Derivatives triptoreline or their pharmaceutically acceptable salts, method of production thereof and pharmaceutical composition

 

(57) Abstract:

The purpose in medicine. The inventive derivatives triptoreline formula:

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where R1lower alkyl having one or two substituent selected from carboxy, esterified carboxy, di-lower alkylcarboxylic, phenyl (lower) alkyl, phenyl fragment which may have halogen, nitro or amino group, and the alkyl fragment is carboxy or esterified carboxy; haloethanol, morpholine, morpholino (lower) alkyl, R2and R3is lower alkyl, X is a bond or NH

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or their pharmaceutically acceptable salts. The retrieval method, which consists in the fact that the reagent I:

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reagent II: Amin: R1NH2the target product is isolated in free form or in salt form; pharmaceutical composition having inhibitory to leukocyte elastase activity, containing as an active ingredient derived triptoreline in the amount of 1 mg to 1 g per daily dose. 3 s and 5 C.p. f-crystals, 4 PL.

The present invention relates to new derivatives of triptoreline.

More specifically, the present invention relates to new derivatives of triptoreline and farghana and to pharmaceutical compositions containing them and to their use.

New derivatives of triftormetilfosfinov of the present invention have the following formula (I):

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where R1is lower alkyl which has one or two substituent selected among carboxyl, esterified carboxyl and di-(lower) allylcarbamate, phenyl(lower)alkyl, phenyl fragment which may have halogen, or nitro, or amino, and alkyl fragment which can be carboxyl, or the esterified carboxyl, aloevera, morpholino or morpholino(lower)alkyl,

R2and R3each is lower alkyl,

X is-or-NH - and

According to the present invention is new derivatives of triptoreline (I) and their salts can be obtained in various ways, which are illustrated in the following reaction schemes:

Y is

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In the above formulas, Rand1is mono - or diesterification carboxy (lower) alkyl and R1is the lowest alkylene, R1is mono - or di-esterified by carboxyla, R1is lower alkyl, and R1R3everyone has these values.

Pharmaceutically acceptable salts of n the ground, such as alkali metal salt (e.g. sodium salt, potassium salt, etc.,), salts of alkaline-earth metal (e.g. calcium salt, etc.,), ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt or etc., and salts accession of organic or inorganic acids, such as methanesulfonate, hydrochloride, sulfate, nitrate, phosphate, or etc.

Preferred examples and illustrations of the various definitions in the above descriptions, which are included in the scope of the present invention, are explained in more detail as follows.

The term "lower" denotes the average of 1-6 carbon atoms, unless otherwise indicated.

Preferred examples of halogen are fluorine, chlorine, bromine and iodine.

Preferred examples of "lower alkyl" may include a residue of straight or branched alkane having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, neopentyl, hexyl, etc., and preferably having 1-4 carbon atoms.

Preferred examples of esterified carboxyl" may include alkalemia esters, namely alkoxycarbonyl, such as lower alkoxycarbonyl.p.), and phenyl (lower) alkilany ether, namely phenyl (lower alkoxycarbonyl, such as benzyloxycarbonyl and benzoyl (lower) alkoxycarbonyl, such as benzoylmethylene, etc.

Preferred examples of "lower alkylene" may include methylene, ethylene, propylene, isopropylene etc.

Preferred examples of the "di-lower alkylcarboxylic" may include N, N-dimethylcarbamoyl, N,N-diethylcarbamoyl etc.

Ways to obtain the target compound (I) or its salts of the present invention are explained in more detail below.

When explaining Methods 1-5 below salts of compounds (I), (Ia(Ifand (II) to (V) may be the salt that is listed as pharmaceutically acceptable salts derived triptoreline (I), as shown previously.

(1) Method 1:

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The compound (I) and its salt can be obtained by the reaction of compound (II) or its salt with the compound (III) or its salt.

The reaction of this method can be carried out as follows.

So, in one case, at the first stage carboxyl group of compound (II) or its salt is usually activate the appropriate way, for example, in the form of galodamadruga acid, azide, any the m (III), to obtain the compound (I), and in the other case, the compound (II) or its salt is introduced to the reaction with compound (III) or its salt directly in the presence of a conventional condensing agent such as N, N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide etc.

This reaction is preferably carried out in a solvent such as N, N-dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methanol, water, etc., under cooling with ice to room temperature, and the reaction in the presence of condensing agent is usually carried out in an anhydrous, but not critical condition.

(2) Method 2:

The compound (IV) _ the Compound (I)

The compound (I) and its salt can be obtained by oxidation of compound (VI) or its salt.

The oxidation is conducted in the traditional way, using an oxidizing agent, which can be used to convert oxymethylene group in the carbonyl group, such as potassium permanganate, chromium compound (e.g., chromic acid, sodium chromate, darmowa acid, sodium bichromate, pyridine chlorproma, pyridine the bichromate, etc., reagent Swarna (dimethyl sulfoxide and oxalicacid), Jones reagent, etc.

Implement any other organic solvent, which has no adverse effect on the reaction, or a mixture thereof.

This reaction is preferably carried out in a fairly mild conditions, such as by heating, at room temperature or under refrigeration.

(3) Method 3:

The compound (Ia) _ Connection (Ib)

Connection (1in) and its salts can be obtained by introducing the compound (1a) or its salt in the reaction deesterification.

The reaction deesterification spend more traditional methods, such as hydrolysis, repair or etc., the details of which are explained below.

1) Hydrolysis.

The hydrolysis is preferably carried out in the presence of acid or base.

Suitable acids are inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, etc.), organic acids (e.g. formic acid, acetic acid, triperoxonane acid, propionic acid, benzosulfimide, n-toluensulfonate acid, etc.,), etc.

Suitable bases are inorganic bases, such as hydroxides of alkaline or alkaline-earth metals or the corresponding carbonates and bicarbonates (e.g., hydroxy who led ammonium, etc. organic bases such as alkoxides or phenoxide the above metals (e.g., ethoxide sodium, sodium methoxide, etc.,), amines such as mono-, di - or trialkylamine (for example, methylamine, ethylamine, N, N-dimethyl-1,3-propandiamine, triethylamine trimethylamine, etc.,), etc.

The hydrolysis is preferably carried out under relatively mild conditions, such as cooling or low heat, in a solvent which has no adverse effect on the reaction, for example, in water, a hydrophilic solvent such as alcohol (e.g. methanol, ethanol, propanol, etc.,), acetone, N,N-dimethylformamide, etc., as solvents can also be used above the liquid acid and base.

Recovery.

Recovery, including chemical reduction and catalytic reduction, carried out the traditional way.

Suitable reducing agents which can be used in chemical reduction are a metal (e.g. tin, zinc, iron, etc. or a combination of such metal and/or metallic compound (e.g. chromium chloride, chromium acetate, etc., and organic or inorganic acids (for example, moravijani acid, etc.

Suitable catalysts which can be used in catalytic reduction are conventional catalysts as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, etc.,), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on charcoal, colloidal palladium, etc., or etc.

Recovery is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc. or etc.

Recovery is preferably carried out under relatively mild conditions, such as cooling or at room temperature, or at a low heat.

(4) Method 4:

The compound (Ic) _ Connection (Id)

Connection (1d) or its salt can be obtained by reduction of compound (1c) or its salt.

Recovery, including chemical reduction and catalytic reduction, carried out the traditional way.

Suitable reducing agents include those agents that are specified for method 3.

Recovery is usually carried out in a solvent such as voiceline mild conditions, for example, while cooling, at room temperature or with mild heating.

(5) Method 5:

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Connection (1f) and its salt can be obtained by the reaction of the compound (1e) or its salt with the compound (V) or its salt.

The reaction is carried out essentially by the same method as in method 1.

Pharmaceutically acceptable salts derived triptoreline (1) can be obtained by conventional method, for example, during processing of compound (I) with an acid or a base. Suitable examples of acids or bases may include those that were given as examples in the explanation of "Hydrolysis" in Method 3.

Starting compound (II) (V) each include new compounds and can be obtained according to the preparation described here or by similar methods.

The target compound (I), including compounds (1a1f), and the starting compound (II) and (IV) include one or more isomers due to asymmetric carbon atoms and all of such isomers are included in the scope of the present invention.

According to the present invention can be obtained mixture diastereoisomers due to the presence of compounds having R and S configure connection.

It should be noted that the optically pure compound is transferred into the mixture of these diastereoisomers in water and/or organic solution.

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In addition, it should be noted that the target compound (I) of the present invention is a hydrated form in aqueous solution, which is included in the scope of the present invention.

Derivatives triptoreline (I) and its pharmaceutically acceptable salts have activity to inhibit human leukocyte to elastase, they are useful as inhibitors of human leukocyte elastase for the treatment or prevention of degenerative diseases, such as emphysema, atherosclerosis, rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, pancreatitis, periodontosis, pulmonary fibrosis, cystic fibrosis, chronic bronchitis, bronchiectasia, diffuse bronchiolitis, respiratory damage, distressful respiratory syndrome adults, etc. and in addition, they are useful for the treatment or prevention of asthma, transplant rejection, nephritis, bubbly rash, disseminated intravascular thrombosis, shock, systemic aromatase erythematosus, clonic disease, ischemic-reperfusion (ROM), corneal sarring or proliferation of fibroblast (eye coagulation, burns, mechanical and chemical damage, kerato-conjunctivitis, etc.) and sepsis. Compounds according to the invention can be classified as non-lethal. To illustrate the usefulness of the derived triptoreline (1) and its pharmaceutically acceptable salts listed below are the data of pharmacological tests.

Test 1: Evaluation of protease inhibition (in vitro) (1) Method.

The buffer used in the analysis represents a 0.1 M S (4)-2-oxyethyl-1-piperazineethanesulfonic acid) containing 0.5 M NaCl, pH 7.5. Mix 25 μm 2 mm methoxyamine-(Ala)2-Pro-Val-n-nitroanilide (100 mm dimethylsulfoxide solution diluted in buffer) and 50 μl of the sample (10 ál of the sample in an organic solvent diluted 5-fold in buffer) in cells and in the circuit Board 96 microeletronic cells. Measure the absorption of the mixture at a wavelength of 415 μl using a reader device for blade. (Corona Electric Co. Ibaraki, Japan). After the measurement, add 25 μl of elastase human sputum with a concentration of 6 µg/ml and leave the mixture for 30 minutes at room temperature. Then measure the absorbance at 415 nm. Determine the percent inhibition of medicine n the minutes of incubation minus absorption before adding the enzyme. The effect of inhibitors against porcine pancreatic elastase Type IV, 5 mg) ml final concentration) estimated similarly, using N-succinyl-(A1A)-n-nitroanilide. SE was obtained from Latin producs company, Inc. MO, USA. All other substrates and proteases were purchased from Sigma chemicals Co.

Inhibitory effect on the activity of some serine proteases (see tab. 1).

Test 2: Determination of activity when induced by elastases lung diseases.

(1) Method.

Use of hamsters under anesthesia by pentobarbital. Physiological solution containing the elastase of human sputum, enter drop by drop intratrahealno through a small incision in the ventral region of the neck, using a syringe 1 ml needle 27 gauge. After 3 hours the animals were killed by Aspicia in CO2the trachea of each animal were expository. Light then washed using aliquots of 2.5 ml of physiological solution, and then discarding a physiological solution, receiving the final volume of approximately 1.5 ml of fluid from bronchoalveolar washings (YOU) from each animal.

Cells from BAL fluid collected by centrifugation, and then diluted with distilled water to CTB dissolved in saline solution or in methylcellulose and administered drop by drop intratrahealno in the same way, as it was used to zakapyvanija elastase, 5 minutes before the instillation of elastase.

(2) Result:

Inhibitory effect on induced Lactasoy hemorrhage in the lung (see table. 2).

Test (3): Effect on tumor paws of the mouse caused by elastases human sputum.

(1) Materials and methods.

Male mice 57BL 7-8 weeks of age were obtained from Japan Clergy Inc.

The elastase of human sputum (SE) bought in Elastin Pro-ducts company, Inc. the subjects of the drug was administered subcutaneously, and after 15 minutes took an injection SE in the right hind paw at a dose of 20 µg/plot for control in the left hind paw was injected with saline. 2 hours after injection SE measured the size of the tumor on the leg by using a device for measuring the thickness, calculate the difference in thickness between the right and left hind legs.

(2) Results:

The effect on tumor paws in mice, caused by elastases (see tab. 3).

Test 4: Effects on experimentally induced emphysema in hamsters.

(1) Materials and methods:

Male Golden Syrian hamsters weighing about 120 g, were obtained from Japan SZC Inc.

Pork pancreatic elastase (PP is believed administered intraperitoneally by pentobarbital. Dissolve the compound of example 19 in physiological solution. Suspended known compounds a and b in 0.5% methylcellulose. Drugs were introduced dropwise intratrahealno through the mouth for 5 minutes before putting 100 µg/plot RRE in 0.2 ml of saline. 3 weeks after putting RRE hamsters analizirovali pentobarbital. He studied the mechanics of respiration in lying supine hamsters using plethysmograph with a single case, constant volume, variable pressure, for measuring volume. Use a water-filled esoterically catheter for estimating pleural pressure. Get quasi-static curves pressure drop volume (P Z) for intraperitoneal introduction deliverin under pressure subcutaneously to the spontaneous suppression of filling the lungs when inhaling to transpulmonary pressure (Z) 30 cm H2O and gently exhale to PZ-20 cm H2O. Determine the quasi-static lung compliance (st) as the slope of the steepest section of exhalation in the P-V curve in the middle of the volume. Vital capacity is defined as the difference in lung volume between Z C25 (volume Z=24 cm H2O) and RV (volume PZ -20 cm H2O).

(2) the Results.

Preprocessing connect what atom, as shown in the following table. Considering st and VC values, we can conclude that the power of the compounds of example 19 exceeds the capacity of the known compounds a and b (see tab. 4).

Well-known compound And (Japanes Kocak Tokio Coho N 61-218518):

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Well-known compound Century Japanese Kocak Tokio Coho N 2-256657):

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The pharmaceutical compositions of the present invention can be used in the form of conventional pharmaceutical forms, such as powders, fine granules, granules, tablets, pills, injection, inhalation, microcapsules, capsules, suppositories, solution, suspension, emulsion, syrup, etc., If desired, in the above composition can be introduced thinners and disintegrators (e.g., sucrose, lactose, starch, crystalline cellulose, low - substituted oxypropylation, synthetic aluminum silicate, etc.,), binding agents (e.g., cellulose, methylcellulose, oxypropylation, oksipropilmetiltselljuloza, polipropilenglicol, polyvinylpyrrolidone, gelatin, gum Arabic, polyethylene glycol, etc.,), coloring agents, podslushivala, lubricant (e.g. magnesium stearate, etc.,), etc.

Dosage specified composition of the present invention depends on the age of GHGs in the form of a target compound or its pharmaceutically acceptable salt, preferably 10-500 mg of the same base, with a frequency of 1-3 times a day. Typical unit doses are 5, 10, 20, 50, 100 mg, etc., although they are only examples and are not limited to.

The following preparations and examples are given to illustrate the present invention.

In the preparations and examples used the following abbreviations WS DM: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

NOT: N oxybisethanol

F: N, N-dimethylformamide

DM SO: dimethylsulfoxide

Preparation 1.

To a solution of 10,86 g of N-(tert.-butoxycarbonyl)-Z-Velina and 12,09 g hydrochloric acid benzyl ether of Z-Proline in 50 ml DMG add 6,76 g NOWT and 7,76 g WS DM while cooling in an ice bath. After 18 hours stirring at room temperature the reaction mixture was concentrated under reduced pressure. The residue is dissolved in 400 ml ethyl acetate and washed with 200 ml of 5% aqueous citric acid, saturated aqueous sodium bicarbonate (200 ml). The solution is dried over magnesium sulfate and evaporated under reduced pressure, receive a grade of 20.06 g of benzyl ester of N-(tert.-butoxycarbonyl)-Z-poured-Z-Proline in the form of butter.

TLC (silikagelevye plate kieselgel 60 F254, Merck).

The same C1).

The following compounds were obtained according to the method of preparation 1.

Preparation 2.

4-(Methoxycarbonyl)phenylcarbamoyl-Z-poured-Z-Proline benzyl ester oil.

TLC: Rf 0,89 (l3MeOH 10:1).

Preparation of 3.

3(RS)-((4-Methoxycarbonyl)phenylcarbamoyl)-Z-poured-Z-prolyl)-amino-1,1,1-Cryptor-2(RS)-hydroxy-4-methylpentan. So pl. 64-67oC.

TLC: Rf 0.63 and 0,60 (l3MeOH 10:1).

Preparation 4.

3/R or S/-//4-Methoxycarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R or S/hydroxy-4-methylpentan.

So pl. 65 75oC.

TLC: Rf Of 0.65 (l3: MeOH 10:1)

()2D256,23o(0,14, Meon).

Preparation 5.

3/R or S /-//4-Benzyloxycarbonylamino/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R or S/-hydroxy-4-methylpentan. So pl. 70-80oC.

TLC: Rf Of 0.65 /CHCl3: MeOH 10:1/.

()2D246,59o(C 0,165, Meon).

Preparation of 6.

3/R or S/-//4-/Benzyloxycarbonylamino/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R or S/hydroxy-4-methylpentan. So pl. 80-90oC.

TLC:Rf 0,60 /CHCl Meon 10:1/.

()2Dcarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R or S/-hydroxy-4-methylpentan.

So pl. 68-85.

TLC: Rf 0,60 /CHCl3MeOH 10:1/.

()2D2= -42,63(C 0,175 Meon/.

Preparation of 8.

Dissolve 20,0, benzyl ether, N-/tert.butoxycarbonyl/-Z-poured-Z-Proline in 4N hydrochloric acid in 30 ml of dioxane while cooling in an ice bath. After 1 hour stirring at room temperature the reaction mixture is evaporated under lowered pressure. The residue is sprayed with ether, get 14,56 g hydrochloric acid benzyl ester Z-poured-Z-Proline. So pl. 66-69oC.

TLC: Rf 0.55 And /CHCl3MeOH 10:1).

Preparation of 9.

The solution 18,53, benzyl ether, N-4-/methoxycarbonyl/phenylcarbinol-Z-valine-Z-Proline 150 SL methanol hydronaut 10% palladium on coal (1.0 g) under hydrogen pressure of 1.5 ATM for 1.5 hours at room temperature. After removal of catalyst by filtration, the filtrate is evaporated under reduced pressure get to 14.20 g of 4-methoxycarbonyl/phenylcarbinol-Z-poured-Z-Proline. So pl. 68-71oC.

TLC: Rf 0,27 (l3MeOH 10:1).

Preparation 10.

To a solution of 0.82 ml of oxalicacid in 5 ml of dichloromethane are added to 1.34 ml of dimethylsulfoxide, and a solution of 2.5 g of 3-/RS/-//4-/4-methoxycarbonyl/-Z-poured-Z-shed/who're asked for one hour at -40oC, add 2,63 ml of triethylamine. The mixture is stirred for further 30 minutes at the same temperature and washed with 15 ml of 0.5 N hydrochloric acid and 15 ml of 5% aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified column chromatography on 50 g of silica gel (chloroform)methanol 50:1 gain of 2.18 g 3/RS/-//4-/4-methoxycarbonyl-phenylcarbamoyl/-Z-poured-Z-shed/amino-1, - 1,1-Cryptor-4-methyl-2-oxapentane. So pl. 67-70oC. TLC: Rf 0,51 (l3:MeOH 10:1).

Preparation of 11.

To a solution of 2.1 G. of 3/RS/-//4-/4-methoxycarbonyl/-phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in 40 ml of methanol was added 15 ml of 1 N aqueous sodium hydroxide while cooling in an ice bath. After 2 hours of stirring the mixture at room temperature to evaporate the methanol. The concentrate was washed with 30 ml of ether, then acidified to pH 21 N hydrochloric acid. Extracted with an aqueous solution of 20 ml of ethyl acetate. The extract is washed with 10 ml brine, dried over magnesium sulfate, receive 1,94 g 3/RS/-//4-carboxypenicillins/-Z-poured-Z-shed/amino-1,1,1-trifter 4-methyl-2-oxapentane. So pl. 215-220oC TLC, Rf 0,63/l3: MeOH:AcOH 8:2:1/.

The following compounds were obtained by the/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/C or S/-hydroxy-4-methylpentan/0,61 g/

So pl. 266-269oC. TLC: Rf 0,42 (benzene:EtOA:AcOH=20:20:1/

()2D2= -49,71(C 0.1, The Meon).

Preparation 13.

3/R or S/-//4-/Carboxy/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R or S (hydroxy-4-methylpentan. So pl. 265-268oC.

TLC: Rf 0.40 in (benzene EtOAc AcOH 20:20:1/.

()2D2= -64,25(0,16, Meon).

Preparation 14.

Add 3 ml of 28% solution of sodium methoxide in methanol to a solution of 3.2 g of hydrochloric acid 3/RS/-amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentane in 30 ml of ethanol at room temperature. After removal of precipitated precipitated sodium chloride by filtration, to the filtrate was added 2.3 g of (2R, 3R)-Z-tartaric acid. The mixture is heated up until tartaric acid is dissolved, and filtered. The filtrate is left for 5 hours at room temperature. Filtered 1,94 g of solid crystalline precipitate and dissolve it in 1 N aqueous sodium hydroxide. The solution is extracted with 10 ml ethyl acetate and the extract is mixed with 4N hydrochloric acid in ethyl acetate. After removal of the ethyl acetate the residue is sprayed with 10 ml of diisopropyl ether, the gain of 1.03 g of hydrochloric acid 3/R or S/-amino-1,1,1-Cryptor-2/R or S/-4-methylpentan is SUP> (C Of 0.13, MeOH).

The following compound was obtained according to the method of preparation 14.

Preparation 15.

3/R or S/-Amino-1,1,1-Cryptor-2/R or S/-4-methylpentan hydrochloric acid. So pl. 165-170oC, TLC: Rf 0.55 And/l3:MeOH 10:1/

()2D2= -10,56(C 1,05, Meon).

Preparation 16.

To a solution of 0.4 g of methyl-n-benzoate in 10 ml of tetrahydrofuran was added 0.31 g of trichloromethylcarbonate and the mixture is left overnight at room temperature. To the solution was added 0,54, benzyl ether of Z-valine and neutralize the mixture with triethylamine. After stirring the mixture for 30 minutes at room temperature the mixture is concentrated under reduced pressure and the residue is extracted with 10 ml ethyl acetate. The extract was washed with 10 ml of 1N hydrochloric acid and 10 ml of aqueous sodium bicarbonate, and then concentrated to dryness, get 1,17 g 4/methoxycarbonyl/phenylenecarbonyl-Z-valine benzyl ester.

TLC: Rf 0.55 And/CHCl3:MeOH 10:1, volume/volume/.

Preparation 17

Get 0,83 g 4/methoxycarbonyl/phenylamino-Z-valine 1 g benzyl ester 4-/methoxycarbonyl/phenylcarbinol-Z-valine according to the method of preparation 9.

TLC: Rf 0,3/l3:MeOH:H265:25:4/. Oil.

TLC: Rf 0,60 (l3:MeOH 10:1). Oil.

Preparation 19.

Get 0,69 g /4-/methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-Proline from 1.0 g of benzyl ether (4-)methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-Proline according to the method of preparation 9.

TLC: Rf 0.35 In (l3:MeOH:H2O 65:25:4). Oil.

Preparation 20.

Get 1,03 g 3/RS/-//4-/methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-propyl/amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentane from 0,69 g /4-/methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-Proline and 0.37 g 3/RS/-amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentane hydrochloride according to the method of preparation 1.

TLC: Rf 0.45 In (HCl3:MeOH 10:1). Oil.

Preparation 21.

Get 0,98 g 3/RS//-//4-Methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpentan of 1.0 g 3/RS/-//4-methoxycarbonyl/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2/R, S/-hydroxy-4-methylpentan according to the method of preparation 10. So pl. 90-100oC. TLC: Rf Of 0.5 (l3:MeOH 10:1).

Preparation 22.

Get 0.2 g 3/RS/-//4-carboxy/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpentane of 0.3 g 3/RS/-//4-methoxycarbonyl/phenylenecarbonyl/-Z-poured-ZP>C.

TLC: Rf 0.50 (A l3:MeOH:H2O 65:25:4).

Preparation 23.

To a solution of 4.35 g N/tert.butoxycarbonyl/-Z-valine and 2.13 g of triethylamine in 40 ml of dry CH2Cl2add 2,87 g isobutylphthalate at -20oC. After 30 minutes of stirring at the same temperature was added a solution is lower than the 5.37 g of benzyl ester of N-(2-indanyl/glycine in 20 ml of dry CH2Cl2at -20oC. the Reaction mixture was stirred for 1 hour at -10oC, then 4 hours at room temperature. After concentrating the reaction mixture under reduced pressure the residue is dissolved in 100 ml ethyl acetate and washed with 100 ml x 2 saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on a column of 50 g of silica gel (CHCl3:AeOEt 10:1) obtain 2.20 g of N-/tert.-butoxycarbonyl/-Z-poured-N-/2-indanyl/glycine benzyl ester in the form of butter.

TLC: Rf 0,78 (hexane:t 2:1).

Preparation 24

Receive 1.83 g of the hydrochloride of Z-poured-N-/2-indanyl/glycine benzyl ester of 2.14 g of benzyl ester of N-/tert.-butoxycarbonyl/-Z-poured-N-/2-indanyl/glycine according to the method of preparation 8. So pl. 162-163oC.

T is carbonyl/ phenylcarbinol/-Z-poured-N-/2-indanyl/glycine out of 1.80 g of the hydrochloride benzyl ether of Z-poured-N-/2-indanyl/glycine and 0,86 g nanometrology ether teleftaios acid according to the method of preparation 1. So pl. 72-76oC.

TLC: Rf 0,60 (l3:MeOH 10:1).

Preparation 26.

Get 0,83, N-/4-/methoxycarbonyl/phenylcarbinol/-Z-cushion-N/2-indanyl/glycine and 1.20 g of N-/2-indanyl/glycine from 1.20 g of N-/4-/-methoxycarbonyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycine benzyl ester according to the method of preparation 9.

So pl. 163-164oC.

TLC: Rf Of 0.48 (l3:MeOH 10:1).

Preparation 27

Obtain 1.06 g 3/RS/-//4-/methoxycarbonyl/phenylcarbinol/-Z-poured-N-/2/indanyl/glycine/amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentane from 0,80 g N-/4-/methoxycarbonyl/phenylcarbinol/-Z-felled N-/2-indanyl/glycine and 385 mg of the hydrochloride of 3-/RS/amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentane according to the method of preparation 1.

So pl. 76-78oC.

TLC: Rf 0,71 (l3:MeOH 10:1).

Preparation 28.

Obtain 0.84 g 3/RS/-//4-methoxycarbonyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane from 1,03, 3/RS/-//4-/methoxycarbonyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-2/RS/-hydroxy-4-methylpentan according to the method of preparation 10.

So pl. 62-64oC.

TLC: Rf 0,74 (l3:MeOH 10:1).

Preparation 29.

Get 0,76 g 3/RS/-//4-carboxy who carbonyl/-Z-poured-N-(2-indanyl)-glycyl/amino-1,1,1-Cryptor-4-methyl-2-octopetala (0,83 g) using the procedure of preparation 11.

So pl. 84-86oC.

TLC: Rf Of 0.15 (l3:MeOH 10:1).

Example 1.

To a mixture of 66 mg of n-toluensulfonate benzyl ester of glycine and 100 ml of 3/RS/-//4-carboxypenicillins/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in 6 ml DMG added 26 mg NOWT and 30 mg WS DM while cooling in an ice bath. After 4 hours stirring at room temperature the mixture is concentrated under reduced pressure. The residue is dissolved in 30 ml ethyl acetate and washed with 20 ml of 5% aqueous citric acid, 20 ml water, 20 ml of 5% aqueous sodium bicarbonate and 20 ml of brine. The solution is dried over magnesium sulfate and evaporated under reduced pressure to obtain 125 mg 2/RS/-//4-/benzyloxycarbonyl/methylaminomethyl/-phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 77-78oC.

TLC: Rf 0.56 To (l3:MeOH 10:1).

The following compounds were obtained according to the method of example 1.

Example 2.

3/RS/-//2-/4-morpholino/ethyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 98-102oC.

TLC: Rf 0,24 (l3:MeOH 10:1).

Example 3.

3/RS/-//4-//3-benzimidazolecarbamic/propylaminoethyl/-phenylcarbinol/-Z-poured-Z-Strait/P> Example 4.

3/RS/-//4//4 morpholino/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 191-193oC.

TLC: Rf 0,59 (l3:MeOH 10:1).

Example 5.

3/RS/-//4-//4-chlorbenzyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 87-89oC.

TLC: Rf Of 0.43 (l3:MeOH 10:1).

Example 6.

3/RS/-//4-//4-nitrobenzyl/aminocarbonyl/phenylcarbinol-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 94-96oC.

TLC: Rf Of 0.57 (l3:MeOH 10:1).

Example 7.

3/RS/-//4-//4-chlorophenyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 71-72oC.

TLC: Rf 0,79 (l3:MeOH 10:1).

Example 8.

3/RS/-//4-///1(R)-benzyloxycarbonyl/-2-phenyl-ethylaminomethyl/phenylcarbinol/-Z-roller-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 65-67oC.

TLC: Rf 0,82 (l3:MeOH 10:1).

Example 9.

3/RS/-//4///1/S/-benzyloxycarbonyl-2-phenyl/ethylaminomethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 108-110oC.

oC.

TLC: Rf 0,83 (l3:MeOH 10:1).

Example 11.

To a solution of 0.09 ml oxalicacid in 2 ml of dichloromethane was added 0.15 ml of dimethylsulfoxide, and a solution of 0.35 g 3/R or S/-//4-/benzyloxycarbonylamino/phenylcarbinol/-Z-poured-Z-shed /amino-1,1,1-Cryptor-2/R or S/-hydroxy-4-methylpentane in 4 ml of dichloromethane at 70oWith consistently. After 1 hour stirring the mixture at -40oC add to 0.29 ml of triethylamine. The mixture is stirred for further 30 minutes at the same temperature and washed with 15 ml of 0.5 N hydrochloric acid and 15 ml of 5% aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on a column of 20 g of silica gel (chloroform: methanol 50: 1), receive 0,22 g 3/R or S/-//4-/benzyloxycarbonylamino/-phenylcarbinol/-Z-poured-Z-propyl/amino-1,1,1-Cryptor-2-oxo-4-methylpentane.

So pl. 159-161oC.

TLC: Rf 0,63 (l3:MeOH 10:1).

()2D2= -39,66 (C 0,105, Meon).

The following compound was obtained according to the method of example 11.

Example 12.

3/R or S/-//4-benzyloxycarbonylamino/phenyl-carbonyl/-Z-poured-Z-shed/aming">

()2D2= -41,90(C 0,15 Meon).

Example 13.

Hydronaut a solution of 70 mg 3/RS/-//4-//-benzyloxycarbonyl/methylaminomethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in a mixture of 10 ml of methanol and 1 ml of water to 1.0 g of 10% palladium on coal under 3 ATM of hydrogen for 3 hours at room temperature. After removal of catalyst by filtration, the filtrate is evaporated under reduced pressure to obtain 61 mg 3/RS/-//4-carboxymethylaminomethyl/phenyl-carbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 99-103oC.

TLC: Rf 0,17 (l3:MeOH:AcOH 8:1:1).

Example 14.

To a solution of 120 mg 3/RS/-//4-//3-benzoylmethylene/propylaminoethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in 5 ml of acetic acid was added 120 mg of zinc powder under cooling in an ice bath. After 2 hours stirring at room temperature the zinc is filtered off. The filtrate is evaporated under reduced pressure to obtain 95 mg 3/RS/-//4-//3-carboxypropyl/aminocarbonyl/phenyl-carbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 84-86oC. TLC: Rf Of 0.32 (l3:MeOH:AcOH 8:1:1).

So pl. 75-120oC.

TLC reversible phase RP-18 WF254S (manufactured by E. Merck) Rf Of 0.55 (MeOH:H26: 5).

()22D/= -35,10(C 0,105, Meon).

Example 16.

3/R or S/-//4-/carboxymethylaminomethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-methylpentan.

So pl. 90-110oC.

TLC (RP-18 WF254S (manufactured by E. Merck) Rf Of 0.50 (MeOH:H2O 6:5),

()2D2= -50,04(C 0,115, Meon).

Example 17.

3/RS/-//4-//1/S/ 3-dicarboxylate/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 74-76oC.

TLC: Rf 0,13 (l3:MeOH:AcOH 8:1:1).

Example 18.

Hydronaut a solution of 50 mg 3/RS/-//4-//4-nitrobenzyl/aminocarbonyl/phenylcarbinol-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in 10 ml of methanol, 10 mg of 10% palladium on coal at a pressure of 4 ATM hydrogen for 2 hours. The catalyst is filtered off and the filtrate is evaporated under reduced pressure to obtain 46 mg of 3/RS/-//4-//4-aminobenzyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

So pl. 90-92oC.

TLC: Rf Of 0.44 (l3:MeOH-AcOH 8:1:1).

oC.

TLC: Rf 0,17 (l3:MeOH:AcOH 8:1:1).

The following connection receive according to the method of example 10.

Example 20.

Sodium salt of 3/RS/-//4-//3-carboxypropyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 66-69oC.

Example 21.

To a solution of 80 mg 3/RS/-//4-//2-/4-morpholino/ethyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane (80 mg) in 1 ml dioxane was added 0.1 ml of 4 N hydrochloric acid in dioxane. The mixture is stirred at room temperature for 10 minutes and evaporated, to obtain 83 mg 3/RS/-//4-//2-/4-morpholino/ethyl/aminocarbonyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxopent hydrochloride. So pl. 64-65oC.

TLC: Rf 0,24 (l3:MeOH 10:1).

Example 22.

3/RS/-//4-/benzyloxycarbonylamino/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methyl-pentane (0.25 g) obtained from 0.2 g 3/RS/-//4-/carboxy/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpentane and 0.13 g of n-toluensulfonate benzyl ester of glycine by the method of example 1. So pl. 65-dimetilaminoetanol/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpentane of 0.2 g 3/R5/-//4-/benzyloxycarbonylamino-carbonyl/phenylenecarbonyl//-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-hydroxy-4-methylpentan by the method of example 13. So pl. 98-128oC.

TLC: Rf 0.25 In (l3:MeOH:H2O 65:25:4).

Example 24.

3/RS/-//4-dimethylaminocarbonylmethyl/phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpropan (0.03 g) is obtained from 3/RS/-//4-/carboxymethylaminomethyl/-phenylenecarbonyl/-Z-poured-Z-shed/amino-1,1,1-Cryptor-2-oxo-4-methylpentane (0.08 g) and hydrochloric acid dimethylamine (0,012 g) by the method of example 1. So pl. 115-125oWITH,

TLC: Rf 0,20 (l3:MeOH 10:1).

Example 25.

Receive 250 mg 3/RS/-//4-//benzyloxycarbonyl/methylaminomethyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane of 18 mg of n-toluensulfonate benzyl ester of glycine and 206 mg 3/RS/-//4-carboxypenicillins/-Z-valine-N-(2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane by the method of example 1. So pl. 64-66oC.

TLC: Rf 0,81 (l3:MeOH 10:1).

White powder.

Example 26.

Get 195 mg 3/RS/-//4-/carboxymethylaminomethyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane of 220 kg 3/RS/-//4-//benzyloxycarbonyl/methylaminomethyl/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane by the method of example 13. So Ravoi salt 3/RS/-//4-/carboxymethylaminomethyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane by the method of example 19. So pl. 203-205oC.

TLC: Rf 0.25 In (l3:MeOH:AcOH 16:1:1).

Example 28.

Receive 180 mg 3/RS/-//4-//2-/4-morpholino/ethyl/aminocarbonyl/phenylcarbinol/-Z-poured-N-/2-indanyl/glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane from 46 mg of 4-/2-amino-ethyl/research and 206 mg 3/RS/-//4-carboxypenicillins/-Z-poured-N-/2-indanyl/glycol/-amino-1,1,1-Cryptor-4-methyl-2-oxapentane by the method of example 1. So pl. 76-80oC.

TLC: Rf Of 0.38 (l3:MeOH 10:1).

Example 29.

Obtain 170 mg of the hydrochloride of 3/RS/-//4-//2-/4-morpholino/ethyl/-aminocarbonyl/phenylcarbinol/-Z-poured-Z-/2-indanyl-glycol/amino-1,1,1-Cryptor-4-methyl-2-oxapentane by the method of example 21.

So pl. 96-99oC.

TLC: Rf Of 0.38 (l3:MeOH 10:1).

Example 30.

3/RS/-//4-/etoxycarbonyl/methylaminomethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxopent was obtained in the same manner as described in example 1. So pl. 96-99oC.

Example 31.

To a solution of 5.0 g 3/RS/-//4-/etoxycarbonyl/-methylaminomethyl/phenylcarbinol/-Z-cut Z-cut Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane in a mixture of 60 mg of methylene chloride, 10 ml of methanol and 25 ml of water was added under cooling in a water bath an aqueous solution of 0.6 g omashu 6 m hydrochloric acid was set equal to 9, and washed with an aqueous solution of 60 ml of methylene chloride. To the water solution was then added 5 g of sodium chloride and 60 ml of ethyl acetate, acidified mixture of 6 n hydrochloric acid to pH 2, washed with an ethyl acetate solution of 30 ml of brine, dried over magnesium sulfate and concentrated under reduced pressure to a volume of 20 ml of This concentrated solution was added dropwise at room temperature to 225 ml of isopropyl ether. Dropdown precipitate was filtered and dried, resulting in the 3,24 g 3/RS/-//4-/carboxymethylaminomethyl/phenylcarbinol/-Z-poured-Z-shed/amino-1,1,1-Cryptor-4-methyl-2-oxapentane. So pl. 99-103oC.

1. Derivatives triptoreline General formula

< / BR>
where R1is lower alkyl which has one or two substituent selected from carboxy, esterified carboxy and Denissenko of allylcarbamate; phenyl(lower)alkyl, phenyl fragment which may have halogen, or nitro, or amino, and alkyl fragment may have carboxy or esterified carboxy; aloevera, morpholino, or morpholino(lower)alkyl;

R2and R3each is lower alkyl,

X is a bond or-NH-;

Y is

< / BR>
and their pharmaceutically acceptable salts.

2. Derivatives eat one or two substituent, selected from carboxyl or esterified carboxyl and Denissenko of allylcarbamate; phenyl(lower)alkyl, phenyl fragment which may have halogen, or nitro, or amino, and alkyl fragment can be carboxyl or esterified carboxyl; gaelicforum; morpholino or morpholino(lower)alkyl,

or their pharmaceutically acceptable salts.

3. Derivatives under item 2, wherein R1is lower alkyl, which is carboxyl or esterified carboxyl, and R2and R3each lower alkyl.

4. Derivatives under item 3, wherein R1is carboxymethyl, and R2and R3each isopropyl.

5. Derivatives under item 4, characterized in that they are 3/RS/-//4-/carboxymethylaminomethyl-carbonyl/-phenylcarbinol/-Z - a-poured-Z-propyl/amino-1,1,1-Cryptor-4-methyl-2-oxopentanoic.

6. Derivatives under item 4, characterized in that they are the sodium salt of 3/RS/-//4-carboxymethylaminomethyl/phenylcarbinol/-Z-poured-Z-propyl/- amino-1,1,1-Cryptor-4-methyl-2-oxapentane.

7. The method of obtaining derivatives of triptoreline General formula I

< / BR>
or their salts,

where R1is phenyl(lower)all(lower)alkyl, lowest alkoxycarbonyl(lower)alkyl, phenyl(lower)alkyl, phenyl fragment which may be chlorine, amino or nitro, phenyl(lower)alkyl, the alkyl fragment which has a phenyl(lower)alkoxycarbonyl, haloperidolum, morpholino, morpholino(lower)alkyl, mono - or dicarboxyl(lower)alkyl, or di(lower)allylcarbamate(lower)alkyl;

R2and R3each of the lower alkyl;

X is a bond or-NH-;

Y is

< / BR>
characterized in that the compound of General formula

< / BR>
or its salt is subjected to reaction with a compound of General formula R1-NH2or its salt and, if necessary, the obtained compound, where R1is phenyl(lower)alkoxycarbonyl(lower)alkyl, diphenyl(lower)alkoxycarbonyl(lower)alkyl, benzoyl(lower)alkoxycarbonyl(lower)alkyl, lower alkoxycarbonyl(lower)alkyl or phenyl(lower)alkyl, the alkyl fragment which has a phenyl(lower)alkoxycarbonyl, is subjected to reaction deesterification and, if necessary, the compound obtained in which R1is the p-nitrobenzyl, restore and, if necessary, the compounds in which R1is HOOC-R1cin kotoryu>NH in which R1d is lower alkyl or its salt, the compounds isolated in free form or in salt form.

8. Pharmaceutical composition having inhibitory to leukocyte elastase activity, including an active ingredient and a pharmaceutically acceptable carrier or excipient, characterized in that as the active ingredient contains a derivative of triptoreline according to any one of paragraphs.1 6 in the amount of 1 mg to 1 g per daily dose.

Priority signs:

31.12.90 when R1lower alkyl which has one or two substituent selected from carboxypropyl or esterified carboxypropyl; phenyl(lower)alkyl, phenyl fragment which may be substituted by halogen or nitro-group, and the alkyl may be carboxypropyl or esterified carboxypropyl; haloethanol; morpholinopropan; morpholino(lower)alkyl; R2R3lower alkyl; X is a bond; Y

< / BR>
16.09.91 when R1lower alkyl, substituted dignissim allylcarbamate,

 

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FIELD: organic chemistry, medicine.

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4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

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64 cl, 35 ex, 35 tbl, 21 dwg

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7 cl, 6 tbl, 6 ex

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6 cl, 9 tbl, 11 dwg, 45 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 and R2 are chosen independently from (C1-C4)-alkyl; R3 represents hydrogen atom or hydroxy-group; R4 represents (C1-C4)-alkyl; R5 represents hydroxy-group, or to its pharmaceutically acceptable salts, esters or amides. Also, invention relates to using these compounds as inhibitors of bile acids transfer in ileum for treatment of hyperlipemia. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions comprising thereof.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to derivatives of 2-hydroxytetrahydrofurane , of general formula (I) , which possess ability to inhibit calpaines and/or ability to catch active oxygen forms and can be used to obtain medication, intended for inhibiting calpaines and/or lipid peroxidation.

EFFECT: medications possess higher efficiency.

9 cl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to α',β'-epoxides of peptides of formulae (III) and (IV) which inhibit chymotrypsin-like activity of 20S proteasome.

EFFECT: increased effectiveness of the compounds.

19 cl, 29 ex

FIELD: chemistry.

SUBSTANCE: claimed is method of obtaining N-pyrazinoyl-(L)-phenylalanyl-(L)-leucine boronic acid or its anhydride with application of reaction of (1S,2S,3R,5S)-pinandiol-(S)-1-clor-3-methylbutane-I-boronate with lithium bis(trimethylsilyl)-amide with formation of (1S,2S,3R,5S)-pinandiol-(R)-1-bis(trimethylsilyl)amino-3-methylbutane-1-boronate, which is subjected to extractive purification with water and is isolated in pure form and with further interaction with trifluoroacetic acid with formation of corresponding acid-additive salt, which is condensed with N-pyrazinoil-(L)-phenylalanine in presence of condensing agent TBTU and diisopropylethylamine in methylene chloride, N-pyrazinoil-(L)-phenylalanine being obtained by condensation of N,O-bis-silyl derivative of (L)-phenylalanine, formed from (L)-phenylalanine under impact of N,O-bis(trimethylsilyl)acetamide, and imidazolyl of pyrazine carbonic acid, with formation of (1S,2S,3R,5S)- pinandiol-N-pyrazinoil-(L)-phenylalanyl-(L)-leucine boronate, which is subjected to acid hydrolysis with formation of N-pyrazinoyl-(L)-phenylalanyl-(L)-leucine boronic acid or its anhydride.

EFFECT: method allows top obtain target product with high output, high purity using simpler and safer technology.

8 ex

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