Heterocyclic compounds possessing elastase-inhibitory activity and their derivatives and pharmaceutical composition and agent based on thereof

C07K5/083 -

A61K38/55 - Protease inhibitors

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention describes heterocyclic compounds represented by the general formula (I): and possessing elastase-inhibitory activity, and intermediate compounds for synthesis of such compounds. In the formula (I) R¹ represents heterocyclic group represented by the formula (II): wherein A represents presence or absence of benzene ring; X represents oxygen atom, sulfur atom or -NH; Y represents nitrogen atom or -CH. Indicated heterocyclic group can be substituted with 1-3 substitutes that can be similar or different and they are chosen from group consisting of lower alkyl, lower alkoxy group and phenyl that can be optionally substituted with halogen-containing lower alkyl, lower alkoxy group or halogen atom; each among R² and R³ represents hydrogen atom or hydroxyl, or R² and R³ can be combined to form oxo group under condition that both are not hydrogen atoms.

EFFECT: valuable biochemical property of compounds.

8 cl, 7 tbl

The technical field to which the invention relates.

The present invention relates to a medicinal product, in particular to a new heterocyclic compound with lactatingebony activity, connection, intermediate for him, and lactatingebony tool that contains the specified new connection as the active ingredient.

The level of technology

Elastase is the common name of proteases that destroy elastin, which is part of the connective tissue. As known elastase neutrophil elastase, pancreatic elastase, metalloelastase etc. the First two structurally similar to proteases and have similar specificity against the substrate.

The neutrophil elastase is semipretioase contained in the granules of neutrophils. A large number of neutrophil elastase released from neutrophils accumulated in the tissue, in the case of infectious diseases or inflammatory diseases. Of neutrophil elastase destroys proteins, components of the interstitium in different tissues of the lung, cartilage, blood vessels, etc. such as elastin, collagen, proteoglycan, fibronectin, etc. it is Also known that neutrophil elastase is involved in the destruction of various other proteins and cellular damage. As a rule, the activity of neutrophil elastase adjusted so that it was not in and betke, inhibitor of endogenous proteases, such as inhibitor α₁protease, etc. However, it is believed that in tissues where there is excessive inflammation, as the number of neutrophil elastase released from neutrophils, increases, and the inhibitor of endogenous protease is inactivated by reactive particles of oxygen formed in this section, neutrophil elastase acts excessively, and therefore, the fabric is damaged. It is therefore desirable to have a drug with inhibitory activity against neutrophil elastase.

To diseases involving neutrophil elastase include chronic obstructive lung disease (including pulmonary emphysema and chronic bronchitis), chronic and acute interstitial pneumonia, idiopathic interstitial pneumonia IIP), diffuse panbronchiolitis, cystic pulmonary fibrosis, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), bronchiectasis, asthma, pancreatitis, nephritis, hepatitis (liver failure), chronic rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontal disease, atherosclerosis, rejection of an organ transplant, tissue damage caused by ischemia/reperfusion, shock, septicaemia, coagulopathy including disseminated intravascular coagulopathy (DIC) and thrombosis of Hluboka veins, conjunctivitis, keratitis, corneal ulcer, Crohn's disease, systemic lupus erythematosus, etc.

In addition, elastase pancreatic source is an exocrine digestive enzyme, but it is believed that in the case of pancreatitis of the pancreatic elastase is involved in the tissue damage of the pancreas due to samoupravleniya.

Thus, although it is believed that neutrophil elastase (pancreatic elastase in the case of pancreatitis) is involved in various chronic and acute diseases, there are a number of compounds showing in practice lactatingebony activity when administered orally and is applicable for chronic diseases. It is therefore considered that lactatingebony agent, which is active in oral introduction, is effective as a therapeutic or prophylactic agent for these diseases.

As expected, there are reports of different inhibitors of elastase. For example, in the publication of the European patent And 189305 revealed several types of compounds with lactatingebony activity. In paragraph 1 of this patent publication describes the connection represented by the following General formula (a-1) (corresponding to the formula Ib in this publication).

where R₁is the Wallpaper alkyl with 1-5 carbon atoms (see s specified publication), R₂represents a group selected from Akilov with 1-10 carbon atoms, etc. (see s specified publication), R₄represents hydrogen, etc. (see s specified publication), And represents-CO -, etc. (see s specified publication) and n is equal to 1 and so on (see s specified publication).

When the above formula (a-1) using the above values of R₁, R₂, R₄And n, we can write the following formula:

Incidentally, R₃in the formula (a-2) is defined on c. 245-259 the specified publication. While this definition is not definitely clear, the definition of R₃in item (VIII), described on s specified publication, regarding concerns compounds of the present invention, as described below. Namely, R₃in item (VIII) is defined as the "aromatic heterocyclic group containing (a) 1-15 carbon atoms and 1-4 heteroatoms, each of which is chosen independently from the group consisting of sulfur atoms, nitrogen and oxygen, and (b) 1-3 five - or six-membered cycles, of which at least one is aromatic, where it is not necessary to 3 carbon atoms of the aromatic cycle(s) may be substituted on any carbon atom, a member of the group comprising fluorine ..., and also provided that any nitrogen atom which may to be substituted by alkyl group, containing 1-6 carbon atoms, provided that when a represents an OCO or NHCO, And then must contact the carbon aromatic heterocycle".

However, in the condition (3), agreed on p.260 specified publication, it is determined that the heteroatom cannot be directly related to the sulfur, nitrogen or oxygen. According to this definition, it is clear that the compounds of the present invention, described below, do not apply to these compounds. In addition, in the aforementioned publication, a particular connection, where R₃in (a-2) corresponds to the above item (VIII), is not described at all.

In addition, in J. Med. Chem., 1997, 40, 1876-1885, describes compounds covered by formula (a-2) of the said publication, and describes the following compounds as compounds that are relatively similar to the compounds of the present invention:

where R represents a 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl or 4-imidazolidinyl.

Although the compound, where R is a 2-pyridylcarbonyl shows weak activity (table 2, s in the above article), it is reported that these compounds are inactive on oral model (C, right column, lines 9-10).

Disclosure of inventions

The present invention relates to a new compound having excellent lactatin yuruyusu activity even during oral administration.

The authors of the present invention have conducted extensive studies and found that the compound obtained by attaching specific unsaturated heterocyclic group in the N-terminal part of peptidyltransferase, shows excellent lactatingebony activity even in oral introduction. Thus made the present invention.

The present invention relates to a heterocyclic compound represented by the following formula (I)

where R¹is a heterocyclic group represented by the formula

where And denotes the presence or absence of benzene cycle, X represents an oxygen atom, a sulfur atom or NH, Y represents a nitrogen atom or CH, and the said heterocyclic group may be substituted by 1-3 identical or different substituents selected from the group consisting of lower alkyl groups, lower alkoxygroup and phenyl group which may be substituted by a lower alkyl group, optionally substituted by halogen atom, lower alkoxy or halogen atom, and

R²and R³represent hydrogen atoms or hydroxy-group, or may be taken together to form a carbonyl group, provided that both are not ATO the AMI hydrogen

and its salts.

The present invention relates, significantly, to the heterocyclic compound represented by formula (I-a)

where R¹has the values listed above,

and its salts, and heterocyclic compound represented by formula (I-b)

where R¹matter mentioned above, R^2band R^3brepresent hydrogen atoms or hydroxy-group, provided that both are not hydrogen atoms

and its salts.

The present invention also relates to pharmaceutical compositions containing the heterocyclic compound represented by the above General formula (I-a), or its pharmaceutically acceptable salt, lactatingebony medium containing as active ingredient a heterocyclic compound represented by the above General formula (I-a), or its pharmaceutically acceptable salt, and the method of treatment of a disease caused by increased elastase activity, comprising the administration to a patient an effective amount of the heterocyclic compound represented by the above General formula (I-a), or its pharmaceutically acceptable salt.

The connection represented by the above General formula (I-a), has excellent lactatingbreasts even in oral introduction. Partial structure represented by the formula

makes a significant contribution to the manifestations of the compound (I-a) of the present invention such excellent properties. Namely, the specified heterocyclic group contains a nitrogen atom, and the nitrogen atom is linked directly to at least one heteroatom to form a loop.

Therefore, the main feature of the chemical structure of the compound (I) of the present invention is the above specific partial structure. The second feature of the chemical structure of the compound (I) of the present invention lies in the combination of the above specific partial structure to the rest of the structure.

The best way of carrying out the invention

Further, the compound (I) of the present invention is described in more detail. Of the compounds represented by the above General formula (I), excellent lactatingebony activity have the compound (I-a), where R²and R³taken together with the formation of the carbonyl group, and preferably a heterocyclic compound represented by formula (I-C)

where R¹matter mentioned above, and its salt.

In addition, the compounds represented by the above formula (I-b), the connection is a group of where R²and R³differ from each other and both are not hydrogen atoms or hydroxyl groups, suitable as intermediate direct connection to obtain the above compound (I-a)with lactatingebony activity. Connection, where R²and R³represent a hydroxy-group, corresponds to the compound obtained by the joining of the water molecule to the compound (I-a), and the connection dehydration (equilibrium reaction) to form compound (I-a).

Heterocyclic group

In the compound of the present invention the heterocyclic group represented by the formula

where A, X and Y have the meanings indicated above, includes, for example, isoxazolyl, isothiazole, 1,2,3-thiadiazolyl, benzo[d]isoxazolyl, pyrazolyl, benzotriazolyl, benzo[3,4-d]-1,2,3-thiadiazole, triazolyl, 1H-indazole etc., preferably isoxazolyl, benzo[d]isoxazolyl and pyrazolyl.

The substituents in the heterocyclic group

Deputies, not necessarily attached to the heterocyclic group include a lower alkyl group, lower alkoxygroup and phenyl group which may be substituted by lower alkyl, optionally substituted by halogen atom, lower alkoxy or halogen atom.

The lower alkyl group indicates whether anou or branched C_1-6is an alkyl group, preferably_1-4is an alkyl group. Examples of the lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

Lowest alkoxygroup denotes a linear or branched C_1-6-alkoxygroup, preferably_1-4-alkoxygroup. Examples of the lower alkoxygroup are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

Phenyl group which may be substituted by lower alkyl, optionally substituted by halogen atom, lower alkoxy or halogen atom, represents phenyl and phenyl substituted 1-5 above-mentioned lower alkyl groups, the above-mentioned lower alkyl groups substituted by a halogen atom, the above-mentioned lower alkoxy or by halogen atoms. The halogen atom means a fluorine atom, chlorine atom, bromine atom and iodine atom. Lower alkyl substituted by halogen atom, refers to a group where at least one (e.g., 1-5, preferably 1-3) the hydrogen atom of the above lower alkyl substituted (same or different) atom(s) halogen (atom(s) fluorine atom(s), chlorine atom(s) of the bromine atom(s) of iodine). His examples are chloromethyl, deformity, trichloromethyl, trip ormetal, 2-bromacil, 2,2,2-triptorelin, pentafluoroethyl, 3,3,3-cryptochromes, 4,4,4-tripcomputer, 5,5,5-tryptophanyl, 6,6,6-triptorelin etc.

Examples mentioned phenyl groups are phenyl, tolyl, xylyl, mesityl, cumenyl, 4-(tert-butyl)phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichloropheny, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-differenl, 2,3-differenl, 2.5-differenl, 3,5-differenl, 3,4-differenl, 4-bromo-2-forfinal, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-acid, 3-triptoreline, 4-triptoreline, 4-chloro-2-methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-chloro-4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 4-methyl-3-chlorophenyl, 3-methyl-4-chlorophenyl, 3-chloro-2-forfinal, 4-chloro-2-forfinal, 2-chloro-4-forfinal, 2-chloro-6-forfinal, 3-chloro-4-forfinal, 4-chloro-2-forfinal etc. the position of the substituent(s) is not limited.

Specified heterocyclic group in R¹compounds of the present invention can have 1-3 above substituent possible(s) position(s) of the cycle, and when the number of substituents is 2 or 3, such substituent are the same or different. The Deputy may be heteroatoms comprising heterocyclic group. Examples of such compounds are the following compounds is of:

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylisoxazol-4-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](benzo[d]isoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(4-methyl-1,2,3-thiadiazole-5-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-ethyl-5-methylisoxazol-4-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methyl-1-phenylpyrazol-4-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methoxyethoxy-5-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[3-(methylethoxy)isoxazol-5-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methylisoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5,6-dimethylbenzo[d]isoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-trifter--(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(4-chlorophenyl)-5-methylpyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[5-methyl-1-(4-methoxyphenyl)pyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(2-forfinal)-5-methylpyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-{5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-4-yl}carboxamide.

The salt of compound (I) of the present invention has no restrictions, but preferably is a pharmaceutically acceptable salt, for example a salt with an organic base such as trimethylamine, triethylamine, N-methylmorpholine, and salt with an inorganic metal base, such as sodium or potassium. In addition, some compounds of the present invention form salts with the accession of organic acids, such as tartaric acid, fumaric acid, acetic acid, lactic acid, succinic acid, methanesulfonate acid, maleic acid, malonic acid, gluconic acid, or amino acids such as aspartic acid, or salt accession inorganic acid such as hydrochloric acid, phosphoric acid, etc.

The compound (I) of the present invention may be in the form of a hydrate or of MES. The AOC is e, the compound (I) of the present invention exists in the form of optically active compounds, stereoisomers or mixtures thereof, and they are all included in the compound of the present invention.

The method of obtaining the compounds of the present invention

The compound (I) of the present invention is novel and can be obtained, for example, by the following method.

where in the formula, R¹has the values listed above.

Stage 1

Stage 1 is the stage of obtaining the compound (I-b′) interaction of compound (II) and compound (III). This phase of the exercise, mixing, under stirring, the compound (II) and the compound (III) in the presence or in the absence of a base, such as triethylamine, without solvent or in a solvent such as pyridine, dichloromethane or dimethylformamide. This stage is carried out preferably in the presence of a condensing agent such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole or N,N′-disuccinimidyl. As to the ratio of the amounts of the compounds (II) and (III), the compound (III) can be used in amounts of from 0.9 to 2 mol, preferably 0.9 to 1.5 mol, per 1 mol of compound (II). The condensing agent can be used in the amount of 1-2 moles, preferably 1-1,5 mol is, 1 mol of compound (II). The reaction is carried out at 0-40°C, preferably 0-25°With, for 1-20 hours, preferably 2 to 15 hours.

Thus obtained compound (I-b′) of the present invention (THE connection) is new and is used as the starting material in the next stage 2 to directly obtain the compound (I-a) of the present invention (ketone), which is new and suitable as lactatingebony tools.

The compound (II) is known and can be obtained, for example, by the method described in WO 00/52032. Almost all compounds belonging to the compound (III)are known, but some are new. These new connections receive according to the method of obtaining the known compounds.

Stage 2

Stage 2 is the stage of oxidation of the hydroxy-group of the compound (I-b′). The oxidation can be accomplished by interaction of the compound (I-b′) with an oxidant in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate or toluene.

Examples of the oxidizing agent is derived odensala, namely the reagent dess-Martin. At this stage, using reagent dess-Martin compound (I-b′) dissolved in the above solvent, and to the solution was added tert-butanol (1-2 mol per 1 mol of compound (I-b′)) and reagent dess-the Artin (1.5 to 3 mol, preferably 1.5 to 2.2 mol per 1 mol of compound (I-b′)). The reaction is carried out at about 0-40°C for 0.5 to 15 hours, preferably 1-2 hours. In addition, it is also preferable to carry out the oxidation of the phosphorus pentoxide in the presence of dimethyl sulfoxide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N′-dicyclohexylcarbodiimide hydrochloridetramadol acid (Cl₂CHCOOH) in the presence of dimethyl sulfoxide, and a combination of oxalicacid and triethylamine (oxidation by Turn).

The compound of the present invention is recovered from the reaction mixture a conventional known method of isolation and purification, for example a concentrated, solvent extraction, filtration, recrystallization, various kinds of chromatography, etc.

Thus obtained compound can be converted into its salt, or can be subjected to demineralization in the usual way. When you get several types of isomers, these isomers are separated in the usual way.

Optically active compound (I-a) can conveniently be achieved using as the starting material an optically active compound (II).

Lactatingebony tool of the present invention

Among compounds (I) of the present invention compounds suitable as lactatingebony funds are compounds (I-a) (ketones), predpochtitel is it the compound (I-C).

The compound (I-a) of the present invention or its salt (sometimes abbreviated as the active ingredient) shows inhibitory activity against elastase neutrophil and inhibitory activity against elastase pancreatic cancer in oral introduction.

An effective amount of the compound (I-a) of the present invention or its salt is administered to a patient suffering from diseases caused by elastases.

The compound (I-a) of the present invention or its salt is administered preferably orally. The dose varies considerably depending on the condition, body weight and age of the patient, etc. for Example, in oral introduction dose of the active ingredient usually makes up from about 0.5 to about 5000 mg per body weight of 60 kg per day, preferably from about 5 to about 2000 mg, preferably from 15 to 300 mg

The compound (I-a) of the present invention or its salt is administered in the form of conventional pharmaceutical preparation such as tablet, capsule, granule, fine granule, powder, aqueous or oily solution, etc. Such preparations may contain the active ingredient in the amount of more than 0.01 wt.%, preferably in the range of 0.1 to 70 wt.%. Such preparations may contain other therapeutically active ingredient.

Such pharmaceutical preparations can be obtained using conventional pharmaceutically acceptable the s components according to a conventional method. Components to obtain drugs can be used as long as they are usually used in this field and do not interact with the active ingredient, such as lactose, Inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partially swelling in cold water starch, sucrose, alumosilicate magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl, calcixerollic, ion exchange resin, methylcellulose, gelatin, Arabic gum, hydroxypropylcellulose (LDCs), hydroxypropylcellulose with a low degree of substitution (nizkozameshhennoj LDCs), hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, carboxypropanoyl vinyl polymer, titanium oxide, arbitarily a fatty acid ester, sodium lauryl sulfate, glycerin, glycerin fatty acid ester, purified lanolin, glycoregulation, Polysorbate, macrogel, vegetable oil, wax, propylene glycol, water, ethanol, gidrirovannoe polyoxyethylene castor oil, sodium chloride, sodium hydroxide, hydrogen chloride, sodium phosphate, sodium dihydrophosphate, citric acid, glutamic acid, benzyl alcohol, Matilda oxybenzoic, metilparagidroksibenzoat etc.

Examples

With explanatory examples, experiments, and examples of preparations of the present invention is illustrated in more detail.

Example 1. The method of obtaining N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](3,5-dimethylisoxazol-4-yl)carboxamide

Stage 1. The method of obtaining N-[(1S)-2-((2S)-2-{N-[(1S,2S)-3,3,3-Cryptor-2-hydroxy-1-(methylethyl)propyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylisoxazol-4-yl)carboxamide

Hydrochloride [(2S)-1-((2S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl]-N-[(1S,2S)-3,3,3-Cryptor-2-hydroxy-1-(methylethyl)propyl]carboxamide - source material for stage 1 - receive according to the method described in WO 00/52032.

Thus obtained hydrochloride [(2S)-1-((2S)-2-amino-3-methylbutanoyl)pyrrolidin-2-yl]-N-[(1S,2S)-3,3,3-Cryptor-2-hydroxy-1-(methylethyl)propyl]carboxamide (2.0 g, of 4.95 mmol) and 3,5-dimethylisoxazol-4-carboxylic acid (0,70 g of 4.95 mmol) dissolved in pyridine (20 ml) and to the solution was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1,00 g, 5,20 mmol). The mixture is stirred for 12 hours at room temperature and then the reaction mixture was concentrated under reduced pressure.

To the residue is added ethyl acetate, the mixture was sequentially washed with 1 N. hydrochloric acid, water is, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the residue is dissolved in acetonitrile. The solution is purified column chromatography medium pressure using a column of CHP-20P (eluent water-acetonitrile). The fraction containing the target compound, evaporated to dryness under reduced pressure and obtain the target compound (1.90 g, 78%).

APCI-MS: 491 (MH⁺).

¹H NMR (300 MHz, CDCl₃that δ): 0,86-1,08 (N, m), 1,94-2,35 (6N, m)to 2.46 (3H, s), 2,62 (3H, s), 3,63-a 3.83 (2H, m), 4,07 is 4.13 (2H, m), 4,50-4,55 (2H, m), 4,79 of 4.83 (1H, m), 6,36 (1H, d), 6,72 (1H, d).

Stage 2. The method of obtaining N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylisoxazol-4-yl)carboxamide

The compound (1.90 g, a 3.87 mmol), obtained in stage 1, was dissolved in dichloromethane (25 ml) and to the solution was added tert-butanol (of 0.39 ml, a 3.87 mmol) and reagent dess-Martin (3,30 g of 7.75 mmol). The mixture is stirred at room temperature for 1 hour and then concentrated under reduced pressure. To the residue is added ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over what svodnik sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in acetonitrile and purified column chromatography medium pressure using a column of CHP-20P (eluent water-acetonitrile). The fraction containing the target compound, evaporated to dryness under reduced pressure and obtain the target compound (1.50 g, 79%).

APCI-MS: 489 (MH⁺).

¹H NMR (300 MHz, CDCl₃that δ): 0,90-1,09 (N, m), 1,89-2,16 (6N, m), 2,47 (3H, s)of 2.64 (3H, s), 3,62-a-3.84 (2H, m), 4,59-to 4.62 (1H, m), 4.80 to 4,89 (2H, m), 6,36 (1H, d), 7,31 (1H, d).

Elemental analysis for C₂₂H₃₁F₃N₄O₅·0,25N₂O.

Calculated: 53,60; N 6,44; F To 11.56; N 11,36.

Found: 53,74; N 6,46; F 11,73; N 11,24.

Examples 2-48

The following connections will receive the same manner as in example 1. The physical properties of the compounds are given in table 1. Mass spectral data indicated in the table, measured by the method of the APCI-MC, unless otherwise noted.

Example 2. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](benzo[d]isoxazol-3-yl)carboxamide.

Example 3. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(4-methyl-1,2,3-thiadiazole-5-yl)carboxamide.

Example 4. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-ethyl-5-methylisoxazol-4-yl)carboxamide.

Example 5. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Crypto is-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylisoxazol-4-yl)carboxamide.

Example 6. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1,5-dimethylpyrazol-3-yl)carboxamide.

Example 7. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](benzotriazol-5-yl)carboxamide.

Example 8. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1H-indazol-3-yl)carboxamide.

Example 9. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-phenylisoxazol-3-yl)carboxamide.

Example 10. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methyl-1-phenylpyrazol-4-yl)carboxamide.

Example 11. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methoxyethoxy-5-yl)carboxamide.

Example 12. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[3-(methylethoxy)isoxazol-5-yl]carboxamide.

Example 13. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(methylethyl)benzotriazol-5-yl]carboxamide.

Example 14. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](benzo[d]-12,3-thiadiazole-5-yl)carboxamide.

Example 15. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methylisoxazol-3-yl)carboxamide.

Example 16. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylpyrazol-4-yl)carboxamide.

Example 17. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5,6-dimethylbenzo[d]isoxazol-3-yl)carboxamide.

Example 18. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methylbenzo[d]isoxazol-3-yl)carboxamide.

Example 19. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methoxyethoxy-4-yl)carboxamide.

Example 20. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methylisoxazol-4-yl)carboxamide.

Example 21. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methylisoxazol-4-yl)carboxamide.

Example 22. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methylisoxazol-5-yl)carboxamide.

Example 23. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl-(3-tert-butylisoxazole-5-yl)carboxamide.

Example 24. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-phenylisoxazol-5-yl)carboxamide.

Example 25. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-tert-butyl-1-methylpyrazole-3-yl)carboxamide.

Example 26. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-methyl-5-phenylpyrazol-3-yl)carboxamide.

Example 27. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-tert-butyl-5-methylpyrazole-3-yl)carboxamide.

Example 28. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-phenylpyrazol-3-yl)carboxamide.

Example 29. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methyl-1-phenylpyrazol-3-yl)carboxamide.

Example 30. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-tert-butyl-1-phenylpyrazol-3-yl)carboxamide.

Example 31. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1,3-dimethylpyrazol-5-yl)carboxamide.

Example 32. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(meth shall later)-2-oxoethyl]-(1-tert-butyl-5-methylpyrazole-4-yl)carboxamide.

Example 33. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-phenylpyrazol-4-yl)carboxamide.

Example 34. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethyl-1-phenylpyrazol-4-yl)carboxamide.

Example 35. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-methyl-3-phenylpyrazol-5-yl)carboxamide.

Example 36. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methyl-1-phenylpyrazol-5-yl)carboxamide.

Example 37. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(4-forfinal)-5-methylpyrazole-4-yl]carboxamide.

Example 38. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(4-chlorophenyl)-5-methylpyrazole-4-yl]carboxamide.

Example 39. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[5-methyl-1-(4-were)pyrazole-4-yl]carboxamide.

Example 40. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[5-methyl-1-(4-methoxyphenyl)pyrazole-4-yl]carboxamide.

Example 41. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]to rebamol}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-tert-butyl-1-methylpyrazole-5-yl)carboxamide.

Example 42. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-tert-butyl-3-methylpyrazole-5-yl)carboxamide.

Example 43. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[(3-methylethoxy)isoxazol-4-yl]carboxamide.

Example 44. N-[(1S)-2-((2S)-2-(N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-tert-butyl-1-phenylpyrazol-5-yl)carboxamide.

Example 45. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(2-forfinal)-5-methylpyrazole-4-yl]carboxamide.

Example 46. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(3-forfinal)-5-methylpyrazole-4-yl]carboxamide.

Example 47. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-{5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-4-yl}carboxamide.

Example 48. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-{5-methyl-1-[3-(trifluoromethyl)phenyl]pyrazole-4-yl}carboxamide.

Table 1

Example No.	MN⁺	Elemental analysis Calculated (found)
2		511 LSIMC	C₂₄H₂₉F₃N₄O₅: 56.47 (56.29), H 5.73 (5.70), F 11.16 (11.17), N 10.97 (10.91)
3		492	C₂₀H₂₈F₃N₅O₄S: 48.87 (48.81), H 5.74 (5.98), F 11.60 (11.48), N 14.25 (14.14), S 6.52 (6.37)
4		503 LSIMC	With₂₃H₃₃F₃N₄O₅: 54.97 (at 54.91), H 6.62 (6.74), F 11.34 (11.17), N 1l.15 (10.93)

Example 5	505 LSIMC	With₂₂H₃₁F₃N₄O₄S: 52.37 (52.20), H 6.19 (6.16), F 11.30 (11.30), N 11.10 (10.95), S 6.36 (6.22)
Example 6	488 LSIMC	C₂₂H₃₂F₃N₅O₄·N₂About: at 53.70 (53.77), N 6.66 (6.76), F 11.58 (11.34), N 14.23 (14.47)
Example 7	511	C₂₅H₃₀F₃N₅O₄: 54.11 (53.92), H 5.73 (5.76), F 11.16 (10.99), N 16.46 (16.31)
Example 8	510	With₂₄H₃₀F₃N₅O₄·N₂O·0.05Et: 55.68 (55.68), H 6.04 (5.94),F 10.92 (10.79), N 13.42 (13.13)
Example 9	537	C₂₆H₃₁F₃N₄O₅·0.25H₂O: 57.72 (57.71), H 5.87 (5.85), F 10.53 (10.49), N 10.36(10.34)
Example 10	550	C₂₇H₃₄F₃N₅O₄·0.25H₂O: 58.53 (58.23), H 6.28 (6.08), F 10.29 (10.16), N 12.64 (12.54)
Example 11	491	With₂₁H₂₉F₃N₄O₆: 51.42 (51.14), H 5.96 (6.17), F 11.62 (11.39), N 11.42 (11.12)
Example 12	519	With₂₃H₃₃F₃N₄O₆: 53.28 (53.02), H 6.41 (6.26), F 10.99 (10.73), N 10.81 (10.68)
Example 13	553 LSIMC	With₂₆H₃₅F₃N₆O₄·N₂About: 56.05 (at 55.75), N 6.42 (6.51),F 10.23 (10.18), N 15.09 (14.92)
Example 14	528 LSIMC	With₂₃H₂₈F₃N₅About₄S·N₂About: 51.83 (51.95), H 5.41 (5.43), F 10.69 (10.40), N 13.14 (13.04, S 6.02 (5.85)

Example 15	475	With₂₁H₂₉F₃N₄O₅·N₂O: 52.66 (52.56), H 6.21 (6.06), F 11.90 (11.81), N 11.70 (of 11.69)
Example 16	488	With₂₂H₃₂F₃N₅O₄·0,50N₂About: 53.22 (53.51), H 6.70 (6.56), F 11.48 (11.34), N 14.10 (13.82)
Example 17	539 LSIMC	With₂₆H₃₃F₃N₄O₅·N₂About: 57.50 (57.60), H 6.22 (6.26), F 10.50 (10.42), N 10.32 (10.24)
Example 18	525 LSIMC	C₂₅H₃₁F₃N₄O₅·N₂About: 56.76 (56.50), H 6.00 (6.04), F 10.77 (10.58). N 10.59 (10.50)
Example 19	491	With₂₁H₂₉F₃N₄About₆·N₂O: 50.50 (50.53), H 6.05 (6.07), F 11.41 (11.44), N 11.22 (11.14)
Example 20	475	C₂₁H₂₉F₃N₄O₅: 53.16 (at 52.87), H 6.16 (6.22), F 12.01 (11.90), N 11.81 (11.66)
Example 21	475	C₂₁H₂₉F₈N₄O₅·0.25H₂O: 52.66 (52.63), H 6.21 (6.20), F 11.70 (11.70), N 11.90 (11.61)
Example 22	475	With₂₁H₂₉F₃N₄O₅: 53.16 (53.08), H 6.16 (6.32), F 12.01 (11.75), N 11.81 (11.62)
Example 23	517	With₂₄H₃₅F₃N₄O₅·N₂O: 55.32 (55.22), H 6.87 (6.91), F 10.94 (10.83), N 10.75 (10.56)
Example 24	537	With₂₆H₃₁F₃H₄O₅·N₂About: 57.72 (57.59), H 5.87 (5.95), F 10.53 (10.29), N 10.36 (10.15)

Example 25	530	With₂₅H₃₈F₃N₅O₄: 56.70 (56.43), H 7.23 (7.44), F 10.56 (10.76), N 13.00 (13.22)
Example 26	550	With₂₇H₃₄F₃N₅O₄·0.25H₂O: 58.53 (58.30), H 6.28 (6.29), F 10.29 (10.18), N 12.64 (12.51)
Example 27	530	C₂₅H₃₈F₃N₅O₄·0.5H₂O: 55.7 (55.87), N 7.30 (7.32), F 10.58 (10.28), N 13.00 (12.98)
Example 28	536	With₂₆H₃₂F₃N₅About₄·N₂About: 57.82 (57.55), H 6.07 (5.98), F 12.97 (12.79), N 10.55 (10.38)
Example 29	550	C₂₇H₃₄F₃N₅O₄·0.25H₂O: 58.53 (58.37), H 6.28 (6.25), F 10.29 (10.22), N 12.64 (12.57)
Example 30	592	With₃₀H₄₀F₃N₅O₄·N₂O: 60.44 (60.24), H 6.85 (6.81), F 9.56 (9.44), N 11.75 (11.49)
Example 31	488	With₂₂H₃₂F₃N₅O₄·N₂O: 53.22 (53.31). N 6.70 (6.55), F 11.48 (11.37), N 14.10 (13.94)
Example 32	530	With₂₅H₃₈F₃N₅O₄·ON₂0:at 55.29 (55.41), N 7.33 (7.31), F 10.49 (10.28), N 12.89 (12.80)
Example 33	536	C₂₆H₃₂F₃N₅O₄·0.25H₂O: 57.82 (57.91), H 6.07 (6.02), F 10.55 (10.50), N 12.97 (12.96)

Example 34	564	With₂₈H₃₆F₃N₅O₄·N₂About: 59.20 (59.09), H 6.48 (6.43), F there is a 10.03 (9.99), N 12.33 (12.32)
Example 35	550	With₂₇H₃₄F₃N₅O₄·N₂O: 58.53 (58,58), H 6.28 (6.23), F 10.29 (10.30), N 12.64 (at 12.67)
Example 36	550	C₂₇H₃₄F₈N₅O₄·N₂About: 58.53 (58.37), H 6.28 (6.30), F 10.29 (10.34), N 12.64 (12.41)
Example 37	568	C₂₇H₃₃F₄N₅O₄· N₂About: 56.69 (56.58), N 5.90 (5.98), F 13.28 (13.23), N 12.24 (12.26)
Example 38	585	With₂₇H₃₃CIF₃N₅O₄·N₂O: at 55.10 (54.86), H 5.74 (5.69), Cl 6.02 (5.98), F 9.68 (9.64), N 11.90 (11.86)
Example 39	564	With₂₈H₃₆F₃N₅O₄·0,5H₂About: 58,73 (58,76), N 6.51 (6.38), F 9.95 (10.01), N 12.23 (12.27)
Example 40	580	With₂₈H₃₆F₃N₅0₅&x000B7; N₂About: 57.57 (57.39), H 6.30 (6.26), F 9.76 (9.58), N 11.99 (11.73)

Example 47

Example 41		530	C₂₅H₃₈F₃N₅O₄·N₂About·0.25AcOEt: 56.15 (56.11), H 7.34 (7.44), F 10.25 (10.34), N 12.59 (12.62}
Example 42		530	C₂₅H₃₈F₃N₅O₄·N₂About: at 55.75 (55.90), H 7.30 (7.31), F 10.58 (10.58), N 13.00 (12.96)
Example 43		519	With₂₃H₃₃F₃N₄O₆·0.5H₂O: 52.37 (52.32), H 6.50 (6.49), F 10.80 (10.80), N 10.62 (10.54)
Example 44		592	With₃₀H₄₀F₃N₅O₄·N₂O: 59.54 (at 59.84), H 6.91 (6.72), F 9.42 (9.12), N 11.57 (11.25)
Example 45		568	C₂₇H₃₃F₄N₅O₄·N₂O: 56.69 (at 56.55), N 5.90 (5.83), F 13.28 (13.23), N 12.24 (12.15)
Example 46		568	With₂₇H₃₃F₄N₅O₄·0.5H₂O: 56.24 (56.38), H 5.94 (5.96), F 13.18 (13.13), N 12.15 (12.12)
	618	With₂₈H₃₃F₆N₅O₄·N₂About: 53,67 (53.63), H 5.47 (5.41), F 18.19 (18.01), N 11.18 (11.18)

Example 48

618

With₂₈H₃₃F₆N₅O₄·0,5H₂O: 53.67 (53.60), H 5.47 (5.43), F 18,19 (18.19), N 11.18 (11.15)

Example 49

The following compounds can be obtained in the same manner as in example 1.


R¹	Chemical name
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,4-dichlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-l-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,3-dichlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3,4-dichlorophenyl) - methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-chloro-2-forfinal)-5-methylpyrazole-4-yl)carboxamide

	N-[(1S)-2-((2S)-2-{N - [(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2-chloro-6-forfinal)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-chloro-4-forfinal)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-chloro-2-forfinal)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,4-differenl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,5-differenl)-5-methylpyrazol-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(regulatel)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,3-differenl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3,5-differenl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2-bromophenyl)-5-methylpyrazole-4-yl)carboxamide

	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-bromophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-bromo-2-forfinal)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-methoxyphenyl)-5-methylpyrazole-4-yl)carboxin is d
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2-methoxyphenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-chloro-4-methoxyphenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(lS)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-l-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-chloro-2-methoxyphenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2-methyl-4-methoxyphenyl)-5-methylpyrazole-4-yl)carboxamide

	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-tert-butylphenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-isopropylphenyl)-methylpyrazol-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-chloro-4-were)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-chloro-3-were)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-ethoxyethoxy-5-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-tert-butoxyethoxy-5-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-toranzo[d]isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methoxybenzo[d]isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(6-methoxybenzo[d]isoxazol-3-yl)carboxamide

	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(tert-butyl)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(4-forfinal)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(4-methoxyphenyl)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(4-chlorophenyl)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(4-bromophenyl)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-(4-were)isoxazol-3-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-(4-forfinal)isoxazol-5-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-(4-chlorophenyl)isoxazol-5-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-(4-were)isoxazol-5-yl)carboxamide

	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-(4-methoxyphenyl)isoxazol-5-yl)carboxamide
	N-(1S)-2-(2S)-2-{N-[(1S)3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3-chlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,5-dichlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(2,6-dichlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(3,5-dichlorophenyl)-5-methylpyrazole-4-yl)carboxamide
	N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-(4-chloro-2-forfinal)-5-methylpyrazole-4-yl)carboxamide

Experiment 1. Inhibitory activity against human neutrophil elastase (HNE).

In this experiment, check inhibitory activity of the compounds of the present invention in vitro against human neutrophil elastase.

To 100 mm buffer solution HEPES {[N-(2-hydroxyethyl)piperazine-N′-(2-econsultancy acid)], pH 7.5}containing 1 M NaCl and 0.001% Brij-35 (polyoxyethyleneglycol ether)add human neutrophil elastase (final concentration of 0.2 u/ml, Elastine Product Co., Inc.) and the compound of the present invention (dissolved in 10% dimethyl sulfoxide; the final concentration of 10^-10˜3×10^-3M). The mixture is pre-incubated for 3 min at 37°C. To the mixture as substrate type MeO-Suc-Ala-Ala-Pro-Val-pNA (methoxybenzylideneamino-p-nitroanilide (Sigma Chemical Co.)) to obtain a final concentration of 0.5 mm and initiate cooperation is the interaction. In such conditions, the degree of formation of the reaction product p-nitroanilide (pNA) at 37°assessed by measuring the absorption at 404 nm for 3 minutes.

Inhibitory activity of the compounds of the present invention against human neutrophil elastase (HNE) is calculated according to the formula below.

The concentration of the compounds of the present invention required to achieve 50% inhibition of HNE (i.e. the IC₅₀), is calculated based on the curve according to the degree of inhibition depends on the concentration of compounds of the present invention.

As a compound for comparison using N-{(1S)-2-((2S)-2-{N-{(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](imidazol-4-yl)carboxamide and carry out the same analysis. Flat structure of this compound is the same as the connection structure (22), described in J. Med. Chem., 1997, 40, 1876-1885.

The results are given below in table 2.

Table 2
Example No.	IC₅₀(nm)	Example No.	IC₅₀(nm)
Example 1	17	Example 21	11
Example 2	8,1	Example 23	15
Example 3	Example 24	15
Example 4	17	Example 32	8,5
Example 5	22	Example 33	12
Example 9	9,2	Example 34	9,8
Example 10	10	Example 37	9,1
Example 11	27	Example 38	8,3
Example 12	16	Example 39	10
Example 13	6,3	Example 40	8,4
Example 14	12	Example 45	8,4
Example 15	24	Example 46	8,1
Example 17	11	Example 47	15
Example 18	12
Connection to compare	78

As can be seen from table 2, the compound of the present invention shows a strong inhibitory activity against human neutrophil elastase.

Experiment 2. Inhibitory activity against elastase pancreas of a pig.

Inhibitory activity is here measured in the same way, as in experiment 1, except that as enzyme-target use the elastase pancreatic pigs (Elastin Products Co., Inc., the final concentration of 40 ng/ml) as substrate Suc-Ala-Ala-Ala-pNA (succinyldicholine-p-nitroanilide, Peptide Research, final concentration 2.5 mm).

The results are shown below in table 3

Table 3
Example No.	IC₅₀(NM)
Example 1	154
Example 2	215
Example 3	155

As can be seen from table 3, the compound of the present invention shows inhibitory activity against elastase pancreatic cancer.

Experiment 3. Inhibitory activity against lung hemorrhage caused by human elastases neutrophils (HNE).

In this experiment, the compound of the present invention are tested for efficacy in vivo. When human neutrophil elastase enter vnutritrahealno the hamster, is induced pulmonary hemorrhage. After a certain time after the introduction of elastase in bronchoalveolar washing liquid obtained by lavage of the lung through the trachea, determine the hemoglobin. In this experiment by measuring the concentration of hemoglobin is should assess how strong is the connection of the present invention suppresses the bleeding.

Hamsters (line Syrian males aged 7-10 weeks) divide into groups of 3-6 individuals and each group is processed, as discussed next.

(A) the Group to which the compound of the present invention is not administered (patient monitor).

Saline solution (0.2 ml), which is dissolved 25 units of human neutrophil elastase (Elastin Product Co., Inc.), enter the hamster vnutritrahealno, and is induced pulmonary hemorrhage. One hour after administration of elastase hamsters worldlet, pulling the blood and the alveoli washed twice transtracheal physiological solution (2.5 ml) and determine the concentration of hemoglobin in bronchoalveolar washing liquid (5 ml), measuring the absorbance at 414 nm.

(B) Group, which administered the compound of the present invention.

A certain number of compounds of the present invention is dissolved in dimethyl sulfoxide (DMSO), to the solution was added 0.5% of tragacanth gums and get the suspension. The suspension is administered to hamsters orally 30 minutes prior to the introduction of human neutrophil elastase (HNE) (final concentration of DMSO 1%) and then injected human neutrophil elastase in the same way as described above in (A). After 1 hour, determine the concentration of hemoglobin in bronchoalveolar washing fluid still the same way as described above in (A).

The activity of inhibiting bleeding compounds of the present invention are as the degree of inhibition of bleeding according to the formula below.

The dose of a compound of the present invention required to achieve 50% suppression of pulmonary hemorrhage (i.e. the ED₅₀), is calculated based on the curve suppress bleeding of the dose.

As an example for comparison is conducted the same experiment with the compound for comparison used in experiment 1.

Some compounds of the present invention to compare the degree of inhibition of bleeding with connection for comparison, a dose of 3 mg/kg

The results are given in table 4 and table 5.

>10

Table 4
Example No.	Inhibitory activity against pulmonary hemorrhage, ED₅₀(mg/kg)
Example 1	2,6
Example 2	0,86
Example 3	1,6
Example 4	2,5
Example 10	1,1
Example 11	1,5
Example 15	0,062
Connection to compare

Table 5
Example No.	The degree of inhibition of pulmonary hemorrhage (%) the dose of 3 mg/kg
Example 12	66
Example 17	59
Example 38	63
Example 40	70
Example 45	58
Example 47	60
Connection to compare	18

As can be seen from table 4 and table 5, the compound of the present invention in this experiment shows a strong inhibitory activity against pulmonary hemorrhage.

Experiment 4. The duration of the inhibitory activity against lung hemorrhage caused by human elastases neutrophils (HNE).

Perform the same procedure as in experiment 3 (C), except that the dose (10 mg/kg) compounds of the present invention administered orally for 150 minutes (instead of 30 minutes) prior to the introduction of human neutrophil elastase (HNE).

As a result, even if the connection of the present invention of example 10 is injected for 150 minutes before the introduction of HNE, the compound of the present invention strongly inhibits pulmonary hemorrhage and shows activity over the long period.

Experiment 5. Acute toxicity.

The compound of the present invention (each connection example 10, example 11, example 15, example 25 and example 40) suspended in 0.5% of tragacanth gums and the suspension is administered orally 7-week old male ICR mice (5 mice) at a dose of 300 mg/kg 24 hours after introduction of the test, the animals died or not; it is established that all animals live.

As can be seen from the experiments described above, the compound of the present invention not only shows inhibitory activity against elastase neutrophil and inhibitory activity against elastase pancreatic cancer in vitro, but also shows excellent lactatingebony activity when administered orally. Therefore, the connection of the present invention are suitable for the prevention and treatment of various diseases caused by increased elastase activity, such as various diseases, caused by increased destruction of proteins by elastases, particularly respiratory diseases.

Below are examples of the preparation. The compound of the present invention is an active ingredient used after grinding to a particle size of 5 microns or less.

Examples a, b and C (pill)

Components for pellets listed in table. 6, granularit according to the usual way and add to them excipients. The mixture is pressed and get pills, moreover, the mass of each is from 120 to 300 mg

Table 6
Component	Amount (mg)
Drug And	Drug	Medication
Granules	Connection example 1	1	10	100
Lactose	84,2	to 75.2	117,5
Corn starch	-	12	-
Nizkozameshhennoj LDCs	12	-	30
LDC	3	3	8
Excipients	Crystalline cellulose	18	18	40
Magnesium stearate	1,2	1,2	3,0
Light anhydrous silicic acid	0,6	0,6	1,5
Total (mg)	120	120	300

Examples D, E and F (granules)

Components for pellets listed in table 7, granularit according to a conventional method, to add excipient and receive granules.

Table 7ComponentAmount (wt.%)The drug DDrugDrug FGranulesConnection example 111050D-Mannitol85,576,536,5Nizkozameshhennoj LDCs101010LDC333ExcipientLight anhydrous silicic acid0,50,50,5Total (%)100100100

Industrial applicability

The compound of the present invention has excellent lactatingebony activity and suitable for the prevention and treatment of various diseases caused by increased elastase activity, such as various diseases, caused by increased destruction of proteins by elastases, particularly respiratory diseases.

1. Heterocyclic compound represented by formula (I)

where R¹represents heterocyclic the action group, represented by the formula

where a represents the presence or absence of benzene cycle, X represents an oxygen atom, a sulfur atom or NH, Y represents a nitrogen atom or CH, and the said heterocyclic group may be substituted by 1-3 identical or different substituents selected from the group consisting of lower alkyl groups; lower alkoxygroup and phenyl group which may be substituted by a lower alkyl group, optionally substituted by halogen atom, lower alkoxy or halogen atom;

R²and R³represent hydrogen atoms or hydroxy-group or may be taken together to form a carbonyl group, provided that both are not hydrogen atoms; or its salt.

2. Heterocyclic compound represented by formula (I-a)

where R¹matter specified in claim 1,

or its salt.

3. Heterocyclic compound represented by formula (I-b)

where R¹matter specified in claim 1, R^2band R^3brepresent hydrogen atoms or hydroxy-group, provided that both are not hydrogen atoms

or its salt.

4. Heterocyclic compound, not only the TES formula (I-c)

where R¹matter specified in claim 1,

or its salt.

5. Heterocyclic compound or its salt according to claim 1 or 2, where R¹,

represented by the formula

represents a group selected from the group consisting of isoxazolyl, isothiazole, 1,2,3-thiadiazolyl, benzo[d]isoxazolyl, pyrazolyl, benzotriazolyl, triazolyl, 1H-indazole and benzo[3,4-d]-1,2,3-thiadiazole, which optionally is substituted.

6. Heterocyclic compound or its salt according to claim 1, where the compound is a compound selected from the group

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3,5-dimethylisoxazol-4-yl)carboxamide;

N - [(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl} pyrrolidinyl)-1-(methylethyl)-2-oxoethyl](benzo[d]isoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(4-methyl-1,2,3-thiadiazole-5-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N - [(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-ethyl-5-methylisoxazol-4-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-about sapropel]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methyl-1-phenylpyrazol-4-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(3-methoxyethoxy-5-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[3-(methylethoxy)isoxazol-5-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methylisoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5,6-dimethylbenzo[d]isoxazol-3-yl)carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(4-chlorophenyl)-5-methylpyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N - [(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[5-methyl-1-(4-methoxyphenyl)pyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-[1-(2-forfinal)-5-methylpyrazole-4-yl]carboxamide;

N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-{5-methyl-1-[4-(trifluoromethyl)phenyl]pyrazole-4-yl}carboxamide.

7. Pharmaceutical composition having lactatingebony activity containing heterocyclic compound, represented by formula (I-a)

where R¹matter specified in claim 1,

or its pharmaceutically acceptable salt and pharmaceutically acceptable component.

8. Lactatingebony a preparation containing as an active ingredient a heterocyclic compound represented by formula (I-a)

where R¹matter specified in claim 1,

or its pharmaceutically acceptable salt and pharmaceutically acceptable component.

9. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(5-methyl-1 - phenylpyrazol-4-yl)carboxamide.

10. N-[(1S)-2-((2S)-2-{N-[(1S)-3,3,3-Cryptor-1-(methylethyl)-2-oxopropyl]carbarnoyl}pyrrolidinyl)-1-(methylethyl)-2-oxoethyl]-(1-tert.-butyl-5-methylpyrazole-4-yl)carboxamide.

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1 ex, 1 tbl

Pharmaceutical composition for treating eye diseases as a result of microcirculation disorders and/or inflammatory processes // 2277411

FIELD: medicine, ophthalmology, chemico-pharmaceutical industry.

SUBSTANCE: the suggested pharmaceutical composition is indicated for local application and contains an inhibitor angiotensin converting enzyme as an active substance and target additions, moreover, the content of active substance corresponds to about 1-20 mg/ml. The composition suggested could be designed as eye drops, spay, gels, solution for local injections. As target additions one should apply water that contains a buffer agent, an isotonic mixtures, a conservant and a prolongator. Additionally, this composition contains preparations chosen out of the following groups: antibiotics, macro- and microelements, vitamins, adrenoblocking agents. The innovation provides anti-ischemic action, improves reparative processes and accelerates the processes of healing.

EFFECT: higher efficiency.

3 cl, 7 ex

Solutions and methods for inhibiting pain, cartilage inflammation and destruction // 2271825

FIELD: medicine.

SUBSTANCE: method involves introducing solutions into articulation to inhibit cartilage destruction. The solutions contain: (a) therapeutically effective amount of anabolic chondroprotective agent selected from a group composed of interleukine antagonists stimulating anabolic processes in cartilage, members of superfamily transforming growth β-factor including TGF-β agonists and agonists of morphogenous bone proteins stimulating anabolic processes in cartilage, insulin-like fibroblast growth factors stimulating anabolic processes in cartilage; (b) therapeutically effective amount of a cartilage catabolism inhibitor selected from a group composed of antagonists of interleukine-1-receptors, antagonists of TGF-α-receptors, specific cyclo-oxygenase-2 inhibitors, nitrogen oxide synthase inhibitors, nuclear kB factor inhibitors, matrix metalloproteinase inhibitors, cell adhesion molecules including integrin agonists and integrin antagonists, anti-chemotaxis agents, intracellular signal transmission inhibitors including protein kinase C inhibitors and tyrosine protein kinase inhibitors, intracellular (protein-tyrosine)-phosphatases and SH2-domain inhibitors inhibiting cartilage catabolism. The solution is locally supplied.

EFFECT: stimulated integration and modulation of anti-inflammatory synoviocyte and chondrocyte responses.

54 cl, 9 dwg, 30 tbl

Method for production of alpha-1-antitrypsin and product useful in medicine // 2268736

FIELD: pharmaceuticals industry, in particular new method for production of alpha-1-antitrypsin and pharmaceutical product containing the same.

SUBSTANCE: alpha-1-antitrypsin is isolated from Cohn fraction IV-1 by solubilization. Then protein admixtures and eventual viral particles are removed by polyethylene glycol, target protein is precipitated with zinc salt, viral inactivation using solvent/detergent is carried out, product is fractionated using Q-sepharose, and non-active alpha-1-antitrypsin is removed with S-sepharose to produced target product. Said product represents concentrate of human serum active alpha-1-antitrypsin having purity more than 98 % and specific activity not less than 40 IU/mg in 0.15 M sodium chloride solution.

EFFECT: increased yield of high pure active alpha-1-antitrypsin.

4 cl

Method for preparing human c-1 esterase inhibitor amd product for using in medicine // 2256464

FIELD: biotechnology, medicine, pharmacy, veterinary science.

SUBSTANCE: method involves addition of DEAE-Sephadex A-50 to cryosupernatant from human blood plasma, incubation, filtration and addition of QAE-Sephadex to filtrate followed by incubation. Filtered off precipitate of QAE-Sephadex is subjected for successive step-by-step washing out with buffer solution at pH 5.5 and 7.5, elution at pH 7.7 and dialysis. Then PEG-6000 is added to dialyzed solution to the concentration 12%, solution is incubated and centrifuged. To the prepared supernatant glycine is added to the final concentration 100 mM and lysine is added to the final concentration 10 mM at pH 7.2, then Twin-80 is added and pH value is corrected to 6.8-7.2 followed by addition of tri-n-butyl phosphate to the final concentration 0.3%. Prepared suspension is stirred, subjected for chromatography on DEAE-Sepharose FF at pH 7.0, chromatography on Zn-chelating Sepharose FF at pH 7.5 and the end product with specific activity from 7.5 ± 0.5 U/mg of protein and above, and with the final concentration of lysine 10 mM, not less, and with the final concentration of glycine 100 mM, not less. Method provides safety of activity in antiviral treatment and preparing product containing the natural C-1 esterase inhibitor from blood plasma with high specific activity.

EFFECT: improved method for preparing.

6 cl, 2 dwg, 1 ex

Method for anesthesiological protection against factors of surgical aggression // 2254131

FIELD: medicine, anesthesiology, traumatology, orthopedics, thoracic surgery.

SUBSTANCE: about 1.5-2 min before spreading the affected lung it is necessary to deepen anesthesia due to injecting phenthanyl at the dosage of 10-12 mcg/kg body weight. The present innovation provides safety of operations of ventral spondyledesis out of transthoracic and thoracodiaphragmatic accesses, stability of arterial pressure level and patient's heart rate, decreases stress loading upon a patient that, in its turn, favors the prophylaxis of intraoperative complications.

EFFECT: higher efficiency of anesthesiological protection.

2 cl, 1 ex

Pharmaceutical preparation containing low-molecular thrombin inhibitor and its pre-medicine // 2252783

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

Immediate-released tablet // 2252751

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to peroral immediate-released drug in solid form, containing low molecular thrombin inhibitor based on peptide with pH-depending solubility. Claimed drug has size particle less than 300 mum and contains combination of microcrystal cellulose and sodium glycolate starch in amount of more than 35 mass % (calculates as preparation mass).

EFFECT: drug with reduced dependence of thrombin inhibitor dissolution from pH and increased releasing rate from tablet.

17 cl, 3 ex, 3 dwg

Essentially crystalline melagatran form // 2243973

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

Application of heparin-binding antagonists in inhibiting bradykinin releasing // 2251433

FIELD: medicine, pharmaceutics, pharmacology.

SUBSTANCE: one should apply mammalian anti-HBP-antibodies. The ways are being suggested to identify monoclonal antibody bound, at least, with one epitope upon native HBP (heparin-binding protein) and methods to detect whether a mammal produces HBR being bound with a monoclonal antibody and, also, the kits for the above-mentioned purpose. The present innovation provides the opportunity to apply the mentioned antibodies in preventing and treating disorders associated with bradykinin releasing.

EFFECT: higher efficiency of application.

25 cl, 11 dwg, 3 ex, 1 tbl

Immediate-released tablet // 2252751

FIELD: pharmaceutical industry, medicine.

EFFECT: drug with reduced dependence of thrombin inhibitor dissolution from pH and increased releasing rate from tablet.

17 cl, 3 ex, 3 dwg

Pharmaceutical preparation containing low-molecular thrombin inhibitor and its pre-medicine // 2252783

FIELD: pharmaceutics.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

Method for anesthesiological protection against factors of surgical aggression // 2254131

FIELD: medicine, anesthesiology, traumatology, orthopedics, thoracic surgery.