Derivatives of dipeptides and method of production thereof

 

(57) Abstract:

Usage: in medicine, as compounds with antagonistically activity to tachykinin, substance G, neurokinin A. the essence of the invention: derivatives of dipeptides F.-ly (I), where R1-phenyl, benzofuran, indazoles, indolyl, n-lower acylinder; Y is a bond or lower albaniles; - carbonyl or sulfonyl; R2is hydroxy or lower alkoxy; R3is hydrogen, lower alkyl, possibly substituted by a hydroxyl or alloctype; R4ar (lower) alkyl, possibly substituted by halogen. The method of obtaining receptors. Reagent 1: the derivative of the dipeptide f-crystals (II) or its reactive derivative, Reagent 2: R-Y-A-OH, or its reactive derivative or its salt, followed, if necessary, diallylammonium compounds F.-ly (I), where R is acyloxy (lower) alkyl, to obtain the target product, where R is hydroxy (lower) alkyl. The structure of the compounds (I) and (II) given in the text description. 2 C. and 7 C. p. F.-ly, 1 table.

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine.

These dipeptide compounds could the East neirokinina or antagonist neirokinina "In" for the treatment and prevention caused by tachykinins diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, sputum, etc., ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc., skin diseases such as contact dermatitis, atopic dermatitis, nettle fever and other eczematoid dermatitis; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, etc., of pain, such as migraine, headache, dental pain, pain from cancer, back pain, etc. and other similar diseases in humans and animals.

The target compound of the invention can be represented by the following General formula (I):

RyAONH where R1phenyl or a group of the formula

where X is CH or N;

Z 0 or N R5where R5hydrogen or lower alkyl;

R2hydroxy or lower alkoxy;

R3hydrogen or lower alkyl optionally substituted by hydroxy or acyloxy;

R4ar(lower)alkyl, optionally substituted with halogen;

As carbonyl or sulfonyl;

Y is a bond or lower albaniles.

In accordance with the invention of new peptide compound (I) can be obtained by the methods provided by the following schema.

The way I

HONH (II) or its derivative at AONH (I) or its salt.

Method 2

y (I-a)

RyAONH (I-b) or its salt, where R1, R2, R3, R4A and Y are each as defined above;

R3areplaced acyloxy (lower) alkyl;

R3bhydroxy lower alkyl.

As for the starting compound (II), it is a new connection and it can be obtained by methods shown in the following diagrams.

Method AND

or its derivative at the amino group or its salt R6OH (Y) or its derivative at carboxy group or its salt

(VI) or its salt

HN (VII) or its derivative at the amino group or its salt

or its salt.

Remove aminosidine group

or its salt

ROOH (X) or its derivative at carboxy group or its salt

RONH (XI) or its salt.

Remove aminosidine group

HONH (II) or its salt, where R2, R2and R4each as defined above;

R6and R7each aminosidine group.

In the description of amino acids, peptides, protective groups, condensing agents, etc. are indicated by abbreviations commonly used in this field. Unless otherwise specified amino acids and their residues when they are indicated by the abbreviations are soedinenii connections are conventional non-toxic salts and include an acidic salt added, for example, organic acid salt (acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, formate, toluensulfonate and so on), inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and so on ) or a salt with an amino acid (arginine, aspartic acid, glutamic acid and so on), metal salt, such as alkali metal salt (sodium salt, potassium salt, etc. and salts of alkaline-earth metal (calcium salt, magnesium salt etc), ammonium salt, salt of the organic base (salt, trimethylamine salt of triethylamine salt of pyridine, pain picoline, salt dicyclohexylamine, N,N-dibenziletilendiaminom and so on) or equivalent.

In the description of the invention, the term "lower" means 1-6, preferably 1-4 carbon atoms, unless otherwise indicated.

Suitable "lower alkyl" may include straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., among which preference is given to the stands.

Suitable "lower Alcanena is having 2-6 carbon atoms and may include vinile, propylen, etc., where preference is given to vinylene.

Suitable "lower alkyl", the optional specified above lower alkyl, hydroxy/lower/alkyl (e.g. hydroxymethyl, hydroxyethyl, etc.,), acyloxy/lowest/the alkyl, for example lower alkanoyloxy/lower/alkyl (for example, acetoacetyl, acetyloxybenzoic, acetoacetyl, acetylaspartic, propionylacetate, butyraldoxime, hexaniacinate, etc.,) and the like.

Suitable "ar/lower/alkyl", optionally substituted with halogen, may include the usual groups that are used in the field of amino acid and peptide chemistry, such as ar/lower/alkyl (for example, trityl, benzhydryl, benzyl, phenethyl and so on ), mono - or di - or trihalogen/ lower/alkyl (for example, o-tormentil, m-tormentil, p-tormentil, o-trifloromethyl, etc.,) and the like.

Suitable "aminosidine groups" can be a conventional protective group used in the field of amino acids in peptide chemistry, i.e., may include acyl such as lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and etc.), lower alkoxy carbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and so on) and others.

Suitable "lower alkoxy" may include straight or razvetchitsya "hydroxy/lowest/the alkyl, acyloxy(lower)alkyl" are as described above.

In particular, the preferred R1, R2, R3, R4A and Y may be the following:

R1phenyl, benzofuran, indazole; or indolyl (for example, 1H-indol-3-yl, and so on ), 1-lower alkyl indolyl (for example, 1-methyl-1H-indol-2-yl, 1-methyl (1H-indol-3-yl, 1-isopropyl-1H-indol-3-yl, and so on);

R2hydroxy; or lower alkoxy (e.g. methoxy, etc.,);

R3hydrogen, lower alkyl (e.g. methyl, etc.,) or hydroxy/lower/alkyl (e.g. hydroxymethyl, hydroxy ethyl and so on);

R4phenyl/lower/alkyl (e.g. benzyl, phenethyl, etc.,) or halophenol(lower) alkyl (e.g., o-tormentil, m-tormentil, p-tormentil and so on );

As carbonyl or sulfonyl;

Y is a bond or lower albaniles (for example, vinile and so on).

Next are described the methods of semi-treatment of the target compound (I).

Method 1.

The target compound (I) or its salt can be obtained by reaction of compound (II) or its derivative at the amino group or its salt with the compound (III) or its derivative at carboxy or sulfogrupp or its salt.

Suitable reactive derivative at the amino group of compound (II) can beerburrum connection such as aldehyde, ketone, etc., derivatives silila obtained by reaction of compound (II) with sillavan compound, such as bis/(trimethylsilyl)/ndimethylacetamide, monochromatic - silyl/ndimethylacetamide, bis/(trimethylsilyl)/urea, etc., a derivative formed by reaction of the compound (II) with phosphorous trichloride or phosgene, etc.

Suitable salts of the compound (II) and its reactive derivative can be treated with salt, specified for the compound (I).

Suitable reactive derivative at the carboxy or sulfogrupp compound (III) may include gelegenheid, carboxylic acid anhydride, activated amide, an activated ester, etc., Suitable examples of the derivatives can be an acid chloride, acid azide, acid anhydride in the acid, such as phosphoric acid (for example, dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc.,), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g., methanesulfonate acid and etc.), aliphatic carboxylic acid (e.g., acetic acid, propionic acid, butyric acid, somalina sour Isleta and etc.) or aromatic carboxylic acid (for example, benzoic acid, etc.,); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (for example, cinematology ester, methoxymethyl ester, dimethylaminomethyl [(CH3)2+N= CH-] ester, vinyl ester, propargilovyh ester, p-nitrophenyloctyl ester, 2,4-dinitrophenoxy ester, trichloranisole ester, pentachlorphenol ester, methylphenacyl ester, phenylazophenyl ester, phenyl thioether, p-nitrophenyl tiefer, p-cresyl tiefer, carboxymethyl tiefer, paranjoy ester, pyridyloxy ester, piperidinyl ester, 8-quinoline tiefer and so on), or an ester with N-hydroxy compound (e.g. N, N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzo - triazole, etc) and others. These reactive derivatives can be arbitrarily selected depending on the compound (III).

Suitable salts of the compound (III) and its reactive derivative can be the salt of the base, such as alkali metal salt (e.g. salt NAT, the ol organic bases (for example, trimethylamine salt, triethylamine salt, pyridine salt, picolina salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc) or equivalent or acidic salt is added, as indicated for compound (I).

The reaction usually takes place in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.,), acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which will not adversely affect the reaction. These solvents can also be used in mixture with water.

In this reaction, when the compound (III) is used in the form of a free acid or a salt thereof, the reaction preferably takes place in the presence of condensing agents, such as N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinylcarbonyl, N-cyclohexyl-N'-(4 - diethylaminophenyl)carbodiimide; N,N'-diethylcarbamoyl, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-methylaminopropyl)carbodiimide, N,N'-carbonylbis- (2-Mei); pentamethylene-N-cyclohexylamine, diphenylmethan-N-cyclohexylamine, ethoxyacetylene; 1-alkoxy-1 - chloro the East trichloride; diphenylphosphoryl; thionyl chloride, oxalicacid, lower alkylsulfonyl (for example, ethylchloride, isopropylcarbamate etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzotriazole salt; 2-ethyl-5-(m-sulfophenyl)ISO - casaliva gidroksida intramolecular salt; benzotriazol-1-yl-oxy-Tris-(dimethylamine)fosfodiesterasa; 1-(p-chlorobenzenesulfonate)-6-chloro-1H - benzotriazol; the so-called reagent of Willsmere obtained by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, etc., or similar.

The reaction also can be carried out in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine, N-(lower)alkalifying, N,N-di(lower)alkylbenzenes and similar.

The reaction temperature does not matter, and it is usually carried out under cooling-heating.

Method 2.

The target compound (I-b) or its salt can be obtained by the reaction of removal hydroxyamino group in R3athe compound (I-a) or its salt.

In this reaction removal apply all the methods of reaction removal hydroxyamino group, nab is eno explains how to obtain the starting compound (II).

Method A.

Method (I).

The compound (VI) or its salt can be obtained by reaction of the compound (IV) or its reactive derivative at the amino group or its salt with the compound (V) or its reactive derivative in carboxylate or its salt.

Suitable salts of the compound (V) can be salt indicated for compound (III).

Suitable salts of the compound (VI) can be salt, specified for the compound (I).

This reaction can be carried out as in method 1, so that its nature and conditions similar reaction method 1.

Method (2).

The compound (VIII) or its salt can be obtained by reaction of the compound (VI) or its salt with the compound (VII) or its reactive derivative at the amino group or its salt.

Suitable salts of the compound (VII) can be salt indicated for compound (II).

Suitable salts of the compound (VIII) can be salt, specified for the compound (I).

This reaction can be carried out as in method 1, so that its nature and conditions similar to reactions of method 1 (reactive derivatives, solvents, temperature and so on).

Method (3).

The compound (IX) or its salt can be on the Sabbath.

Suitable salts of the compounds (VIII) and (IX) may be salts specified for the compound (I).

This reaction is carried out in accordance with customary methods, such as hydrolysis, recovery, etc.

The hydrolysis reaction takes place mainly in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and organic base, such as alkali metal (e.g. magnesium, calcium, etc.,), the hydroxide or carbonate or bicarbonate, hydrazine, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo(4.3.0) non-5-ene, 1,4-diazabicyclo(2.2.2)octane, 1,8-diazabicyclo(5,4,0)undec-7-ene, or similar.

Suitable acid may include an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifter-acetic acid and so on), inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.,) and compound acid salt of accession (for example, pyridine hydrochloride, and so on).

Remove using a Lewis acid is a logical preferably carried out in the presence of the arresting cations substances (for example, the anisole, phenol and so on).

The reaction usually takes place in a solvent such as water, alcohol (e.g. methanol, ethanol and so on), methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, a mixture thereof or any other solvent which does not affect adversely on the reaction. Liquid base or acid can also be used as solvent. The reaction temperature is never an issue, and the reaction usually proceeds at a cooling heat.

The recovery method used for the reaction of removal may include chemical reduction and catalytic reduction.

Suitable substances of recovery used in chemical reduction are a metal link (for example, tin, zinc, iron, and so on) or metallic compound (e.g. chromium chloride, chromatin and so on) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluensulfonate acid, hydrochloric acid, Hydrobromic acid, and so on ).

Suitable catalysts used in the reaction catalytic reduction are conventional catalysts, such latina, the platinum oxide, platinum wire, etc.,), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.,), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, and so on), iron catalysts (e.g., skeletal catalyst, etc.,), copper catalysts (for example, the recovered copper, skeletal copper catalyst and so on) and similar.

Recovery usually takes place in a conventional solvent which does not affect adversely on the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide or a mixture thereof. In addition, the above-mentioned acid used in chemical recovery in a liquid, can also be used as solvent. A suitable solvent used in the reaction catalytic reduction may be the above-mentioned solvent or other solvent, such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The reaction temperature of this recovery is never an issue, and it usually takes place during cooling of the heat.

Method (4).

Suitable salts of the compound (X) can be salt indicated for compound (III).

Suitable salts of the compound (XI) can be salt, specified for the compound (I).

This reaction can be carried out in the same manner as in method 1, so the nature of the reaction and its conditions (for example, reactive derivatives, solvents, reaction temperature and so on), such as in method 1.

Method (5).

The compound (II) or its salt can be prepared by the reaction of the compound (XI) or its salt, remove aminosidine group.

This reaction may proceed in the same manner as in method (3), so the nature of the reaction and its conditions (e.g., bases, acids, reducing agents, catalysts, solvents, reaction temperature and so on) are the same as in method (3).

Obtained by the above methods, compounds may be isolated and purified in the usual way, such as spraying, recrystallization, chromatography column, pereosazhdeniya etc.

It should be noted that the compound (I) and other compounds can include one or more stereoisomers due to asymmetric carbon atoms and all of these isomers and their mixtures are included in the volume of infusion is practical activity, such as antagonism to tachykinin, especially the antagonism to substance P antagonism to neirokinina And or antagonism to neirokinina In, and are therefore used for the treatment or prevention caused by tachykinins diseases, particularly diseases caused by substance P, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, sputum, etc., ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, etc., skin diseases such as contact dermatitis, atopic dermatitis, nettle fever and other eczematoid dermatitis; inflammatory diseases such as rheumatoid atric, osteofit etc. pain (e.g. migraine, headache, dental pain, pain from cancer, back pain and so on) and other similar diseases.

The target compound (I) can be used in the treatment or prevention of ophthalmologic diseases such as glaucoma, uveitis, etc., such gastro-intestinal diseases like ulcer, ulcerative colitis, mucous colitis, food allergies, etc. inflammatory diseases, such as nephritis, etc., such diseases of circulatory organs such as hypertension, stenocardia, cardiac failure, thrombosis, etc., epilepsy, Paralia immunosuppressive substances.

For therapeutic purposes, the compounds (I) and their pharmaceutically acceptable salts can be used in the form of pharmaceutical preparation containing one of these compounds as an active ingredient with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external and inhalation use. Specified pharmaceutical preparation may be in the form of capsules, tablets, pills, granules, solution, suspension, emulsion, etc., optionally in the preparation may include excipients, stabilizers, wetting agents, emulsifying agents and other commonly used additives.

The dose of the compounds (I) will depend on the age and condition of the patient, usually an average dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg of the compound (I) can be effective for the treatment of asthma and related diseases. Typically, the amount of 0.1 mg/person up to about 1000 mg/person can be applied in day.

The following are pharmaceutical data of some compounds (I) to show the beneficial properties of the target compound (I).

Experienced connection:

(a)

(b)

(c)

Umertvlâl male Guinea pigs by decapitate. Removed the trachea and lung, and homogenized in a buffer solution (0.25 M sucrose, 500 mm Tris-HCl, pH 7.5, 0.1 mm ethylenediaminetetraacetic acid) using Polytron (kinematics). Then the homogenate was centrifuged (1000 hCG, 10 min) to remove aggregated tissue and centrifuged supernatant (Hg, 20 min) to obtain the pills. Pills again suspended in a buffer solution (5 mm Tris-HCl, pH 7.5), homogenized with titanuim homogenizer and centrifuged (Hg, 20 min) to obtain the output of the pills, which are raw materials of the shell. Received pills before use and kept at -70aboutC.

b) Binding of H-substance P with the preparation of the shell.

Frozen raw faction membranes were thawed and suspended in medium I (50 mm Tris-HCl pH 7.5, 5 mm MnCl, 0,02% bullish zavorotnova albumin, 2 mg/ml hemostasia, 4 mg/ml lapetina, 40 mg/ml bacitracin). 3-N. a substance II (1 nm) was incubated with 100 ml of the shell in the environment, I, 4aboutC for 30 min in a final volume of 500 ml At the end of the incubation period, reaction mixture was rapidly filtered through a glass Whatman GF/B filter (cotributing solution (50 mm Tris-HCl, pH 7.5). Measured radioactivity in 5 ml of Aquasol-2 counter scintillation Packard (Packard Tri-Carb 4530).

The results of the experiment.

Experimental Inhibition,

connection

(0,1 /ml)

(a) 96

(b) 94

(b) 100

(g) 96

(2) the Effects of oral administration on bronchial edema in Guinea pigs caused by substance P.

The methodology of the experiment.

Male Guinea pigs (300-400 g) were injected intravenously blue solution of Evans (20 mg/kg) containing heparin (2000 IU/kg) and substance II (mmol/kg). Each experimental compound (100 mg/kg), dissolved in dimethyl sulfoxide, was administered orally 30 min prior to injection. After 10 min, animals were omertvlenie and perfesional light with 50 ml of saline solution. Cut the trachea and bronchi, which then was dissolved in 0.5 ml of 1N KOH at 37aboutC for 6 hours After extraction with 4.5 ml of acetone phosphate (0,6 NH3PO4: acetone:5:13) was calculated content of tissue in a blue solution of Evans colorimetric analysis, which was equal to 620 nm.

The results of the experiment.

Experienced compounds Inhibition,

(100 mg/kg)

(a) 94

(b) 82

(C) 60

(g) 96

The following examples are given for detailed illustrated is e, the accepted IUPAC:

Ac is acetyl;

Vos t-butoxycarbonyl;

The BSA batrineteasinguratatea;

Bzl benzyl;

Bzl (O-F) o-terbisil;

Bzl (m-F) m-terbisil;

Bzl (p-F) p-terbisil;

NOT N-hydroxybenzotriazole;

IPE isopropyl ether;

IU methyl;

1 Nal 3-(1-naphthyl)alanine;

2 Nal 3-(2-naphthyl)alanine;

NMM N-methylmorpholine;

4N-HCl/DOX 4N-hydrogen chloride in 1,4-dioxane;

Ph is phenyl;

Pri isopropyl;

Pro (40H) 4-hydroxyproline;

Pro (40 Me) 4-methoxypropan;

Thea the triethylamine;

IFA triperoxonane acid;

THF tetrahydrofuran;

WSC 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.

The table below gives the parent compound and target compound obtained in the following ways to obtain and examples where the upper formula is the formula of the original substance, and the bottom formula target compound.

Preparation 1. To a suspended mixture of starting compound (2.0 g) in a mixed solvent of water (30 ml) and acetone (30 ml) was added under cooling with ice, triethylamine (1,94 ml). To the solution was added a solution of di-tert-BUTYLCARBAMATE (2,43 g) in acetone (10 ml) and the solution was stirred at the same temperature for 2 hours and another 2 hours at room temperature, was added di-tert-boutigny layer was then acidified to pH by the addition of 6N hydrochloric acid and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporation was crystallizable the residue from a mixture solvent of diisopropyl ether and n-hexane, collected by filtration and dried, which gave the target compound (2,46 g).

So pl. 91-93aboutC.

X (Nujol): 3390, 1720, 1690, 1520, 1274, 1250, 1170 (cm-1).

NMR (DMCO-d6, ): of 1.28 (9H, c) of 3.00 (1H, d, ABg, J 13.7 and 10.1 Hz), 3,20 (1H, d, ABg, J 13.7 and a 4.7 Hz), 4,20 (1H, m), 7,16 (1H, d, J 8.5 Hz), 7,4-7,6 (3H, m), 7,7-7,9 (1H, m).

Preparation 2. It chilled with ice to a solution of starting compound (1,34 g), N-methylbenzylamine (0,49 ml) and N-hydroxybenzotriazole (0.51 g) in methylene chloride (30 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (0.95 g). The solution was stirred at the same temperature for 4 h and overnight at room temperature. After evaporation of the reaction mixture was extracted with ethyl acetate and washed the organic layer successively with water and aqueous sodium carbonate solution, 0.5 N hydrochloric acid, water and aqueous solution of sodium chloride, then dried over sodium sulfate. Evaporation gave the target compound in the form of oil (1,74 g).

X (CHCl3): 3300, 1710, 1640, 1490, 1170 (cm-1).

NMR (DMCO-d6,): is the target parent compound (1,74 g) in methylene chloride (17 ml) was added 4N-hydrogen chloride in 1,4-dioxane (17 ml). The solution was stirred at the same temperature for 5 min. Then remove the cooling bath and the solution was stirred at room temperature for 30 min, it was added 4N-hydrogen chloride in 1,4-dioxane (8,4 ml). After evaporation the residue was ground into a powder and dried over sodium hydroxide in vacuo, which gave the target compound (1.54 g).

So pl. 141-145aboutC.

X (Nujol): 3320, 2700, 1660, 1605, 1580, 1495, 1280 (cm-1).

NMR (DMCO-d6, ): 2.65; and a 2.71 (3H, s), 3.1 to 3.4 (2H, m), 4.09 to, 4,59, and 4.35, 4,56 (2H, two ABq, J 16.2 and of 14.9 Hz, respectively), 4,7-4,8 (1H, m), 7,0-of 7.25 (5H, m), 7,35 and 7.6 (3H, m), 7,8-8,0 (4H, m), 8,51 (3H, s).

Preparation 4. It chilled with ice to a solution of starting compound (1.5 g), t-butoxycarbonyl-(2,2, R)-4-hydroxyproline-HE (0,98 g) and N-hydroxybenzotriazole (0,57 g) in a mixed solvent of methylene chloride (40 ml) and dimethylformamide (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0,77 ml). The solution was stirred at the same temperature for 1 h and at room temperature over night. After evaporation, the reaction mixture was extracted with ethyl acetate and washed the organic layer successively with an aqueous solution of hydrogencarbonate sodium, water, 0.5 N hydrochloric acid, water and an aqueous solution of chloride NAF), using as solvent a mixed solvent of chloroform and methanol (50: 1) and obtained the target connection (1,74 g) as amorphous solids.

X (CHCl3): 3320, 3250, 1690, 1680, 1640, 1500, 1160 (cm-1).

NMR (DMCO-d6, ): 1,19 and 1,39 (N, C), a 1.75-of 2.05 (2H, m) 2,5-2,9 (3H, m), 3.0 to 3.5 (4H, m), 4,1-5,2 (6N, m), 6,95 of 7.3 (5H, m), 7,4-7,6 (3H, m), 7,75-of 7.95 (4H, m), 8.6 out of 8.7 (1H, m).

Preparation 5. It chilled with ice to a solution of the original substance (1.07 g) in methylene chloride (11 ml) was added 4N-hydrogen chloride in 1,4-dioxane (8.2 ml). The solution was stirred at the same temperature for 5 min and at room temperature for 55 minutes After evaporation the residue was ground into powder with diisopropyl ether, collected by filtration and dried, after which he received from the target connection (0,90 g).

X (Nujol): 3330, 2700, 1670, 1640, 1550 (cm-1).

NMR (DMCO, d6, ): 1.7 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2,78, and to 2.85 (3H, s), of 3.0-3.4 (4H, m), 4,2-4,6 (4H, m), 5,0-5,2 (1H, m), 5,55-5,6 (1H, m), of 6.9 to 8.0 (13H, m), 9,24 (1H, d, J 7,6 Hz).

Preparation 6. The target compound was obtained in a manner analogous to the method of obtaining 1.

So pl. 90-91aboutC.

X (Nujol): 3370, 1730, 1660, 1400, 1250, 1165 (cm-1).

NMR (DMCO-d6, ): of 1.28 (9H, c) 3,20 (1H, DD, J 2.4 and 10.4 Hz) and 3.59 (1H, DD, J 17.8 and a 3.9 Hz), 4,16-4,27 (1H, is ω preparation 2.

(1) X (CHCl3): 3310, 2995, 1705, 1640, 1490, 1365, 1250 (cm-1).

NMR (DMCO-d6, ): 1,21 and 1.34 (N, C), 2,53 and a 2.71 (3H, s), 3,3-of 3.45 (2H, m), 4,2-4,55 (2H, m), 4.75 V-of 4.95 (1H, m), 6,95-8,2 (13H, m).

(2) So pl. 161-163aboutC.

X (Nujol): 3360, 1650, 1660, 1305, 1245, 1185 (cm-1).

NMR (DMCO-d6, ): of 1.28 (9H, c) to 2.99 (1H, DD, J 13.1 and 5.5 Hz), 4,2-4,4 (3H, m), 7,05-7,25 (6N, m), 7,4-of 7.55 (3H, m), 7,7-7,9 (4H, m), to 8.45 (1H, d, J 5.8 Hz).

Mass: M+1404.

(3) X (CHCl3): 3450, 3310, 1705, 1635, 1605, 1365 (cm-1).

NMR (DMCO-d6,) is 1.1 and 1.35 (9H, m), 2,53 to 3.0 (4H, m), 2,77, and 2,84 (3H, s), 3,2-3,7 (2H, m), 4,5-4,7 (1H, m), 7,05-7,95 (13H, m).

(4) X (CHCl3): 3320, 1705, 1640, 1595 (cm-1).

NMR (DMCO-d6, ): of 1.15 to 1.4 (9H, m), a 2.75 to 3.2 (5H, m), a 4.3-4,85 (3H, m), 6,8-the 7.65 (8H, m), 7,7-7,9 (4H, m).

(5) X (CHCl3): 3450, 3320, 1710, 1640, 1590, 1365 (cm-1).

NMR (DMCO-d6, ): 1.1 to 1.4 (9H, m), 2,79 and 2.94 (3H, s), 2.8 to 3.15 in (2H, m), 4,45-4,85 (3H, m), of 6.8 to 7.6 (8H, m), 7,65-of 7.95 (4H, m).

(6) So pl. 122-123aboutC.

X (Nujol): 3350, 1690, 1650, 1525, 1320, 1270 (cm-1).

NMR (DMCO-d6, ): of 1.26 (9H, c) to 2.66 (2H, t, J 7.0 Hz), 2,8-3,1 (2H, m), 3,2-3,4 (2H, m), 4,15-up was 4.3 (1H, m), 6,92 (1H, d, J 8,48 Hz), 7,15-to 7.35 (5H, m), between 7.4 to 7.5 (3H, m), 7,7-7,9 (4H, m), 7.95 is to 8.1 (1H, m).

(7) X (CHCl3): 3470, 3330, 1710, 1645, 1610, 1370 (cm-1).

NMR (DMCO-d6, ): 1,15-to 1.14 (9H, m), 2,7-3,2 (5H, m), 4,35-4,85 (3H, m), 6,85-8,0 (N, the-methylmorpholin (0,90 ml). The solution was cooled to approximately (-22)-(-20)aboutWith and at the same temperature was added dropwise isobutylparaben (1,04 ml), dissolved in methylene chloride (2 ml). The solution was stirred 15 min, and the temperature was maintained at a level of from -25 to -20aboutC. Then the solution was cooled to -30aboutWith and was added N-benzylethanolamine (1,21 g) dissolved in methylene chloride (3 ml). The solution was stirred for 2 hours, while the temperature was raised to 20aboutC. After concentration, the residue was extracted with ethyl acetate and the organic layer was sequentially washed with water, sodium carbonate solution, water, 0.5 N hydrochloric acid and sodium chloride solution and dried over magnesium sulfate. After concentration the crude product was purified on silikagelevye column (50 g), using as solvent first chloroform and then a mixture of chloroform and methanol (1.5%) and received the target connection (2,69 g).

X (CHCl3): 3430, 3300, 1700, 1630 (cm-1).

Weight: 448.

Preparation 9. To a solution of starting compound (2.65 g) and pyridine (4,67 g) in tetrahydrofuran was added acetylchloride (0,928 g) under cooling with ice. After the addition the mixture was stirred 1 h at the same temperature. After concentration the residue actos, a solution of sodium carbonate, sodium chloride solution and dried with magnesium sulfate. Concentration gave the target compound (2,82 g) in the form of butter.

X (HCl3): 3330, 1742, 1710, 1640 (cm-1).

Preparation 10. The target compound was obtained in accordance with method 3.

(1) X (Nujol): 3495, 1645, 1625, 1510, 1495, 1265 (cm-1).

NMR (DMCO-d6, ): 3,2 is-3.45 (1H, m) to 3.36 (3H, s), a 3.87 (1H, DD, J 8.6 and 4.3 Hz), 4,28 (2H, s), with 4.64 (1H, DD, J 7.4 and 4.4 Hz), 6.75 in-8,15 (N, m), 8,73 (2H, sh.S.).

(2) So pl. 183-185aboutC.

X (Nujol): 3430, 1675, 1600, 1575, 1545, 1250, 1160 (cm-1).

NMR (DMCO-d6, ): 3,26 (2H, d, J 7,1 Hz), 4,1-of 4.25 (2H, m), 4,36 (1H, DD, J 15.1 and 6.4 Hz), 6,9-7,2 (5H, m), 7,4-7,6 (3H, m), 7,7-of 7.95 (4H, m), 8,48 (3H, sh.C.), 9,05 (1H, t, J 5.7 Hz)

(3) X (CHCl3): 3500-3350, 1650, 1600, 1500 (cm-1).

NMR (DMCO-d6, ): 2,3-2,8 (5H, m), 3,05-3,70 (4H, m), 4,55-4,7 (1H, m) and 7.1 and 7.6 and 7.7 to 8.0 (N, m), 8,42 (3H, sh.S.).

(4) X (CHCl3): 3420, 1785, 1655, 1640, 1620, 1595 (cm-1).

NMR (DMCO-d6, ): 2,67 and a 2.71 (3H, s), 3,15-3,4 (2H, m), 4,05-4,85 (3H, m), 6,8-8,0 (11N, m), 8,51 (3H, sh.S.).

(5) X (CHCl3): 3500-3350, 1785, 1655-1645, 1600, 1585, 1370 (cm-1).

NMR (DMCO-d6, ): a 2.71 (3H, c), 3.1 to 3.4 (2H, m), 4,1-4,9 (3H, m), 6,85-8,0 (11N, m), charged 8.52 (3H, sh.S.).

(6) X (CHCl3): 3450-3150, 1665, 1600, 1455, 1370, 1120 (cm-1).

NMR (DMC. 45aboutC (decomposition).

X (Nujol): 3450, 1650, 1605, 1510, 1285, 1225 (cm-1).

NMR (DMCO-d6, ): 2,64 and 2,69 (3H, s), 3.1 to 3.4 (2H, m), 4,05-4,85 (3H, m), 6,85-7,1 and 7.35-8,0 (11N, m), 8,53 (3H, sh.S.).

(8) X (CHCl3): 3450-3370, 1740, 1650, 1600, 1365 (cm-1).

NMR (DMCO-d6, ): 1,89 and 1.96 (3H, m), 3,0-3,8 (6N, m), 3.9 to a 4.9 (3H, m), of 7.0 and 7.6 (8H, m), 7,7-8,0 (4H, m), 8,55 (2H, sh.sec.)

The method of preparation 11. The target compounds were obtained in accordance with the method of preparation 4.

(1) X (Neat): 3300, 1690, 1640 (cm-1).

NMR (DMCO-d6, ): 1,18 (c) and 1.39 in (C) (N), of 1.5-1.8 (1H, m), 1,9-2,3 (1H, m), 2,7-2,9 (3H, m), 2,9-3,3 (2H, m), 3,3-3,5 (2H, m), of 3.7-3.9 (1H, m), 4,0-5,2 (4H, m), of 6.8 to 7.3 (5H, m), and 7.3 and 7.6 (3H, m), 7,6-7,94 (4H, m), and 8.4 to 8.5 (1H, m).

(2) X (CHCl3): 3420, 3300, 1680, 1630, 1520, 1490, 1400 (cm-1).

NMR (DMCO-d6, ): to 1.32 and 1.41 (S, (C), of 1.6-1.8 (1H, m), 1,8-2,0 (1H, m), 2.44 and 2,66 and is 2.74 (3H, m), 3,2-3,5 (4H, m), 4,15-4,60 and 4.9 and 5.3 (6N, m), 6,70 at 8.60 (13H, m).

(3) So pl. 205aboutC (decomposition).

X (Nujol): 3400, 3350, 3280, 3100, 1680, 1645, 1570, 1540, 1290, 1170 (cm-1).

NMR (DMCO-d6, ): a 1.08 and 1.34 (M, (C), of 1.5-1.8 (1H, m), 1,8-2,05 (1H, m), 2.95 and-3,5 (4H, m), 4,05 and 4.4 and 4.45 of 4.8 and 4.9 to 5.0 (6N, m), 7,0-of 7.25 (5H, m), 7,35 is 7.5 (3H, m), 7,7-7,9 (4H, m), 8,1-8,3 (1H, m), an 8.5 and 8.6 (1H, m).

Mass: M+1517.

(4) X (CHCl3): 3420, 3300, 1690-1670, 1630, 1370 (cm-1).

NMR (DMCO-d6, ): 1.1 to 1.25 and 1.3 to 1,) X (CHCl3): 3450-3250, 1700-1655, 1595 (cm-1).

NMR (DMCO-d6, ): 1.1 to 1.4 (9H, m), 1,55-1,75 (1H, m), 1,8-2,0 (1H, m), 2,7-3,5 (7H, m), 4,1-5,2 (6N, m), the 6.7 to 7.3 and 7.4 and 7.6 and 7.7 to 7.9 (11N, m), and 8.4 to 8.5 (1H, m).

(6) X (CHCl3): 3450-3300, 1690-1630, 1640, 1370, 1160 (cm-1).

NMR (DMCO-d6, ): 1,1-of 1.45 (9H, m), of 1.6-1.8 (1H, m), 1.85 to was 2.05 (1H, m), 2,7-3,5 (7H, m), 4.1 and 4.7 and 4,9-5,2 (6N, m), 6,7-7,94 (11N, m), 8,35 to 8.5 (1H, m).

(7) So pl. 202-203aboutC.

X (Nujol): 3360, 3270, 3070, 1665, 1635, 1535, 1420, 1285, 1170 (cm-1).

NMR (DMCO-d6,) with 1.07 and 1.40 (N, C), 1,5-1,75 (1H, m), 1,8-2,0 (1H, m), 2,55-2,7 (2H, m), 2,9-3,4 (6N, m), 4,0-4,2 and 4.25 with 4.65 (3H, m), is 4.93 (1H, D. D. J 9,78 and to 6.43 Hz), 7,1-of 7.55 and the 7.65 8,2 (14N, m).

(8) X (CHCl3): 3450-3300, 1690-1670, 1640, 1370, 1160 (cm-1).

NMR (DMCO-d6, ): 1.0 to 1.5 (9H, m), of 1.6-1.8 (1H, m), 1.85 to was 2.05 (1H, m), 2,7-2,9 (3H, m), 3.0 to 3.5 (4H, m), 4,1-5,2 (6N, m), 6,8-7,05 and 7.4-7,95 (11N, m), 8,35 to 8.5 (1H, m).

(9) X (HCl3): 3450-3430, 1740, 1695-1680, 1365, 1160 (cm-1).

NMR (DMCO-d6, ): 1,1-1,5 (N, m), 1,5-1,75 (1H, m), of 1.8-2.0 (4H, m), 2,9-3,9 (8H, m), 3.9 to 5.2 to (6N, m), 6,95-8,0 (N, m), and 8.4 to 8.5 (1H, m).

The method of preparation 12. The target compounds were obtained in accordance with the method of preparation 5.

(1) X (CHCl3): 3350-3200, 3050, 1685, 1645-1630, 1550, 1495, 1450 (cm-1).

NMR (DMCO-d6, ): 1,60-1,90 (1H, m), 2,15-to 2.40 (1H, m), 2,39, and 2,69 (3H, m), 3.0 to 3.6V (4H, m), 4.1 and 4.5 and 5.1-6,75 (6N, m), 6,9-8,35 and 9, the m-1):

NMR (DMCO-d6, ): 1,75-of 1.95 (1H, m), 2,25-2,4 (1H, m), 3.0 to 3.5 (4H, m), 4,15-of 4.45 (4H, m), 4,65-4,8 (1H, m), 5,52 (1H, sh.C.), of 7.0 to 7.2 (5H, m), 7,45-of 7.55 (3H, m), 7,75-7,9 (4H, m), 8,56 (1H, sh.C.), a total of 8.74 (1H, t, J 5,9 Hz), 9,04 (1H, d, J 8.1 Hz), 9,83 (1H, sh.C).

(3) X (CHCl3): 3400-3200, 1680, 1630 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2,5-2,75 (2H, m), 2,79, and of 2.83 (3H, s), 2.95 and-3,2 3,2-4,7 (6N, m), 4,2 is 4.45 and 4.9 to 5.1 (4H, m), 7,05-of 7.55 and the 7.65 8,0 (N, m), and 8.6 (1H, sh.C.), 9,1-a 9.25 (1H, m), becomes 9.97 (1H, sh.C).

(4) X (CHCl3): 3400-3200, 1680, 1640, 1590 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2,78 and 2.88 (3H, m), of 3.0-3.4 (4H, m), 4,2-of 4.75 and 5.0 and 5.2 and 5.5 to 5.7 (6N, m), 6,8-7,95 (11N, m), and 8.6 (1H, sh.C), 9,26 (1H, d, J 7,6 Hz), 9,95 (1H, sh.C).

(5) X (CHCl3): 3350-3200, 1680, 1640, 1550 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2.8 and of 2.92 (3H, s), 3.0 to 3.5 (4H, m), 4,2-4,85 and 5,0-5,2 (6N, m), 6,7-7,95 (11N, m), and 8.6 (1H, sh. C), 9,26 (1H, d, J 7,72 Hz), of 10.05 (1H, sh.C).

(6) So pl. 259-261aboutC.

X (Nujol): 3300, 2700, 1670, 1645, 1555, 1290, 1250 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 2,25-2,4 (1H, m) to 2.65 (2H, t, J 7,12 Hz), 2,9-3,45 (6N, m), 4,2-4,7 (3H, m) 5,54 (1H, d, J 2,91 Hz), 7,1-of 7.55 and 7.7 to 7.9 (N, m), 8,5-8,7 (2H, m), 8,97 (1H, d, J 8,24 Hz) to 9.9 (1H, s).

(7) X (CHCl3): 3400-3220, 1680, 1640, 1610, 1225 (cm-1).

NMR (DMCO-d6,) of 1.75 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2,75 and 2,84 (3H, s), of 3.0-3.4 (4H, m), 4,2-4,65 and 5.1 to 5.7 (6N, m), 6.8 or 7.1 and 7.3-7,95 (11, 535, 1340, 1250, 1225 (cm-1).

NMR (DMCO-d6, ): 1,65-of 1.85 (1H, m), 1.85 to was 2.05 (1H, m), of 3.0-3.4 (2H, m), and 3.6 to 4.4 (5H, m), 3,86 (3H, s), 4,5-4,7 (2H, m), 5,04 (1H, d, J 3.3 Hz), 7,0 is 7.3 (7H, m), and 7.3 and 7.6 (4H, m), 7,7-8,0 (5H, m), of 8.09 (1H, d, J 7.7 Hz), 8,2-to 8.45 (2H, m).

(3) So pl. 130-134aboutC.

X (Nujol): 3400, 3270, 3070, 1650, 1630, 1600, 1565, 1535, 1320 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), a 2.5 to 2.74 (2H, m), 2,72, and 2,78 (3H, s), 2,9-3,7 (6N, m) of 3.84 (3H, m), 4,15-up was 4.3 (1H, m), 4,6-4,8 (1H, m), 4.95 points-of 5.05 (2H, m), 7,0-7,55 (11N, m), 7,75 was 7.9 (5H, m), to 8.0 and 8.1 (1H, m), 8,3-8,5 (1H, m).

(4) So pl. 129aboutC (decomposition).

X (Nujol): 3420, 3290, 3060, 1655, 1625, 1600, 1560, 1535, 1320 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), 2,71 and 2.82 (3H, s), of 3.0-3.4 (2H, m), up 3.6-3.7 (1H, m), 3,85 (3H, s), 3,8-4,0 (1H, m), 4,2-5,2 (6N, m), 6,8-8,1 (N, m), an 8.5 and 8.6 (1H, m).

(5) So pl. 134-136aboutC.

X (Nujol): 3380, 3060, 1685, 1655, 1590, 1545, 1335, 1250 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 1,9-2,1 (1H, m), 2,72 are 2.87 (3H, s), 3,1 is-3.45 (2H, m), 3,6-of 3.75 (1H, m), 3,8-4,0 (1H, m), 3,85 (3H, s), 4,2-5,2 (6N, m), 6,8-8,2 (N, m), 8,53 (1H, sh.C).

(8) X (CHCl3): 3320-3180, 1740, 1685, 1640, 1365 (cm-1).

NMR (DMCO-d6, ): 1,7-2,0 (4H, m), 2,1-2,4 (1H, m), of 3.0 to 3.7 and 4.0 to 4.2 (8H, m), 4,25-5,7 (6N, m), 7,0-8,0 (N, m), and 8.6 (1H, sh.C), 9,2-a 9.35 (1H, m), 9,94 (1H, sh.C).

The method of preparation 13. To a solution of starting compound (10.0 g) in methylene chloride (20 ml) EXT and evaporated under vacuum. The residue was led by addition of ether (50 ml) and was filtered, washed with ether and dried, after which he received from the target connection (9,26).

So pl. 157-159aboutC.

X (nujol): 3400, 3330, 3150, 1670, 1625, 1565, 1495, 1200 (cm-1).

NMR (DMCO-d6, ): 1,7-of 1.95 (1H, m), 2,2-of 2.45 (1H, m), 2,79 are 2.87 (3H, s), of 3.0-3.4 (4H, m), 4.2 to 4.7 and 5.0 to 5,15 (6N, m), 6,9-8.0 and 9,15-9,3 (N, m), 8,65 (1H, sh.C.), 9,71 (1H, sh.S.).

P R I m e R 1. It chilled with ice to a solution of 1 methylindol-3-carboxylic acid (0.33 g), starting compound (0.88 g) and N-hydroxybenzotriazole (0.25 g) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0,34 ml). The solution was stirred at the same temperature for 1 h and at room temperature over night. After evaporation of the reaction mixture was extracted with ethyl acetate and then washed the organic layer with an aqueous solution of sodium carbonate, water, 0.5 N hydrochloric acid, water and aqueous solution of sodium chloride, then dried over magnesium sulfate. After evaporation the residue was purified on silikagelevye column (50 g), using as eluent a mixture of chloroform and methanol (50:1). Collected containing the desired compound fractions and evaporated. The residue was then crystallizable from ethyl acetate, collected by filtration I, 3300, 1656, 1640, 1600, 1574, 1535 (cm-1).

NMR (DMCO-d6, ): 1.7 to 2.2 (2H, m), 2,71, and 2,80 (3H, s), a 3.0 to 3.25 (2H, m), up 3.6-3.7 (1H, m), 3,85 (3H, s), 3,8-4,0 (1H, m), 4,2-4,55 (3H, m), 4,65-4,8 (1H, m), 5,0-5,2 (2H, m), the 6.9 and 7.3 (7H, m), 7,4-of 7.55 (4H, m), of 7.7 to 7.9 (5H, m), 8,08 (1H, q, J 7.4 Hz), an 8.5 and 8.6 (1H, m).

Elemental analysis calculated for C36H36N4O4H2O:

C 72,27, H OF 6.31, N 9,23.

Experimental With 72,17, N 6.42 Per, N 9,04.

P R I m m e R 2. The target compounds were obtained in a manner analogous to the method of example 1.

(1) X (CHCl3): 3420-3300, 3005, 1645, 1630, 1595, 1530, 1470, 1370 (cm-1).

NMR (DMCO-d6, ): 1,6-1,9 (1H, m), 1,9-to 2.15 (1H, m), 2,42 and 2,63 (3H, s), 3,35-4,0 (4H, m), a 3.87 (3H, s), 4,2-4,4 (3H, m), 4,6-5,3 (3H, m), 6,7-8,15 (17H, m), 8,54 (1H, sh.C).

(6) So pl. 195-197aboutC.

X (nujol): 3350, 3270, 3100, 1660, 1630, 1590, 1570, 1535, 1310, 1245 (cm-1).

NMR (DMCO-d6, ): 1,65-of 1.85 (1H, m), 1.85 to a 2.0 (1H, m), 2,45 of 2.6 (2H, m), a 3.0 to 3.35 (4H, m), 3,65 of 4.1 (2H, m), 3,88 (3H, s), 4,25-4,6 (3H, m), of 5.05 (1H, q, J 3,13 Hz), of 7.0 and 7.6 (11N, m), 7,45-8,05 (6N, m), 8,15-of 8.25 (2H, m).

(7) X (CHCl3): 3450-3320, 1745, 1650-1635, 1375 (cm-1).

NMR (DMCO-d6, ): 1.7 to 1.9 (4H, m), 1,9-2,1 (1H, m), a 3.0 to 4.1 (11N, m), 4,2-5,2 (6N, m), 6,9-7,95 (N, m), 8,0-of 8.15 (1H, m), 8,5-8,65 (1H, m).

(8) So pl. 105aboutC (decomposition).

X (nujol): 3450, 3270, 1665, 1640, 1605, 1575, 1535, 1510, 1245 (cm-1).

I have m).

P R I m e R 3. To a suspended mixture of 1-methylindol-2 carboxylic acid (225 mg) and N-hydroxybenzotriazole (173 mg) in methylene chloride (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl HCl (246 mg) at room temperature. The solution was stirred at the same temperature 1 h

In another reaction vessel was dissolved in methylene chloride (10 ml) of the original compound (700 mg) was added to the solution under cooling with ice, triethylamine (0,20 ml). After stirring at room temperature for 15 min the solution was added the above solution. The solution was stirred 6 h, then was added triethylamine and stirred overnight. After concentration, the residue was extracted with ethyl acetate, the organic layer was sequentially washed with a saturated solution of sodium carbonate, water, 0.5 N hydrochloric acid and sodium chloride solution and dried over magnesium sulfate. After concentration the residue was led by addition of acetone, filtered, washed with acetone and dried at 40aboutWith the vacuum, has been the target connection (0,47 g).

So pl. USD 183.0-184,0aboutC.

X (nujol): 3350, 3275, 3110, 1670, 1640, 1577, 1530, 1495, 1465, 1355, 1340, 1318, 813, 735, 693 (cm-1).

NMR (DMCO-d6, ): 1,65-of 2.20 (2H, m), 2,730, 2,822 (3H, the fair for C36H36N4O4: C 73,34, H 6,16, N 9,52.

Experimental: C 73,44, H 6,17, N 9,50.

P R I m e R 4. The target compounds were obtained by the method of example 3.

(1) X (CHCl3): 3300, 3000, 1630, 1560, 1450, 1420 (cm-1)

NMR (DMCO-d6, ): 1.7 to 1.9 (1H, m), 2,2-2,4 (1H, m), 2,6-2,8 (3H, m), 3,0-3,3 (2H, m) to 3.36 (1H, m) to 3.67 (1H, m), 3,8-5,2 (6N, m), 6,8-7,9 (17H, m), 8,65 cent to 8.85 (1H, m).

(2) So pl. 111-114aboutC.

X (nujol): 3420, 3280, 1655, 1630, 1600, 1530, 1225 (cm-1).

NMR (DMCO-d6, ): is 1.51 (6H, sh.C), a 1.7-2.1 (2H, m), 2,7-2,9 (3H, m), 3,0-3,3 (2H, m), 3,6-of 3.75 (1H, m), 3,9-4,1 (1H, m), 4,2-4,55 (3H, m), 4,7-5,2 (4H, m), the 6.9 and 7.3 (7H, m), 7,4-7,95 (N, m), 8,07 (1H, m), 8,55 (1H, m).

Elemental analysis for C38H40N4O4:

WITH 74,00, N IS 6.54, N REMAINING 9.08.

Experimental: C 73,53, H 6,48, N 8,95.

(3) So pl. 219-222aboutC.

X (nujol): 3460, 3250, 3100, 1678, 1640, 1570 (cm-1).

NMR (DMCO-d6, ): 1,8-2,1 (2H, m), 2,6-2,9 (3H, m), 3,1-3,3 (2H, m), 3,7-4,2 (2H, m), 4,2-4,8 (3H, m), 5,0-5,4 (3H, m), 6,7-7,9 (15 NM, m), and 8.2 (1H, m), 8,65 (1H, m) to 13.6 (1H, sh.C).

P R I m e R 5. The target compound was obtained according to the method of preparation 5 and example 1.

X (nujol): 3300, 1635, 1610, 1535 (cm-1).

NMR (DMCO-d6, ): 1,7-2,0 (1H, m), 2,0-2,3 (1H, m), 2,71 (s) 2,81 (s) (3H), 2,9-3,3 (2H, m), 3,13 (s) and 3.15 (C) (3H), 3,7-4,0 (namamu ice to a solution of starting compound (0.5 g) in methylene chloride (15 ml), was added bis-trimethylsilylacetamide (0.68 ml) and indole-3-carbonylchloride (0.20 g). The solution was stirred at the same temperature for 1 h and during this time was added in three portions indole-3 carbonylchloride (0,20, 0.08 and 0.20 g) and bestemmelsessted (0.3 ml). After concentration the residue was dissolved in tetrahydrofuran (10 ml) was added under ice cooling N-hydrochloric acid (1 ml). The solution was stirred at the same temperature for 15 minutes After concentration, the residue was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of sodium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography with silica gel, using as eluent first ethyl acetate and then a mixture of chloroform, methanol and ethyl acetate (4:1:1), then got a target compound in the form of an amorphous solid (0.28 g).

X (nujol): 3275, 1630, 1530 (cm-1).

NMR (DMCO-d6, ): 1,65 is 2.00 (2H, m), 2,708, 2,809 (3H, s) 3,00-3,25 (2H, m), 3,60-4,00 (2H, m), 4,20-5,20 (6N, m), 6,80-8,10 (17H, m), 8,40 at 8.60 (1H, sh.C) 11,60 (1H, s).

P R I m e R 7. To a suspended mixture of starting compound (1.0 g) in methylene chloride (20 ml) was added triethylamine (0.51 ml) and cinnamoroll (0.31 g) under cooling with ice. The solution was stirred what was strayaway with ethyl acetate and then washed the organic layer with an aqueous solution of sodium carbonate, water, 0.5 N hydrochloric acid, water and aqueous solution of sodium chloride, dried over magnesium sulfate. After evaporation the residue was purified on silikagelevye column (50 g), using as eluent a mixture of chloroform and methanol (40:1). Collected fractions containing the target compound, and evaporated. Then the residue was crystallisable from isopropyl ether, collected by filtration, dried, received the target compound (0.66 g).

IX (CHCl3): 3400, 3300, 3000, 1640, 1600, 1545, 1495, 1450, 1420 (cm-1).

NMR (DMCO-d6, ): 1,6-2,3 (2H, m), 2,6-2,9 (3H, m), 2,9-3,3 (2H, m), of 3.5-3.9 (2H, m), 4,2-5,2 (6N, m), 6,65-7,9 (N, m), 8,45 to 8.6 and 8.9-9,05 (1H, m).

P R I m e R 8. The target compound was obtained in accordance with the method of example 7.

X (CHCl3): 3400, 1635, 1510, 1490, 1450, 1340, 1145 (cm-1).

NMR (DMCO-d6,) is 1.6-1.8 (1H, m), 1,8-2,0 (1H, m), 2,77 and 2.86 (3H, s), a 3.0 to 3.35 (3H, m), 3.45 points-of 3.65 (1H, m), 4.1 and 4.7 and 4,95-5,2 (6N, m), 6,95-7,9 (N, m), 8,4-8,55 (1H, m).

P R I m e R 9. It chilled with ice to a solution of starting compound (0,72 g) in methanol (15 ml) was added 1N sodium hydroxide (1.1 ml). The solution was stirred 3 h at room temperature. After concentration of the substance was extracted with ethyl acetate and then washed the organic layer with water, rastali with ethyl acetate, was filtered, dried, received the target connection (0,60 g).

So pl. 115aboutC (decomposition).

X (nujol): 3470, 3290, 1665, 1620, 1605, 1575, 1535, 1250 (cm-1).

1. Derivatives of dipeptides of General formula I

< / BR>
where R1is phenyl or a group

< / BR>
X is CH or N;

Z is oxygen or NR5where R5is lower alkyl or hydrogen;

Y is a bond or lower albaniles;

A - carbonyl, sulfonyl;

R2is hydroxy or lower alkoxy;

R3is hydrogen, lower alkyl, possibly substituted by a hydroxyl or alloctype;

R4ar(lower)alkyl, possibly substituted by halogen.

2. Derivatives of dipeptides p. 1, wherein R1- phenyl, benzofuran, indazoles, indolyl or n-lower acylinder, R3is hydrogen, lower alkyl, hydroxy(lower)alkyl or acyloxy(lower)alkyl, R4the phenyl (lower)alkyl or halogenfrei(lower)alkyl.

3. Derivatives of dipeptides under item 1, wherein R1- benzofuran, indazoles, indolyl or 1-lower acylinder, And is carbonyl, Y is a bond.

4. Derivatives of dipeptides p. 1, wherein R1- benzofuran, indazoles, indolyl, 1-methylindolin or 1-isopropylindole, R2guide is l, m-terbisil or p-terbisil.

5. Derivatives of dipeptides on p. 1, wherein selected from the group consisting of

< / BR>
< / BR>
< / BR>
6. Derivatives of dipeptides under item 1, wherein R1- phenyl, A - carbonyl, sulfonyl, Y-lower albaniles.

7. Derivatives of dipeptides under item 1, wherein R2is hydroxy, R3- benzyl and Y - vinile.

8. Derivatives of dipeptides under item 7, wherein selected from the group consisting of

< / BR>
9. The method of producing dipeptides of General formula I

< / BR>
where R1- phenylene or a group:

< / BR>
X is CH or N;

Z is oxygen or NR5where R5is lower alkyl or hydrogen;

Y is a bond or lower albaniles;

A - carbonyl, sulfonyl;

R2is hydroxy or lower alkoxy;

R3is hydrogen, lower alkyl, possibly substituted by a hydroxyl or alloctype;

R4ar(lower)alkyl, possibly substituted by halogen,

characterized in that a derivative of the dipeptide of the General formula II

< / BR>
or its reactive derivative at aminogroup subjected to interaction with the compound of the formula III

R1- Y - A - OH,

where R1is phenyl or a group of the formula

< / BR>
A - carbonyl, sulfonyl or its reactive derivative,

or its salt, followed, if necessary, diallylammonium compounds of formula I, where R3- acyloxy (lower)alkyl with obtaining the target product, where R3hydroxy(lower) alkyl.

 

Same patents:

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FIELD: organic chemistry, medicine.

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EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

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EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

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EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: medicine, gastroenterology.

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EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: biotechnology, biochemistry.

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EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

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EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

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,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

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

23 cl, 61 ex

FIELD: medicine, pharmacy.

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EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: veterinary science, pharmacy.

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EFFECT: valuable medicinal properties of composition.

6 cl, 9 tbl, 11 dwg, 45 ex

FIELD: organic chemistry, pharmaceutical compositions.

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EFFECT: new pharmaceutical compounds inhibiting dipeptidyl-peptidase IV.

5 cl, 1 dwg, 4 tbl, 12 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1) or its pharmaceutical salts wherein A means

R1 means hydrogen atom (H), (C1-C6)-alkyl (including branched alkyl and cycloalkyl), -(CH2)aNHW1, -(CH2)bCOW2, -(CH2)cOW3, -CH(Me)OW4, -(CH2)d-C6H4-W5, -(CH2)eSW6 wherein a = 2-5; b = 1-4; c = 1-2; d = 1-2; e = 1-3; W1 means -COW6, -CO2W6, -SO2W6; W2 means -OH, -NH2, -OW6, -NHW6; W3 means hydrogen atom (H), W6; W4 means H, W6; W5 means H, -OH, -OMe; W6 means (C1-C6)-alkyl, benzyl, optionally substituted phenyl wherein optional substitutes (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, fluorine (F) and/or chloride (Cl) atoms; R2 means H, -(CH2)nNH-C5H3N-Y wherein n = 2-4; Y means H, F, Cl atoms, -NO2 and -CN; or R1 and R2 represent in common -(CH2)p- wherein p = 3 or 4; X is taken among: (i) one L-alpha-aminoacyl group taken among Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, or two such groups that represent Arg and Ile; (ii) groups -R3CO wherein R3 represents H, (C1-C6)-alkyl (including branched alkyl and cycloalkyl) or phenyl; (iii) groups -R4COOC, -(R5)(R6)OCO wherein R4 means H, (C1-C6)-alkyl (including branched alkyl and cycloalkyl), benzyl or optionally substituted phenyl wherein substituted (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, F and Cl atoms; each R5 and R6 means independently H or (C1-C6)-alkyl; or R5 and R6 mean in common -(CH2)m- wherein m means a whole number 4-6; and (iv) methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl groups; R7 is taken among pyridyl and optionally substituted phenyl wherein substitutes (up to two groups) are taken among (C1-C3)-alkyl, (C1-C3)-alkoxy-group, F, Cl atoms, -NO2, -CN and -CO2H; R8 means H or (C1-C3)-alkyl; R9 means H, (C1-C6)-alkyl, phenyl or (C1-C6)-alkoxy-group and under condition that indicated compound doesn't represent N(Z-Val)-2-cyanopyrrolidine. Compounds of the formula (1) are inhibitors of DP-IV and can be used in pharmaceutical compositions in treatment of the tolerance disturbances to glucose and diabetes mellitus of type 2.

EFFECT: valuable medicinal properties of compounds and compositions.

26 cl, 2 tbl, 19 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

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