroxy-group (OH), (C1-C6)-alkyl; R5 represents the group (O)m wherein m = 0 or 1; n = 1 or 2; R6 is taken among the group including hydrogen atom (H), (C1-C6)-alkyl, -C(O)R24 and -C(O)OR5 under condition that carbon atoms comprising carbon-carbon double bond of indicated (C3-C6)-alkenyl are not the addition point to nitrogen atom to which R6 is joined; R24 is taken among the group consisting of hydrogen atom (H), and (C1-C6)-alkyl; R25 represents (C1-C6)-alkyl; each among R7, R8, R9, R10, R11, R12, R13 and R14 is taken independently among the group including hydrogen atom (H) and (C1-C6)-alkyl; Ar is taken among the group including:

, and . Compounds of the formula (I) inhibit HIV-1 that allows proposing their applying in medicine.

EFFECT: valuable medicinal and antiviral properties of compounds.

22 cl, 13 sch, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

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

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

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

26 cl, 1 tbl, 119 ex

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

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines of the general formula (1)

that are effective inhibitors if caspase-3 that can be used for preparing medicinal agents and for experimental (in vitro, in vivo) investigation of apoptosis processes as "pharmacological tools". Also, invention proposes pharmaceutical composition and a method for their preparing and applying. In the general formula (1) radicals R1, R2, R3 and R8 represent independently of one another hydrogen atom, halogen atom, CF3, CN, inert substitute, optionally substituted hydroxyl group, optionally substituted carboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group; R4 represents hydrogen atom, halogen atom, inert substitute, optionally substituted amino-group, substituted hydroxyl group; R5 represents hydrogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; R6 and R7 represent independently of one another hydrogen atom, inert substitute, optionally substituted amino-(C1-C7)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group; or R6 and R7 in common with nitrogen atom to which they are bound represent optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur, 3-10-membered cycle; or R6 and R7 in common with nitrogen atom to which they are bound represent condensed heterocycle being optionally substituted and optionally additionally including heteroatom taken among group: oxygen, nitrogen or sulfur.

EFFECT: improved preparing method and treatment.

9 cl, 19 sch, 7 tbl, 25 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

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

SUBSTANCE: invention relates to a new improved method for preparing 6-methyl-2-(4-methylphenyl)-imidazolo[1,2-a]pyridine-3-(N,N-dimethylacetamide) of the formula (I) or its pharmaceutically acceptable acid additive salts. Method involves interaction of ester of the general formula (II) (wherein R is a lower alkyl or phenyl-lower alkyl) with dimethylamine in polar aproton solvent and if necessary conversion of synthesized compound of the formula (I) to pharmaceutically acceptable acid additive salt. Compound of the formula (I) is the known effective sedative agent used in therapy. Also, invention relates to intermediate compounds of the general formula (II) wherein R is a lower alkyl or phenyl-lower alkyl using in this method. Method provides preparing highly pure product for a single stage being without applying harmful and toxic reagents.

EFFECT: improved method for preparing.

16 cl, 15 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new imidazoquinolines of the formula (1): wherein R, R1, R2 and n have values given in the description. Compounds elicit effect of immunomodulating agents inducing biosynthesis of cytokines in animals in treatment of different pathologies, among them viral and neoplastic diseases. Also, invention relates to a pharmaceutical preparation used for inducing interferon-α or tumor necrosis α-factor, to a method for inducing biosynthesis of cytokines in animals and to methods for treatment of viral diseases and neoplasm pathologies in animals. Invention provides preparing new biologically active compounds.

EFFECT: improved inducing method, valuable properties of compounds and pharmaceutical preparation.

23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

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

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

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

8 cl, 94 ex

FIELD: organic chemistry, chemical technology, agriculture.

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

EFFECT: improved preparing methods, valuable properties of compounds.

13 cl, 5 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, chemical technology, explosive substances.

SUBSTANCE: invention relates to a method for preparing 4,4'-bis-[4-aminofurazan-3-yl-N(O)N-azoxy]-3,3'-azofurazane of the general formula (1):

that is a new thermostable explosive substance with improved exploitation indices. Method for preparing compound of the formula (1) involves treatment of 4,4'-diaminoazoxyfurazane with potassium bromate solution (KBrO3) in hydrochloric acid medium or its mixture with organic acid. Proposed compound can be used as a component of explosive compositions, solid rocket fuels and power-consuming compositions of different designations exploited at elevated temperatures (for example, in blast-hole drilling in depth mines).

EFFECT: improved preparing method, valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

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