Derivatives of indole or benzimidazole for modulation of ikb kinase

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

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

6 cl, 67 ex

 

The invention relates to derivatives of indole or benzimidazole, inhibiting IkB-kinase, the method of their preparation and their use as pharmaceuticals.

In the application WO 94/12478 amongst describes indole derivatives inhibiting platelet aggregation. In applications WO 01/00610 and WO 01/30774 describes derivatives of indole and benzimidazole, which can modulate NFkB.

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

Diseases, such as rheumatoid arthritis (inflammation), osteoarthritis, asthma, myocardial infarction, Alzheimer's disease, type II diabetes, inflammatory bowel disease "inflammatory bowel disease" or arteriosclerosis, NFkB is activated in excess of the normal measures. Inhibition of NFkB is also used in the treatment of cancer, as it is used in this case by itself or DL the strengthening of cytostatic treatment. It has been shown that drugs such as glucocorticoids, salicylates, or gold salts that are used in the treatment of rheumatism, ingibiruet are embedded in different sites of the signal chain that activates NFkB, or directly interfere with gene transcription.

The first step in these signaling cascades is the breakdown of IkB. This phosphorylation is regulated by specific IkB kinase. Still unknown inhibitors, inhibiting specific IkB-kinase.

A disadvantage of the known inhibitors of IkB kinase is often insufficient specificity of inhibition of only one class of kinases. For example, most inhibitors of IkB kinase inhibit several different kinases, since the catalytic domains of these kinases have similar structure. As a consequence, inhibitors undesirable impact on many enzymes, as well as enzymes with vital function.

In the application WO 01/30774 have already been described derivatives of indole, which can modulate NFkB and have a strong inhibitory effect on IkB-kinase. Compounds described in the application WO 01/30774, those shown in the examples, however, have a strong inhibitory effect on other kinases such as cAMP-dependent protein kinase, protein kinase C or caseinline II. However, some of these indole derivatives p and improving specificity are reduced inhibition of IkB kinase. Next, the achievable level of blood plasma through the connections described in the application WO 01/30774 insufficient for oral administration of these derivatives.

When searching for an effective compounds for the treatment of rheumatoid arthritis (inflammation), osteoarthritis, asthma, myocardial infarction, Alzheimer's disease, cancer (potentiation of cytotoxic therapy) or arteriosclerosis was found that derivatives of indole and benzimidazole according to the invention does not have the aforementioned disadvantages. Derivatives of indole and benzimidazole according to the invention are powerful inhibitors of IkB kinase, very selectively inhibit kinase and is characterized by high level of blood plasma after oral administration.

Thus, the invention concerns the compounds of formula I

and/or stereoisomeric forms of the compounds of formula I and/or physiologically compatible salts of the compounds of formula I, and

X and M are the same or different and independently of one another denote an N atom or CH,

R1 and R11 are the same or different and independently of one another denote

1. a hydrogen atom,

2. F, Cl, Br J or,

3. -(C1-C4)-alkyl,

4. -CN

5. -CF3,

6. -OR5where R5denotes a hydrogen atom or -(C1-C4)-alkyl,

7. -N(R5)-R6 where R5and R6independently from each other represent a hydrogen atom or -(C1-C4)-alkyl,

8. -C(O)-R5where R5denotes a hydrogen atom or -(C1-C4)-alkyl, or

9. -S(O)X-R5where x denotes the integer zero, 1 or 2 and R5denotes a hydrogen atom or -(C1-C4)-alkyl,

R2 denotes

1. heteroaryl residue from the group comprising 3-hydroximino-2,4-dione, imidazole, imidazolidine, imidazoline, indazole, isothiazol, isothiazolin, isoxazol, 2-isoxazolidine, isoxazolidine, isoxazole, morpholine, oxazole, 1,3,4-oxadiazole, oxadiazolidine, oxadiazole, 1,2,3,5-oxadiazol-2-oxide, 5-oxo-4,5-dihydro-[1,3,4]oxadiazole, 5-oxo-1,2,4-thiadiazole, piperazine, pyrazin, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyrimidine, tetrazole, thiadiazole, thiazole, thiomorpholine, triazole or triazole, and heteroaryl residue is unsubstituted or, independently of one another, one, two or three times substituted

1.1. -C(O)-R5where R5denotes a hydrogen atom or -(C1-C4)-alkyl,

1.2. -(C1-C4)-alkyl,

1.3. -O-R5where R5denotes a hydrogen atom or -(C1-C4)-alkyl,

1.4. -N(R5)-R6where R5and R6independently from each other represent a hydrogen atom or -(C1-C4)-alkyl,

1.5. halogen,

1.6. the UTB-balance

2. -C(O)-R5where R5denotes a hydrogen atom or -(C1-C4)-alkyl,

3. -C(O)-OR5where R5denotes a hydrogen atom or -(C1-C4)-alkyl, or

4. -C(O)-N(R7)-R8where R7and R8independently from each other represent a hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,

R3 denotes a hydrogen atom or -(C1-C4)-alkyl,

R4 denotes

1. heteroaryl residue from the group comprising pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazol, tetrazole, 1,2,3,5-oxadiazol-2-oxides, triazolone, oxadiazole, isoxazole, oxadiazolidine, triazole, 3-hydroxyprop-2,4-diones, 5-oxo-1,2,4-thiadiazole, pyridine, pyrazin, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, cinoxacin, hinzelin, cinnolin, β-carbolin and benzenediamine, cyclopent - or cyclohexa-derivatives of these heteroaryl residues, and heteroaryl residue is unsubstituted or one-, two -, or three times substituted independently of one another, (C1-C5)-alkyl, -(C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4/sub> -alkoxycarbonyl, or

2. aryl residue from the group comprising phenyl, naphthyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl, and the aryl residue is unsubstituted or one-, two -, or three times substituted independently of one another, (C1-C5)-alkyl, -(C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4-alkoxycarbonyl.

The invention relates further compounds of formula I, and X and M are the same or different and independently of one another denote an N atom or CH,

R1 and R11 are defined as in above in paragraphs 1-9,

R2 denotes

1. heteroaryl residue from the group including imidazole, isothiazol, isoxazol, 2-isoxazolidine, isoxazolidine, isoxazole, 1,3,4-oxadiazol, oxadiazolidine, 1,2,3,5-oxadiazole, oxazole, 5-oxo-4,5-dihydro-[1,3,4]oxadiazol, tetrazole, thiadiazole, thiazole, triazole or triazole, and heteroaryl residue is unsubstituted or, independently of one another, one, two or three times substituted

1.1. keto-balance

1.2. halogen or

1.3. -(C1-C2)-alkyl, or

2. -C(O)-N(R7)-R8where R7and R8independently of the other, represent a hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,

R3 denotes a hydrogen atom, methyl or ethyl,

R4 denotes

1. heteroaryl residue from the group of unsaturated, partially saturated or fully saturated cycles formed from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, triazole or isothiazole, and heteroaryl residue is unsubstituted or one-, two -, or three times substituted independently of one another, (C1-C4)-alkyl, -(C1-C4)-alkoxy, F, Cl, J, Br, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl or -(C1-C4-alkoxycarbonyl, or

2. phenyl, and phenyl unsubstituted or one-, two -, or three times substituted independently of one another, F, Cl, J, Br, CF3, -OH, (C1-C4)-alkyl or -(C1-C4)-alkoxy.

Further, the invention concerns compounds:

[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[(S)-1-(5-OK, what about the-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-1-(4H-[1,2,4]triazole-3-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-carbarnoyl-2-(phenyl-thiazol-2-yl-amino)-ethyl]-amide (S)-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-methoxycarbonyl-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide (S)-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)pirimidil-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-(2-hydroxy-ethylcarbamate)-2-(phenyl-pyrimidine-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

(S)-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amino]-propionic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-(5-methyl-pyrimidine-2-yl)-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

((S)-1-carbarnoyl-2-diphenylamino-ethyl)-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzoimidazol-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)-pyrimidine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid or/p>

{1-carbarnoyl-2-[(phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzoimidazol-5-carboxylic acid.

The term "halogen" mean fluorine, chlorine, bromine or iodine. Under the terms "-(C1-C5)-alkyl or-(C1-C5)-alkoxy" mean hydrocarbon residues, carbon chain which are unbranched or branched and contain from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, n-butyl, pentyl or tert.-butyl. The term "heteroaryl residue from the group of unsaturated, partially saturated or fully saturated cycles formed from pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazole" mean, for example, compounds such as piperazine, pyrazoline, imidazoline, pyrazolidine, imidazolidine, tetrahydropyridine, isoxazolin, isoxazolidine, morpholine, isothiazolin, isothiazolin, tetrahydro-1,4-thiazin or piperidine.

Obtaining compounds of the formula I is carried out, for example, as described in applications WO 01/00610 and WO 01/30774. Source substances for chemical transformations are known or can be easily obtained by the literature methods.

Further, the invention concerns a method of obtaining the compounds of formula I and/or stereoisomeric forms of the compounds of formula I and/is whether physiologically compatible salts of the compounds of formula I, characterized in that

a) compound of formula IV

where R1, R2 and R4 are defined as in formula I, is subjected to the interaction with the acid chloride or activated complex ester compounds of the formula III

moreover, D1 denotes-COOH, and R11, X, M and R3 are defined as in formula I, in the presence of a base or, if necessary, the drying means in the solution, and transferred to the compound of formula I,

b) the compound of formula I obtained by the method (a), due to their chemical structure exists in enantiomeric forms, separated by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or turning by means of chiral enantiomerically pure compounds such as amino acids, separation of the resulting diastereomers, and the removal of the chiral auxiliary groups in the pure enantiomers, or

c) the compound of formula I obtained by the method (a) or (b)allocate or free-form, or, in the case of acidic or basic groups, was transferred to a physiologically compatible salt.

Preparation of derivatives of indole or benzimidazolecarbamic acids is carried out according to the method described in Houben-Weyl "Methods der Org. Chemie", Band E6-2A or E6-2B. Thus, to obtain the derivatives of the Indo is - or benzimidazolecarbamic acids of the formula III preferably may be interaction hydrazinobenzene acid and aryl - or heteroarylboronic, in the presence of polyphosphoric acid as a solvent at 145aboutC. obtaining the necessary hydrazinobenzene acids by prominent specialists of ways, for example, from the corresponding anilines of benzoic acid, aryl - or heteroarylboronic also get accepted among specialists of ways, for example, from the corresponding acid chlorides of the acids or NITRILES by reaction with, for example, ORGANOMETALLIC compounds.

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

The condensation may be carried out under standard conditions. During condensation, as a rule, it is necessary that the existing areagirls amino groups were protected by reversible protective groups. This applies equally to not participating in the reaction carboxy who inim groups, that during the condensation are preferably in the form -(C1-C6)-alilovic esters, benzyl esters or tert.-butyl esters. Protection of the amino groups is unnecessary, if the amino groups are in the form of stage predecessor as nitro or ceanography, and are formed only after condensation by hydrogenation. After condensation of the existing protective group otscheplaut suitable way. For example, NO2group (guanidine protecting the amino acids), benzyloxycarbonyl group and benzyl group in the benzyl esters can be removed by hydrogenation. The protective group is tert.-Putilkovo type hatshepsuts in acidic conditions, while the remainder of the 9-fluorenylmethoxycarbonyl residue removed by secondary amines.

The invention also applies to medicines, different effective content of at least one of the compounds of formula I and/or one physiologically compatible salts of the compounds of formula I, and/or, if necessary, one stereoisomeric forms of the compounds of formula I, together with a pharmaceutically suitable and physiologically compatible carrier, additive and/or other biologically active and auxiliary substances.

Due to the pharmacological properties of the compounds according to the ISO is retenu suitable for the prevention and treatment of all diseases, the course which is due to increased activity of IkB kinase. These include, for example, chronic diseases of the musculoskeletal system, such as inflammatory, immunological or metabolic activity due to acute and chronic arthritides, arthropathies, rheumatoid arthritis, or degenerative joint diseases such as osteoarthritis, spondylosis, type II diabetes, inflammatory bowel disease, degenerative cartilage after joint injuries or long position of rest replacement after damage to the meniscus or kneecap, or torn ligaments or connective tissue disease such as collagen and periodontal disease, myalgia and metabolic bone, or diseases caused by overexpression of tumor necrosis factor alpha (TNFα) or high concentration of TNFα such as exhaustion, multiple sclerosis, traumatic brain injury, Crohn's disease and ulcers of the intestine, or diseases such as arteriosclerosis, stenosis, ulcerate, Alzheimer's disease, dissimilation muscle, cancer (potentiation of cytotoxic therapy), myocardial infarction, gout, sepsis, septic shock, endotoxic shock, viral infections such as influenza, hepatitis, severe viral infection (HIV infection), AIDS, or diseases caused by adenoviruses or herpesviruses is, parasitic infections such as malaria or leprosy, fungal or yeast infections, inflammation of the meninges, chronic inflammatory pulmonary disease such as chronic bronchitis or asthma, acute respiratory distresse syndromes, acute synovitis, tuberculosis, psoriasis, diabetes, treatment of acute or chronic rejection reactions of the body of the recipient against the transplanted organ, chronic graft versus host disease and inflammatory vascular diseases. These diseases can be treated with compounds according to the invention mainly specifically and with a minimum range of side effects, as most inhibited only IkB-kinase.

Medicinal product according to the invention can be entered orally, by inhalation, rectally or percutaneously, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Preferably oral administration.

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

Suitable t is erdimi or galenovye preparative forms are ready, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations with prolonged release of biologically active substances, to obtain using conventional excipients, as holders, dispensers, binders, chemicals for coatings, swelling agents, substances imparting slipperiness or lubricants, flavorings, sweeteners and agents of dissolution. As commonly used auxiliary substances called magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, like cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and the solvent, as, for example, sterile water, and one - or polyhydric alcohols as glycerol. Preferably, the pharmaceutical preparations are made and administered in single doses, each dose contains as an active ingredient one particular dose of a compound of formula I according to the invention. Solid single doses in the form of tablets, capsules, coated tablets or suppositories, this dose can be up to about 1000 mg, preferably from about 50 to 300 mg, and for injection solutions in the form of ampoules in Loti to about 300 mg, preferably from about 10 to 100 mg For the treatment of adult patients weighing about 70 kg, depending on the effectiveness of the compounds according to formula I, shown daily dose of from about 20 to 1000 mg of biologically active substances, preferably from about 100 to 500 mg Under certain conditions, however, can also be used in larger or smaller daily doses. The introduction of the daily dose can be carried out by one-time injection in the form of a separate single dose or several smaller doses, or by repeated administration of divided doses at specific intervals.

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

Examples of receipt.

A) Obtaining aniline.

A.1.) 2-(p-foronline)-pyridine(3)

A mixture of 29,34 g (0,264 mol) 4-foronline (1and of 29.98 g (0,264 mol) of 2-chloropyridine (2) was heated for 2 hours at 150aboutC. After cooling to room temperature (CT) was distributed between 500 ml of 1 N. NaOH and 500 ml of ethanol is about ester of acetic acid. The aqueous phase is 2 times were extracted with ethyl acetate (300 ml) and the combined organic phases were dried with magnesium sulfate. After evaporation of the solvent the residue was consumed 500 ml of ethyl acetate was added 40 g of activated charcoal. 10 minutes was stirred at RT and then was filtered through diatomaceous earth. Activated charcoal 4 times washed with ethyl acetate (1 l). The solvent is kept under vacuum and the residue was kneaded from 120 ml of ethyl acetate. The solid was aspirated and 50aboutWith dried under vacuum. Got 41 g of 2-(p-foronline)-pyridine (3); yield 83%.

Total formula C11H9N2; MV=188,21; MS (M+H) 189,1.

1H NMR (CDCl3) 6,68 to 6.75 (m, 2H), to 6.88 (s, 1H), 7,05 (t, 2H), 7.24 to 7,32 (m, 2H), 7,43-7,49 (m, 1H), 8,18 (d, 1H).

A.2.) 2-(aniline)-pyrimidine (6).

Of 16.2 g of aniline (4through similar transformations, described in paragraph (A.1.), through 2-chloropyrimidine (5) got to 9.15 g (31%) of anilinopyrimidines6.

Total formula C10H9N3; MV=171,08; MS (M+H) 172,2.

B) Synthesis of amino acids via Z-serine lactone8

B.1) Methyl ester of (S)-2-amino-3-diphenylamino-propionic acid (11)

B.1.1.) N-benzyloxy-carbonyl-L-serine-β-lactone (8)

of 54.8 g (0,209 mol) of triphenylphosphine suspended in 600 ml of acetonitrile and cooling gap is Ali to a temperature of from -35 to -45 aboutWith the exclusion of moisture. At this temperature for 50 minutes was added dropwise of 36.4 g (0,209 mol) diethyl ester of azodicarboxylic acid. Then stirred for 15 minutes at -35aboutC. To this mixture is then slowly bury solution of 50 g (0,209 mol) N-benzyloxycarbonyl-L-serine (7) in 500 ml of acetonitrile, so that the temperature did not rise above -35aboutC. Then 12 hours was stirred at 5aboutC. On termination of the reaction, the reaction solution under reduced pressure was freed from solvent, and the crude product was purified by chromatography (medium pressure kieselgel (DCM/acetonitrile (AcCN):25/1). After removal of solvent received from 20.8 g of N-benzyloxy-carbonyl-L-serine-β-lactone (8in the form of thin needles; yield 45% (see also Org. Synth. 1991 (70) 1ff.).

Total formula C11H11NO4; MV=221,2; MS (M+H) 222,1.

1H NMR (DMSO-d6) 4,30 (m, 1H), 4,45 (m,1H) 5,10 (s, 2H), 5,22 (m, 2H), 7,45 (m, 5H), to 8.20 (d, J=9.8 Hz, 1H).

B.1.2.) (S)-2-benzyloxycarbonylamino-3-difeniloliropana acid (9)

5.0 g (22,6 mmol) serinette (5) was mixed into 20 g (118,2 mmol) of diphenylamine and 2 hours was heated at 100aboutC. the Crude product was purified by chromatography (medium pressure kieselgel (DCM/methanol:9/1, then EA(ethyl acetate)/n-heptane:4/1). After removal of solvent received the 3.65 g (yield 42%) of pure 2-benzyloxy is Beniamino-3-diphenylbenzophenone acid ( 9).

Total formula C23H22N2O4; MV=390,44; MS (M+H) 391,2.

1H NMR (DMSO-d6) of 3.85 (m, 1H), 4,18 (m, 1H), 4,3 (m, 1H), 4,9 (m, 2H), 6,9 (m, 5H), 7,25 (m, 10H).

B.1.3.) methyl ester of (S)-2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (10)

To 75 ml of methanol was bury when -5aboutWith 6.5 ml (89,1 mmol) of thionyl chloride and was stirred 15 min. Then added 3.6 g (which 9.22 mmol) dissolved in 75 ml of methanol 2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (9) and further stirred for 3 hours at room temperature. After evaporation of the solvent the residue was absorbed by ethyl acetate and extracted with sodium carbonate solution. After purification by flash chromatography (n-heptane/ethyl acetate 7:3) received 2.76 g (50% yield) of the methyl ester of 2-benzyloxycarbonylamino-3-diphenylamino-propionic acid (10). Total formula C24H24N2O4; MV=404,47; MS (M+H) 405,2.

1H NMR (DMSO-d6) to 3.58(s, 3H), 3,95(m, 1H), 4,18(m,1H) 4,4(m,1H), 4.95 points(m, 2H), 6,9(m, 6H), and 7.3(m,9H), a 7.85(d,J=9.8 Hz, 1H).

B.1.4.) methyl ester of (S)-2-amino-3-diphenylamino-propionic acid (11)

For removal of protective Z-group 2.7 g (of 6.68 mmol) derived (10)protected Z-group, was dissolved in 500 ml of methanol and was added in a protective nitrogen atmosphere, 100 mg of catalyst (10% Pd(OH)2-C). Then was replaced by the inert gas large hut the ball of hydrogen and 2 hours was shaken in a hydrogen atmosphere. After completion of the reaction the catalyst was filtered and the filtrate was concentrated. Received of 1.65 g (yield 91%) of methyl ester 2-amino-3-diphenylamino-propionic acid (11).

Total formula C16H18N2O2; MV=270,32; MS (M+H) 271,2.

1H NMR (DMSO-d6) to 3.45 (s, 3H), to 3.58 (m, 1H), and 3.8 (m, 1H), 3,95 (m, 1H), 6,9 (m, 6H), and 7.3(m, 4H).

B.2.) The synthesis of amino acids via acrylic acid13

B.2.1.) Separation of enantiomers

Racemic amino acids obtained through acrylic acid, can be separated into the enantiomers by preparative HPLC (HPLC) with chiral phases, as, for example, Chiralpak AD (Daicel) 100x380, CT, a flow of 300 ml/min. purity of the enantiomers could be determined by analytical HPLC as Chiralpak AD-H (Daicel) 4,6x250, 30aboutWith a flow of 1 ml/min, room temperature).

B.2.2.) methyl ether (3-(N-4-forfinal-N-2-pyridyl)-amino)-2-(di-tert.-butyloxycarbonyl)-amino-propionic acid (14)

B.2.2.1.) methyl ester of 2-(di-tert.-butyloxycarbonyl)-amino-acrylic acid (13)

50 g (0,228 mol) Boc-serine (12) was dissolved in 300 ml of acetonitrile. Added 107 g (0,493 mol) of Boc-anhydride and 2.64 g (22 mmol) of DMAP. Left for the night mixed by CT, drove away the solvent under vacuum and the residue was consumed 500 ml of ethyl acetate. The organic phase is washed with 500 ml of 1 N. HCl and dried Sul is blockhead magnesium. By crystallization from 200 ml of heptane at -30aboutAfter sucking received 23 g of acrylic acid13. The mother liquor was concentrated and the residue was dissolved in 140 ml of acetonitrile. Added 31 g (0,142 mol) of Boc-anhydride and 1.26 g (10 mmol) of DMAP. After heating to 50aboutWith over 8 hours drove the solvent under vacuum and the residue was consumed 500 ml of ethyl acetate. The organic phase is washed with 400 ml of 1 N. HCl and dried over magnesium sulfate. After removal of the solvent under vacuum by crystallization from heptane then got to 31.5 g of acrylate13. The output of 54.5 g (0,181 mol), 79%. Total formula C14H23NO6; MV=301,34; MS ((M*2)+Na+) 625,7.

1H NMR (DMSO-d6) of 1.40 (s, 18H), 3,74 (s, 3H), of 5.85(s, 1H), 6,28(s, 1H).

B.2.2.2.) methyl ether (3-(N-4-forfinal-N-2-pyridyl)-amino)-2-(di-tert.-butyloxycarbonyl)-amino-propionic acid (14)

11.5g (38,2 mmol) acrylate13was mixed with 7.2 g (38,2 mmol) of aniline3and 37.3 g (114 mmol) of cesium carbonate. Added 100 ml of acetonitrile and left 2 days mixed with 55aboutC. then left the next 2 days to mix at room temperature. The solid was sucked out through kieselguhr and 3 times washed with acetonitrile (100 ml). From the combined organic phase under vacuum drove the solvent and the residue was chromatographically on kieselgel with eluent hept is n/ethyl acetate 4:1. Yield: 14 g (75%)14.

Total formula C25H32FN3O6; MV=489,55; MS (M+H) 490,6.

1H NMR (CDCl3) of 1.28 (s, 18H), and 3.72 (s, 3H), 4,25(DD, 1H), and 4.75(DD, 1H), of 5.83(DD, 1H), from 6.22(d, 1H), 6,56-of 6.61(m, 1H), 7,05 for 7.12(m, 2H), 7,19-7,26(m, 3H), 8,18(d, 1H).

B.2.3.) methyl ether (3-(N-phenyl-N-2 pirimidil)-amino)-2-(di-tert.-butyloxycarbonyl)-amino-propionic acid (15)

Of 35 g6,a similar transformation described in paragraph (B.2.2.2.), received 3 g (7%) amino acids15.

Total formula C24H32N4O6; MV=472,23; MS (M+H) 473,1.

C.) the Synthesis of the heterocyclic core fragments

C.1.) Synthesis of indole core fragment:

2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (20)

C.1.1.) 1-dimethylamino-4,4-dimethoxy-Penta-1-EN-3-one (18)

100 g (0,76 mol) of 3,3-dimethoxy-2-butanone (16) at 120aboutWith was stirred for 48 hours from 90.2 g of N,N-dimethylformamide-dimethylacetal (17) (from 0.76 mol). The methanol formed in the reaction was continuously removed from the reaction solution by distillation. Upon cooling, the solution began spontaneous crystallization, which with the small addition of heptane reached completion. Thus received 128,24 g crude product 18 (yield 90%)which was subjected to transformation no Yes is inasa cleanup.

Total formula C9H17NO3; MV=187,24; MS (M+H) 188,2.

1H NMR (DMSO-d6) to 1.22(s, 3H), 2,80(s, 3H), 3,10 (s, 9H), of 5.39(d,J=15 Hz, 1H), to 7.59(d,J=15 Hz, 1H).

S.) [4-(1,1-dimethoxy-ethyl)-pyrimidine-2-yl]-methyl-amine (19)

1.22 g (53 mmol) of sodium was dissolved in 100 ml of absolute ethanol. To it under stirring was added 5.8 g (53 mmol) of metilprednisolone and 10 g (53 mmol) of 1-dimethylamino-4,4-dimethoxy-Penta-1-EN-3-one (184 hours was heated to boiling. Upon completion of the reaction evaporated ethanol. Thus obtained product19without further purification was used in subsequent reactions. The output of 11.5 g (58 mmol, quantitative).

Total formula C9H15N3O2; MV=197,24; MS (M+H) 198,2.

1H NMR (DMSO-d6) 1,45(s, 3H), 2,78(s, 3H), 3,10 (s, 6H), to 6.75(d, J=3 Hz, 1H), 7,0-7,1 ((ush.), 1H), 8,30(d, J=3 Hz, 1H).

S.) 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (20)

To 150 ml of 50%sulfuric acid at room temperature under stirring was added 5 g (25 mmol) [4-(1,1-dimethoxy-ethyl)-pyrimidine-2-yl]-methylamine (19) and 3.85 g of 4-hydrazinobenzene acid and 4 hours was heated at 130aboutC. the Methanol formed in the reaction was continuously removed from the reaction solution by distillation. After cooling to 10aboutTo the reaction mixture was poured into 200 ml of ice and using concentrated rest the RA of sodium hydroxide was set to a pH of about 5.5. The resulting precipitate of sodium sulfate and the product mixture was filtered and the precipitate from the filter was extracted repeatedly with methanol. The combined methanol extract was concentrated and the product20was purified by flash chromatography (DCM/methanol 9:1). Output 0,76 g (11%).

Total formula C14H13N4O2; MV=268,28; MS (M+H) 269,1.

1H NMR (DMSO-d6) 2,95 (s, 3H), 6.90 to-7,10 ((ush.), 1H), 7,18 (d, J=3 Hz, 1H), and 7.4(s, 1H), 7,58(d, J=4.5 Hz, 1H), 7,80 (d, J=4.5 Hz, 1H), 8.30 to(s, 1H), 7,80(d, J=4.5 Hz, 1H), scored 8.38 (d, J=3 Hz, 1H), 11,85(s, 1H), 12,40-12,60 ((ush.), 1H).

C.2.) Synthesis of benzimidazole core fragment:

2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5 carboxylic acid (25)

S) 4-dimethylamine-1,1-dimethoxy-but-3-EN-2-he (22)

300 g (307 ml, 2.54 mol) of methylglucosedioleate (21) at 110aboutWith was stirred for 4 hours with 300 g (337 ml, 2.54 mol) of N,N-dimethylformamide-dimethylacetal (17). The methanol formed in the reaction was continuously removed from the reaction solution by distillation. After cooling, the solution was extracted with heptane and evaporated the solvent. Received 303 g of crude product 22 (yield 70%), which was subjected to transformation without further purification.

Total formula C8H15NO3; MV=173,21; MS (M+H) 174,1.

1H NMR (DMSO-d6) 2,10(s, 1H), 2,80(s, 3H), 3,1 (s, 3H)at 3.25 (s, 3H), and 3.3 (s, 3H), 4,42 (s, 1H), 5,19 (d(ush.), J=12,8 Hz, 1H), 7,60 (d, J=15 Hz, 1H).

S.) (4-dimethoxymethyl-pyrimidine-2-yl)-methyl-amine (23)

0.33 g (14.4 mmol) of sodium was dissolved in 50 ml of absolute ethanol. To it under stirring was added of 1.57 g (14.4 mmol) of metilprednisolone and 2.48 g (14.4 mmol) of 4-dimethylamine-1,1-dimethoxy-but-3-EN-2-it (22and 3 hours was heated to boiling. Upon completion of the reaction evaporated ethanol. Thus obtained product23used without further purification. Yield 2.6 g (quantitatively).

Total formula C8H13N3O2; MV=183,21; MS (M+H) 184,1.

1H NMR (DMSO-d6) 2,78(s, 6H), 3,10(s, 3H), 5,02 (s, 1H), 6,62 (d, J=3 Hz, 1H), 8,30 (d, J=3 Hz, 1H).

C.2.3.) 2-methylamino-pyrimidine-4-carbaldehyde (24)

10 g (54 mmol) (4-dimethoxymethyl-pyrimidine-2-yl)-methyl-amine (23) was dissolved in 54 ml of 2 N. sulfuric acid and stirring was heated for 3 hours to 80aboutC. After refrigeration of the reaction, the reaction solution is then gently brought to a pH of about 9 solid Na2CO3and 3 times were extracted with ethanol. United dried extract after evaporation of the solvent contained the title aldehyde24with 60%yield (4,47 g).

Total formula C6H7N3O; MV=137,12; MS (M+H) 138,2.

1H NMR (DMSO-d6) 2,60-2,80 ((ush.), 3H), 6,95 (d, J=3 Hz, 1H), 7,40-7,60 ((ush.), 1H), 8,55 (d, J=3 Hz, 1H).

S.) 2-(2-methylamine-PIR is midin-4-yl)-1H-benzoimidazol-5-carboxylic acid ( 25)

4.3 g (31,3 mmol) methylamine-pyrimidine-4-carbaldehyde (24) and 4.8 g (31,1 mmol) of 3,4-diamino-benzoic acid 2 hours was heated in 300 ml of nitrobenzene to 150aboutC. After cooling to 0aboutWith the residue of benzimidazole was separated from nitrobenzene by filtration, and the product25was purified by flash chromatography (DCM/methanol 4:1). The output of 2.66 g (32%).

Total formula C13H11N5O2; MV=269,28; MS (M+H) 270,2.

1H NMR (DMSO-d6) 2,95 (s, 3H), 7,50 (d, J=3 Hz, 1H), of 7.75 (d, J=4.5 Hz, 1H), of 7.90 (d, J=4.5 Hz, 1H), 8,35(s, 1H), 8,55 (d, J=3 Hz, 1H), 8,70-9,05 ((ush.), 1H).

D.) Target product indole

D.1.) [(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (28)

D.1.1.) methyl ether 3-diphenylamino-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-(S)-amino}-propionic acid (26)

5.0 g (18,64 mmol) of 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (20) was dissolved in 1.2 l of dimethylformamide (DMF), and one after another was added 7.9 g (to 24.08 mmol) of TOTU (O-[(cyano-(etoxycarbonyl)methylidene)amino)-1,1,3,3-tetramethyl]uranium-tetrafluoroborate) and 7.9 ml (46,45 mmol) ethyldiethanolamine. Was stirred 20 min at 5aboutWith and added to a solution of 0.73 g (or 3.28 mmol) of methyl ester of (S)-2-amino-3-diphenylbenzophenone acid (11). After 15 h is remesiana the reaction mixture was concentrated under reduced pressure, the residue was absorbed by n-butanol, and the organic phase for separation of by-products were extracted with a saturated solution of sodium bicarbonate. After drying over MgSO4and concentrating the organic phase was isolated methyl ester the title compound26by flash chromatography on kieselgel (DCM:methanol=19:1). Yield 4.3 g (98%).

Total formula C30H28N6O3; MV=520,22; MS (M+H) 521,3.

1H NMR (DMSO-d6) 2,95 (c(ush.), 3H), of 3.60 (s, 3H), 4,19-4,58 (m, 2H), 4,85 (kV, 1H), 6.90 to-7,10 (m, 7H), 7,18 (d, J=3 Hz, 1H), 7,25-7,40 (m, 5H), 7,50 (d, J=4.5 Hz, 1H), 7,65 (d, J=4.5 Hz, 1H), with 8.05 (s, 1H), 8,35 (d, J=3 Hz, 1H), 8,70 (d, J=3,75Hz, 1H), 11,85 (s, 1H).

D.1.2.) ((S)-2-diphenylamino-1-hydrazine-carbonyl-ethyl)-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (27)

1.0 g (1.92 mmol) of the methyl ester of 3-diphenylamino-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-(S)-amino}-propionic acid (26) was dissolved in 10 ml of methanol, was added to 0.48 g (9,95 mmol) of hydrazine hydrate is added and 15 h was stirred at room temperature. The precipitated product (0.3 g) was separated from the mother liquor by filtration. From the concentrated mother liquor was further allocated hydrazide27(0.1 g) by flash chromatography on kieselgel (DCM:methanol=19:1). Yield 0.4 g (40%).

Total formula C29H28N8O2; MV=520,6; MS (M+H) 521,4.

1H NMR (DMSO-d6) 2,95(s(ush.), 3H), 402-4,58 (m, 2H), and 4.4 (s, 2H), 4,85 (kV, 1H), 6.90 to-7,10 (m, 7H), 7,18 (d, J=3 Hz, 1H), 7,20 was 7.45 (m, 5H), 7,50 (d, J=4.5 Hz, 1H), 7.62mm (d, J=4.5 Hz, 1H), to 7.99 (s, 1H), 8,25 (d, J=3 Hz, 1H), 8,35 ((ush.), 1H), of 9.30 (s, 1H), 11,70 (s, 1H).

D.1.3.) [(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (28)

200 mg (0.384 mmol) ((S)-2-diphenylamino-1-hydrazine-carbonyl-ethyl)-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (27) suspended in 20 ml of methylene chloride and, at 0aboutWith bury under stirring 20%solution of phosgene in toluene (0,398 mmol). Next was stirred 15 h at room temperature and concentrated the solvent. Then oxadiazole28was isolated by flash chromatography on kieselgel (DCM:methanol=9:1). Yield 160 mg (76%).

Total formula C30H26N8O3; MV=546,6; MS (m+H) 547,3.

1H NMR (DMSO-d6) 2,95 ((ush.), 3H), as 4.02-4,58 (m, 2H), 4,85 (kV, 1H), 6.90 to-7,10 (m, 7H), to 7.15 (d, J=3 Hz, 1H), 7,20-7,40 (m, 6H), 7,52 (d, J=4.5 Hz, 1H), 7,68 (d, J=4.5 Hz, 1H), 8,10 (s, 1H), of 8.92 (d, J=3 Hz, 1H), 11,78 (s, 1H), 12,15-12,40 ((ush.), 1H).

D.2.) {1-carbarnoyl-2-[(4-forfinal)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (30)

D.2.1.) methyl ester of 3-[(4-forfinal)-pyridine-2-yl-amino]-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-propionic acid (29)

0.75 g (1.53 mmol)of14/b> was dissolved in 10 ml of dioxane and cooled to 0aboutC. was Added 10 ml of 4 N. HCl in dioxane, was kept for 2 hours at room temperature and 12 h after mixing. The solvent is kept under vacuum. The residue was absorbed 10 ml of DMF (the solution). 617 mg acid20was dissolved in 20 ml of DMF and cooled to 0aboutC. was Added to 1.05 g of HATU and 1.6 ml of DIEA. After stirring for 40 min at 0aboutWith addedthe solution. Kept at room temperature and after was stirred for 4 hours. The solvent is kept under vacuum and the residue was distributed between 100 ml of saturated solution of NaHCO3and 100 ml of ethyl acetate. The aqueous phase 3 times were extracted with ethyl acetate (50 ml)and the combined organic phases are washed with 100 ml saturated NaCl solution. The organic phase was dried with magnesium sulfate. The solvent is kept under vacuum and the residue was chromatographically on kieselgel with eluent heptane/ethyl acetate 1:3. Got 560 mg (68%) of ester29. Total formula C29H26FN7O3; MV=539,57; MS (M+H) 540,2.

D.2.2.) {1-carbarnoyl-2-[(4-forfinal)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (30)

320 mg (0,593 mmol) of ester 29 was dissolved at 0aboutWith 50 ml of methanol, saturated with ammonia. Was stirred for 24 h at room temperature. The solvent from anjali under vacuum, and the precipitate was kneaded with 5 ml of ethyl acetate. The solid was aspirated and 50aboutWith dried under vacuum. Obtained 270 mg (87%) of amide30.

Total formula C28H25FN8O2; MV=524,56; MS (M+H) 525,2.

1H NMR (DMSO-d6) of 2.45 (s, 3H), 4,10 (d, 1H), to 4.52-of 4.66 (m, 2H), of 6.26 (d, 1H), 6,77 (t, 1H), 7,02 (USS, 1H), 7,09-7,17(m, 2H), 7,22-to 7.32 (m, 5H), 7,38-7,46 (m, 1H), 7,47-7,58 (m, 3H), 7,92(s, 1H), 8,27-at 8.36 (m, 2H), 8,59(d, 1H), 11,70 (s, 1H).

D.3.) [(S)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (33)

D.3.1.) methyl ether (3-(N-phenyl-N-2-pyridyl)-amino)-2-(di-tert.-butyloxycarbonyl)-amino-propionic acid (31)

4,96 g (16.5 mmol) acrylate13was mixed with 5.6 g (32,9 mmol) of 2-anilinopiperidine and 32,16 g (98,7 mmol) of cesium carbonate. Added 50 ml of acetonitrile and within 2 days was stirred at 45aboutC. the Solid was sucked out through kieselguhr and 3 times washed with acetonitrile (100 ml). The combined organic phases were concentrated and the residue was chromatographically on kieselgel with eluent heptane/diethyl ether 1:1. Got to 5.66 g (73%) of ester31.

Total formula C25H33N3O6; MV=471,56; MS (M+H) 472,2.

D.3.2.) Separation of the enantiomers was carried out as described in PV.).

D.3.3.) methyl ester 2-{[2-(2-methylamino-pyrim the DIN-4-yl)-1H-indole-5-carbonyl]-amino}-3-(phenyl-pyridin-2-yl-amino)-propionic acid ( 32)

2.9 g of S-enantiomer31was dissolved in 30 ml of dioxane and cooled to 0aboutC. was Added 30 ml of 4 N. HCl in dioxane was left at room temperature and then 12 hour mixed. The solvent is kept under vacuum. The residue was absorbed 30 ml of DMF (the solution). 2,47 g (9.2 mmol) of acid20was dissolved in 50 ml of DMF and cooled to 0aboutC. was Added 4,21 g of HATU and 6.4 ml of DIEA. After stirring for 45 min at 0aboutFrom left at room temperature and was added tothe solution. Kept at room temperature for 12 hours. The solvent is kept under vacuum and the residue was distributed between 300 ml of a saturated solution of NaHCO3and 300 ml of ethyl acetate. The aqueous phase 3 times were extracted with ethyl acetate (100 ml) and the combined organic phases are washed with 400 ml of a saturated solution of NaCl. The organic phase was dried with magnesium sulfate. The solvent is kept under vacuum and the residue was chromatographically on kieselgel with eluent heptane/ethyl acetate 1:3. Received 1.78 g (55%) of ester32.

Total formula C29H27N7O3; MV=521,58; MS (M+H) 522,2.

D.3.4.) [(S)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (33)

1.78 g (3.4 mmol) of ester 32 was dissolved in 30 ml of methanol. Added 0,83 ml of hydrazine hydrate is added and peremeci the Ali 5 hours at 40 aboutC. then was added to 1.6 ml of hydrazine hydrate is added and stirred 15 hours at room temperature. The solvent is kept under vacuum and the residue was absorbed 80 ml of dichloromethane. Added 3.2 ml of 20%solution of phosgene in toluene and kept under stirring for 3 days. Then the solvent was removed under vacuum and the residue was distributed between 80 ml of water and 80 ml of ethyl acetate. Thus precipitated solid was sucked out. The organic phase was concentrated, the residue was combined with the solid and chromatographically on kieselgel with eluent heptane/ethyl acetate 1:5. Received 390 mg (21%) oxadiazoline33.

Total formula C29H25N9O3; MV=547,58; MS (M+H) 548,2.

1H NMR (DMSO-d6) 2,96(s, 3H), 4,30 (DD, 1H), 4,67 (DD, 1H), of 5.40 (DD, 1H), 6,32 (d, 1H), 6,70 to 6.75 (m, 1H), 6,98 (ush. s, 1H), 7,16 (d, 1H), 7,22-7,33 (m, 4H), 7,38-7,46 (m, 3H), 7,52(d, 1H), 7,63 (d, 1H), 8,08 (s, 1H), 8,21 (d, 1H), 8,31-8,35 (m, 1H), 9,00 (d, 1H), 11,72 (s, 1H), 12,15 (s,1H).

D.4.) {1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (35)

D.4.1.) methyl ester of 3-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-2-{[2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-propionic acid (34)

750 mg14,during the transformation, similar to that described in paragraph D.2.1.), received 370 mg (46%) of a compound methyl ester34.

The total shape is and 28H24FN7O3; MV=525,55; MS (m+H) 526,2.

D.4.2.) {1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (35)

150 mg34when the transformation is similar to that described in paragraph D.2.2.), got 95 mg (65%) of amide35.

Total formula C27H23FN8O2; MV=510,54; MS (M+H) 511,2.

1H NMR (DMSO-d6) 4,08-4,17 (m, 1H), 4,54 with 4.65 (m, 2H), 6,29 (d, 1H), 6,54 (s, 2H), 6,74-to 6.80 (m, 1H), 7,10 (s, 1H), 7,18(d, 1H), 7,22-7,31 (m, 4H), 7,38-7,56 (m, 6H), 7,92 (s, 1H), 8,29-8,35 (m, 2H), total of 8.74 (d, 1H), 11,80 (, 1H).

D.5.) [2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-1-(4H-[1,2,4]-triazole-3-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (36)

30 mg (0.25 mmol) of amide35was dissolved in 10 ml of DMF. Added 40 μl DMF-dimethylacetal and was heated for 4 hours to 90aboutC. the Solvent is kept under vacuum and the residue was absorbed 3.5 ml of acetic acid. After adding 27 ml of hydrazine hydrate is added left to mix for 18 hours. The solvent is kept under vacuum and the residue was purified by preparative HPLC. Got 84 mg (50%) of the triazole36.

Total formula C29H25FN10O; MV=548,59; MS (M+H) 549,2.

1H NMR (DMSO-d6)totaling 3.04 (s, 3H), 4,36-4,43(m, 1H), 4,49-4,59(m, 1H), ceiling of 5.60-5,67 (m, 1H), 6,50 (d, 1H), 6,78(t, 1H), 7,17-7,37(m, 7H), 7,45-the 7.65(m, 4H), 8,02(s, 1H), 8,19(d, 1H), 8,35(d, 1H), 8,39(d, 1H), 11,85(s, 1H).

D.6.) [1-it is rebamol-2-(phenyl-thiazol-2-yl-amino)-ethyl]-amide S-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid ( 42)

D.6.1.) phenyl-thiazol-2-yl-amine (39)

10 g (for 65.7 mmol) phenyltoloxamine37was dissolved in 100 ml of acetic acid. Was added to 9.9 ml of acetal38and was heated for 2 hours to 100aboutC. the Solvent is kept under vacuum and the residue was distributed between 300 ml of 1 N. NaOH and 300 ml of ethyl acetate. The aqueous phase was twice extracted with ethyl acetate (100 ml) and the combined organic phases were dried with magnesium sulfate. The solvent is kept off and the residue was kneaded from 50 ml of diisopropyl ether. The solid was aspirated and dried at 50aboutWith under vacuum. Received 2.5 g of aniline39. The mother liquor diisopropyl ether was concentrated and the residue was chromatographically on kieselgel with eluent heptane/ethyl acetate 2:1. Thus obtained 3.5 g39. Yield 6.0 g (52%).

Total formula C9H8N2S; MV=176,24; MS (M+H) 177,1.

D.6.2.) methyl ether (3-(N-phenyl-N-2-thiazolyl)-amino)-2-(di-tert.-butyloxycarbonyl)-amino-propionic acid (40)

Of 3.8 g (12.5 mmol) acrylate13with 2.2 g (12.5 mmol) of aniline39and 20 g of cesium carbonate analogously to the transformation described in paragraph D.3.1.), received 4.5 g (75 %) of ester40.

Total formula C23H31N3O6S; MV=477,58; MS (M+H) 478,2.

D.6.3.) Separation of the enantiomers was carried out as described in PV.)

D.6.4.) methyl ester of S-2-{[2-(2-m is thylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-(phenyl-thiazol-2-yl-amino)-propionic acid ( 41)

From 1.07 g (2.2 mmol) of ester40and901 mg(3.3 mmol) of acid20similarly described in paragraph (D.3.3.) turning, he received 640 mg (55%)41.

Total formula C27H25N7O3S; MV=527,61; MS (M+H) 528,1.

D.6.4.) [1-carbarnoyl-2-(phenyl-thiazol-2-yl-amino)-ethyl]-amide S-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (42)

From 500 mg (0.95 mmol)of41,as described in paragraph D.2.2.) turning, received 340 mg (70%) of amide42.

Total formula C26H24N8O2S; MV=512,60; MS (M+H) WAS 513.3.

1H NMR (DMSO-d6)of 2.97 (s, 3H), 4,23-4,30 (m, 1H), 4,39-4,48 (m, 1H), 4,71-4,78 (m, 1H), 6,78 (d, 1H), 7,16 (d, 1H), 7,28-7,35 (m, 3H), 7,37-of 7.60 (m, 7H), 7,98 (s, 1H), with 8.33 (d, 1H), to 8.62 (d, 1H), 11,70 (s, 1H),

D.7.) [1-methoxycarbonyl-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide S-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (43)

80 mg (0.95 mmol) of the hydrochloride of O-methylhydroxylamine was dissolved in 10 ml of THF and cooled to -40aboutC. was Bury of 0.95 ml (1.9 mmol) of a 2M solution Isopropylamine-chloride in THF. Within 1 hour and kept at -20aboutC. Then bury a solution of 100 mg (0,19 mmol) of ester32in 3 ml of THF. Within 4 hours kept at room temperature and stopped the reaction by adding 5 ml of water. THF drove under vacuum and the residue was distributed between 20 ml nasusunog the solution of ammonium chloride and 20 ml of ethyl acetate. The aqueous phase 3 times were extracted with ethyl acetate (20 ml) and the combined organic phases were dried with magnesium sulfate. The solvent is kept under vacuum and the residue was purified by preparative HPLC. Received 60 mg (61%) of methylhydroxylamine43.

Total formula C29H28N8O3; MV=536,60; MS (M+H) 537,2.

1H NMR (DMSO-d6)2,95 (s, 3H), 3,52 (s, 3H), 4.09 to 4,18 (m, 1H), 5,51-to 4.62 (m, 2H), 6,33 (d, 1H), 6,78 (t, 1H), 7,00 (USS, 1H), 7,18 (d, 1H), 7,25-7,33 (m, 4H), 7,49-to 7.61 (m, 5H), 7,98 (s, 1H), 8,29-at 8.36 (m, 2H), 8,79 (d, 1H), to 11.31 (s, 1H), 11,75 (s, 1H).

D.8.) {1-carbarnoyl-2-[(phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (45)

D.8.1.) methyl ester of 3-[(phenyl)-pyridine-2-yl-amino]-2-{[2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-propionic acid (44)

From 540 mgrac-10(the rat.-10),as described in paragraph B.1.4.) and D.1.1.) turning, received 816 mg (80%) of a compound methyl ester44.

Total formula C29H26N6O3; MV=506,56; MS (M+H) 507,37.

D.8.2.) {1-carbarnoyl-2-[(phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (45)

150 mg44as described in paragraph D.2.2.) transforming the received 162 mg (67%) of amide45.

Total formula C28H25N7O2; MV=491,56; MS (M+H) 492,32.

1H NMR (DMSO-d6 ) 3,18 ((ush.), 3H), 4,05 is 4.13 (m, 2H), 4,85 (kV, 1H), 6,58 ((ush.),2H), 6,88-to 7.59 (m, 19H), 7,98 (s, 1H), 8,25 (d, J=3 Hz, 1H), 8,35 (d, J=2 Hz, 1H), 11,78 (s, 1H).

D.9.) {1-carbarnoyl-2-[(phenyl)pirimidil-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (47)

D.9.1.) methyl ester of 3-[(phenyl)pirimidil-2-yl-amino]-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-propionic acid (46)

Out of 2.36 g15as described in paragraph D.2.1.) transforming the received 1.75 mg (67%) of a compound methyl ester46.

Total formula C28H26N8O3; MV=522,57; MS (M+H) 523,3.

D.9.2.) {1-carbarnoyl-2-[(phenyl)pirimidil-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (47)

From 700 mg46as described in paragraph D.2.2.) transforming the received 440 mg (65%) of amide47.

Total formula C27H25N9O2; MV=507,21; MS (M+H) 508,4.

1H NMR (DMSO-d6) 3,0 ((ush.), 3H), 4,20-4,32 (m, 1H), 4,45-4,59 (m, 2H), 4.75 V-the 4.90 (m, 1H), 6.75 in (m, 1H), 7,10-of 7.60 (m, 12H), 7,95 (s, 1H), 8,35-to 8.45 (m, 4H), 11,85 ((ush.), 1H).

D.10.) [1-(2-hydrooximethylcarbamil)-2-(phenyl-pyrimidine-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (49)

D.10.1) 2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-(phenyl-pyrimidine-2-yl-amino)-propionic acid (48)

4.0 g of complex methyl ester46was dissolved in 400 ml of methanol. To this was added 40 ml of 2 N. aqueous solution of NaOH and 12 h was stirred at room temperature. After evaporation of the solvent the residue was dissolved in water and a saturated solution of NaH2PO4drove pH˜5. The resulting precipitate was filtered and washed with water. Obtained 1.3 g (yield 93 %) acid48.

Total formula C29H26N6O3; MV=506,21; MS (M+H) 507,3.

D.10.2) [1-(2-hydroxy-ethylcarbamate)-2-(phenyl-pyrimidine-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (49)

200 mg acid48was dissolved in 2 ml of absolute DMF. To this was added 94 mg of HOAt and 158 μl DIEA. Then bury 56 μl ethanolamine, was cooled to 0aboutC and added 195 mg EDC. After 2 days stirring at room temperature, the solvent evaporated and the crude product is purified by medium pressure chromatography (MPLC) (eluent: DCM:methanol=9:1). Yield 108 mg (50%) of the target amide49.

Total formula C31H31N8O2; M,,=549,64; MS (M+H) 550,4,

1H NMR (DMSO-d6) 1,2 (t, 2H), 3,0 ((ush.), 3H), the 3.35 (t, 1H), 4,00-4,32 (m, 2H), 4.80 to 4,99 (m, 1H), 6,95 (m, 1H), 7,00-the 7.65 (m, 7H), of 7.90 (m, 1H), 8,35-to 8.40 (m, 1H), 11,90 ((ush.), 1H).

D.11.) (S)-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amino]-propionic acid( 54)

D.11.1) phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amine (51)

Out of the 5.1 g of aniline (4) and 5 g of chloropyrimidine50as described in PA.) transforming the received 5,1 g (78%) of aniline51.

Total formula C11H8F3N3; MV=239,20; MS (M+H) 240,1.

D.11.2.) methyl ether (3-(N-phenyl-N-4-cryptomaterial-2-yl)-amino)-2-di-tert.-butyloxycarbonyl)-amino-propionic acid (52)

Of 2.5 g (8.4 mmol) acrylate13,3 g (12.5 mmol) of aniline51and 16 g (50 mmol) of cesium carbonate as described in paragraph D.3.1.) transforming the received 3,9 g (86%) of ester52.

Total formula C25H31F3N4O6; MV=540,54; MS (M+H) 541,2.

D.11.3.) Separation of the enantiomers was carried out as described in paragraph (B.2.1.)

D.11.4.) methyl ester of S-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amino]-propionic acid (53)

Out of the 743 mg (1,375 mmol) of S-enantiomer of ester52and 550 mg (1,436 mmol) acid20as described in p. D.3.3.) transforming the received 467 mg (58%)53.

Total formula C29H25F3N8O3; MV=590,57; MS (M+H) 591,7.

D.11.5.) (S)-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amino]-propionic acid (54)

97 m is (0,164 mmol) of ester 53as described in paragraph (D.10.1.) transforming the received 38 mg (40%) acid54.

Total formula C28H23F3N8O3; MV=576,54; MS (M+H) 577,7,

1H NMR (DMSO-d6) 2,95 (s, 3H), 4,27-4,34 (m, 1H), 4,54-4,63 (m, 1H), a 4.83-4.92 in (m, 1H), 6.90 to (USS, 1H), 7,15 (d, 2H), 7,19-of 7.23 (m, 1H), 7,27 was 7.36 (m, 5H), 7,45-of 7.55 (m, 2H), of 7.96 (s, 1H), 8,32 (s, 1H), to 8.41 (USS, 1H), 8,66 (d, 1H), 11,70 (s, 1H).

D.12.) {1-carbarnoyl)-2-[(4-forfinal)-(5-methyl-pyrimidine-2-yl)-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (61)

D.12.1.) pentafluorophenyl ester 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (55)

6,38 g (23,78 mmol) acid20suspended in 100 ml of THF. To this was added a 5.25 g (28,54 mmol) pentafluorophenol and 5.47 g (28,54 mmol) of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC*HCl). Kept for 15 hours under stirring at room temperature, solvent was removed under vacuum and the residue was distributed between 300 ml of a saturated solution of NaHCO3and 300 ml of ethyl acetate. The solid was filtered through diatomaceous earth and the residue 2 times washed with ethyl acetate (100 ml). The phases were separated and the aqueous phase is 2 times were extracted with ethyl acetate (100 ml). The combined organic phases are washed with 200 ml saturated NaCl solution and then dried MgSO4. After removal of the solvent under vacuum, the residue chromatography which was referable on kieselgel with eluent heptane/ethyl acetate 1:1. Received 4.7 g (46%)pentafluorophenyl ether complex55.

Total formula C20H11F5N4O2; MV=434,33; MS (M+H) 435,4.

D.12.2.) 2-chloro-5-methyl-pyrimidine (57)

10.0 g (61,35 mmol) of 2,4-dichloro-5-methylpyrimidine (56) was dissolved in 50 ml of THF. Added 12,93 g (184 mmol) of zinc was heated under reflux. Then slowly bury solution 3,51 ml (61,35 mmol) of acetic acid in 10 ml of THF. After adding another 1 hour and heated under reflux. Further bury 1.5 ml of acetic acid in 5 ml of THF and 1 hour and heated under reflux. Then left to cool to room temperature, filtered through diatomaceous earth and washed 2 times, each time with 20 ml THF. The solvent is kept under vacuum and the residue was chromatographically on kieselgel. Received 4.7 g (60%) of chloropyrimidine57.

Total formula C5H5ClN2; MV=128,56; MS (M+H) TO 129.2.

D.12.3.) (4-fluoro-phenyl)-(5-methyl-pyrimidine-2-yl)-amine (58)

Of 2.5 g (19,45 mmol) 2-chloro-5-methylpyrimidine (57)and 2.7 g (24,31 mmol) 4-foronline (1) similar to that described in paragraph (A.1.) transforming the received 1.8 g (45%) of aniline58.

Total formula C11H10FN3; MV=203,22; MS (M+H) 204,2.

D.12.4.) methyl ether (3-(N-4-fluoro-phenyl-N-5-methyl-pyrimidine-2-yl)-amino)-2-di-tert.-butyloxycarbonyl)-amino-propionic acid( 59)

From 2.67 g (8,86 mmol) acrylate10,1.8 g (8,86 mmol) of aniline58and 8,66 g (26,58 mmol) of cesium carbonate as described in paragraph D.3.1.) transforming the received 2,88 g (64%) of ester59.

Total formula C25H33FN4O6; MV=504,56; MS (M+H) 505,6.

D.12.5.) methyl ester of 3-[(4-fluoro-phenyl)-(5-methyl-pyrimidine-2-yl)-amino]-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-propionic acid (60)

500 mg (0,991 mmol) of ester59was dissolved in 10 ml dichloromethane and cooled to 0aboutC. To this was added 5 ml of TN, kept for 1 hour at room temperature and was stirred. Solvent was removed under vacuum. The residue was absorbed in 10 ml DMF was added 430 mg (0,991 mmol)55and 1.38 ml (to 7.93 mmol) DIEA. Was stirred for 15 h at room temperature, solvent was removed under vacuum and the residue was chromatographically on kieselgel with eluent heptane/ethyl acetate 1:3. Received 423 mg (77%)60.

Total formula C29H27FN8O3; MV=554,59; MS (M+H) 555,2.

D.12.6.) {1-carbarnoyl)-2-[(4-forfinal)-(5-methyl-pyrimidine-2-yl)-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (61)

From 260 mg (0,469 mmol) of ester60as described in paragraph D.2.2.) transforming the received 250 mg (99%) of amide61.

Total formula C28H26FN9O2; MV=539,58; MS M+H) 540,2.

1H NMR (DMSO-d6) 2,11(s, 3H), 2.95 and(s, 3H), 4,21 (DD, 1H), 4,48(DD, 1H), 4.75 V-4,80(m, 1H), 7,01 (USS, 1H), 7,10-7,16(m, 4H), 7,22-7,30(m, 3H), 7,43(s, 1H), 7,47-7,53(m, 2H), to $ 7.91(s, 1H), compared to 8.26(s, 2H), 8,29-to 8.34(m, 2H,), 11,70(s, 1H).

F.) of the Target product benzimidazole

F.1.) ((S)1-carbarnoyl-2-diphenylamino-ethyl) - amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid (63)

F.1.1.) methyl ether 3-diphenylamino-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}-propionic acid (62)

2.6 g (9.6 mmol) of 2-(2-methylamine-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid (25) was dissolved in 300 ml of DMF and consistently added 3,17 g (9.6 mmol) of TOTU and 1.6 ml (11.6 mmol) of ethyldiethanolamine. Was stirred 20 min at 5aboutWith and added to a solution of 2.6 g (9.6 mmol) of methyl ester of (S)-2-amino-3-diphenylamino-propionic acid (11). After stirring for 16 h then concentrated under reduced pressure, then was isolated methyl ester62by flash chromatography on kieselgel (DCM:methanol=9:1). The output of 1.61 g (32%).

Total formula C29H27N7O3; MV=521,58; MS (M+H) 522,3.

1H NMR (DMSO-d6) 2,95 ((ush.), 3H), of 3.60(s, 3H), 4,19-and 4.40 (m, 2H), 4,90(kV, 1H), 6.90 to-7,10(m, 6H), 7,25-7,35 (m, 6H), 7,40 (d, J=4.5 Hz, 1H), 7,60-7,80 (d(ush.), 1H), 8,05 is 8.25(d(ush.), 1H), 8,45 (d, J=3 Hz, 1H), 8,90 ((ush.), 1H), 11,85 ((ush.), 1H).

F.1.2.) ((S)1-carbarnoyl-2-diphenylamino-ethyl)and the ID 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid ( 63)

50 ml of methanol (absolute.) at 0aboutWith saturated ammonia. To this was added 0.5 g (0,959 mmol) of methyl ester of 3-diphenylamino-2-{[2-(2-methylamine-pyrimidine-4-yl)-1H-benzimidazole-5-carbonyl]-(S)-amino}-propionic acid (62and 24 hours was stirred at room temperature. After evaporation of the solvent and excess ammonia were isolated amide63by flash chromatography on kieselgel (DCM:methanol=19:1). The yield of 0.43 g (89%).

Total formula C29H28N8O2; MV=506,57; MS (M+H) 507,2.

1H NMR (DMSO-d6) 2,95 ((ush.), 3H), as 4.02 is 4.35 (m, 2H), 4,85 (kV, 1H), 6,80-7,10(m, 6H), 7,15-7,25 (m, 5H), 7,40 (d, J=4.5 Hz, 1H), 7,58 ((ush.), 1H), 7,68 ((ush.), 1H), 8,06-8,19 (d(ush.), 1H), 8,40-8,58 (m, 2H), 13,10(s, 1H).

F.2.) {1-carbarnoyl-2-[(phenyl)-pyrimidine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzoimidazol-5-carboxylic acid (65)

F.2.1.) methyl ester of 3-[(phenyl)-pirlimycin-2-yl-amino]-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (64)

Of 657 mg15as described in paragraph D.2.1.) transforming the received 210 mg (29%) complicated methyl ester64.

Total formula C27H25N9O3; MV=523,56; MS (M+H) 524,2.

F.2.2.) {1-carbarnoyl-2-[(phenyl)-pyrimidine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid (65)

Of 200 m is 64as described in paragraph D.2.2.) transforming the received 110 mg (65%) of amide65.

Total formula C26H24FN10O2; MV=508,55; MS (M+H) 509,3.

1H NMR (DMSO-d6) 3,00 ((ush.), 3H), 4,20-4,32 (m, 1H), to 4.41-4,55(m, 2H), 4.80 to the 4.90(m, 1H), 6.75 in (m, 1H), 7,10-to 7.50 (m, 10H), 7,65 (kV, 2H), 8,10 (s, 1H), -8,45(d, 2H), and 8.50(d, 1H), 8,58(d, 1H), 12,95 ((ush.), 1H).

F.3.) {1-carbarnoyl-2-[(phenyl)-pyridyl-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid (67)

F.3.1.) methyl ester of 3-[(phenyl)-pyridyl-2-yl-amino]-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (66)

From 3,44 g31as described in paragraph D.2.1.) transforming the received 0,85 g (22%) complicated methyl ester66.

Total formula C28H26N8O3; MV=522,57; MS (M+H) 523,3.

F.3.2.) {1-carbarnoyl-2-[(phenyl)-pyridyl-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid (67)

From 200 mg66as described in paragraph D.2.2.) transforming the received 160 mg (98%) of amide67.

Total formula C27H25N9O2; MV=507,56; MS (M+HCOO-) 552,3.

1H NMR (DMSO-d6) 3,0 ((ush.), 3H), 4,20-4,32 (m, 1H), to 4.41-4,55(m, 2H), 4,70-4,80(m, 1H), 6,63 (m, 1H), 6,85 (m, 1H), 7,20 to 7.75 (m, 14H), 8,10 (s, 1H), -8,20 (d, 2H), and 8.50(d, 1H), 8,88(d, 1H).

The drugs examples

Solid-phase immunopharm ntny assay (ELISA) IkB-kinase:

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

Analysis

For more complex kinase 10 ml HeLa S3-extract S 100 cells were diluted with 40 ml of 50 mm HEPES, pH 7.5, were placed in a 40% ammonium sulfate and incubated on ice for 30 minutes Besieged granulate was dissolved in 5 ml of SEC buffer (50 mm HEPES, pH 7.5, 1 mm dithiothreitol DTT (DTT), 0.5 mm EDTA ethylenediaminetetraacetate (EDTA), 10 mm 2-glycerol), was centrifuged at 20000 x g for 15 minutes and filtered through a filter with pores of 0.22 μm. The sample was applied in 320 ml Superose-6 column HPLC (FPLC) (Amersham Pharmacia Biotech AB, Uppsala, Schweden), which was balanced by the SEC - buffer and operated at 4aboutWith a flow rate of 2 ml/min Fraction, the running time which coincided with the time the mileage is conventional molecular weight of 670 kDa, connected for activation. Activation provided by a 45-minute incubation with 100 nm MEKK1Δ 250 μm Mgatp, 10 mm MgCl2, 5 mm dithiothreitol (DTT), 10 mm 2-glycerol, 2.5 μm microcystin-LR at 37aboutC. the Activated enzyme was stored at -80aboutC.

The test substance (2 ml), dissolved in DMSO, pre-incubated for 30 min at 25aboutWith 43 μl of activated enzyme (diluted 1:25 in the reaction buffer: 50 mm HEPES, pH 7.5, 10 mm MgCl2, 5 mm DTT, 10 mm β-glycerol, 2.5 μm microcystin-LR). Then added 5 μl of substrate peptide (Biotin-(CH2)6-DRHDSGLDSMKD-CONH2) (200 μm), incubated for 1 hour and stopped the process by 150 μl of 50 mm HEPES, pH 7.5, with 0.1 % bovine serum albumin BSA (BSA), 50 mm EDTA, antibody [1:200]. 100 µl of the inhibited reaction mixture or diluted number of standard phosphopeptide, (Biotin-(CH2)6-DRHDS[PO3]GLDSMKD-CONH2) then transferred to the tablet with protein A (Pierce Chemical Co., Rockford, IL, USA) and 2 hours and incubated with shaking. After 3-stage rinsing the substrate binding protein (PBS), was added 100 μl of 0.5 μg/ml streptavidin-HRP (horseradish peroxidase) (diluted in 50 mm HEPES/ 0.1 % BSA) for 30 min After a 5-stage washing PBS was added 100 μl of TMB substrate (Kirkegaard &Perry Laboratories, Gaithersburg, MD, USA) and stop the color development by adding 100 μl of 0.18 M the agreement acids. The absorbance was measured at 450 nm. A standard curve was obtained by linear regression of the corresponding 4-parameter relation dose-result. Based on this standard curve quantify the enzyme activity or its inhibition by the tested substances.

The value of the IC50[(S)-2-diphenylamine-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamine-pyrimidine-4-yl)-1H-indole-5-carboxylic acid was 0,050 mm.

Content in the blood plasma [(S)-2-diphenylamine-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamine-pyrimidine-4-yl)-1H-indole-5-carboxylic acid.

The compound[(S)-2-diphenylamine-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamine-pyrimidine-4-yl)-1H-indole-5-carboxylic acid, hereinafter referred to as the connection28introduced the male species mice C57/BL6. For this purpose, in each case, was administered orally (via stomach tube) about 25 mg of the compound28per kg of body weight of the mouse, milled in a 0.5% hydroxyethyl cellulose (HEC) in suspension. The drawing of blood samples took place through 0,25; 0,5; 1; 2; 4; 6 and 8 hours (each named time the blood was collected from the two dead animals in each case). Blood samples were converted into the heparin-plasma. Plasma samples prior to analysis were stored at -20aboutC.

Analysis.

Plasma samples were thawed. Then the plasma proteins that interfere with the analysis, precipitated with acetonitrile.

Treatment: 50 ál plasma+20 ál of internal standard (5 ug/ml)+50 μl buffer (2 mmol solution of ammonium formate, pH 2,6/acetonitrile, 40:60, about./about.) mixed for about 10 seconds on a vortex mixer. Then add 150 μl of acetonitrile and again mixed for about 10 seconds. Then the sample was centrifuged (Hettlich, EBA 12, 12,000 rpm). Supernatant (200 μl) was transferred into a glass vessel. 70 μl of the supernatant were injected with.

From the corresponding supernatant was determined by the content of the connection13in plasma by LC-MS/MS (liquid chromatography with mass spectrometry) according to the following procedure:

The HPLC system: Agilent 1100

Software: Analyst

Column: Hm Nucleosil 120 5 C18 (Machery&Nagel)

The column length: 125 mm

Detection: LC-MS/MS

MS-instrument: PE-Sciex API 365 (triplet-quadrupolar mass spectrometer)

Software: MasQuan Software (PE-Sciex)

Race detection: MS/MS (MRM)

Flow rate: 0.5 ml/min

Volume of injection: 70 ál

Internal standard: SK-7 in acetonitrile

Mobile phase: acetonitrile/2 mmol of a solution of ammonium formate, pH 2,6 (70:30, vol/about.)

The retention time (Rt):

Internal standard: 4,4 minutes

Connection28: 3,9 minutes

The boundary of the validity of the method is 0.01 mg/ml

The results:

The contents of the connection28in a plasma with what was the maximum of 4.3 µg/ml Exposure, measured as the area (AUC) under the curve, amounted to 5.4 μg/ml x hour.

Proteincontaining

As an example of the specificity of the detected inhibition of IkB kinase was determined by the value of the IC50for enzyme proteincontaining.

Activity proteincontaining was determined with a test kit from Upstate Biotechnologie according to the instructions of the manufacturer when the concentration of ATP (ATP) 50 µm. Instead phosphocellulose filter used multi-layer tablets (Multi-Screen-Platten) (Millipore; phosphocellulose MS-PH, Kat. MAPHNOB 10, or Durapore PVDF, Kat. MADVNOB 50) with an appropriate exhaust system. As the substrate of the test Suite used Poly(Glu, Tyr 4:1) (Sigma cat. P0275), concentration tests 1 mg/ml Then the tablets were measured in a Wallac MicroBeta acquired scintillation counter. As needed used 100 μm test substance.

Each test substance was tested twice. The definition of the IC50conducted with the software GraFit 3.0.

IC50for[(S)-2-diphenylamine-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid (compound28) is in the analysis proteincontaining of 82.5 μm. Comparative experience:

Connection

received as described in WO 01/30774 in the future were identified as relatively the connection. Comparative compound was administered to male individuals NMRI mice. For this purpose, in each case, was administered orally (via stomach tube) of about 50 mg comparative connections0.5% HEC in suspension (per kg of body weight of a mouse). Sampling of blood was produced through 0,25; 0,5; 1; 2; 4; 6 and 8 hours (each named time the blood was collected from the two dead animals in each case). Blood samples were converted into the heparin-plasma. Plasma samples prior to analysis were stored at -20aboutC.

Analysis. Analysis was performed by HPLC/ultraviolet (HPLC/UV).

Treatment: 50 ál plasma+20 ál of internal standard (5 ug/ml)+50 μl of buffer (1% formic acid/acetonitrile, 40:60, about./about.) mixed for about 10 seconds on a vortex mixer. Then add 150 μl of acetonitrile and again mixed for about 10 seconds. Then the sample was centrifuged (Hettich, EBA 12, 12,000 rpm./min). Supernatant (200 μl) was transferred into a glass vessel. 100 µl of the supernatant was injected in the injection.

For the corresponding supernatant was determined by the content of the comparative compounds in plasma by HPLC/UV using the following method:

The HPLC system: Gynkoteck P580 HPG-Pumpe+Gilson Abimed XL-231 Autosampler

Software: Mass-chrom

Column: Hm Protocol 120 3 ODS AQ 3 (firm Bischoff)

The column length: 125 mm

Detection: LC-MS/MS

MS-instrument: PE-Sciex API 365 (triplet-quadropolar the ACC spectrometer)

Software: MasQuan Software (PE-Sciex)

Race detection: MS/MS (MRM)

Flow rate: 0.5 ml/min

Volume of injection: 100 ál

Internal standard: SK-7 (firm Aventis) in acetonitrile

Mobile phase: acetonitrile/2 mmol of a solution of ammonium formate, pH 2,6 (70:30, vol/about.)

The retention time (Rt):

Internal standard: 4 minutes

Comparative connection: 1,5 minutes

The boundary of the validity of the method is 0.01 mg/ml was identical to the same determined by LC-MS/MS in the example of the connection28.

Results

The content of the comparative compounds in the plasma accounted for a maximum of 1.5 μg/ml Exposure time, measured as the area (AUC) under the curve, was 1.7 µg/ml x hour.

In comparison with example connections28the maximum content in plasma was approximately 60% lower than in the comparative experience, although the comparative compounds was taken as 50 mg/kg two times more than the connection28. A similar result also showed the average AUC for comparative connections.

The value of the IC50for comparative connections accounted for in the above analysis proteincontaining 46,35 μm. Thus, the IC50clearly better than for the connection28.

Even more clearly improved specificity relative to the IkB-kinase, if you map the ratio of the values of the IC50about enterokinase to IkB-kinase. This figure is for connection 28 1650 (82,5/0.05) and for comparative connections 46,35 (46,35/1,0; according to WO 01/30774).

Similarly, it was determined the ratio of the specificity and the level of plasma and exposure the following examples (see table):

> means better than...

1. The compound of the formula I

and/or a stereoisomeric form of the compounds of formula I and/or physiologically compatible salt of the compounds of formula I, and

X and M are identical or different and, independently of one another, denote the N atom or CH,

R1 and R11 are the same or different and independently of one another denote

1. a hydrogen atom,

2. F, Cl, Br J or,

R2 denotes

1. heteroaryl residue from the group comprising 1,3,4-oxadiazol, oxadiazolidine, oxadiazole, thiazole, and

heteroaryl residue is unsubstituted or independently from each other one-, two - or three-replaced

1.1. keto-balance

2. -C(O)-R5where R5denotes a hydrogen atom or -(C1-C4)-alkyl, or

3. -C(O)-N(R7)-R8where R7and R8independently from each other represent a hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,

R3 convoy is achet a hydrogen atom or -(C 1-C4)-alkyl,

R4 denotes

1. heteroaryl residue from the group including thiazole, isothiazol, pyridine, pyrazin, pyrimidine, and heteroaryl residue is unsubstituted or one-, two -, or three times substituted independently of one another -(C1-C5)-alkyl, halogen, trifluoromethyl, or

2. aryl residue from the group comprising phenyl.

2. The compound of formula I according to claim 1,

where X and M are the same or different and independently of one another denote an N atom or CH,

R1 and R11 are the same or different and independently of one another denote

1. a hydrogen atom,

2. F, Cl, Br J or,

R2 denotes

1. heteroaryl residue from the group comprising 1,3,4-oxadiazol, oxadiazolidine, 1,2,3,5-oxadiazole, thiazole, and heteroaryl residue is unsubstituted or independently from each other one-, two - or three-replaced

1.1. keto-balance

2. -C(O)-N(R7)-R8where R7and R8independently from each other represent a hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl,

R3 denotes a hydrogen atom, methyl or ethyl,

R4 denotes

1. heteroaryl residue from the group of unsaturated, partially saturated or fully saturated cycles formed from pyridine, pyrazine, PIR is Medina, thiazole, or isothiazole,

and heteroaryl residue is unsubstituted or one-, two -, or three times substituted independently of one another -(C1-C4)-alkyl, F, Cl, J, Br, trifluoromethyl, or

2. phenyl.

3. The compound of formula I according to claim 1 or 2, representing

[(S)-2-diphenylamino-1-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[(S)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[2-[(4-fluoro-phenyl)-pyridine-2-yl-amino]-1-(4H-[1,2,4]triazole-3-yl)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-carbarnoyl-2-(phenyl-thiazol-2-yl-amino)-ethyl]-amide (S)-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-methoxycarbonyl-2-(phenyl-pyridin-2-yl-amino)-ethyl]-amide (S)-2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)-pyridine-2-yl-amino]-ethyl}-amide 2-(2-amino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)-iremedi-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

[1-(2-hydroxy-ethylcarbamate)-2-(phenyl-pyrimidine-2-yl-amino)-ethyl]-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

(S)-2-{[2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carbonyl]-amino}-3-[phenyl-(4-trifluoromethyl-pyrimidine-2-yl)-amino]propionic acid,

{1-carbarnoyl-2-[(4-fluoro-phenyl)-(5-methyl-pyrimidine-2-yl)-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-indole-5-carboxylic acid,

((S)-1-carbarnoyl-2-diphenylamino-ethyl)-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzoimidazol-5-carboxylic acid,

{1-carbarnoyl-2-[(phenyl)pirimidil-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid, or

{1-carbarnoyl-2-[(phenyl)-pyridyl-2-yl-amino]-ethyl}-amide 2-(2-methylamino-pyrimidine-4-yl)-1H-benzimidazole-5-carboxylic acid.

4. The method of obtaining the compounds of formula I according to one or more of claims 1 to 3, characterized in that

a) compound of formula IV,

where R1, R2 and R4 are defined as in formula I, is subjected to the interaction with the acid chloride or activated complex ester compounds of the formula III,

moreover, D1 denotes-COOH, and R11, X, M and R3 are defined as in formula I, in the presence of a base or, if necessary, the drying means in the solution, and transfer the t in the compound of formula I,

b) the compound of formula I obtained by the method (a), due to their chemical structure exists in enantiomeric forms, separated by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or turning by means of chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers, and the removal of the chiral auxiliary groups in the pure enantiomers, or

(C) a compound of formula I obtained by the method (a) or (b)allocate or free-form, or, in the case of acidic or basic groups, was transferred to a physiologically compatible salt.

5. Drug with activity against IkB-kinase, different effective amount of at least one of the compounds of formula I and/or one physiologically compatible salts of the compounds of formula I and/or, if necessary, one stereoisomeric forms of the compounds of formula I, together with a pharmaceutically suitable and physiologically compatible carrier, additive and/or other biologically active and auxiliary substances.

6. The use of the compounds of formula I according to one or more of claims 1 to 3 to obtain drugs for prevention and treatment of all diseases, the occurrence of which is connected with increased activity of IkB kinase.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazoles of the general formula (I): , wherein R1 represents hydrogen atom (H), direct or branched (C1-C4)-alkyl or COO-(C1-C4)-alkyl or phenyl optionally substituted with one or some substitutes chosen from halogen atom; R2 represents H, direct or branched (C1-C4)-alkyl, COO-(C1-C4)-alkyl. Method for synthesis involves addition to aqueous solution of 4-R1-5-R2-1-hydrazino-1,3-thiazole hydrochloride of the formula (II): , wherein R1 and R2 have above given values of N-cyanoguanidine of the formula (III): in the mole ratio (II) : (III) = (1.10-1.20):100. Prepared mixture is heated at temperature 80-95°C followed by its neutralization, filtering off and recrystallization. Method provides preparing 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazole from inexpensive and available raw and without using complex technological procedures. Synthesized compounds can be used in synthesis of medicinal and biologically active substances.

EFFECT: improved method of synthesis.

10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes novel substituted pyrazoles of the general formula (I): wherein values of radicals Ar, Ar2, W, G, R5-R8, RZ and n are given in the invention claim. Also, invention relates to a pharmaceutical composition based on these compounds, using this pharmaceutical composition for manufacturing agent designated for treatment of asthma, and a method for inhibition of activity of cathepsin S. Compounds indicated above can be used in medicine.

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

27 cl, 3 tbl, 352 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel nitrogen-containing aromatic derivatives of the general formula (I): wherein X1 means nitrogen atom (N) or group -CR10= wherein R10 means hydrogen atom (H), halogen atom or -CN; X2 means N or group -CR11= but X1 and X2 can't mean N simultaneously; Y means oxygen atom (O) or group -NRY- wherein RY means hydrogen atom or (C1-C6)-alkyl group; R1 means phenoxy-group, group -NR12aR12b, group , group and other values; each radical among R3, R4, R5, R6 and R11 means hydrogen atom; R7 means hydrogen atom or (C1-C6)-alkyl group; R8 means hydrogen atom or (C1-C6)-alkyl group; R10 means hydrogen atom, halogen atom or cyano-group; R9 means group -NR16aR16b or group of the formula: wherein T2 means pyrrolidine, piperazine ring possibly substituted with (C1-C6)-alkyl group, or morpholine ring; R12a and R12b mean independently hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R2 means hydrogen atom or (C1-C6)-alkyl; R16a means hydrogen atom or (C1-C6)-alkyl, and R16b means (C1-C6)-alkyl possibly substituted with phenyl, (C1-C6)-alkoxy-group, (C1-C6)-alkylthio-group or di-(C1-C6)-alkylamino-group, (C3-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl possibly substituted with halogen atom, thiazolyl or piperidinyl possibly substituted with (C1-C6)-alkyl, and their salts or hydrates. Also, invention describes a pharmaceutical composition, method for treatment or prophylaxis of tumor diseases and using the novel compounds for preparing an agent useful in treatment abovementioned diseases.

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

26 cl, 17 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

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

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel polycyclic compounds of the formula (I): wherein radicals and symbols have values given in the invention claim. Compounds of the formula (I) possess properties of H3 receptors antagonist. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I). Also, invention relates to a method for treatment of disease of group comprising difficulty in nasal breath, obesity, somnolence, narcolepsy, attention deficiency with hyperactivity, Alzheimer's disease and schizophrenia that involves using compounds of the formula (I) and, optionally, in combination of H receptor antagonist.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

39 cl, 3 tbl, 31 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and R8 represent hydrogen atom or (C1-C6)-alkyl; T represents oxygen atom; V represents N<; X1 represents phenyl substituted with 1-2 substitutes chosen from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, cyano-group or trifluoromethyl; X2 represents a bicyclic heteroaryl comprising 7 carbon atoms and 1-2 heteroatoms chosen from oxygen (O), nitrogen (N) and sulfur (S) atoms optionally substituted with (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or phenyl substituted with halogen atom; Y represents monocyclic heteroarylenyl comprising 3-5 carbon atoms and 1-3 heteroatoms chosen from N and O; Z1 and Z2 represent independently (C1-C4)-alkylene. Compounds of the formula (I) are used in preparing a pharmaceutical composition used in treatment of morbid state in mammal that can be relieved using inhibitor of oxidation of aliphatic acids. Also, invention relates to a pharmaceutical composition inhibiting oxidation of aliphatic acids and comprising at least one pharmaceutically acceptable excipient and the therapeutically effective dose of compound of the formula (I). Invention provides using substituted piperazine compounds as inhibitors of oxidation of aliphatic acids.

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

19 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, hematology, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): in all their stereoisomeric forms and their mixtures taken in any ratio and their physiologically acceptable salts possessing properties of inhibitors of factor Xa and/or factor VIIa, and to a medicinal agent based on thereof. Also, invention relates to a method for synthesis of these compounds and their using for preparing pharmaceutical agents for inhibition of activity of factor Xa and/or factor VIIa or for their effect on blood coagulation or fibrinolysis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 1 tbl, 276 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinone of the general formula (VI): wherein R1, R2, R3 and R4 are chosen independently from group consisting of hydrogen atom (H) and halogen atom; each R5 means independently (C1-C12)-alkyl; R6 means -NR8-(CH2)mR9, -NR10R11 under condition that from 1 to 4 groups -CH2- can be substituted optionally with -OH; R8 means H; R9 means -NR10R11 wherein R10 and R11 mean (C1-C12)-alkyl, or R10 and R11 in common with nitrogen atom to which they are bound can form a heterocyclic group chosen from morpholinyl, pyrrolidinyl and piperidinyl under condition that the heterocyclic group can be substituted optionally with morpholino-group; J means -NH; L means carbon atom (C), and group -C(O)R6 is bound with L; K and M means -CR5; m = 1, 2, 3 or 4; p = 2. Method for synthesis of these compounds involves the addition reaction of compound of the general formula (III): wherein R* means R with compound of the formula (IV): wherein values R1, R2, R3 and R4 are given above with amine of the general formula (V): HR6 (V) wherein R6 is given above to form indolinone of the general formula (VI). Method provides synthesis of indolinone derivatives with the yield 25-85%.

EFFECT: improved method of synthesis.

20 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I): or its pharmaceutically acceptable salts or esters hydrolyzed in vivo and possessing properties of selective inhibitor of cyclin-dependent kinases, such as CDK-2, and inhibiting proliferation of cells. Compounds can be used in preparing medicinal agents used in treatment of cancer diseases. In compounds of the formula (I) R1 represents halogen atom; p = 0 or 1; R2 represents sulfamoyl or group B-E-; q = 0 or 1 wherein p + q = 1; R3 represents hydrogen atom, (C1-C6)-alkyl wherein R3can be substituted optionally at carbon atom with one or some M; R4 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl wherein R4 can be substituted optionally with one or some M; or R3 and R4 taken with nitrogen atom to which they are bound form heterocyclic ring substituted optionally at carbon atom with one or some M wherein if indicated heterocyclic ring comprises group -NH then nitrogen atom can be substituted optionally with group chosen from Q; B is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein B can be substituted optionally at carbon atom with one or some D and wherein indicated heterocyclic group comprises group -NH- then nitrogen atom can be substituted optionally with group chosen from G; E represents -S(O)r- or -N(Ra)SO2- wherein Ra represents hydrogen atom or (C1-C6)-alkyl and r = 2; D is chosen independently from halogen atom, nitro-, cyano-, hydroxy-, amino-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N-(C1-C6)-alkylamino-, N,N-((-C1-C6)-alkyl)2-amino-, (C1-C6)-alkanoylamino-group, (C1-C6)-alkyl-S(O)a wherein a = 0-2, wherein D can be substituted optionally at carbon atom with one or some V; M is chosen independently from halogen atom, nitro-, cyano-, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-, N,N-((C1-C6)-alkyl)2-amino-group, (C1-C6)-alkoxycarbonyl, (C3-C8)-cycloalkyl or heterocyclic group wherein M can be substituted optionally at carbon atom with one or some P; P, X and Y are chosen independently from hydroxy-group, methyl, methoxy-, dimethylamino-group; G and Q are chosen independently from (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkoxycarbonyl wherein Q can be substituted optionally at carbon atom with one or some X. Also, invention relates to methods for synthesis of compounds, preparing pharmaceutical compositions based on thereof and to a method for inhibition of proliferation of cells.

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

15 cl, 2 sch, 133 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of indoline of the formula (I): wherein (i) R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means -A1-NR5R6 wherein each substitute R5 and R6 means independently H, (C1-C4)-alkyl; A1 means -(CH2)m, -(CH2)n-A2-(CH2)p or -(CH2CH2O)qCH2CH2 wherein m means a whole number from 2 to 10; each n and p means a whole number from 1 to 6; A2 means -CH=CH, phenylene, biphenylene, cyclohexylene or piperazinylene; q = 1, 2 or 3; (ii) R1 and R2 represent in common -A3-NR7-A4 wherein each A3 and A4 means independently -(CH2)r or -(CH2CH2O)sCH2CH2 wherein r means a whole number from 2 to 6; s = 1, 2 or 3; R7 means H, (C1-C4)-alkyl; (iii) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl that comprises a substitute of the formula: -A5-R8 at 4 position wherein A5 represents (C1-C4)-alkylene, and R8 represents piperidin-4-yl; or (iv) R1 and R2 in common with nitrogen atom to which they are bound form piperidinyl, and each R3 and R4 means independently H, or its pharmaceutically acceptable salt. Proposed compounds inhibit tyrosine kinase receptors that allow their using as components of pharmaceutical compositions for treatment. Also, invention describes methods for synthesis of compounds of the formula (I).

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

15 cl, 1 tbl, 24 ex

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