Derivative cyclopentane - or cyclopenten- amino acids and their salts, the composition is active against strains of s. aureus candida and trichophyton

 

(57) Abstract:

The proposed cyclopentane - or cyclopenten--amino acids of the formula I, where A, B, D, E, G, L, M and T denote H, halogen, OH, possibly substituted C1-C8-alkyl, or B and D, E and G or L and M denote the residue formula =CR6R7or = N-OH, or E and G or B and D together denote =0, R1- H, C1-C8-alkyl; R2- H, aminosidine group, C1-C8-alkyl, C1-C8-acyl, benzoyl or the rest aminosilane-CO-CHR9-OTHER10; R3- H, possibly substituted C1-C8-alkyl, and their salts. The compounds of formula I are biologically active compounds and can be used in compositions active against strains of S. aureus, Candida and Trichophyton. 2 S. and 3 C.p. f-crystals, 5 PL.

The invention relates to new chemical compounds with valuable properties, in particular the derivative of cyclopentane - or cyclopenten--amino acids of General formula (I)

< / BR>
where A, B, D, E, G, L, M and T are identical or different and denote hydrogen, halogen, hydroxyl, linear or branched alkyl with 1 to 8 carbon atoms which may be substituted with halogen, hydroxyl, phenyl, benzyloxy or carboxypropyl or a group of the formula-NR4R5where R carbon atoms

moreover, at least one of the substituents A, B, D, E, L, M, and T does not mean hydrogen,

or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
where R6and R7the same or different and mean hydrogen, halogen, linear or branched alkyl with 1 to 8 carbon atoms, benzyl or phenyl, or E and G or B and D together denote a residue =0,

R1means hydrogen or a linear or branched alkyl with 1 to 8 carbon atoms,

R2means hydrogen, aminosidine group, a linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by formyl or a linear or branched acyl with 1 to 6 carbon atoms, or phenyl or benzoyl, linear or branched acyl with 1 to 8 carbon atoms, benzoyl or a residue of the amino acid formula

< / BR>
where R9means hydrogen or cycloalkyl with 3 to 8 carbon atoms, a linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by a group of the formula-NR11R12or R13-OC-, where R11and R12independently from each other denote hydrogen, a linear or branched alkyl with 1 to 8 carbon atoms or phenyl, R13means of hydrosil, besikci, alkoxy with 1 to 6 carbon atoms is OSVETLENIE alkyl with 1 to 8 carbon atoms, possibly substituted by phenyl,

and their salts.

Under salts see, in particular, an acid additive salt. Preferred are physiologically tolerated salt.

To acids, forming salts, are preferably kaleidotrope acid, such as hydrochloric acid and Hydrobromic acid, in particular hydrochloric acid, then phosphoric acid, nitric acid, sulfuric acid, mono - and bifunctional carboxylic acids and hydroxycarbonate acid, such as acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic, lactic acid, and sulphonic acids, such as p-toluensulfonate, 1,5-naphthalenedisulfonate or camphorsulfonate.

Protective groups in the framework of the present invention are generally used in peptide chemistry remains.

These include benzyloxycarbonyl, 3,4-dimethoxybenzophenone, 3,5-dimethoxybenzoquinone, 2,4-dimethoxybenzoquinone, 4-methoxybenzenesulfonyl, 4-nitrobenzyloxy the pet-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzenesulfonyl, 3,4,5-trimethoxybenzylamine, phthaloyl, 2,2,2-trichlorocyanuric, 2,2,2-trichloro-tert. butoxycarbonyl, methyloxycarbonyl, 4-nitrophenoxyacetic, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-TRIFLUOROACETYL, 2,2,2-trichloroacetyl, benzoyl, benzyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimidopropyl, isovaleryl or benzyloxyphenyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl or 2-nitrophenyloctyl.

The proposed connection can exist in stereoisomeric forms, which are available as image and mirror image (enantiomers) or are not available as image and mirror image (diastereomers), preferably as a mixture of diastereoisomers or in the form of pure CIS - or TRANS-isomers. The invention relates also to the antipodes, racemates, mixtures of diastereomers, as well as pure isomers. Racemate forms, like the diastereomers, can be divided in a known manner on pure stereoisomeric components. The separation of the pure stereoisomers carried out, for example, by chromatographic racemate splitting of the diastereomeric ester is>Preferred are compounds of General formula (I),

where A, B, D, E, G, L, M and T are identical or different and denote hydrogen, halogen, hydroxyl or linear or branched alkyl with 1 to 6 carbon atoms which may be substituted with halogen, hydroxyl, benzyloxy or a group of the formula-NR4R5where R4and R5the same or different and mean hydrogen or a linear or branched alkyl with 1 to 4 carbon atoms, and at least one of the above substituents A, B, D, E, G, L, M, and T does not mean hydrogen,

or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
where R6and R7the same or different and mean hydrogen, fluorine, chlorine, bromine, linear or branched alkyl with 1 to 6 carbon atoms, benzyl or phenyl, or E and G or B and D together denote a residue =0,

R1means hydrogen or a linear or branched alkyl with 1 to 6 carbon atoms,

R2means hydrogen, tert.butoxycarbonyl, benzyl, 9-fluorenylmethoxycarbonyl, linear or branched alkyl with 1 to 6 carbon atoms which may be substituted by formyl, linear or branched acyl with 1 to 4 carbon atoms, phenyl or benzyl, linear or rasvet hydrogen, linear or branched alkyl with 1 to 6 carbon atoms, R10means hydrogen, tert.butoxycarbonyl, fluorenyl-9-methoxycarbonyl,

R3means hydrogen, a linear or branched alkyl with 1 to 6 carbon atoms or benzyl,

and their salts.

Especially preferred are the compounds of formula (I),

where A, B, D, E, G, L, M and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, hydroxyl or linear or branched alkyl with 1 to 4 carbon atoms which may be substituted by hydroxyl or benzyloxy,

moreover, at least one of the above substituents does not mean hydrogen,

or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
where R6and R7the same or different and mean hydrogen, fluorine, chlorine, bromine, linear or branched alkyl with 1 to 4 carbon atoms, or phenyl, or E and G, or B and D, respectively, together mean residue =0,

R1means hydrogen or a linear or branched alkyl with 1 to 4 carbon atoms,

R2means hydrogen, benzyl, tert.butoxycarbonyl, 9-fluorenylmethoxycarbonyl, linear or branched alkyl with 1 to 4 carbon atoms, linear or branched acyl with 1 to 4 avitsenny alkyl with 1 to 4 carbon atoms, R10means hydrogen, tert.butoxycarbonyl or 9-fluorenylmethoxycarbonyl,

R3means hydrogen or a linear or branched alkyl with 1 to 4 carbon atoms,

and their salts.

The new compounds of General formula (I) can be obtained by ways of peers, for example in the following ways:

a) compounds of General formula (II)

< / BR>
where A, B, D, L, M and T have the above significance, is transferred in an organic solvent, preferably dioxane, at first with (C1-C3)-trialkylsilyl, then with ether, in the presence of water in the compounds of General formula (III)

< / BR>
where A, B, D, L, M and T have the above meaning, and in the next stage with the help of acid, preferably hydrochloric acid, is transferred with the opening of the ring in the compounds of General formula (Ia)

< / BR>
where A, B, D, L, M and T have the abovementioned meaning,

followed by separation, if necessary, an acid, preferably hydrochloric acid, or

b) compounds of General formula (IV)

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where A, B, D, E, L, M and T have the above meaning, interaction with chlorosulfonylisocyanate translated first into compounds of General formula (V)

< / BR>
where A, B, D, E, L, M and T have the above knowledge is new and carboxyl function, or

C) compounds of General formula (VI)

< / BR>
where B, D, E, G, L, M and T have the above significance and R15means1-C4-alkyl,

interaction with amines of General formula (VII)

H2N-R16(VII)

where R16means benzyl which may be substituted with halogen, a nitro-group, a cyano or alkyl containing up to 4 carbon atoms, or a residue of formula-CH(C6H4-nOCH3)2translate in an organic solvent, optionally in the presence of a base in compounds of General formula (VIII)

< / BR>
where B, D, E, G, L, M, R15and R16have the above meaning,

and then double hydrogenation of first restore the double bond, then release aminophenol and in the last operation omelet acid ester of carboxylic acid, and receive derivative Vice-a - T, if necessary, with the preliminary blocking AMINOPHENYL processing of the protective groups by conventional methods, for example by oxidation, repair or alkylation, and in the case of acid omelet ester by conventional means, and in the case of pure enantiomers spend the splitting of the racemate.

The methods can be explained by the following schema:

The
Ernie organic solvents, do not change under the reaction conditions. These include alcohols, such as methanol, ethanol, propanol, isopropanol, ethers, such as, for example, a simple diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran, onomatology and dimethyl ethers of glycol, halogenated hydrocarbons like chloroform or methylene chloride, or amides, such as dimethylformamide, dimethylacetamide or triamide hexamethylphosphoric acid or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine. Preferred are diisopropyl ether, diethyl ether, dioxane, methanol, ethanol and dichloromethane.

The reaction temperature varies in a wide range. Primarily operate at temperatures from -78oC to +150oC, preferably from -10oC to +100oC.

The interaction is carried out at normal pressure but also at elevated or reduced pressure (for example 0.5 to 80 bar). Mostly working at normal pressure or at elevated pressures of from 3 to 80 bar.

When exercising the options method a), b) and C) the ratio of participating in the reaction substances can be anything. Mostly working, however, with the molar ratios of the reagents. Isolation and purification from the received if necessary, after cooling with ice, the crystalline residue is recrystallized from a suitable solvent. In some cases it may be necessary compounds obtained clear chromatography.

As a suitable oxidant, such as hydrogen peroxide, periodate sodium, nagkalat as m-chloroperbenzoic acid, or potassium permanganate. Preferred is hydrogen peroxide, m-chloroperbenzoic acid and periodate sodium.

As grounds suitable organic amines (trialkyl(C1-C6)amines) such as triethylamine, or heterocycles as pyridine, methylpiperidine, piperidine or morpholine. Preferred is triethylamine.

As acids for the disclosure of the rings (V) suitable mainly mineral acid. Preferred are hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid or mixtures of the aforementioned acids. Preferred is hydrochloric acid.

As acids for release (III) fit1-C6-carboxylic acids, for example acetic or propionic. Preferred is acetic acid.

The acid used is(V).

Saponification of ester of carboxylic acid is conducted in the usual ways, treating the ester in an inert organic solvent of conventional bases, and the resulting first salt may be converted by treatment with acid into the free carboxylic acid.

Saponification of esters of carboxylic acids can be carried out with one of the above acids.

As a basis you can use commonly used for the saponification of inorganic bases. Preferably use a hydroxide of an alkaline or alkaline-earth metals, such as sodium hydroxide, potassium or barium, or carbonates of alkali metals, such as sodium carbonate or potassium, or sodium bicarbonate, or an alcoholate, such as methylate or sodium ethylate, methylate or ethylate or potassium tert.butyl potassium. Particularly preferable to use sodium hydroxide or potassium.

As the solvent when the saponification is possible to use water or organic solvents normally used for saponification. It is preferable to use alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, ethers, such as tetrahydrofuran or dioxane, dimethylformamide or demopanel. It is also possible to use mixtures of these solvents.

Generally, the saponification is carried out at a temperature from 0oC to +100oC, preferably from +20oC to +80oC.

Usually saponification carried out under atmospheric pressure. However, it is also possible to carry it out under increased or reduced pressure, for example under a pressure of from 0.5 to 5 bar.

When carrying out the saponification of the base or the acid is usually used in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol based on 1 mol of ester. Particularly preferably, use molar quantities of the reactants.

If the reaction is first receive offer salt compounds as intermediates, which can be distinguished. The offered acid is produced by processing carboxylates usual inorganic acids. To them, preferably belong mineral acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid or phosphoric acid. When obtaining carboxylic acids suitable turned out to be the acidification of the primary saponification reaction mixture in the second stage without allocation of carboxylates. Sutent simply be obtained by conventional means, for example, by dissolving the compounds of formula (I) in a suitable solvent and adding the acid, for example hydrochloric, selected in a known manner, for example by filtration, and optionally purified by washing inert organic solvent.

Cleavage aminosidine groups takes place in a known manner.

Translation of double bonds in a carbonyl function is by ozonolysis and restore ozonide reducing agent, for example dimethylsulfoxide, zinc or (C1-C3-trialkylphosphines.

Recovery alkoxycarbonyl compounds or aldehydes to the corresponding alcohols is usually carried out with hydrides, such as sodium borohydride or potassium, preferably sodium borohydride, in an inert solvent, such as ethers, hydrocarbons or alcohols or their mixtures, preferably in environment, ethers, as for example diethyl ether, tetrahydrofuran or dioxane, or alcohols, such as ethanol, in the case of aldehydes, preferably with sodium borohydride in ethanol at a temperature of 0oC - 150oWith, preferably 20 - 100oC, at atmospheric pressure.

Vvedenie or allseeingeye connection preferably with 2-nitrophenylhydrazine and tri-n-butylphosphine and subsequent removal of the waste groups, foundations, preferably one of the above organic atoms, or the removal of selegiline groups by oxidation, preferably hydrogen peroxide in a mixture of water and tetrahydrofuran.

As solvents for the alkylation fit all common organic solvents, which does not change under the reaction conditions. To them, preferably belong ethers like diethyl ether, dioxane, tetrahydrofuran, glycolytically ether, or hydrocarbons, such as, for example, benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons, such as, for example, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or complex ethyl ester acetic acid, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, amide hexamethylphosphoric acid, acetonitrile, acetone or nitromethane. In addition, it is also possible to use mixtures of the mentioned solvents. Preferably using dichloromethane.

The alkylation is carried out in the abovementioned solvents at temperatures from 0oC to +150oC, preferably at room temperature to +100oSince, under normal pressure.

Hydrogenation (in the as alcohols, for example methanol, ethanol or propanol, in the presence as catalyst of rare metal such as platinum, platinum on charcoal, palladium, palladium on animal coal or Raney Nickel, in the case of the double bond of compounds of General formula (VIII) is preferred hydrogenation with hydrogen with platinum or palladium.

As the catalyst used mainly acid. These include preferably an inorganic acid, for example hydrochloric or sulphuric acid, or organic sulfo or carboxylic acids, such as methanesulfonate, econsultation, benzosulfimide, toluensulfonate, acetic or propionic acid.

The hydrogenation is carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar).

Catalysts and bases are mainly used in quantities of 0 to 10 mol, preferably 1.5 to 3.5 mol based on 1 mol of the compounds of General formulas (IV), (V), (VI) or (VIII).

The acid is generally used in amounts of 2 to 30 mol, preferably 5 to 15 mol based on 1 mol of the compounds of General formulas (IV), (V), (VI) or (VIII).

Compounds of General formula (II) for the most part are new and can be obtained, for example, the fact that soedinivshee dicarboxylic acid first alkaline saponification, preferably lithium hydroxide in water in one of the abovementioned solvents, preferably tetrahydrofuran, followed by treatment of the anhydride propionic acid.

Compounds of General formula (IX) are known or can be obtained by known methods (see H. J. Gais, J. Org. Chem. 1989, 54, 5115).

Compounds of General formula (V) and (VIII) are new and can be obtained one of the above methods.

Compounds of General formula (IV) by themselves are known or can be obtained by known methods.

Compounds of General formula (VI) for the most part known or can be obtained are described in the literature (see Joc. 1983, 48, 5364; JACS, 1951, 73, 4286; JACS, 1978, 100, 6728).

Amines of General formula (VII) are known and can be obtained by known methods or are commercially available.

Compounds of General formula (Ia) are novel and can be obtained one of the above methods.

Pure enantiomers can be obtained from the racemate in that first block aminopentyl protecting group, preferably fluorenyl-9-methoxycarbonyl, then after interaction with chiral amines, such as phenethylamines or (-)-quinine, before the group, for example, with liquid ammonia.

This method can be explained by the following scheme:

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A further object of the invention is active against strains of S. aureus, Candida and Trichophyton composition containing the compound of the above General formula (I) or its salt in an effective amount and a pharmaceutically acceptable carrier.

Activity proposed composition is confirmed by the following experiments.

Experience AND

Logarithmically breeding a culture of S. aureus 133 diluted with physiological saline so that you can type mice by injection of 0.25 ml of 1 108the bacteria. Treatment of infected animals occurs after 0.5 and 3 hours after infection. Survival of mice was recorded until the 6th day after infection. The results of the experiment are shown in tables 1 and 2.

Connection example 32 shows compared to the untreated control in a dose-dependent therapeutic activity.

Were similarly obtained are shown in table 3 the results of the tests. When the compounds were given either subcutaneously (hereinafter PC), or orally (later on).

Experience B

Through experience with a gradient rasb braking (ICB), which compound of example N 32. While preparing a series of agar plates containing the active substance in a declining by double dilution concentrations. On agar plates using a Multipoint device (Denley) serves indicated in table 4 strains that were pre-diluted with obespechenie content of 104forming colonies of particles in each spot. The thus prepared agar tiles incubated at temperature 37oWith, and the growth of the strains determined after approximately 20 hours. The MKT value (kg/ml) is the minimum concentration of the active substance, in which the naked eye were observed growth. The results of the experiment are summarized in table 4.

Table 4

The minimum concentration of inhibition (μg/ml):

Strain - MKT connection example N 32 µg/ml

S. aureus 133 - 2

S. aureus 48N - <0,25
S. aureus 25701 - 0,5

The experience IN

Similarly, experience B determine the ICB connection example N 32 in mg/l against strains listed in table 5.

Table 5

Strain - MKT connection example N 32 mg/l

Candida albicans - 0,25

Candida krusei - 1,0

Candida tropicalis - 4,0

Candida glabrata - 0,4

Trichophyton mentagrophytes - <1

The active substance can be on one or more carriers or be in microencapsulated form.

The above pharmaceutical compositions may contain in addition to the compounds according to the invention also other pharmaceutical compounds.

Preparative forms can be obtained by adding to the active substance solvents and/or carriers, optionally using emulsifiers and/or dispersants, and using water as a diluent can be used organic solvents as auxiliary solvents.

The introduction of the drug occurs in the usual way, the actual injection can be used solutions of the active substance using a suitable liquid carrier.

Basically, to achieve the desired result is preferable to the introduction of the active substance in quantities of 0.5 to 500, preferably 5 to 100 mg/kg of body weight every 24 hours, optionally in the form of multiple doses. A single dose contains the active substance in quantities of 1 to 80, in particular 3 to 30 mg/kg body weight.

Usually is preferable to achieve effective results with intravenous dosage of 0.001 - 10 mg/kg, preferably 0.01 to 5 mg/kg, and in oral introduction dosage of 0.01 - 25 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

It is also possible deviations from these quantities, depending on the body weight or route of administration, the individual's relationship to the medication, dosage, time and frequency of administration of the drug. So, in some cases, are a sufficient amount less than the minimum, and in other cases more than the maximum amounts. In the case of the introduction of large quantities is appropriate reusable dosage during the day.

The following examples illustrate how to obtain the source and intermediate compounds for the production of the final products of the formula (I).

Example I

1,2-CIS-4-methylene-cyclopentane-1,2-dicarba,0 g; 84 mmol) in 100 ml of tetrahydrofuran was added dropwise at 0oWith the solution of hydrate of lithium hydroxide (7,8 g, 185 mmol) in 150 ml of water. The resulting solution was stirred for 20 hours at room temperature, removed in vacuum tetrahydrofuran and the residue is extracted with 40 ml of ethyl ether. Adjusted with 10% hydrochloric acid aqueous phase to pH 2 and extracted three times with 200 ml of ether acetic acid. The combined ether phases are dried over sodium sulfate and the solvent is removed in vacuum.

Output: 13,4 g (93% of theory)

So pl.: 116 - 120oWITH

C8H10O4(M. C. 170,2)

Example II

Anhydride 1,2-CIS-4-methylene-cyclopentane-1,2-dicarboxylic acid

< / BR>
A solution of the compound from example I (13,0 g; a 76.5 mmol) in 65 ml of propionic anhydride acid is boiled for 3 hours under reflux. The solvent is removed at 60oWith/of 0.5 Torr and the residue is distilled.

Yield: 10.0 g (86% of theory)

So Kip.: 130 - 140oC/0.1 Torr

So pl.: 47 - 49oWITH

C8H8O3(M. C. 152,1)

Example III

6-methylene-cyclopentane[3,4-d]oxazin-2,4-(1H)-dione

< / BR>
A solution of the compound from example II (8.8 g, 58 mmol) and trimethylsilane (7.9 g, 69 mmol) in 60 ml of heated 2 hours at 80oC. the Solvent prowess is ut and incubated for 2 days at 6oC. the Precipitated product is filtered and washed with diethyl ether.

Output: 4.2V g (43% of theory)

So pl.: 145oC (decomp.)

C8H9NO3(M. C. of 167.2)

Example IV

Methyl ether 1,2-CIS-2-N-(tert. butyloxycarbonyl)-amino-4-(2-nitrophenyl)-seleny-cyclopentane-carboxylic acid

< / BR>
A solution of the compound from example 63 (3,30 g; 12.7 mmol) in 50 ml of tetrahydrofuran is mixed in argon with 2-nitrophenylhydrazine (of 3.46 g, and 15.2 mmol) and then with tri-n-butylphosphine (is 3.08 g, and 15.2 mmol). The mixture is stirred for 1 hour at room temperature, the solvent is removed in vacuo and the residue chromatographic on silica gel (eluent mixture of ether and petroleum ether 2 : 1).

Output: 4,45 g (79% of theory)

The ratio of diastereomers D1: D2= 3 : 1

Rf= 0.28 and 0.39 to (ether/petroleum ether 2 : 1)

C18H24N2O6Se (M. C. 443,4)

General description of the methyl esters of 2-benzylamino-cyclopent-1-ene-carboxylic acid

< / BR>
A solution of substituted methyl ether, 2-hydroxy-cyclopentane-carboxylic acid (160 mmol) and benzylamine (34,2 g, 320 mmol) in 540 ml of dichloromethane is mixed with n-toluensulfonate and 108 g of molecular sieves (4A) and heated 24 hours before matography on silica gel.

Example V

Methyl ester 2-benzylamino-4,4-dimethyl-cyclopent-1-ene-carboxylic acid

< / BR>
Similar to the above recipe get the target connection.

Output: 30.0 g (72% of theory)

Rf= 0,49 (petroleum ether/ether acetic acid 3 : 1)

C16H21NO3(M. C. 259,3)

Example VI

Methyl ester 2-benzylamino-5-methyl-cyclopent-1-ene-carboxylic acid

< / BR>
Similar to the above recipe get the target connection.

Output: 27.9 g (71% of theory)

Rf= 0,42 (ether/petroleum ether 5 : 1)

C15H19NO2(M. C. 245,3)

Example VII

Methyl ester 2-benzylamino-3-methyl-cyclopent-1-ene-carboxylic acid

< / BR>
Similarly to the above registration get the target connection.

Output: 20,0 g (51% of theory)

Rf= 0,45 (ether/petroleum ether 5 : 1)

C15H19NO2(M. C. 245,3)

Example VIII

Diethyl ether 4-ethylidene-cyclopentane-1,2-dicarboxylic acid

< / BR>
To a solution of tert.butanolate potassium (24,8; 220 mmol) in 1000 ml of diethyl ether is added at room temperature in argon ethyl-triphenylphosphonium (100 g, 270 mmol) and stirred for 20 hours at room temper) in 120 ml of diethyl ether and stirred for 1 hour at 0oC. is Mixed with 300 ml of water, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and removed in vacuo solvent. The remainder chromatographic on silica gel (petroleum ether/ether 2 : 1).

Yield: 13.1 g (79% of theory) of a mixture of CIS/TRANS diastereomers.

1H-NMR (date. chloroform): b = 1,23 (t, 6N), was 1.58 (m, 3H), of 2.3 to 2.6 (m, 4H), 3,0 - up 3.22 (m, 2H), 4,17 (kV, 4H), 5,35 (cm, 1H)

WITH13H20O4< / BR>
Example IX

4-ethylidene-cyclopentane-1,2-dicarboxylic acid

< / BR>
To a solution of the compound from example VIII (13,1 g; of 54.5 mmol) in 70 ml of tetrahydrofuran was added dropwise at 0oWith the solution of hydrate of lithium hydroxide (51,1 g; 120 mmol) in 130 ml of water. The solution is stirred for 20 hours at room temperature, removed in vacuum tetrahydrofuran and the residue is extracted once with 40 ml of ether. The aqueous phase was adjusted to 10% hydrochloric acid to pH 2 and extracted three times with 200 ml of ether acetic acid. The combined acetic ester phases are dried over sodium sulfate and the solvent is removed in vacuum.

Yield: 9.0 g (90% of theory) of a mixture of diastereomers

So pl.: 170oWITH

WITH9H12O4(M. C. 184,2)

Example X

Anhydride 1,2-CIS-4-ethylidene-the Cyclops is about acid is boiled for 3 hours under reflux. The solvent is removed at 60oWith/of 0.5 Torr and the residue is distilled.

Yield: 2.0 g (27% of theory)

So pl.: 150oC/0.1 Torr (redistilled in a ball tube)

WITH9H18O2(M. C. to 166.2)

Example XI

6-ethylidene-cyclopentane[3,4-d]oxazin-2,4-(1H)-dione

< / BR>
A solution of the compound from example X (2.0 g; to 12.0 mmol) and trimethylsilane (1.66 g; 14.4 mmol) in 12 ml of dioxane is heated for 2 hours at 80oC. the Solvent is removed in vacuo, the residue contribute in 13 ml of ether and mixed with water (0,22 g; 12 mmol). The mixture is intensively stirred for 5 minutes and incubated for 3 hours with a 6oC. the Precipitated product is filtered and washed with ether.

Output: 0,48 g (22% of theory) diastereoisomeric mix

So pl.: > 250oC (decomp.)

WITH9H11NO3(M. C. 181,2)

Example XII

Diethyl ether 4-benzylidene-cyclopentane-1,2-dicarboxylic acid

< / BR>
To a solution of tert. butanolate potassium (22,0 g, 196 mmol) in 1200 ml of diethyl ether is added at room temperature in argon chloride benzyl-triphenylphosphane (95,4 g, 245 mmol) and stirred for 4 hours at room temperature. In conclusion, was added dropwise a solution of diethyl ether 4-Cyclopentanone-1,2-dicarboxylic acid (14.0 g; 61,3 mmol) at 0o

Yield: 15.9 g (86% of theory) of CIS/TRANS-isomers

Rf= 0,37; of 0.43 (petroleum ether/ether 5 : 1)

1H-NMR (date. chloroform) : = 1,25 (2m, 6H), 2,70 - to 3.35 (m, 6N), 4,17 (square, 4H), 6,38 (cm, 1H), 7,12 - 7,40 (m, 5H)

WITH18H22O4(M. C. 302,37)

Example XIII

4 benzyliden-cyclopent-1,2-dicarboxylic acid

< / BR>
The target connection receive analogously to example IX.

Yield: 12.8 g (100%)

So pl.: 172oWITH

WITH14H14O4(M. C. 246,26)

Example XIV

Diethyl ether 1,2-CIS-4-deformation-cyclopentane-1,2-dicarboxylic acid

< / BR>
To a solution of diethyl ether 1,2-CIS-4-Cyclopentanone-1,2-dicarboxylic acid (20,0 g; of 87.6 mmol) and dibromodifluoromethane cases (36.8 g, 175 mmol) in tetrahydrofuran (400 ml) was added dropwise at 0oWith argon for 30 min Tris-(dimethylamino)-phosphine (57,1 g, 350 mmol). Slowly warmed to room temperature and stirred for another hour at this temperature. Mixed with triethylamine (17.6 g; 175 mmol) and stirred for 15 hours at room temperature. After adding 500 ml of water the reaction mixture is extracted with diethyl ether (3 x 500 ml) and the combined organic phases are washed with saturated sodium chloride solution (2 x 300 ml), dried over sodium sulfate and thicken the 3 g (27% of theory)

1H-NMR (date. chloroform) : = of 1.28 (t, 6H), 2,55 - 2,90 (4H), 3,17 (dt. , 2H), 4,17 (square, 4H)

WITH12H16F2O4(M. C. 262,4)

Example XV

1,2-CIS-4-deformation-cyclopentane-1,2-dicarboxylic acid

< / BR>
The target connection receive analogously to example IX.

Output: 3,86 g (85% of theory)

So pl.: 147 - 149oWITH

WITH8H8F2O4(M. C. 206,1)

Example XVI

Anhydride 4-deformation-cyclopentane-1,2-dicarboxylic acid

< / BR>
The target connection receive analogously to example X.

Yield: 2.25 g (65% of theory)

So pl.: 140 - 145oWith/0,05 mbar (distillation with ball tube)

WITH8H6F2O3(M. C. 188,1)

Example XVII

6-deformation-cyclopentano[3,4-d]oxazin-2,4-(1H)-dione

< / BR>
The target connection receive analogously to example XI.

Yield: 1.40 g (59% of theory)

So pl.: 130oC (decomp.)

WITH8H7F2NO3(M. C. 203,1)

Example XVIII

Diethyl ether 4,4-debtor-cyclopentane-1,2-dicarboxylic acid

< / BR>
To a solution of diethyl ether 4-Cyclopentanone-1,2-dicarboxylic acid (to 6.43 g; of 28.2 mmol) in 100 ml of toluene was added dropwise at 0oWith diethylaminocoumarin sulfur (11,28 g; 70 mmol) and stirred for 5 draganescu phase over sodium sulfate and remove the solvent in vacuo. The remainder chromatographic on silica gel (petroleum ether/diethyl ether 1: 1).

Output: 3,79 g (56% of theory) diastereomeric mixture.

Rf= 0,65 (petroleum ether/diethyl ether 1 : 1)

1H-NMR (deiter. chloroform) : = 1,28 (t, 6N), 2,52 (cm, 4H), 3,29 (cm, 2H), 4,18 (kV, 4H)

WITH11H16O4F2(M. C. 250,2)

Example XIX

4,4-debtor-cyclopentane-1,2-dicarboxylic acid

< / BR>
The target connection receive analogously to example XI.

Output: 4,40 g (77% of theory)

So pl.: 128oWITH

WITH7H8O4F2(M. C. 194,1)

Example XX

Anhydride 4,4-debtor-cyclopentane-1,2-dicarboxylic acid

< / BR>
The target connection receive analogously to example X.

Output: 2,90 g (75% of theory)

So Kip.: 150oC/0,15 mbar (distillation in a ball tube)

WITH7H6F2O3(M. C. 176,12)

Example XXI

6,6-debtor-cyclopentano[3,4-d]oxazin-2,4-(1H)-dione

< / BR>
The target connection receive analogously to example XI.

Output: 2,33 g (74% of theory)

So pl.: 116oC (decomp.)

WITH7H7F2NO3(M. C. 191,1)

Example XXII

Ethyl ester-3-benzoyloxymethyl-cyclopentane-2-one-1-carboxylic acid

< / BR>
It races the thief 2-benzoyloxymethyl-cyclopentane-2-it (23,5 g; 115 mmol) in 100 ml of tetrahydrofuran and stirred for 30 min at -78oC and 10 min at -40oC. At -78oC was added dropwise 1,3-dimethylether-2-(1H)-pyrimidone (14,7 g, 115 mmol) was added dropwise and then the resulting solution at -78oC to the solution of the ethyl ether of zanarini acid (22,8 g, 230 mmol). After 10 minutes pour the reaction mixture into 200 ml of water, is removed in vacuum tetrahydrofuran and contribute the remainder in 1100 ml of diethyl ether. The organic phase is washed with water (3 x 10 ml), dried over sodium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (petroleum ether/diethyl ether 2 : 1).

Output: 19.3 g (61% of theory)

Rf=0,34 (petroleum ether/diethyl ether 2 : 1)

WITH16H20O4(M. C. 276,3)

Example XXIII

Ethyl ester-2-benzylamino-3-benzoyloxymethyl-cyclopent-1-ene-1-carboxylic acid

< / BR>
Ph =phenyl

The target connection receive analogously to example V according to the connection example XXII.

Yield: 14.2 g (54% of theory)

Rf=0,62 (petroleum ether/diethyl ether 2 : 1)

WITH24H27NO3(M. C. 377,48)

The following examples illustrate how to obtain the final products of the formula (I).

Example 1

The hydrochloride of ethyl EFI; with 23.3 mmol) in 48 ml of ethanol was added dropwise acetylchloride (3,01 g, 38.4 mmol). The solution is stirred for 20 hours at room temperature

Output: 4,79 g (100%)

Rf=0,48 (ether: acetonitrile: conc. ammonia 10 : 1: 0,1)

WITH9H15NO2x HCI (M. C. 169,2 x 36,5)

Example 2

Hydrochloride 1,2-CIS-2-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example III (0,500 g; 3.00 mmol) in 30 ml of 0.1 N. malaney acid is stirred for 4 hours at room temperature. The solvent is removed in vacuum at 30oC and the residue is dried for 12 hours at 30oC/0.1 Torr.

Output: 0,513 g (96% of theory)

So pl.: 190oC

WITH7H11NO3x HCI (M. C. 141,2 x 36,5)

Example 3

Ethyl ester of 1,2-CIS-2-N-(tert. butyloxycarbonyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
A solution of compound of example 1 (15,4 g; 75,0 mmol) and triethylamine (22,8 g, 225 mmol) in 225 ml of dichloromethane is mixed at 0oC with di-tert.BUTYLCARBAMATE (24.8 g; 112 mmol) and stirred for 4 hours at room temperature. The solvent is removed in vacuo and the residue chromatographic on silica gel (ether/petroleum ether 1 : 3).

Yield: 18.0 g (91% of theory)

Rf=0,29 (ether/petroleum ether 1 : 3)

the-4-oxocyclopent-1-carboxylic acid

< / BR>
VOS=butyloxycarbonyl

Through a solution of the compound from example 3 (18.0 g; 67,0 mmol) passed at -70oC ozone until a blue coloration and in conclusion, oxygen until the discoloration. Mixed with dimethyl sulfide (24.8 g; 0.40 mmol), warmed to room temperature and stirred at this temperature for another 2 hours. The solvent is removed in vacuum, the residue is stirred with diisopropyl ether, filterout and washed with diethyl ether.

Output: 15,1 g (83% of theory)

So pl.: 132oC

WITH13H21NO5(M. C. 271,3)

Example 5

Hydrochloride ethyl ester 1,2-CIS-2-amino-4-oxo-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 4 (0,980 g; of 3.60 mmol) in 5 ml of 4 N. hydrochloric acid in a solution of dioxane is stirred for 3 hours at room temperature. The solvent is removed in vacuum and the residue is dried for 20 hours at 50oC/0.1 Torr.

Output: 0,734 g (98% of theory)

1H-NMR (deiter. dimethyl sulfoxide): / =1,24 (t, J=7 Hz, 3H); 2,14 is 2.80 (m,4H); 3,49-3,62 (m,1H); as 4.02-to 4.28 (m,3H); 8,53 (s,W, 3N)

WITH8H13NO3x HCI ( M. C. 171,2 x 36,5)

Example 6

Hydrochloride 1,2-CIS-2-amino-4-oxo-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 5 (0,500 g; 2,41 is 20 hours at 50oC/0.1 Torr.

Output: 0,432 g (100%)

1H-NMR (deiter. dimethyl sulfoxide): =2,42 was 2.76 (m,4H); 3.42 points of 3.56 (m, 1H); 4,08 (s,W, 1H); to 8.45 (s,W, 3N)

WITH6H9NO3x HCI (M. C. 141,3 x 36,5)

Example 7

Ethyl ester of 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-hydroxy-cyclopentane-1-carboxylic acid

< / BR>
Vos=butyloxycarbonyl

A solution of the compound from example 6 (5,00 g; 18.5 mmol) in 150 ml of methanol is mixed with 5oC with sodium borohydride (0,345 g; 9.0 mmol) and 1 hour and stirred at room temperature. The solvent is removed in vacuo, the residue absorb water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and removed in vacuo solvent.

Yield: 4.9 g (97% of theory)

The ratio of diastereomers D1: D2= 3 : 1

Rf=0.42 and 0,48 (broadcast)

WITH13H23NO5(M. C. 273,3)

Example 8

Hydrochloride ethyl ester 1,2-CIS-2-amino-4-hydroxy-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 7 (1.10 g; 4.0 mmol) in 6 ml of 4 N. hydrochloric acid in dioxane is stirred for 1 hour at room temperature. The solvent is removed in vacuum and the residue is dried for 20 hours at 50oC/0.1 Torr.

Output: 0,82 g (97% of theory)
NO3x HCI (M. C. 173,2 x 36,5)

Example 9

Hydrochloride 1,2-CIS-2-amino-4-hydroxy-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 8 (210 mg; 1.0 mmol) in 13 ml of 3 N. hydrochloric acid is stirred for 2 hours at 80oC. the Solvent is removed in vacuum and the residue is dried for 20 hours at 50oC/0.1 Torr.

Yield: 151 mg (83% of theory)

The ratio of diastereomers D1: D2= 3 : 1

Mass spectrum (Sep.from.): m/z =146 (M+H)

WITH16H11NO3x HCI (M. C. 145, 2mm x 36,5)

Example 10

Methyl ether 1,2-CIS-2-benzylamino-4,4-dimethylcyclopentene-1-carboxylic acid

< / BR>
A solution of the compound from example VI (8,15 mmol) in 70 ml of ethanol is mixed with 1 g of platinum (5% on charcoal ) and hydronaut hydrogen for 20 hours at 35oC and a pressure of 80 bar. The catalyst is filtered off, the residue chromatographic, the filtrate is concentrated in vacuo and the residue chromatographic on silica gel.

Output: 2,13 g (51% of theory)

Rf=0,49 (acetic ester/petroleum ether 1 : 2)

WITH16H23NO2(M. C. 261,3)

Example 11

Methyl ether 1,2-CIS-2-benzylamino-5-methyl-cyclopentane-1-carboxylic acid

< / BR>
Analogously to example 10 to obtain the target compound.

The output on the SUB> =0,59 g (29%)

Rf=0,34 (acetic ester/petroleum ether 1 : 2)

WITH15H21NO2(M. C. 247,34)

Example 12

Methyl ether 1,2-CIS-2-benzylamino-3-methyl-cyclopentane-1-carboxylic acid

< / BR>
Analogously to example 10 to obtain the target compound.

Output: 1,41 g (71% of theory)

The diastereomers D1: D2= 4 : 1

Rf=0,49 and 0.31 (acetic ester/petroleum ether 1 : 4 )

WITH15H21NO2(M. C. 247,34)

Example 13

Hydrochloride methyl ester 1,2-CIS-2-amino-4,4-dimethyl-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 10 (of 7.70 mmol) in 77 ml of 0.1 G. of hydrochloric acid (of 7.70 mmol), 80 ml of water and 110 ml of ethanol is mixed with 710 mg of palladium (10% on charcoal) and hydronaut hydrogen for 20 hours at room temperature and 3 bar. The catalyst is filtered off, the filtrate is concentrated in vacuum and the residue is dried for 12 hours at 50oC/0.1 Torr.

Yield: 1.52 g (95% of theory)

So pl.: 148oC

WITH9H17NO2x HCI ( M. C. 171,2 x 36,5)

Example 14

Hydrochloride methyl ester 1,2-CIS-2-amino-5-methyl-cyclopentane-1-carboxylic acid

< / BR>
Analogously to example 10 to obtain the target compound.

Output: diastereoisomer A: 1,43 g ( M century 157,2 x 36,5)

Example 15

Hydrochloride methyl ester 1,2-CIS-2-amino-3-methyl-cyclopentane-1-carboxylic acid

< / BR>
Analogously to example 10 to obtain the target compound.

Yield: 1.50 g (100%)

2 diastereoisomer D1: D2= 4 : 1 .

Rf=0,45 (ether/acetonitrile/conc. ammonia 10 : 1 : 0,1)

WITH8H15NO2x HCI (M. C. 157,2 x 36,5)

Example 16

Hydrochloride 1,2-CIS-2-amino-4,4-dimethyl-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 13 (4.20 mmol) in 70 ml of 3 N. hydrochloric acid is refluxed for 2 hours. The solvent is removed in vacuum, the residue is washed with tetrahydrofuran and dried for 20 hours at 50oC/0.1 Torr.

Output: 0,81 g (100%)

So pl.: 190oC (decomp.)

WITH8H15NO2x HCI (M. C. 157,2 x 36,5)

Example 17A and 17B

Hydrochloride 1,2-CIS-2-amino-5-methyl-cyclopentane-1-carboxylic acid

< / BR>
Analogously to example 16 to obtain the target compound.

Output: diastereoisomer A: 0,61 g (81% of theory) (example 17A)

So pl.: 134oC

the diastereoisomer In: 0.73 g (97% of theory) (example 17B)

So pl.: 200oC (decomp.)

WITH7H13NO2x HCI (M. C. 143,2 x 36,5)

Example 18

Hydrochloride 1,2-CIS-2-amino-3-m

Yield: 0.68 g (90%)

The ratio of diastereomers D1: D2= 4 : 1

So pl.: 206oC .

WITH7H13NO2x HCI (M. C. 143,2 x 36,5)

Example 19

Hydrochloride 1,2-CIS-2-amino-2-methyl-cyclopentane-1-carboxylic acid

< / BR>
15 g (0.12 mol) of 2-methyl-6-azabicyclo[3,2,0]heptane-7-it portions are suspended in 100 ml of concentrated hydrochloric acid and stirred suspension until the enlightenment when 40oC. the Solution is extracted with diethyl ether and thicken the aqueous phase to dryness. After drying in high vacuum obtain 20.7 g (96%) of a white solid.

So pl.: 194oC

WITH7H13NO2x HCI (M. C. 143 x 36,5)

Example 20

1,2-CIS-2-amino-4-methyl-cyclopentane-1-carboxylic acid

< / BR>
3 g (0,024 mol) of 4-methyl-6-azabicyclo[3,2,0] heptane-7-move it together with 15 ml conc. solar acid for 2 hours at room temperature. After removal of the ether is condensed to dryness. The residue is dried at 40oC in high vacuum.

Yield: 2.9 g (67% of theory)

So pl.: 188,5oC

WITH7H13NO2x HCI (M. C. 143 x 36,5)

Example 21

1,2-CIS-2-N-(9-fluorenylmethoxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of the compound from example 2 (methoxycarbonylamino)-succinimide (0,995 g; 2,95 mmol) in 10 ml of dioxane. The mixture is stirred for 12 hours at room temperature and extracted three times with ether and 10 ml. of the Aqueous phase at 0oC lead conc. hydrochloric acid to pH 2 and extracted twice with ether to 40 ml. of the Ether phase is dried over sodium sulfate and removed in vacuo solvent.

Output: 0,940 g (92% of theory)

So pl.: 137oC

WITH22H21NO4x HCI (M. C. 363,4)

Example 22 and Example 23

1,2-CIS-2-N-(9-fluorenylmethoxycarbonyl)amino-4-methyl-cyclopent-3-ene-1-carboxylic acid (example 22)

< / BR>
1,2-CIS-2-N-(9-fluorenylmethoxycarbonyl)amino-4-methyl-cyclopent-4-ene-1-carboxylic acid (example 23)

< / BR>
A solution of the compound from example 2 (0,870 g; 4,90 mmol) in 20 ml of 10% hydrochloric acid is stirred for 20 hours at room temperature and then evaporated in vacuum. The residue is dissolved in 25 ml of 10% sodium carbonate solution and mixed at 0oC with a solution of N-(9-fluorenylmethoxycarbonyloxy)-succinimide (1,65 g, 4.30 mmol) in 15 ml of dioxane. Stirred for 48 hours at room temperature, add 50 ml of water and twice extracted with ether and 20 ml At 0oC set the pH of the aqueous phase equal to 2 and extracted twice with ether, 50 ml. of the Ether phase is dried over sulfate n CLASS="ptx2">

Output: 0,211 g (12%) (example 22)

Rf=0,31 (methylene chloride/methanol 20 : 1) (example 22)

Output: 0.187 g (11%) (example 23)

Rf=0,28 (methylene chloride/methanol 20 : 1) (example 23)

WITH22H21NO4x HCI (M. C. 363,4)

Example 24

1,2-CIS-2-amino-4-methyl-cyclopent-4-ene-1-carboxylic acid

< / BR>
A solution of the compound from example 2 (0,870 g; 4,90 mmol) in 20 ml of 10% hydrochloric acid is stirred for 20 hours at room temperature and then evaporated in vacuum. The residue is dissolved in 8 ml of ethanol, mixed with 15 ml of ether and incubated for 5 days at 0oC. the Precipitated product is filtered and washed with ether.

Output: 0,246 g (28% of theory)

So pl.: 196oC

WITH7H11NO2x HCI (M. C. 141,2 x 36,5)

Example 25

1,2-CIS-2-amino-4-methyl-cyclopent-4-ene-1-carboxylic acid

< / BR>
A solution of the compound from example 23 (0,380 g; 1.05 mmol) in 30 ml of liquid ammonia is stirred for 10 hours. The ammonia is evaporated, mixed with 50 ml of ether, stirred for 1 hour at room temperature, filtered and washed the residue with 20 ml of ether. The rest bring in 5 ml of water and stirred for 10 min. Filtered, washed with 3 ml of water and the filtrate concentrated in vacuum. The residue is recrystallized from 80% aqueous ethanol.

Output: 0,082-2-amino-4-methyl-cyclopent-3-ene-1-carboxylic acid

< / BR>
A solution of the compound from example 22 (0,410 g; 1.13 mmol) in 30 ml of liquid ammonia is stirred for 10 hours. The ammonia is evaporated, mixed with 50 ml of ether, stirred for 1 hour at room temperature, filtered and washed the residue with 20 ml of ether. The rest bring in 5 ml of water and stirred for 10 minutes. Filtered, washed with 3 ml of water and the filtrate concentrated in vacuum. The residue is recrystallized from 80% aqueous ethanol.

Output: 0,112 g (70% of theory)

So pl.: 221oC

WITH7H11NO2(M. C. 141,2)

Example 27

Hydrochloride 1,2-CIS-2-amino-4-methyl-cyclopent-3-ene-1-carboxylic acid

< / BR>
Connection example 2 (0,110 g; 0.78 mmol) dissolved in 7,80 ml (0.78 mmol) of 0.1 N. hydrochloric acid. Then the solution is evaporated in vacuum.

Output: was 0.138 g (100% of theory)

So pl.: 188oC (decomp.)

WITH7H11NO2x HCI (M. C. 141,2 x 36,5)

Example 28

(R)-phenethylamine salt of (+)-1,2-CIS-2-(9-fluorenylmethoxycarbonyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 21 (10.0 g; 27.5 mmol) in 4.5 ml of tert. butyl methyl ether and 15 ml of ethanol is mixed with (R )-(+)-phenethylamine (3.33 g; 27.5 mmol). The mixture is refluxed and added dropwise to it about 80 ml of ethane is revival the crude product and washed with 20 ml of a mixture of tert.butyl methyl ether with ethanol 3 : 1. The crude product is then recrystallized from 30 ml of tert.butyl methyl ether and 70 ml of ethanol.

Output: 3,49 g (26% of theory)

So pl.: 163oC (decomp.)

[]2D0=+17,1 (C=1, methanol)

WITH20H21NO4x8H11N (M century 363,4 x 121,2)

Example 29

(S)-phenethylamine salt of (-)-1,2-CIS-2-(9-fluorenylmethoxycarbonyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The receipt is the same as described in example 28 using (S)-phenethylamine instead of (R )-phenethylamine.

Output: 3,48 g (26% of theory)

So pl.: 165oC

[]2D0=about 17.8 mln (=0,73, methanol)

WITH20H21NO4x8H11N (M century 363,4 x 121,2)

Example 30

(-)-1,2-CIS-2-(9-fluorenylmethoxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
Connection example 29 (3,49 g, 7.20 mmol) is suspended in 40 ml water and 40 ml of acetic ether. Mix with 1 N. hydrochloric acid to establish a pH of 2, split phase and the aqueous phase is extracted with 2 times 40 ml of acetic ether. The combined ether phases are dried over sodium sulfate and the solvent is removed in vacuum.

Output: 2,46 g (94% of theory)

[]2D pressure Heraldic AU)

WITH22H21NO4(M. C. 363,4)

Example 31

(+)-1,2-CIS-2-(9-fluorenylmethoxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
Receiving takes place as described in example 30.

Output: 2,46 g (94% of theory)

[]2D0=+18,4 (=0,48, methanol)

So pl.: 137oC

The enantiomer purity = 99.5% pure (liquid chromatography under pressure, Hiralal AU)

WITH22H21NO4(M. C. 363,4)

Example 32

Hydrochloride (-)-1,2-CIS-2-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The compound from example 31 (1.35 g; 3,71 mmol) is mixed with 100 ml of liquid ammonia, stirred for about 10 hours and then distilled ammonia. The residue is mixed with 120 ml of ether and stirred for 1 hour at room temperature, filtered and the residue bring in 5 ml of water, again filtered, washing the residue 3 ml of water and the filtrate concentrated in vacuum. The residue is recrystallized from 80% aqueous ethanol. Received a free amino acid (0,451 g; 3,19 mmol) is mixed with 1 N. hydrochloric acid (31.9 per ml; 3,19 mmol) and the resulting solution was concentrated in vacuum and the residue is dried in vacuum at 50oC/0.1 Torr.

Output: 0,567 g (86% of theory)

So pl.: 184oC

[]2D02-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
Receiving takes place analogously to example 32.

Output: 0,566 g (86% of theory)

So pl.: 186oC

[]2D0=+11,4 (C=1.04 million, water)

WITH7H11NO2x HCI (M. C. 141,2 x 36,5)

Example 34

Hydrochloride 1,2-CIS-2-amino-4-ethylidene-cyclopentane-1-carboxylic acid

< / BR>
Connection example XI (0,30 g; of 1.66 mmol) is mixed with 0.1 G. of hydrochloric acid (16.6 ml; of 1.66 mmol). The mixture is stirred for 5 hours until a clear solution is formed. The solvent is removed in vacuum and the residue is dried for 12 hours at 30oC/0.1 Torr.

Yield: 0.32 g (100%) of a mixture of diastereomers

So pl.: 188oC

WITH8H13NO2x HCI (M. C. 155, 2mm x 36,5)

Example 35

(-)-1,2-CIS-2-(tert. butyloxycarbonyl)amino-4-methylene-1-carboxylic acid

< / BR>
A solution of the compound from example 32 (2.0 g; 11.3 mmol) in 20 ml of dioxane is mixed with a 16.8 ml of 1 M potassium carbonate solution and at 0oC with di-tert.-BUTYLCARBAMATE (2,68 g; 12.3 mmol). Stirred for 20 hours at room temperature, add 30 ml of acetic ester and bring 10% hydrochloric acid solution pH to 2. The aqueous phase is twice extracted with 30 ml of acetic ether, the combined organic phases are washed with saturated common salt solution, dried on anal)

WITH12H19NO4(M. C. 241,3)

Example 36

Ethyl ester of (-)-1,2-CIS-2-(tert. butyloxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of the compound from example 35 (2,73 g; 11.3 mmol) of 4-dimethylaminopyridine (0.14 g; 1.1 mmol) and methanol (1,09 g; 34 mmol) in 30 ml dichloromethane was added dropwise at 0oC solution dicyclohexylcarbodiimide (to 2.57 g; 12.5 mmol) in 10 ml of dichloromethane. Stirred for 2 hours at room temperature, filtered, dropped dicyclohexylphosphino and washed with 50 ml of dichloromethane. The precipitate was washed with 30 ml of 0.1 G. of hydrochloric acid and 30 ml saturated sodium bicarbonate solution, dried over sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (petroleum ether/acetic ether 3 : 1).

Output: a 2.36 g (82% of theory)

T square: 64oC

[]2D0= -86,8 (=of 1.02, methanol)

WITH13H21NO4< / BR>
Example 37

Hydrochloride methyl ester (-)-1,2-CIS-2-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of the compound from example 36 (2,10 g, 8.20 mmol) and 2,6-Luigina (1,76 g; 16.5 mmol) in 50 ml dichloromethane was added dropwise at room temperature in argon (tert.butultimately)silloway ether triftorbyenzola is extracted with 100 ml of ether. The organic phase was washed with saturated saline, dried over magnesium sulfate and concentrated in vacuum. The residue is dissolved in 50 ml of tetrahydrofuran and mixed with water (0,30 g; 16.5 mmol) and tetrabutylammonium fluoride (1.1m solution in tetrahydrofuran, 7.5 ml; 8.2 mmol) at 0oC. Stirred for 1 hour at 0oC, add 100 ml of water, adjusted pH to 9 with concentrated ammonia is added 15 g of sodium chloride and extracted three times with 80 ml of acetic acid. The organic phase is dried over magnesium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (ether/acetonitrile/conc. ammonia 10 : 1 : 0,1).

Output: 1,15 g (73%)

So pl.: 146oC

[]2D0= -4,2 (=1,23, water)

WITH8H13NO2x HCI (M. C. 155, 2mm x 36,5)

Example 38

Methyl ester of (-)-1,2-CIS-2-(N-(tert. butyloxycarbonyl)-glycinyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of the compound from example 36 (0.40 g; 2,09 mmol) hydrate (1-hydroxy-1H-benzotriazole (0,282 g; 2,09 mmol), N-ethylmorpholine (0,261 g; 2,09 mmol) and N-(tert.butyloxycarbonyl)glycine (0,366 g; 2,09 mmol) in 18 ml of tetrahydrofuran was added dropwise in an argon atmosphere at 0oC solution dicyclohexylcarbodiimide (0,430 g; 2,09 mmol) in the ut 10 ml of tetrahydrofuran and concentrated in vacuum. The residue is dissolved in 40 ml of acetic ether, washed with 20 ml saturated sodium bicarbonate solution and 20 ml of saturated common salt solution, dried over sodium sulfate and concentrated in vacuum.

Output: 0,585 g (100%)

1H-NMR (datr. dimethyl sulfoxide):

/ = 1,38 (s,5H); 2,18-by 2.73 (m,4H); is 3.08 (dt, 1H); 3,18 and 3.46 (AB of AVH, 2H); of 3.57 (s, 3H); 4,40 (DDT, 1H); 4,90 (m, 2H); 6,88 (X from AVH, 1H); 7,71 (d, 1H)

WITH15H24N2ABOUT5(M. C. 312,4)

Example 39

Methyl ester of (-)-1,2-CIS-2-(N-(tert. butyloxycarbonyl(S)-alanyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 38.

Output: 0,630 g (86% of theory)

1H-NMR (datr. dimethyl sulfoxide):

= 1,09 (d, 3H); of 1.36 (s, N); 2,22-of 2.72 (m, 4H); 3,10 (dt, 1H); to 3.52 (s, 3H); 3,95 (DQC, 1H); 4,40 (DDT, 1H); 4,90 (cm, 2H); is 6.78 (d, 1H); 7,83 (d, 1H)

WITH16H26N2ABOUT5(M. C. 326,4)

Example 40

Hydrochloride methyl ester (-)-1,2-CIS-2-(N-glycidyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of compound from example 38 (0.52 g; of 1.66 mmol) and 2,6-lutidine (0,59 g; of 5.50 mmol) in 10 ml dichloromethane was added dropwise at 0oC in argon (tert. butultimately) silloway broadcast triftoratsetata (1.10 g; 4,15 mmol) and every extracted with 50 ml of ether, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and removed under vacuum of the solvent. The rest bring in 10 ml of tetrahydrofuran, mixed with water (0.06 g; 3.3 mmol) and added dropwise at 0oC 1.1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.0 ml; 3.3 mmol). Stirred for 1 hour at 0oC, mixed with 20 ml of water and adjusted the pH of the solution concentrated ammonia to 9. Add 4 g of sodium chloride, and extracted three times with 20 ml of acetic ether, the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (acetic ether/methanol/conc. ammonia 10: 1: 0). The obtained free base make 10 ml, 0.1 G. of hydrochloric acid and the solvent is removed in vacuum. The residue is dried for 12 hours at 30oC/0.1 Torr.

Output: 0,202 g (49% of theory)

1H-NMR (datr. dimethyl sulfoxide):

= 2,25 - of 2.72 (m, 4H); 3,12 (dt, 1H); 3.40 in - 3,62 (m, 2H); 3,59 (s, 3H); 4,49 (DDT, 1H); 4.92 in (cm, 2H); with 8.05 (s,W, 3H); 8,42 (d,1H),

WITH10H16N2ABOUT3(M. C. 212,2 x 36,5)

Example 41

Hydrochloride methyl ester (-)-1,2-CIS-2-(N-(S)-alanyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target compounds is=1,1, water)

WITH11H18N2O3x HCI

Example 42

(-)-1,2-CIS-2-[N-(9-fluorenylmethoxycarbonyl)-(S)-Norvaline] amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
FMOC =9-fluorenylmethoxycarbonyl.

To a solution of the compound from example 32 (3.00 g; of 16.9 mmol) and sodium bicarbonate (2,84 g, 33.8 mmol) in 60 ml of water was added dropwise a solution of 9-fluorenylmethoxycarbonyl-Norvaline-0-succinimide (7,38 g; of 16.9 mmol) in dimethoxyethane (72 ml) and stirred over night at room temperature. Mixed with tetrahydrofuran (180 ml) and adjusted pH of a solution of 10% hydrochloric acid to 2. Extracted with ether (3 x 300 ml), wash the combined ether phase with water (100 ml) and a saturated solution of sodium chloride (100 ml), dried over sodium sulfate. The solvent is removed in vacuo and the residue chromatographic on silica gel (dichloromethane/methanol 10:1).

Output: 4,58 g (59% of theory)

So pl.: 124oC

Rf=0,43 (dichloromethane/methanol 10:1)

WITH27H30N2O5(M. C. 462,54)

Example 43

(-)-1,2-CIS-2-[N-(9-fluorenylmethoxycarbonyl)-(S)-norall] amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
FMOC =9-fluorenylmethoxycarbonyl

The target connection receive similar the ol 10:1)

WITH28H32N2O5(M. C. 476,57)

Example 44

(-)-1,2-CIS-2-[N-(9-fluorenylmethoxycarbonyl)-(S)-leucyl] amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
FMOC =9-fluorenylmethoxycarbonyl

The target connection receive analogously to example 42.

Output: 3,17 g (47% of theory)

[]2D0= -28,3 (=1,24, methanol)

Rf=0,21 (dichloromethane/methanol 20:1)

WITH28H32N2O5(M. C. 476,57)

Example 45

Hydrochloride (-)-1,2-CIS-2-(N-(S)-Norvaline)amino-4-methylene-cyclopentane-1-karbouli acid

< / BR>
Connection example 42 (a 4.53 g; 9,80 mmol) is mixed with 150 ml of liquid ammonia, stirred for 10 hours and then distilled ammonia. The residue is mixed with 200 ml of ether and stirred for 1 hour at room temperature. Filtered and contribute the remainder in 60 ml of water, again filtered, washing the residue with 20 ml water and the filtrate concentrated in vacuum. The residue is dissolved in 89 ml of 0.1 G. of hydrochloric acid, the solvent is removed in vacuum and the residue is dried in vacuum over pjatiokisi phosphorus.

Yield: 2.50 g (92%)

T square: 130-135oC

[]2D0= -27,1 (=of 1.05, methanol)

WITH12H20N2O3x HCI (M. C. 240,3 x 36,5)

Example 46

Hydrochloride (-)-1,2-TSI is logically example 45.

Yield: 1.63 g (54% of theory)

So pl.: 108oC

[]20D/= -34,4 (=1,27, methanol)

WITH13H22N2O3x HCI (M. C. 254,3 x 36,5)

Example 47

Hydrochloride (-)-1,2-CIS-2-(N-(S)-leucyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 45.

Yield: 1.82 g (96% of theory)

So pl.: 70-80oC

[]2D0= of-21.5 (C =1.4%, in methanol)

WITH13H22N2O3x HCI (M. C. 254,3 x 36,5)

Example 48

Methyl ester of (-)-1,2-CIS-2-(N-(tert. butyloxycarbonyl)-(S)-leucyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 38.

Output: 0,584 g (56%)

So pl.: 124oC

WITH18H30N2O5(M. C. 354.5 TWh excluding)

Example 49

Hydrochloride methyl ester (-)-1,2-CIS-2-(N)-(S)-leucyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 40.

Output: 0,259 g (65%)

T square: 70oC

[]2D0= -52,1 (C =1.04 million, water)

WITH14H24N2O3x HCI (M. C. 268,4 x 36,5)

Example 50

Hydrochloride 1,2-CIS-2-amino-4-benzylidene-cyclopentane-1-carbon is patat 3 hours under reflux. The solvent is removed at 60oC/0,5 Torr and the residue is dried for 30 min at 100oC/0.1 Torr and dissolved in 60 ml of dioxane. After adding trimethylsilane (6,84 g; to 59.4 mmol) the reaction mixture is heated 2 hours at 80oC. the Solvent is removed in vacuo, the residue bring in 200 ml of ether and mixed with 0,78 g (a 43.4 mmol) of water. Intensively stirred for 30 min and incubated the mixture for 2 days at 5oC. the Precipitate is filtered and removed. (The sediment consists mainly of the compound from example XIII). The filtrate is concentrated to approximately 50 ml and cooled 12 hours before the 0oC, this leads to crystallization of 6-benzyliden-cyclopentane-[3,4] oxazin-2,4-(1H)-dione (2,52 g), filtered, the crystals washed with a small amount of ether and mixed solid with 103 ml of 0.1 G. of hydrochloric acid. Stirred for 1 hour at room temperature, filtered and the filtrate concentrated in vacuum. The residue is dried in vacuum over phosphorus pentoxide.

Yield: 0.95 g (7%) of a mixture of isomers E/Z =5:1

So pl.: 234oC

1H-NMR (deiter. dimethyl sulfoxide): / =2,70 - 3,55 (m,5H), 3,70 (cm, 1H), 6.48 in (s, 1H), 7,12 - 7,42 (m,5H)

WITH13H15NO2x HCI (M. C. 217,3 x 36,5)

Example 51

Hydrochloride 1,2-CIS-2-amino-4-deformation-cyclopentane-1-carboxylic acid

the HP)

WITH7H9F2NO2x HCI (M. C. 177,2 x 36,5)

Example 52

Hydrochloride 1,2-CIS-2-amino-4,4-debtor-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 2.

Yield: 1.85 g (83%)

So pl.: 222oC (decomp.)

WITH6H9F2NO2x HCI (M. C. 165,1 x 36,5)

Example 53

Hydrochloride (-)-1,2-CIS-2-amino-4-methyl-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 23 (400 mg; 2.25 mmol) in 30 ml of ethanol and 5 ml of water hydronaut in the presence of 50 mg of palladium on charcoal (10%) at 3 bar and room temperature for 3 hours. Filtered through silica gel and the filtrate concentrated in vacuum. The residue is dried for 12 hours at 25oC/0.1 mbar.

Output: 396 mg (98%) of a mixture of diastereoisomers at C-4 =5:1

So pl.: 156oC

WITH7H13NO2x HCI (M. C. 143,2 x 36,5)

Example 54

Hydrochloride (-)-1,2-CIS-2-amino-4-ethyl-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 53 from the compound obtained in example 34.

Yield: 140 mg (93%) of a mixture of diastereomers 16:1

So pl.: 205oC (decomp.)

WITH8H15NO2x HCI (M. C. 157,2 x 36,5)

Example 55

Hydrochoride 1,2-CIS-2-amino-4-benzyl-qi is example 50.

Yield: 198 mg (90%) of a mixture of diastereoisomers at C-4 =3:1

So pl.: 104oC (decomp.)

WITH13H17NO2x HCI (M. C. 219,3 x 36,5)

Example 56

1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
A solution of the compound from example 2 (30.0 g; 170 mmol) in 350 ml of dioxane and 252 ml of 1 n solution of sodium carbonate are mixed at 0oC with di-tert.BUTYLCARBAMATE (40,5 g, 185 mmol) and stirred for 16 hours at room temperature. The dioxane is removed in vacuo and the aqueous residue is mixed with 200 ml of acetic ether. The addition of 1 N. aqueous solution of potassium bisulfate set the pH value of the aqueous phase equal to 2 to 3. Separate the organic phase and the aqueous phase is extracted with acetic ether (2 x 200 ml). The combined organic phases are washed with water (2 x 100 ml), dried over sodium sulfate and concentrated in vacuum.

Output: 38,3 g (93%)

1H-NMR (deiter. dimethyl sulfoxide): =1,39 (s,N), 2,30 - of 2.72 (m,4H), of 3.00 (dt, 1H), 4,12 (dt, 1H), around 4.85 (s, 2H), 6,78 (d, 1H), 12,08 (s,1H)

WITH12H19NO2x HCI (M. C. 214,3)

Example 57

Methyl ether 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

A solution of the compound from example 56 (54,5 g; wet at 0oC with a solution of dicyclohexylcarbodiimide (51,4 g; 250 mmol) in 200 ml of dichloromethane. After stirring for 2 hours at room temperature, filtered, the filtrate washed with 0.1 G. of hydrochloric acid (300 ml), saturated sodium bicarbonate solution and water (300 ml), dried over sodium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (petroleum ether/acetic ether 3:1).

Output: 42,0 g (73%)

So pl.: 55oC

Rf= 0,30 (petroleum ether/acetic ether 3:1)

WITH13H21NO4(M. C. 255,3 )

Example 58

Methyl ether 1,2-CIS-2-N-(tert.butyloxycarbonyl)amino-4-oxo-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example 4 from the compound from example 57.

Output: 34.4 g (92%)

So pl.: 135oC

WITH12H19NO5(M. C. 257,3)

Example 59

Ethyl ester of 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-oximino-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

A solution of the compound from example 58 (500 mg, 1.94 mmol), pyridine (0,80 ml; 9,80 mmol) and hydroxylamine hydrochloride (148 mg; 2.25 mmol) is refluxed in 10 ml of ethanol for 20 hours. Rostasy washed with water (1 x 10 ml), dried over sodium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (diethyl ether).

Output: 269 mg (51%)

Rf= 0,67/0,71 (diethyl ether)

WITH12H20N2O5(M. C. 272,3)

Example 60

Hydrochloride methyl ester 1,2-CIS-2-amino-4-oximino-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 5 from the compound from example 59.

Yield: 103 mg (54%)

So pl.: 90 - 95oC (decomp.)

WITH7H12N2O3x HCI (M. C. 223,1 x 36,5)

Example 61

Methyl ether 1,2-TRANS-2-N-(tert.butyloxycarbonyl)-amino-4-methylene-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

A solution of the compound from example 57 (1,00 g; 3.9 mmol) and 1,8-diazabicyclo[5.4.0] -undec-7-ene (0,90 g; 5.9 mmol) in 20 ml of methanol is refluxed for 12 hours. The solvent is removed in vacuo, the residue contribute in acetic ether (30 ml), washed with 1 N. hydrochloric acid (10 ml) and water (10 ml), dried over sodium sulfate and concentrated in vacuum. The remainder chromatographic on silica gel (petroleum ether/acetic ether 3:1).

Yield: 520 mg (52%)

So pl.: 140oC

Rf= 0,26 (petroleum ether/acetic ether 3:1)

WithBorovoy acid

< / BR>
The target connection receive analogously to example 37 from the compound from example 61.

Yield: 141 mg (30%)

1H-NMR (dimethylsulfoxide): =2,30 - 2,50, 2,67 - 2,90 (2m,4N), is 3.08 (dt,1H), 3,68 (s, 3H), and 3.72 (dt,1H), 4.95 points (s, 2H), 8,40 (s, 3H)

WITH8H13NO2x HCI (M. C. 155, 2mm x 36,5)

Example 63

Methyl ether 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-hydroxy-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example 7 from the compound of example 58.

Output: 3,30 g (97%) of a mixture of diastereoisomers = 3:1

1H-NMR (deiter. chloroform): =1,45 (s,N), 3.14, and 3,32 (dt,1H), 3,68 and 3.70 (2s, 3H), 4,40 and 4,46 (dt, 1H), of 5.40 (d, 1H)

WITH12H21NO5(259,3)

Example 64

Methyl ether 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-4-cyclopenten-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

A solution of the compound from example IV (3,90 g; 8,80 mmol) in 87 ml of tetrahydrofuran is slowly mixed at 0oC with 30% hydrogen peroxide (5,23 g; and 46.3 mmol) and stirred for 3 hours at room temperature. After adding 100 ml of ice water, extracted with dichloromethane (3 x 100 ml), the combined organic phases are washed with saturated sodium chloride solution (100 ml), milovy ether 2:1, Rf= 0,33). Get 1,32 g (62%) of a mixture (35:65) of target compound and the corresponding 3-cyclopentenone isomer. After fractional crystallization from n-hexane (target connection is in the mother liquor) get the target connection.

Yield: 142 mg (7%)

1H-NMR (deiter. chloroform): / = 1,48 (s,N), 2,37, 2,70 (AB part of the system AWH, 2H), 3,70 (s,3H), 3,71 (m, 1H), to 4.62 (dt, 1H), 5,20 (d, 1H), 5,71 (m, 1H), 5,96 (m,1H)

WITH12H19NO4(M. C. 241,3)

Example 65

Hydrochloride methyl ester 1,2-CIS-2-amino-4-cyclopenten-1-carboxylic acid

< / BR>
The target connection receive analogously to example 5 from the compound from example 64.

Yield: 93 mg (89%)

1H-NMR (deiter. dimethyl sulfoxide): =2,40 - to 2.85 (m,2H), 3,86 (m,1H), 4,01 (dt, 1H), USD 5.76 (m, 1H), 5,97 (m, 1H), 8,10 (s, 3H)

WITH7H11NO2x HCI (M. C. 141,2 x 36,5)

Example 66

Ethyl ester of 1,2-CIS-2-benzylamino-3-benzoyloxymethyl-cyclopentane-1-carboxylic acid

< / BR>
PH = phenyl

The target connection receive analogously to example 10 from the compound of example XXIII.

Output: scored 8.38 g (76%)

So pl.: 215oC (decomp.)

The ratio of diastereomers D1: D2= 6:1

Rf= 0,43 (D1), 0,34 (D2) (petroleum ether/diethyl ether 1:1)

ethyl-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 13 from the compound of example 66.

Output: 3,14 g (97%)

The ratio of the isomers D1: D2= 6:1

1H-NMR (deiter. chloroform): =1,28, 1,29 (2T,3H), 1,72 - of 2.30 (m,4H), 2,71 (D2) and 2.88 (D1) (2T, 1H), 3,06 (D2) 3.27 (D1) (2m, 1H), 3,50 - 3,90 (m, 3H), 4,10 - 4,32 (m,3H), 8,40 (s,3H)

WITH9H17NO3x HCI (M. C. 187,2 x 36,5)

Example 68

Ethyl ester of 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-3-hydroxymethyl-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example 3 from the compound from example 67.

Output: 2,98 g (98%)

The ratio of diastereomers D1: D2= 5 : 1

1H-Yarm (deiter. chloroform): = 1,28 (2T, 3H), 1,45 (2C, N), 1,65-of 2.38 (m, 5H), to 3.02 (D2), 3,06 (D1) (Dt, 1H), 3,22-of 3.60 (m, 2H), 3.95 to and 4.40 (m, 4H), 4.95 points (D1), 5,61 (D2) (2D, 1H)

C14H25NO5(M. C. 287,4)

Example 69

Ethyl ester of 1,2-CIS-2-N-(tert.butyloxycarbonyl)amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

To a solution of compound from example 68 (2.25 g; 7,83 mmol) in 210 ml of tetrahydrofuran was added dropwise in an argon atmosphere at room temperature for 2 nitrophenylamino for 30 min was added dropwise 30% hydrogen peroxide (1,33 g; is 39.2 mmol) and stirred overnight at room temperature. After adding water (500 ml), extracted with acetic ether (3 x 250 ml), the combined organic phases are washed with saturated sodium bicarbonate solution (200 ml), dried over magnesium sulfate and the solvent is removed in vacuum. The remainder chromatographic on silica gel (petroleum ether/diethyl ether 2:1)

Output: 1,67 g (79%)

So pl.,: 64oC

WITH14H23NO4(M. C. 269,3)

Example 70

1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example IX of the compound from example 69.

Output: 1,71 g (97%)

So pl.,: 135oC

WITH12H19NO4(M. C. 241,3)

Example 71

Methyl ether 1,2-CIS-2-N-(tert. butyloxycarbonyl)amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example 57 from the compound from example 70.

Output: 1,59 g (91%)

So pl.: 44oC

WITH13H21NO4(M. C. 255,3)

Example 72

Hydrochloride 1,2-CIS-2-amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
To a solution of dimethyl)silloway broadcast triftoratsetata (1.64 g; 6.21 mmol) at room temperature in argon. Stirred for 3 hours, add 10 ml of saturated solution of ammonium chloride, extracted with ether (2 x 20 ml), washed the combined organic phases with saturated sodium chloride solution (10 ml), dried over sodium sulfate and removed under vacuum of the solvent. The rest make of 20.7 ml of 0.1 G. of hydrochloric acid and 20 ml of tetrahydrofuran, stirred for 20 hours, remove the vacuum tetrahydrofuran, washing the residue with ether (10 ml) and concentrated in vacuo the aqueous phase. The residue is dissolved in 7 ml of probenecid and 30 min refluxed. Filtered precipitated solid is washed with ether, and contribute the remainder (136 mg) in 9.6 ml of 0.1 G. of hydrochloric acid. The solvent is removed in vacuum and the residue is dried in vacuum over phosphorus pentoxide.

Yield: 190 mg (52%)

So pl.,: 208oC (decomp.)

WITH7H11NO2x HCI (M. C. 141,2 x 36,5)

Example 73

Hydrochloride methyl ester 1,2-CIS-2-amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 37 from the compound from example 71.

Yield: 145 mg (39%)

So pl.: 143oC

WITH8H13NO2(M. C. 155, 2mm x 36,5)

Example 74

Methyl e is oxycarbonyl

The target connection receive analogously to example 61 from the compound from example 71.

Yield: 410 mg (82%)

So pl.: 74oC

Rf=0,43 (petroleum ether/acetic ether 3:1)

WITH13H21NO4(M. C. 255,3)

Example 75

Hydrochloride methyl ester 1,2-TRANS-2-amino-3-methylene-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 37 from the compound from example 74.

Output: 228 mg (82%)

So pl.: 166oC

WITH8H13NO2x HCI (M. C. 155, 2mm x 36,5)

Example 76

Methyl ester of 2-N-(tert.butyloxycarbonyl)amino-cyclopentane-3-one-carboxylic acid

< / BR>
VOS = butyloxycarbonyl

The target connection receive analogously to example 4 from the compound from example 71.

Output: 898 mg (89%)

2 diastereoisomer CIS :TRANS = 2:1

So pl.: 98oC

WITH12H19NO5(M. C. 257,3)

Example 77

Methyl ester 2-amino-cyclopentane-3-one-1-carboxylic acid

< / BR>
The target connection receive analogously to example 5 from the compound from example 76.

Yield: 139 mg (92%)

2 diastereoisomer CIS: TRANS = 2:1

So pl.: 250oC

WITH7H11NO3x HCI (M. C. 157,2 x 36,5)

Example 78

Methoxycarbonyl

The target connection receive analogously to example XVIII of the compounds according to example 76.

Yield: 176 mg (32%) CIS : TRANS = 2:1

1H-NMR (deiter. chloroform): =a 1.46 (s,N), 2,10 - to 2.42 (m,2H), 2,49 - 2,70 (m, 2H), 2,72 (dt, 2H), and 3.72 (s, 3H), 4,30 - to 4.52 (m, 1H), 4,85 (CIS,s, 1H), 5,20 (TRANS,s,1H)

WITH12H19FO4(M. C. 279,3)

Example 79

Methyl ester 2-amino-3,3-debtor-cyclopentane-1-carboxylic acid

< / BR>
The target connection receive analogously to example 5 from the compound from example 78.

Yield: 61 mg (48%), CIS/TRANS = 2:1

So pl.: 118oC

WITH7H11F2NO2x HCI (M. C. 176,2 x 36,5)and

1. Derivative cyclopentane - or cyclopenten -- amino acids of General formula I

< / BR>
in which A, B, D, E, G, L, M and T are identical or different and denote hydrogen, halogen, hydroxyl, linear or branched alkyl with 1 to 8 carbon atoms which may be substituted with halogen, hydroxyl, phenyl, benzyloxy or carboxypropyl or a group of the formula - NR4R5where R4and R5the same or different and denote hydrogen, phenyl or linear or branched alkyl with 1 to 6 carbon atoms, and at least one of the substituents A, B, D, E, G, L, M, and T does not mean hydrogen or B and D, E and G or L and M Soi different and mean hydrogen, halogen, linear or branched alkyl with 1 to 8 carbon atoms, benzyl or phenyl, or E and G or B and D together denote a residue = 0;

R1means hydrogen or a linear or razvetvlennye alkyl with 1 to 8 carbon atoms;

R2means hydrogen, aminosidine group, a linear or branched alkyl with 1 to 8 carbon atoms; which may be substituted by formyl or a linear or branched acyl with 1 to 6 carbon atoms, or phenyl or benzoyl, linear or branched acyl with 1 to 8 carbon atoms, benzoyl,

or the remainder of the amino acid formula

< / BR>
where R9means hydrogen, cycloalkyl with 3 to 8 carbon atoms, a linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by a group of the formula-NR11R12or R13-OC-, where R11and R12independently from each other denote hydrogen, a linear or branched alkyl with 1 to 8 carbon atoms, or phenyl;

R13means of hydrosil, benzyloxy, alkoxy with 1 to 6 carbon atoms, R10means hydrogen or aminosidine group;

R3means hydrogen, a linear or branched alkyl with 1 to 8 carbon atoms, possibly substituted by phenyl,

and their salts.

2. Derivatives CEC is achut hydrogen, halogen, hydroxyl or linear or branched alkyl with 1 to 6 carbon atoms which may be substituted with halogen, hydroxyl, benzyloxy, or a group of the formula-NR4R5where R4and R5the same or different and mean hydrogen or branched alkyl with 1 to 4 carbon atoms, and at least one of the above substituents A, B, D, E, G, L, M, and T does not mean hydrogen, or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
or = N-OH,

where R6and R7the same or different and mean hydrogen, fluorine, chlorine, bromine, linear or branched alkyl with 1 to 6 carbon atoms, benzyl or phenyl,

E and G or B and D together denote a residue = 0,

R1means hydrogen or a linear or branched alkyl with 1 to 6 carbon atoms;

R2means hydrogen, tert.butoxycarbonyl, benzyl, 9-fluorenylmethoxycarbonyl, linear or branched alkyl with 1 to 6 carbon atoms which may be substituted by formyl, linear or branched acyl with 1 to 4 carbon atoms, phenyl or benzoyl, linear or branched acyl with 1 to 6 carbon atoms, benzoyl,

or the remainder of the amino acid formula

< / BR>
where R9means vodorodny, 9-fluorenylmethoxycarbonyl;

R3means hydrogen, a linear or branched alkyl with 1 to 6 carbon atoms or benzyl,

and their salts.

3. Derivative cyclopentane - or cyclopenten -- amino acids of General formula I on p. 1, where A, B, D, E, G, L, M and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, hydroxyl or linear or branched alkyl with 1 to 4 carbon atoms which may be substituted by hydroxyl or benzyloxy, and at least one of the above substituents does not mean hydrogen, or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
or = N-OH,

where R6and R7the same or different and mean hydrogen, fluorine, chlorine, bromine, linear or branched alkyl with 1 to 4 carbon atoms, or phenyl,

or E and G or B and D, respectively, together mean residue = 0,

R1means hydrogen or a linear or branched alkyl with 1 to 4 carbon atoms;

R1means hydrogen, benzyl, tert.butoxycarbonyl, 9-fluorenylmethoxycarbonyl, linear or branched alkyl with 1 to 4 carbon atoms, linear or branched acyl with 1 to 4 carbon atoms,

or the remainder of the amino acid formula

< / BR>
where R9OSN butoxycarbonyl or 9-fluorenylmethoxycarbonyl;

R3means hydrogen, a linear or branched alkyl with 1 to 4 carbon atoms, and their salts.

4. Derivative cyclopentane - or cyclopenten -- amino acids of General formula I on PP.1 to 3, characterized in that they are available as single isomer or an acid additive salt.

5. Composition active against strains of S. aureus, Candida and Trichophyton containing cyclic amino acid derivative as an active principle and a pharmaceutically acceptable carrier, characterized in that it contains as derived cyclic amino acid compound under item 1 or its salt in an effective amount.

Priority points:

29.05.92. - p. 1, in which A, B, D, E, G, L, M and T are identical or different and denote hydrogen, hydroxyl, linear or branched alkyl with 1 to 8 carbon atoms which may be substituted with halogen, hydroxyl, phenyl, or carboxypropyl or a group of the formula-NR4R5where R4and R5the same or different and denote hydrogen, phenyl or linear or branched alkyl with 1 to 6 carbon atoms, or B and D, E and G or L and M, respectively, together mean the rest of the formula

< / BR>
where R6and R7the same or different and mean in the up balance = 0;

R1means hydrogen or a linear or branched alkyl with 1 to 8 carbon atoms;

R2means hydrogen, aminosidine group, a linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by formyl or a linear or branched acyl with 1 to 6 carbon atoms, or phenyl or benzoyl, linear or branched acyl with 1 to 8 carbon atoms, benzoyl,

or the remainder of the amino acid formula

< / BR>
R9means hydrogen, cycloalkyl with 3 to 8 carbon atoms, a linear or branched alkyl with 1 to 8 carbon atoms which may be substituted by a group of the formula-NR11R12or R13-OC-, where R11and R12independently from each other denote hydrogen, a linear or branched alkyl with 1 to 8 carbon atoms, or phenyl;

R13denotes hydroxyl, benzyloxy, alkoxy with 1 to 6 carbon atoms;

R10means hydrogen or aminosilane group;

R3means hydrogen, a linear or branched alkyl with 1 to 8 carbon atoms, possibly substituted by phenyl.

27.01.93 - p. 1, in which A, B, D, E, G, L, M and T are identical or different and denote halogen, linear or branched alkyl with 1 to 8 carbon atoms, which may be the

 

Same patents:

The invention relates to new compositions of chemical compositions, namely the composition of natural amino acids and trace elements, which has anti-tumor and antihypoxic activity, and may find application in medicine

The invention relates to medicine, in particular, to pharmacology
The invention relates to medicine, namely to dentistry

The invention relates to the field of ophthalmology, and in particular to methods for the prevention and treatment of expressions cornea
The invention relates to the pharmaceutical industry, namely pharmaceutical forms, and can be used in medicine for the treatment of mucosal lesions caused by viral, physico-chemical, mechanical, etc

The invention relates to compounds of General formula

< / BR>
where

X is selected among H, OH

R is the remainder, which being associated with

< / BR>
forms an amino acid; their enantiomers and racemic mixtures; and to their pharmaceutically acceptable salts

FIELD: medicine, narcology.

SUBSTANCE: one should detect satisfaction insufficiency syndrome due to performing genetic analysis by the presence of, at least, one of the genes coding the exchange of neuromediators being the constituents of human satisfaction system. One should compensate satisfaction insufficiency due to performing, at least, one complex of physical exercises. Moreover, in case of availability of pathological gene allele of dopamine D2 receptor and/or protein gene of reverse dopamine capture in patient one should apply the complex of physical exercises including those to provide sedative effect, and in case of availability of pathological gene allele of dopamine-beta-hydroxylase protein one should apply the complex of physical exercises including those that induce an activating effect. In case of availability of pathological gene allele of dopamine D2 receptor and/or protein gene of reverse dopamine capture one should apply additional food biologically active additives based upon amino acids being the precursors of neuromediators, such as taurine, D-, L-phenylalanine in combination with 5-hydroxytryptophan, hypericin and vitamin B6, and in case of pathological gene allele of dopamine-beta-hydroxylase protein one should additionally apply food biologically active additives based upon amino acids being the precursors of neuromediators, such as: taurine, tyrosine and/or dimethylaminoethanol, lecithin and group B-vitamins. The present innovation enables to take into account pathological disease mechanism.

EFFECT: higher efficiency of prophylaxis.

14 cl, 5 ex

FIELD: medicine, oncology, amino acids.

SUBSTANCE: invention relates, in particular, to the development of an antitumor preparation based on natural substances. Invention relates to an amino acid preparation comprising at least one modified essential amino acid obtained by treatment of amino acid by ultraviolet radiation (UV) at wavelength 250-350 nm for 12-80 h at temperature 15-30oC or with ozone at temperature 15-25oC. The modified amino acid has no toxicity for health cells. Also, invention relates to a method for preparing such preparation. Invention provides the development of an antitumor preparation based on modified amino acids and expanded assortment of antitumor preparations being without cytotoxicity for normal cells.

EFFECT: valuable medicinal antitumor properties of preparation.

8 cl, 4 tbl, 2 dwg, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds designated for applying in photochemotherapy or diagnosis and indicated compounds represent 5-aminolevulinic acid aryl-substituted esters, their derivatives or pharmaceutically acceptable salts. In particular, invention provides preparing compounds of the general formula (I): R

22
N-CH2COCH2CH2CO-OR1 wherein R1 represents aryl-substituted C1-alkyl group, preferably C1-alkyl group substituted with non-heteroaromatic aryl wherein indicated group aryl is substituted group, and especially preferable this radical is substituted with one or more alkyl groups (for examples, (C1-C2)-alkyl), alkoxy- (for example, methoxy-) groups, fluorine, chlorine atoms, nitro- or trifluoromethyl groups; R2 being each of that can be similar or different represents hydrogen atom or alkoxycarbonyloxy-; indicated alkyl group is broken optionally with one or more groups: -O-, -NR3-, -S- or -PR3- wherein R3 represents hydrogen atom or (C1-C6)-alkyl group, and their salts for applying in diagnosis and photochemotherapy of injures and disorders of internal and external surfaces of body, and products and sets for realization of this invention also.

EFFECT: valuable medicinal properties of compounds.

18 cl, 17 dwg, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out analysis of clinical manifestations in patients having satisfaction deficiency syndrome. Clinical manifestations like obsessive compulsive disorders occurring, physical training exercises acting upon visceral organs as a result of abdominal wall muscle and inferior and superior small pelvis diaphragm muscle contraction. Clinical manifestations like irritation and aggressiveness being observed, physical training exercises like slow diaphragm-type breathing with deep muscle relaxation or alternating hyperventilation and deep diaphragm-type breathing are to be done. Clinical manifestations like hyperactivity taking place, physical dynamic exercises causing activating action are done in combination with slow deep breathing. Clinical manifestations like emotional disorders being observed, physical training exercises causing sedative action are applied. The exercises are based on alternating muscle and tendon extension and following relaxation. Dietetic low hydrocarbon content nutrition is additionally applied with one of the following diets: low hydrocarbon content diet having animal proteins and saturated with fat, or vegetarian diet having mainly vegetable proteins, moderate hydrocarbon content and large amount of vegetable fibers, or ketogenic diet being protein-and-fat diet containing large amount of fat with fatty acids like triglycerides of chain having not more than 12 carbomers.

EFFECT: enhanced effectiveness of prophylaxis and correction procedures.

11 cl

FIELD: cosmetic industry.

SUBSTANCE: the present innovation deals with preparations to fix, strengthen, restructure, restore or stabilize keratin fibers, especially damaged fibers. For this purpose one should apply creatine, creatinine and/or their salts to provide improves glare, volume or combing capacity of one's hair, as well. Earlier these preparations had been known as hair moisturizers.

EFFECT: higher efficiency of application.

12 cl, 9 ex

FIELD: medicine.

SUBSTANCE: preparation is a crushed and UV-radiation activated β-(3-indolyl)-α-aminocapronic acid obtained by treating dry initial preparation (native aminocapronic acid) crushed to 1-5 mcm large particles with UV-radiation during 12-18 h to the moment the substance decomposition starts. Method involves crushing dry substance of β-(3-indolyl)-α-aminocapronic acid by means of vibration mill with 1500-3000 oscillations per min to 1-5 mcm large particles, activating the crushed product by exposing it to UV-radiation of 250-280 nm wavelength during 12-18 h to the moment the initial substance decomposition starts. The moment is determined by 3-5% large initial mass loss.

EFFECT: enhanced effectiveness of the preparation with no adverse side effects.

6 cl, 3 tbl

FIELD: medicine, dermatology.

SUBSTANCE: one should apply an applicator onto affected parts of skin that contains 5-aminolevulinic acid at concentration of 5-20%. After keeping and removing the applicator it is necessary to irradiate with light at wave length being 630 ± 10 nm and energy density of 10-1200 J/sq. cm. Control should be carried out due to evaluating the concentration of photosensitizer at affected parts of skin due to fixing fluorescence ranges at all basic stages of photodynamic therapy. The method enables to adjust skin relief and achieve scars' whitening and their regression.

EFFECT: higher efficiency of therapy and control.

6 cl, 2 dwg, 3 ex

FIELD: medicine, gynecology, anesthesiology.

SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.

EFFECT: improved assistance method.

7 tbl, 4 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates, in particular, to a composition for interaction of ligands wherein the composition comprises a noncovalent associate of multiple separate conjugates being each of that comprises a head group and a tail group wherein tail groups of conjugates form hydrophobic aggregate. Conjugates are mobile within the associate and in the presence of ligand at least two head groups are places by a method corresponding to the epitope formation that is able to interact with ligand stronger as compared with each separate head group. Invention provides applying conjugates in combinatory approach for detecting effective combinations to induce the desirable interaction in binding in receptor-specific treatment of patients.

EFFECT: valuable properties of epitopes.

31 cl, 2 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: physiologically acceptable sodium salt is dissolved in purified apyrogenic water in the concentration 5-10 g/100 ml and colloidal substance of polymeric nature is added at temperature of solution 40-70C at stirring up to disappearance of polymer solid phase from the surface solution. Solution is stirred for 30-60 min and then subjected for high-temperature treatment at 90-100°C for 15-30 min and successive filtration through micro- and sterilizing filters of pores diameters 0.8 and/or 0.45 and then 0.22 mcm, respectively, and in gradual increasing the pressure value from 0.5 to 3.0 atm and final packaging. Invention provides preparing microimpurity-free hypertonic colloidal solution that is stable in storage and effective in using. Invention can be used in methods for preparing preparations used in reanimatology, intensive therapy and in emergency medicine.

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

8 cl, 3 ex

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