The method of inhibition of retroviral proteases

 

(57) Abstract:

The invention relates to biochemistry. The invention is: to inhibit retroviral proteases enter the compound of the General formula where A, Y, R2,R3,R4,R5,R6and balances with the sign*have the appropriate determination. table 2.

The invention relates to biochemistry and relates to a method of inhibition of retroviral proteases by the introduction of protease inhibitor.

We know only a small number of inhibitors of HIV protease. The first of them was opened pepstatin A. IC50which is equal to about 0.5 mmol. It was later described several other inhibitors with moderate to high activity.

Large doses of pepstatin And was in the process of biosynthesis inhibit the formation of nucleoprotein R24.

Discovered a new class of compounds, inhibiting enzyme in the text with high efficiency of HIV-protease.

According to this invention proposes a method of inhibition of retroviral proteases by the introduction of protease inhibitor, characterized in that the inhibitor is used as a compound of General formula

R (Y)l- ((I), where Y is estato>/BR>D (E)n- (F)o(G)p(IV)

D*- (E*)n*(F*)o*(G*)p*(IV*) where D is the radical R1or a radical of the formula V, VI or VII;

D*the radical R*1or a radical of the formula V*VI*or VIII*< / BR>
R1- - CO - (V) R1* - O - (V*)

R1-- CO- (VI) R1*- CO- (VI*)

R1-O--CO- (VII) R1*-O-CO- (VII*)

where n, n*, 0, 0*, P, P*- independently from each other 0 or 1;

E, E*, F, F*, G and G*- independently from each other mean amino acids from the group of: Val, Ls, Ls (Z), Phe, hg, Ser, Asn, Gly, Ile, bg, Nva or Npg;

R1and R*1independently from each other signify hydrogen, carboxyl, methylsulphonyl, tert. butylsulfonyl, tert. -butoxycarbonyl, 2-hydroxyarylalkyl, 1,2,3-trihydroxypropane, 1,2,3-triacetoxy, benzyloxycarbonyl, 4-methylphenylsulfonyl, 4-chlorobenzylthio, bansilalpet, 4-chlorobenzenesulfonyl, hexadecacarbonyl, 4-amino-1-piperidinylcarbonyl, N-tert. -butoxycarbonyl-4-amino-1-piperidinyl-were radioactive, 4-amino-1-piperidyl-carbonyl, N-tert.butoxycarbonyl-4-amino-1-piperidyl-carbonyl, 2-amino-3-phenyl-propyl, N-tert.butoxycarbonyl-2-AMI the l, 2-pyridylethyl, 4-pyridylacetate, 2-hinolincarbonova, 1-naphthylacetyl, 1-naphthaleneacetic, 1-(4-pyridyl)-ethylsulfonyl, 12-aminobutanol, 4-(N-oxidability), tert.-butylthio, 4-z-n-tert.-butoxycarbonylamino - kilcarbery, 4-pyridyl, deletion, phenyl, amino or tert.-butoxycarbonylamino-group;

R2and R*2means independently of one another: hydrogen, 2-(4-pyridyl)-ethyl, isopropyl, isobutyl, n-pentyl, benzyl, 3,4-methylenedioxybenzyl, 2,4-dimethoxybenzyl, 4-tert.-butylbenzyl, 2-phenylethyl or cyclohexylmethyl;

R3and R*3, R4and R*4, R6and R*6, R7, R10and R*10mean hydrogen;

R5and R*5mean independently from each other hydrogen or hydroxyl;

R8and R*8mean hydrogen or together with R9or R*9and related atoms form a 1,2,3,4-tetrahydroquinoline-3,4;

R9and R*9independently of one another denote hydrogen, hydroxyl, acetoxy, n-propyl, isopropyl, isobutyl, aminomethyl, 4-aminobutyl, hydroxymethyl, tert. -butoxymethyl, aminocarbonylmethyl, 2-benzyloxycarbonylation, tert. -butoxycarbonylamino, z-naphthalenyloxy, cyclohexylmethyl, benzyl, 2-phenylethyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-tert. -butoxymethyl, 1-naphthylmethyl, 2-thienylmethyl, 1-imidazolidinyl, 3-indolylmethane, 4-pyridylmethyl, 4-(N-oxidability)-methyl, 2-methylthioethyl, 2-methylsulfonylmethyl, tert.-butylsulfonyl or 2-carboxyethyl;

R11and R*11independently of one another denote hydrogen, hydroxyl, acetoxy, and in the formula I, one or more amide groups (-CONH-) in the main objectives can be replaced by a group-CH2NH - or-CH(OH)CH2or a physiologically tolerated salts of these compounds.

Under the salts of the compounds of formula I are meant, in particular, pharmaceutically acceptable or non-toxic salts. Such salts can be, for example, is formed by compounds of formula I having acidic groups, for example carboxy group, and alkali or alkaline earth metals such as, for example Na, K, Mg and CA, as well as physiologically acceptable organic amines, such as, for example, triethylamine and Tris(2-hydroxy-ethyl)-amine.

The compounds of formula I having a basic group such as amino or guanidino-group, form salts with inorganic acids such as, for example, sulfuric, hydrochloric or phosphoric acid, or maleic, fumaric, tartaric and n-toluensulfonate acid. Preferred are the compounds of formula I, in which the remains and symbols with or without asterisks respectively the same. Preferred further are compounds of the formula I, symmetric with respect to C2.

The compounds of formula I get the fact that exercise combined fragment with terminal carboxyl groups or its reactive derivative with the corresponding fragment with the free amine groups, otscheplaut introduction (if desired) temporarily to protect other functional groups of the protective group and the compound obtained is optionally transferred to its physiologically acceptable salt.

Fragments of the compounds of formula I with terminal carboxyl groups can have, for example, the following formula: D-HE (VIII) D-E-IT (IX) D-F-OH (X) D-G-OH (XI) D-E-F-HE (XII)_ D-E-G-OH (XIII) D-F-G-OH (XIV) D-E-F-G-IT (IV)

The same applies to similar residues marked with an asterisk.

Fragments of the compounds of formula I with the terminal amino group can be, for example, the following formula: N-Z-N (XV) H-G-Z-G*-N (XVI) N-F-Z-F*-N (VIa) N-E-Z-E*-N (VI) H-F-G-Z-G*-F*-H (XVII) H-E-G-Z-G*-E*-H (VIIa) N-E-F-Z-F*-E*-N (the case of asymmetrical molecules of the target compounds could be used and other in addition to the formulas XV-XVIII, fragments, an end amino group which may be protected.

Methods that can be used to produce amide linkages, are widely described. It is preferable to use the following methods: method, activated ester with N-oxysuccinimide, 1-oxibendazole or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine as an alcohol component, the combination with a carbodiimide, such as dicyclohexylcarbodiimide (DCC) or the anhydride of n-papapostolou acid (PPA) and the method of mixed anhydrides using pivaloyloxy or ethyl or isobutyl ether of Harborview acid, or the reaction mix with phosphonium derivatives, such as benzotriazol-1-yl-oxy-Tris- (dimethylaminoethylmethacrylate) (THIEF) or derivatives, for example 2(1H-benzotriazol-1-yl)-1,1,3,3 - tetramethylethylenediamine (V).

Fragments of formula V or V*can be synthesized by ordinary methods of obtaining amino acids;

formula VI or VI*can be synthesized, for example, from the corresponding amino acids, and this preserves the chiral center of the latter. Diazotization at -20 50oIn the environment of diluted mineral telfonaktiebolaget acids, which can be subjected to interaction with containing residues RIand RIIaccordingly, RI*and RII*, nucleophile, or obtained using as starting compounds, esters of malonic acid, alkylation of which leads to the formation of mono - or disubstituted malonic esters, which, after saponification by decarboxylation translated to the desired derivative;

formula VII or VII*synthesized on the basis of the corresponding amino acids, and this preserves the chiral center of the latter. Diazotization at -20 50oC in the environment of diluted mineral acids leads to the formation of milk acids, which can be subjected to interaction with the electrophile containing substituent RIor RI*.

Fragments of formulas IX, X, XII and XIII, XIV and IVa synthesized by the known methods used to produce amino acids and pentelow.

Fragments of formula XV receive, using as starting compounds optically active-amino acids or sugars or their derivatives. So, for example, to obtain fragments with m = 1, l = 0, R5= R5*HE = and R6= R6*= H amino acids in a known manner perioa metals or electrochemically in an N-protected deamination. With this purpose, the N-protected aldehyde is dissolved in, for example, tetrahydrofuran, and at -30 60oC, preferably at -10 to+30oC, by adding a solution of samarium iodide (II) in tetrahydrofuran was transferred to N-protected deamination, when the removal of the protective group formed by compounds of the formula (XV). The result is a mixture of diastereomers on with IT-groups, which can be separated into individual isomers by known methods, e.g. by fractional crystallization and/or chromatography.

During the synthesis using as starting compounds sugars or their derivatives chiral centers of the source material is retained or inverted. HE is the group that you want to save, protect accordingly.

The remaining activated by interaction with, for example, acid chloride sulfonic acid, and can be replaced by a nucleophile. The target products are formed in the form of an individual stereoisomer.

Using as a starting compound, for example, D-mannitol, hydroxy group prolile in position 3 and 4 protect by treatment with a mixture of acetone and sulfuric acid and then an aqueous solution of acetic acid, the floor is oralfacial and pyridine and subsequent treatment with potassium carbonate in methanol get 1,2 R-5R,6-diepoxy-3,4-0-isopropylidene-3R,4R-diol. Processing of this diepoxide the cuprates in the environment, for example, tetrahydrofuran leads to the uncovering of the epoxide and the introduction of substituents in position 1 and 6. After activation of the Oh-groups at positions 2 and 5 by reacting with, for example, the acid chloride sulfonic acid exchange by interacting with azide. The recovery of both azide groups, for example, by catalytic hydrogenation and removal of the acetonide protective group using a mixture of HCl and methanol leads to the formation of derivatives balance (XV).

Fragments of formula XV with m = 1, l = 1, and y is a residue of formula III is produced by the interaction of N-protected aldehyde amino acids (see above) in a reducing environment (e.g NaB3JV) with a corresponding amine. For this purpose, the aldehyde is dissolved, for example, in methanol and subjected to interaction with, for example, ammonium acetate, and, for example, cyanoborohydride sodium as a reducing agent. After removal of the protective groups to obtain the target fragment.

To obtain fragments of formula XV with m = 0, l = 0, R5= OH, R6= N the corresponding nitro derivatives deprotonated by reacting with bases, such as tetramethylguanidine, and then spend the reaction prisoedinites Raney and removal of protective groups to obtain the compounds of formula XV in the form of diastereomers, sharing in this way.

Fragments of formula XVI, VIa, VI, XVII, VII, VII and XVIII synthesize well-known methods of obtaining amino acids and peptides.

Peptide analogs of this type can be obtained by known methods.

Necessary to obtain the compounds of formula I of the preliminary and final operations such as the introduction and removal of protective groups are known. Salts of compounds of formula I, having soleobrazutaya group, get in a known manner, for example by reacting the compounds of formula I with a core group with a stoichiometric amount of a suitable acid or by reacting the compounds of formula I c acid group with a stoichiometric amount of a suitable base.

The mixture of stereoisomers, in particular a mixture of diastereomers, which may be formed during the synthesis of compounds of formula I can be separated by known methods, by fractional crystallization or by chromatography.

The compounds of formula I in accordance with this invention have an inhibitory effect on the enzymes, in particular, they inhibit the action of retroviral aspartate, such as HIV-ProCredit as follows.

The principle of this test.

As a substrate for HIV protease was previously used, in particular heptapeptide H-ser-phe-asn-phe-pro-gln-Ile-OH. HIV protease cleaves the specified substrate between the second phe and pro.

Quite unexpectedly it was found that substitution in the sequence of the Proline 5-oxoproline gives the substrate, which can split HIV protease much faster, enabling the analysis faster and with less consumption of the enzyme.

Recipe for testing inhibitors of HIV protease

a) Preparation of substrate solution

2 mg of H-ser-phe-Asn-phe-opr-gln-Ile-HE (H-opr-HE=5-oxopropyl) dissolved in 1 ml of buffer MG15 (perhaps the use of ultrasound) and the resulting solution was filtered through a sterile filter (0.45 µm).

b) Preparation of a solution of the inhibitor.

Take a portion of the inhibitor in an amount 2.5 times greater than required by both molarity in 1 ml of solution, and dissolve it in DMSO (10% final volume). Dilute the resulting solution was buffer MG15 up to final volume and filter it through a sterile filter (0.45 µm).

C) Preparation of a solution of protease

5 μl of the solution of the HIV protease was diluted to the desired concentration buterere (h) with a screw cap. For the blind of experience in the test tube is taken with a pipette 10 ál of buffer MG15 containing 10% DMSO. In the other test tube add 10 ál of inhibitor solution. The tube was incubated for 5-10 min at 37oC, then to each tube add 5 μl of protease solution. After reaction for 2 h at 37oC from each sample was pipetted in 10 or 20 µl (depending on the sensitivity of the device for high-performance liquid chromatography), pour them into micro-bubbles and diluted with 120 µl used for high performance liquid chromatography mobile phase.

d) Conditions for high performance liquid chromatography Mobile phase: 80% 0.1 M phosphoric acid, pH 2.5 to 20% (wt.%) acetonitrile Column: Merck LICHROSORB RP18 (5 μm) 250 4 Speed flow 1 ml/min column Temperature: 42oC Parameters of the detector 215 nm 0,08 AUF, 18,2oC the analysis Duration 11 min retention Time of the substrate to 8.1 min retention Time of tetrapeptide with terminal N-atom: 3,9 minutes

Solvent used

1) buffer MG15:

20 mm morpholinepropanesulfonic (MES)

15% (W/V) glycerol

0,1% vol. Triton X100

5 mm EDTA

0.5 M such as NaCl

1 mm phenylmethyl is 25% (W/V) glycerol and 1 mm dithiothreitol (D).

Into the flask Erlenmeyer download MES, EDTA, NaCl, DTT and PMSF, dissolve them in a little water and set the pH of the solution is equal to 6. In a volumetric flask make the appropriate addition of glycerol and measure the pipette Triton x100. The aqueous solution is transferred into a volumetric flask and the volume was adjusted to the mark with water.

3) the Mobile phase for high performance liquid chromatography.

Prepared from orthophosphoric acid (FLUKA, including D. A.) 0.1 M solution. Using triethylamine (FLUKA, H. D. (a) the pH of this solution is set equal to 3.5. The solution is weighed and added to it the appropriate amount of acetonitrile (under traction). The mixture is thoroughly mixed and rinsed for about 5 min with helium to remove gases.

g) Evaluation

When the selected conditions heptapeptide separated from the resulting enzymatic degradation of tetrapeptide with terminal N-atom. The percentage of peaks tetrapeptide in relation to the amount of tetrapeptide and heptapeptide characterizes the rate of cleavage.

In table.1 shows the values of the IC50representing the concentration of inhibitor at which the rate of cleavage is reduced by half.

The target peptide was obtained with the Irma Novabiochem (loading of about 0.5 mmol/g resin). The loaded resin was 1, Synthesis was performed according to the program of synthesis, modified for Fmos method.

Used the following derivatives of amino acids: OH, Fmoc-opr-OH, Fmoc-phe-oobt, Fmoc-asn-OH and Fmoc-ser/t-b/-oobt. For the synthesis of Fmoc-opr-OH was synthesized H-opr-OtBu according to the method Vasella and others (J. S. S. hem. Somme. 1981, 97-98 C.) and then subjected him to interact with Fmoc-osu in a mixture of dioxane and water at a ratio of 1:1 in the presence of NaHCO3. Subsequent cleavage butyl ether triperoxonane acid is formed Fmoc-opr-HE.

In cartridges of the reactor was loaded on a 1 mmol derived amino acid with a free carboxyl group and 0.95 mmol OObt. Pre-activation of these amino acids was performed directly in the cartridges by dissolving in 4 ml of DMF and adding 2 ml of 0.55 M solution of diisopropylcarbodiimide in dimethyl. OObt - esters of other amino acids was dissolved in 6 ml of NMP and then, just as in the case of pre-activated in situ amino acids, have been combined with previously released 20% solution of piperidine in DMF the resin. After completion of the synthesis was conducted cleavage of the peptide (with simultaneous removal of the protective groups of the side chains) by processing triperoxonane acid used is Socrate insisted with acetic ether and centrifuged.

The residue after centrifugation was subjected to chromatographic separation on dextranomer gel using as mobile phase of 10% acetic acid. Containing pure peptide fraction was evaporated and dried using freeze-drying.

Mass spectrum (FAB): 854 (M+N+)

Amino acid analysis: asp: 0,98, SEG: 0,80, glu: 1,00, Ile: 1,05, phe: 2,10, NH3: 1,76.

The invention relates to the use of compounds of the formula I as medicaments and pharmaceutical preparations containing these compounds. Preferred is their use for the treatment of primates, in particular humans.

The pharmaceutical preparations contain an effective amount of the active substance of the formula I in combination with inorganic or organic pharmaceutical acceptable carrier. The proposed remedies you can use nasal, intravenous, subcutaneous or oral. The dosage of the active substance depends on the species of warm-blooded animals, their weight, age and method of administration. The pharmaceutical preparations according to the invention receive known ways: by dissolving, mixing, granulating, tabletting.

To obtain oral forms of active soy is militatry or inert diluents, and using conventional methods to form mixtures of the desired form, for example tablets, coated tablets, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers can be used, for example, gum Arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose, fumarate magnesium or starch, in particular corn starch. This composition can be obtained in the form of dry and wet granulate. As oily carriers or solvents can be used, for example, vegetable or animal oils, such as sunflower oil and fish oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, optionally in combination with commonly used for such purposes, the materials, such as agents, dissolving, emulsifying agents or other adjuvants, are prepared in the form of solutions, suspensions or emulsions. As solvents it is possible to use water, physiological salt solutions or alcohols, for example ethanol, propandiol or glycerol, as well as solutions of sugars such as glucose or mannitol, or a mixture of these dissolve the drugs you can use, for example, crystalline suspensions, microcapsules, sticks or implants, the latter can be made of dumisa polymers, in particular biodegradable polymers, for example on the basis of copolymers of polylactic and polyglycolic acids, or human albumin.

Abbreviations used to denote amino acids that correspond to the one adopted in the chemistry of peptides three-letter code (described, for example, in EIG. J. Biochem. 138. 1984, 9-37). Unless otherwise specified in the mentioned amino acids have-configuration.

Other abbreviations:

FAB - fast atom bombardment

M - molecular peak

SIDE - tert.-butoxycarbonyl

P R I m e R 1. N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L - felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

100 mg of N,N'bis-(L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride, mg N-tertbutoxycarbonyl-L-phenylalanine, or 0.57 ml of N-ethylmorpholine and 60 mg oxibendazole was dissolved in 1.5 ml of dimethylformamide. Once added to a solution of 85 mg DAC at 0oC stirring continued for a further hour at 0oC and then overnight at room temperature. After that, the solvent is kept in vacuum, the residue rascasse phase was dried anhydrous NaSO4and was evaporated. The residue was recrystallized from a mixture of ethanol and water. The yield was 92 mg.

MS (FAB): 993 (M+H)+, 975, 893, 793

NMR (270 MHz, DMSO<D>): 0,72 (d, GC, 6N); 0.75 in (d, GC, 6N); of 1.29 (s, N); to 1.86 (m, 2H); 2,60-2,96 (m, 8H); 3,30 (m, 2H); to 4.17 (m, 2H); of 4.45 (m, 2H); and 4.68 (m, 2H); 7.03 is (d, 9 Hz, 2H); 7,05-7,30 (m, 22N); 7,53 (d, 9 Hz, 2H).

P R I m m e R 2. N,N'bis-(L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-bildegalleri

220 mg of N, N'bis-(tertbutoxycarbonyl-L-felled)-2S, 5S-diamino-1,6-diphenyl-3,4-0-isopropylidene-3R, 4R-diol was dissolved in approximately 10 ml of 3 n Hcl solution in a mixture of dioxane and methanol at a ratio of 1:1 and stirred the solution for one hour at room temperature. Volatile components of the solution is kept in vacuum and dried the residue in high vacuum. The resulting material was used without further purification in the subsequent stage. The output 184 mg.

Mass spectrum (FAB): 499 (M+N)+, 481, 463.

P R I m e R 2.1. N,N'bis-(tert.-butoxycarbonyl-L-felled)-2S, 5S-diamino-1,6-diphenyl-3,4-0-isopropylidene-3R, 4R-diol.

136 mg of 2S, 5S-diamino-1,6-diphenyl-3,4-0-isopropylidene-3R, 4R-diol, 0,54 mg NEM and 260 mg of N-tertbutoxycarbonyl-L-valine was dissolved in 2 ml of dry ethyl acetate. If -10oC to photoperiodically for one hour at 0oC and then overnight at room temperature. After this, the solution was diluted with ethyl acetate and sequentially was extracted with a saturated solution of NaHCO310% solution of KHSO4and water. The organic phase was dried over anhydrous MgSO4, was evaporated to a residue that was subjected to purification using chromatography on silica gel (mobile phase: a mixture of dichloromethane and methanol at a ratio of 97:3). The yield of the target compound 230 mg.

Mass spectrum (FAB): 739 (M+N)+, 681, 639, 569, 539.

P R I m e R 2.2. 2S, 5S-diamino-1,6-diphenyl-3,4-0-isopropylidene-3R, 4R-diol.

2.3 g 2S, 5S-diazido-1,6-diphenyl-1,6-0-isopropylidenebis-3R, 4R-diol was dissolved in 50 ml of methanol and the prepared solution was subjected to hydrogenation for 2 hours at normal pressure in the presence of about 0.2 g of palladium on coal (10%). The catalyst was then filtered and after evaporation of the solution, the residue was subjected to chromatographic separation on silica gel (mobile phase: a mixture of dichloromethane and methanol at a ratio of 99:1). The output of 1.33 g

Mass spectrum (FAB): 341 (M+N)+< / BR>
NMR (270 MHz, DMSO<D>): 1,29 (m, 4H); to 1.37 (s, 6N); 2,71 (double d, 12 Hz, 5 Hz, 2H); 2,870 (m, 2H); of 3.32 (m, 2H); of 3.95 (s, 2H); 7,12-7,33 (m, 10H).

P R I m e R 2.3. 2S the-3,4-0-isopropylidene-3S, 4S-diol was dissolved in 300 ml of DMF, and the prepared solution was heated for 4 h at 50oC approximately 9.2 g NaN3and 6.3 g of 18-crown-6. A large part of the solvent then drove in a vacuum, the residue was dissolved in ether and extraction was performed in an aqueous solution of NaHCO3. After washing with water the organic phase was dried and evaporated. The residue was subjected to chromatographic separation on silica gel (mobile phase: a mixture of toluene and n-hectan in the ratio 2:5-2:3). The result obtained is 2.37 g of the target compound.

NMR (270 MHz, DMSO<D>): 1,48 (C, 6N); 2,92-of 3.12 (m, 4H); 3,74 (double d, 10 Hz, 5 Hz, 2H); 4,15 (s, 2H); 7,21-7,30 (m, 10H).

P R I m e R 2.4. 2R, 5R-di-(4-nitrophenylacetylene) -1,6-diphenyl-3,4-0-isopropylidene-3S, 4S-diol.

5.6 g 2R, 5R-deoxy-1,6-diphenyl-3,4-0-isopropylidene-3R, 4R-diol, 7.9 g of 4-dimethylaminopyridine was dissolved in 300 ml of chloroform. To the prepared solution was added at room temperature 14.5 g of p-nitrobenzenesulfonamide and the mixture was stirred for 3 h at 50oC. then it was diluted with methylene chloride and was extracted sequentially with solutions of bicarbonate, KHSO4and NaCl. After drying the organic phase was evaporated. Output: 11,8,

Mass spectrum (FAB): d 15 Hz, 3 Hz, 2H); to 4.41(c,2H); 5,07 (DM, 9 Hz, 2H); 6,95-7,11 (m, 10H); 7,73 (d, 9 Hz, 4H); 8,18 (d, 9 Hz, 4H).

P R I m e R 2.5. 2R, 5R-deoxy-1,6-diphenyl-3,4-0 - isopropylidene-3R, 4R-diol 1.12 g of 1,2 R-5R,6-diepoxy-3,4-0-isopropylidene-3R-4R-diol was added in an argon atmosphere at -78oC to a solution of 36 mmol (C6H5)2uLi in 60 ml of dry ether. After that, remove the cooling bath and under stirring, the mixture was heated to room temperature. Then it was mixed with 250 ml ethyl acetate and was extracted three times with a mixture of 25% aqueous ammonia and ammonium chloride. The ethyl acetate phase was washed with NaCl solution, dried and evaporated. The residue was subjected to purification using chromatography on silica gel (mobile phase: a mixture of dichloromethane and ethyl acetate at a ratio of(97:3)-(90:10). As a result received 1.86 g of the target compound.

Mass spectrum (FAB): 343 (M+N)+, 327, 285, 267.

NMR (270 MHz, DMSO<D>): 1,39 (C, 6N); 2,58 (double d, 13 Hz, 9 Hz, 2H); 3.43 points (double d, 13 Hz, 3 Hz, 2H); 3,68 (m, 2H), 3,83 (m, 2H); of 5.05 (d, 6 Hz, 2H); 7,14-to 7.32 (m, 10H).

P R I m e R s 3-5. 3) N,N'bis-(tert.-butoxycarbonyl)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

4) N,N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

5) N,N'bis-(tert.-butoxycarbonyl)-2S, 5S-di is tetrahydrofuran and cooled the solution to 0oC in argon atmosphere. Then thereto was added over about 20 min 1 l of 0.1 M solution SmI2in tetrahydrofuran and the mixture was stirred for 30 min at room temperature, acidified 0.1 N. aqueous solution of Hcl to pH 1-2, diluted IT, separating the organic phase and carried out the extraction of 0.1 N. Hcl, twice with a solution of Na2S2O3and twice with water. After drying over MgSO4it was evaporated and subjected to chromatography on silica gel (mobile phase: a mixture of ethyl acetate and petroleum ether in the ratio 1:2).

The fraction containing 3R, 4R-isomer was recrystallized from a mixture of ethanol and water.

From the fractions containing 3S, 4S - 3R, 4S-isomer, 3S, 4S-isomer could be obtained by crystallization from a mixture of dichloromethane, isopropyl ether and heptane. To obtain the 3R, 4S-isomer making the solution was subjected to chromatographic separation on silica gel R R18 (the mobile phase; the mixture of acetonitrile and water at a ratio of 4:6).

Output: 3R, 4R-isomer of 1.61 g; 3S, 4S-isomer of 1.00 g; 3R, 4S-isomer of 0.71 g

Rf: silica gel, a mixture of HER and hexane at a ratio of 1:2; 3R, 4R-isomer of 0.18; 3S, 4S-isomer 0,41; 3R, 4S-isomer of 0.39.

Mass spectrum (FAB): 501 (M+N)+, 401, 345, 327, 301 - 3R, 4R-isomer; 501 (who gt;) are presented in table.2.

Identification of the 3R, 4S-isomer was carried out by a double set of signals, 3R, 4R and 3S, 4S-isomers were distinguished by comparison with synthetic samples, obtained from D-mannitol (see example 3.1). The determination of the constants of the combination after removal of tertbutoxycarbonyl groups and translation of isomers with phosgene in dual 2-oxazolidinone system gave the matching results.

P R I m e R 3.1. Definition of stereoconfiguration isomers in accordance with examples 3-5.

N, N'bis-(tert.-butoxycarbonyl)-2S, 5S-diamino-1,6-diphenyl-hexane-3R, 4R-diol

140 mg of 2S,5S-diamino-1,6-diphenyl-3,4-0 - isopropylidene-3R,4R-diol was dissolved in a mixture of 5 ml of 1 N. Hcl in methanol and 5 ml of 5 N. Hcl in dioxane and stirred the solution for 4 h at room temperature. Volatile components were released to the vacuum. The residue was dried in high vacuum and the resulting 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-bildegalleri (mass spectrum (FAB): 301 (M+N)+free base) without additional purification used at a later stage.

45 mg of 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-dialdegidzelllozu was dissolved in 5 ml of dry dichloromethane and stirred for 3 h at room temperature with 40 μl of triethylamine and 75 mg AI solutions KHSO4, NHCO3and NaCI. After drying over anhydrous Na2SO4the organic phase was evaporated and the residue was purified by chromatography on silica gel, using as mobile phase a mixture of acetonitrile and DCM in the ratio of 1:8. Exit 23 mg.

Mass spectrum (FAB): 501 (M+H)+, 401, 345, 327, 301.

The compound obtained was identical to the most polar of the isomers in accordance with examples 3-5.

P R I m e R 6. N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L - felled)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol

38 mg of N,N'bis-(tertbutoxycarbonyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol was treated for 30 min 5 N. HCl in dioxane. Volatile components were removed in vacuum and the residue was dried. Thus obtained N, N'bis-(L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol-dihydrochloride together with 40 mg of tertbutoxycarbonyl, 22 mg of hydroxybenzotriazole and 51 mg of tetrafluoroborate 2-(1H-benzotriazolyl-1)-1,1,3,3 - tetramethyluronium (TBTU) was dissolved in 1 ml of dry dimethylformamide. To the solution was added 60 μl of ethyldiethanolamine and the mixture was stirred for 15 min at room temperature. Dimethylformamide drove away, the residue was dissolved in ethyl acetate and extcheck phase was concentrated, moreover, this was accompanied by the precipitation of a crystalline precipitate, which was filtered, washed with ether and was obtained 30 mg of target compound.

Mass spectrum (FAB): 1015 (M+Na)+, 993 (M+H)+, 893, 793.

NMR (270 MHz, DMSO < D6>): 0,79 (m, N); 1.28 (in C, N); of 1.85 (m, 2H); 2,68-2,82 (m, 4H); 2,85-3,03 (m, 4H); 3,37 (m, 2H); 4,00-4,13 (m, 4H); is 4.21 (m, 2H); of 4.66 (d, 7 Hz, 2H); 7.03 is (d, Hz, 2H); 7,05-7,34 (m, 2HE); a 7.62 (d, Hz, 2H); to 7.68 (d, 8gts, 2H).

P R I m e R 7. N,N'bis-(tertbutoxycarbonyl-L - i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4S-diol.

The target compound was synthesized in the manner similar to that described in example 6, using as starting compound N,N'bis-(tributoxyethyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4S-diol.

Mass spectrum (FAB), 1015 (M+Na)+, 993 (M+H)+, 893, 793.

NMR (270 MHz, DMSO < D6>): 0,68-0,85 (m, N); 1.28 (in C, N); of 1.30 (s, N); 1,75-2,03 (m, 2H); about 2.5-3,30 (m, 8H); about 3.3-3,51 (m, 2H); 4,05-4,30 (m, 5H); 4,43 (m, 1H); 4,74 (d, 4 Hz, 1H); 5,32 (d, 7 Hz, 1H); 6,93-7,35 (m, 22N); to 7.61 (d, 8 Hz, 1H); to 7.67 (d, 7 Hz, 1H); a 7.85 (d, 8 Hz, 1H); 7,92 (d, 7 Hz, 1H).

P R I m e R 8. N,NIbis-(tributoxyethyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

164 mg N, N'bis-(tributoxyethyl)-2S, 5S-D. Lucie components were then removed in vacuum and the residue was dried. Thus obtained 2S, 5S-diamino-1,6-diphenyl-hexane-3S, 4S-diol dihydrochloride was dissolved together with 178 ml tertbutoxycarbonyl-L-valine and 0.56 ml of NEM in 15 ml of dry dimethylformamide. To the resulting solution was added at -5oC of 0.53 ml of a 50% aqueous solution of anhydride n-propyl-phosphonic acid (PFA) in ethyl acetate, the mixture was stirred for one hour at 0oC and then overnight at room temperature, the solvent drove in a rotary evaporator, the residue was dissolved in ethyl acetate and subjected to extraction with water, solution NaHCO3and KHSO4and again with water. After drying over anhydrous Na2SO4the organic phase was evaporated in vacuum. When processing of the residue in diethyl ether precipitated crystalline precipitate the product, which was recrystallized from a mixture of ethanol and water. Exit 59 mg.

Mass spectrum (FAB): 699 (M+H)+, 599, 499.

P R I m e R 9. N,N'bis-(tertbutoxycarbonyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R,4S-diol.

The synthesis was carried out in the same manner as in example 8, using as starting compound N,N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-diphenylhexane-3R,4S-dio the Mino-1,6-diphenylhexane-3R, 4R-diol-tetrahydrochloride.

The synthesis was carried out in the same manner as in example 2 from the compound in accordance with example 11.

Mass spectrum (FAB, LiI), 761 (M+Li)+, 755 (M+N)+, 737.

P R I m e R 11. N,N'bis-(N < tertbutoxycarbonyl>-L-lysyl-L-felled) 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol-dihydrochloride.

36 mg of N,N'bis-(<N-tertbutoxycarbonyl>L-lysyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol synthesized in the same manner as in the case of example 1, from N-benzyloxycarbonyl-N-tributoxyethyl-L-lysine and N,N'bis-(L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride was first made in the presence of palladium catalyst on charcoal in the medium of methanol, the pH of the solution with a solution of Hcl in methanol was maintained equal to examples 3-4. After filtering off the catalyst and concentrating received 26 mg of the target product.

Mass spectrum (FAB, LiI): 961 (M+Li)+< / BR>
NMR (270 MHz, DMSO < D6>): 0.75 in (d, 5 Hz, 6N); 0,78 (d, 5 Hz, 6N); about 1.13 is 1.60 (m, about N); to 1.38 (s, N); of 1.88 (m, 2H); about 2,50 of 2.68 (m, 2H); 2,72-to 2.94 (m, 6N); and 3.72 (m, 2H); 4,22 (m, 2H); 4,37 (m, 2H); to 4.41-4,55 (m, 4H);4.72 in (m, 2H); 6,76 (m, 2H); 7,05-of 7.23 (m, N); 7,66 (d, 8 Hz, 2H); 8,15 (d, 9 Hz, 2H).

The synthesis was carried out in the same manner as in example 11.

Mass spectrum (FAB): 1051 (M+H)+, 951.

P R I m e p 13. N,N'bis-<[2S-(1,1-dimethylaminocarbonylmethyl) -3-(1-naphthyl)-propionyl]-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

57 mg of N,N'bis-(L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride, 95 mg of [2S-(1,1-dimethylaminocarbonylmethyl)-3-(1-naphthyl)]-propionic acid, 41 mg of hydroxybenzotriazole, and 96 mg TBTO was dissolved in 1 ml of dry dimethylformamide. At room temperature the solution was added to 0.11 ml of N-ethyldiethanolamine and the mixture was stirred for one hour. The solvent is then drove away in a rotary evaporator, the residue was dissolved in 30 ml of ethyl acetate and subjected to extraction solution bisulfate, bicarbonate and water. After drying over Na2SO4and concentrating the obtained product was subjected to purification using chromatography on silica gel (mobile phase: a mixture of dichloromethane and methanol at a ratio of 97:3). As a result received 31 mg of the target compound.

Mass spectrum (FAB), 1153 (M+ Na)+, 1131 (M+H)+, 716.

NMR (270 MHz, DMCO < D6>: 0.69 (d, 7 Hz, 6N); 0,76 (d, 7 Hz, 6N); 1,10 (s, N); to 1.86 (m, 2H); 2.63 in-2,87 (m, 6N); is 3.08 (m, 2H); about 3.25 to 3,44 (P> P R I m e R 14. N,N'bis-(L-seryl-L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R,4R-bildegalleri.

The synthesis was carried out in the same manner as described in example 16.

Mass spectrum (FAB, LiI): 973 (M+Li)+, 967 (M+H)+.

P R I m e R 15. N,N'bis[tertbutoxycarbonyl-L- (0-tributylstannyl)-L-i.e. phenylalanyl-L-valil]-2S,5S-diamino-1,6-diphenyl-hexane-3 R,4R

52 mg of N,N'bis-(L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride, 18 mg of hydroxybenzotriazole, and 15.3 μl of N-ethylmorpholine and 35 ml Of tert.-butyl-N-tertbutoxycarbonyl-L-serine was dissolved in 1 ml dry DMF and the resulting solution was mixed at 0oC from 25.3 mg of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (HDCI). The mixture was stirred for one hour at 0oC and then overnight at room temperature. The solvent is then drove away in a rotary evaporator, the residue was dissolved in ethyl acetate and subjected to extraction solution bisulfate, bicarbonate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to purification using chromatography on silica gel. The result obtained 28 mg of the target compound.

Mass spectrum (FAB): 1301 is); to 1.38 (s, N); to 1.82 (m, 2H); 2,61 are 2.98 (m, 8H); approximately 3,15 is-3.45 (m, approximately 6N); to 3.92 (m, 2H); 4,11 (double d, 8 Hz, 6 Hz, 2H); 4,47 (m, 2H); 4,63 (m, 4H); to 6.58 (d, 8 Hz, 2H);? 7.04 baby mortality-7,25 (m, 2HE); 7,46 (d, 9 Hz, 2H); to 7.77 (d, 8 Hz, 2H); 7,83 (d, 8 Hz, 2H).

P R I m e R 16. N,N-bis-(L-i.e. phenylalanyl-L-avril)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride.

100 mg of N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol (example 1) were treated for 30 min at room temperature with a mixture of 2 ml of 5 n Hcl dioxane and 1 ml of Hcl in methanol. Volatile components were removed in vacuo, the residue was washed with ether and dried in high vacuum. Exit 59 mg.

Mass spectrum (FAB): 793 (M+H)+, 775.

P R I m e R 17. N,N'bis-(L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-bildegalleri.

The synthesis was carried out using a method similar to that described in example 16.

Mass spectrum (FAB): 793 (M+H)+, 775.

P R I m e R 18. N,N'bis-(L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4S-diol dihydrochloride.

The synthesis was carried out using a method similar to that described in example 16.

Mass spectrum (FAB): 793 (M+H)+, 775.

P R I m e R 19. N,N'bis-(L-series L-phenylalaninol described in example 14.

Mass spectrum (FA): 967 (M+H)+.

P R I m e R 20. N,N'bis-(L-seryl-L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4S-diol dihydrochloride.

The synthesis was carried out according to the method similar to that described in example 14.

Mass spectrum (FAB): 967 (M+H)

P R I m e R 21. Bis-[N-(L-i.e. phenylalanyl-L-felled)-2S - amino-3-phenylpropyl] -amitriptaline.

The synthesis was carried out according to the method similar to that described in example 16, the compound in accordance with example 22.

Mass spectrum (FAB): 776 (M+H)+.

P R I m e R 22. Bis-[(N-tertbutoxycarbonyl-L-i.e. phenylalanyl-L-felled)-2S-amino-3-phenylpropyl]-amine.

The synthesis was carried out according to the method similar to that described in example 6, the compounds in accordance with example 23.

Mass spectrum (FAB, LiI): 982 (M+Li)+, 976 (M+H)+.

NMR (270 MHz, DMCO < D6>): 0,81 (m, N); of 1.29 (s, N); 1,89) (m, 2H); about 2.45-2,98 (m, about N); of 3.97 (m, 2H); 4,05-of 4.25 (m, 4H); 7,03 (d, 9 Hz, 2H); 7,10-7,31 (m, 20N); the 7.65 (d, 8 Hz, 2H); to 7.84 (d, 8 Hz, 2H).

P R e m a R 23. Bis-[N-(L-felled)-2S-amino-3-phenylpropyl]-Amin trihydrochloride.

The synthesis was carried out by a method similar to that described in example 16, the compound in accordance with example 24.

Mass spectrum (Synthesis was performed using the method, similar to that described in example 16 from example 25.

Mass spectrum (FAB): 682 (M+H)+.

NMR (270 MHz, DMCO < D6>): 0,73 (d, 6 Hz, 6N); 0,77 (d, 6 Hz, 6N); to 1.38 (s, N); of 1.65 (m, 1H); to 1.82 (m, 2H); 2,42 - about of 2.53 (m, about 4H); 2,64 (double d, 14 Hz, 8 Hz, 2H); 2,84 (double d, 14 Hz, 6 Hz, 2H); 3,68 (m, 2H); 3,93 (m, 2H); of 6.50 (d, 9 Hz, 2H); 7,12-7,28 (m, 10H); a 7.62 (d, 8 Hz, 2H).

P R I m e R 25. Bis-(N-tertbutoxycarbonyl-2S-amino-3 - phenylpropyl)-amidohydrolase.

9.6 tertbutoxycarbonyl-L-phenylalanine, 30.5 g NH4OAc and 1.7 g of NaBH3CN was dissolved in 300 ml of methanol and stirred the solution for 6 h at room temperature. Using concentrated Hcl, the solution was acidified to pH < 2. In addition, the product precipitated, which insisted with diethyl ether and water, and dried in high vacuum. The result was obtained 3.1 g of the target compound.

Mass spectrum (FAB): 484 (M+H)+, 428, 372.

NMR (270 MHz, DMCO < D6): of 1.33 (s, N); 2,55-2,90 (m, 8H); 3,82 (m, 2H); 6.75 in (m, 2H); 7,12-7,325 (m, 20N).

P R I m e R 26. N,N'bis-(5S-amino-4S-hydroxy-7-methyloctanoic)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out according to the method similar to that described in example 16.

Mass spectrum (FAB): 643 (M+H)+, 625.

P R I m e R 26.1. N,N'bis-(N-tertbutoxycarbonyl-5S - amino-7-methyl-4S)-tert-butyldimethylsilyl(oxy octanoyl)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

and 88.5 mg of N,N'bis-tertbutyloxycarbonyl-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol was treated for 30 min at room temperature, 2 ml of 5 n Hcl in dioxane. Volatile components were released to the vacuum, and the residue was dried in high vacuum. Received 2S, 5S-diamino-1,6-diphenylhexane-3S, 5S-diol dihydrochloride were dissolved together with 211 mg N-tertbutyloxycarbonyl-5S-amino-7-methyl-4S-(tributylammonium) -oxooctanoate acid, synthesized from (5S)-5-<(1S)-1-(N-BOC-amino)-3-methylbutyl> dihydrofuran-2-(3H)-she, 72 mg of hydroxybenzotriazole (peso) and 28.5 microtron N-ethylmorpholine (N-EM) in 5 ml of dry dimethylformamide. At 0oC to the resulting solution was added 101 mg HDCI, the solution was stirred at this temperature for one hour and then overnight at room temperature. The solvent is then drove away in a rotary evaporator, the residue was dissolved in ethyl acetate and subjected to extraction solutions KHSO4, NaHCO3and NaCl. After wyszukiwania phase: a mixture of dichloromethane and acetonitrile at a ratio of 5:1).

Exit 129 mg.

Mass spectrum (FAB): 1093 (M+H)+, 1071 (M+H)+, 971,871.

NMR (270 MHz, DMCO < D6>): 0,02 (C, 6N); 0,08 (C, 6N); 0,77 with 0.93 (m, 3OH); about 1.1 to 1.4 (m, approximately 6N); 1,45-to 1.63 (m, 4H); 1.91 a (m, 2H); 2,02-of 2.16 (m, 2H); 2,67 (double d, 11 Hz, 14 Hz, 2H); to 3.36 (m, 2H); 3.42 points of 3.56 (m, 4H); 3,95 (m, 2H); to 4.81 (d, 6 Hz, 2H); 6,44 (d, 8 Hz, 2H); 7,08-7,30 (m, 10H); 7,79 (d, 9 Hz, 1H).

P R I m e R 27. N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L - felled)-3S, 6S-diamino-1,8-di-(4-pyridyl)-octane-4R, 5R-diol.

The synthesis was carried out according to the method similar to that described in example 6, using as starting compound 3S, 6S-diamino-1,8-di-(4-pyridyl)-octane-4R, 5R-diol tetrahydrochloride.

NMR (270 MHz, DMCO < D6>): 0,85 (d, 6 Hz, N); 1,20 (s, 18 h); of 1.66 (s, 2H); of 1.78 (m, 2H); 2,00 (m, 2H); about 2,48 (m, 4H); to 2.74 (m, 2H); 2,98 (m, 2H); about of 3.31 (m, 2H); 4,08 (m, 2H); 4,19 (m, 2H); 4,30 (m, 2H); and 4.68 (m, 2H); 7,01 (d, 8 Hz, 2H); 7,10-7,30 (m, 14N); a 7.62 (d, 8 Hz, 2H); 7,74 (d, 8 Hz, 2H); 8,43 (d, 4.8 Hz, 4H).

Mass spectrum (FAB): 1023 (M+H)+; 923, 823.

P R I m e R 27.1. 3S, 6S-diamino-1,8-di-(4-pyridyl) -octane-4R,5R-diol tetrahydrochloride.

The synthesis was carried out similar to that described in example 2, 2.2, 2.3 and 2.4 by the way, using as starting compounds 1,2 R-5R,6-diepoxy-3,4-0-isopropylidene-3R,4R-diol and 4-picalilli.

YAM 7 Hz, 4H); 8,18 (m, 6N); 8,88 (d, 7 Hz, 4H).

Mass spectrum (FAB): 331 (M+H)+.

P R I m e R 28. N,N'bis-(2S-<2S-amino-3-phenyl-propyl> -amino-3-methyl-butanoyl)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol tetrahydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 765 (M+H)+.

P R I m e R 29. N,N'bis-(2S-<2S-tertbutoxycarbonyl-3-phenylpropyl>-amino-3-methylbutanoyl)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol

Taken in a quantity of 50 mg of N,N'bis-(tertbutoxycarbonyl) -2S,5S-diamino-1,6-diphenylhexane-3S, 5S-dialo was tsalala similar to that described in example 8 by way of the protective group. The resulting 2S, 5S-diamino-1,6-diphenylhexane-3S, 5S-diol dihydrochloride together with 70 mg of 2S-(2S-tertbutoxycarbonyl-3-phenylpropyl)-amino-3-methylbutanoic acid, synthesized by reductive combination tertbutoxycarbonyl-L-phenylalanine hydrochloride and L-valintatalo ether with NaBH3CN and subsequent normal cleavage of the methyl ester, 41 mg of hydroxybenzotriazole and 12.6 ág N-EM was dissolved in 5 ml of dry dimethylformamide. At 0oTo the resulting solution was added 57 mg HDCI and the mixture was stirred for one hour is e, the residue was dissolved in dichloromethane and washed with solutions of KHSO4, NaHCO3and NaCl. After drying the organic phase and concentration, the residue triturated with diethyl ether.

Exit 33 mg.

Mass spectrum (FAB): 965 (M+H)+, 865, 765.

NMR (270 MHz, DMCO < D6>): 0,74 (d, 7 Hz, 6N); 0,78 (d, 6 Hz, 6N); of 1.33 (s, N); and 1.63 (m, 2H); 1,94-of 2.16 (m, 4H); about 2.5 m, about 4H); of 2.64 (m, 2H); 2,81 (double d, 14 Hz, 5 Hz, 2H). 3,13 (LW.m, 14 Hz, 2H); 3.42 points (m, 2H); of 3.56 (m, 2H); 4,10 (m, 2H); 4,90 (m, 2H); to 6.58 (d, 9 Hz, 2H); 7,05-7,30 (m, 2HE); a 7.85 (d, 8 Hz, 2H).

P R I m e R 30. N,N'bis-(L-i.e. phenylalanyl-L-felled)-2R, 5R-diamino-1,6-diphenylhexane-3R, 4R-diol-dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 793 (M+H)I< / BR>
P R I m e R 31 N,N'bis-(L-i.e. phenylalanyl-L-felled)-2R,5R - diamino-1,6-diphenylhexane-3S, 4S-diode dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FA): 793 (M+H)+< / BR>
P R I m e R 32. N,N'bis-(L-i.e. phenylalanyl-L-felled)-2R, 5R-diamino-1,6-diphenylhexane-3R, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 793 (M+H)+.

P R and m is

Mass spectrum (FAB): 993 (M+H)+, 893, 793.

NMR (270 MHz, DMCO < D6>): 0,48 (d, 7 Hz, 6N); 0,54 (d, 6 Hz, 6N), 1,25 (s, 18 H); to 1.70 (m, 2H); 2,60 (t, 13 Hz, 2 Hz, 2H); 2,74 (double d, 14 Hz, 11 Hz, 2H); 2,96 (double d, 13 Hz, 4 Hz, 2H); 3,13 (double m, 14 Hz, 2H); 3,39 (m, 2H); as 4.02-4.25 in (m, 6N); 4,88 (d, 4 Hz, 2H); 7,02 (d, 9 Hz, 2H); 7,07-7,33 (m, 2OH); 7,60 (d, 9 Hz, 2H); 8,24 (d, 9 Hz, 2H).

P R I m e R 34. N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L-felled)-2R,5R-diamino-2,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 993 (M+N)+, 893, 793.

P R I m e R 35. N,N'bis-(tertbutoxycarbonyl-L - i.e. phenylalanyl-L-felled)-2R, 5R-diamino-1,6-diphenylhexane-3R, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 993 (M+H)+, 893, 793.

P R I m e R s 36-38.

36) N,N'bis-(tertbutoxycarbonyl)-2R,5R-diamino-1,6-diphenylhexane-3R, 4R-diol.

37) N,N'bis-(tertbutoxycarbonyl)-2R,5R-diamino-1,6-diphenylhexane-3S, 4S-diol

38) N,N'bis-(tertbutoxycarbonyl)-2R,5R-diamino-1,6-diphenylhexane-3R, 4S-diol.

The synthesis was carried out analogous to those described in examples 3-5 way, using as starting compound trebu their enantiomers in accordance with examples 3-5.

P R I m e R 39. N,N'bis-[L-(1-naphthyl)alanyl-L-valil]-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB. LiI): 899 (M+Li)+, 893 (M+H)+, 875.

P R I m e R 40. N,N'bis-[tertbutoxycarbonyl-L- (1-naphthyl)alanyl-L-valil]-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1093 (M+H)+, 993.

NMR (270 MHz, DMCO < D6>): 0,76 (m, N); of 1.23 (s, N); 1,89 (m, 2H); 2,60-2,87 (m, 4H); 3,12 (double d, 14 Hz, 10 Hz, 2H); about to 3.33 (m, 2H); 3,52 (double m, 4 Hz, 2H); 4,16 is 4.35 (m, 4H); of 4.44 (m, 2H); 4,70 (s, 2H); 7,00-7,27 (m, N); 7,37-7,44 (m, 4H); 7,46-to 7.68 (m, 8H); 7,79 (m, 2H); 7,92 (d, 8 Hz, 2H); 8,13 (d, 8 Hz, 2H).

P R I m e R 41. N,N'bis-[(2-(2-acetylsulfapyridine) -3-phenylpropionyl)-L-valil]-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 13 by the way.

Mass spectrum (FAB): 1007 (M+H)+.

P R I m e R 42. N,N-bis-[L-i.e. phenylalanyl-L-valil]-2S, 5S-diamino-1,6-dicyclohexylmethane-3R, 4R-diol-dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (F is Xan-3S, 4S-diol-dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 805 (M+H)+, 787.

P R I m e R 44. N,N'bis-(tertbutoxycarbonyl-L-i.e. phenylalanyl-L-2S, 5S-diamino-1,6-dicyclohexylmethane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1005 (M+H)+, 987, 905, 805.

P R I m e R 45. N,N'bis-(tertbutoxycarbonyl-L - i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-dicyclohexylmethane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1005 (M+H)+; 987; 905; 805.

NMR (270 MHz, DMCO <D>): 0,86 (m, N), 0,99-to 1.67 (m, about 24N); 1.28 (in C, N; of 1.74 (m, 2H); to 1.98 (m, 2H); 2,75 (double d, 14 Hz, 11 Hz, 2H); 2,96 (double d, 14 Hz, 4 Hz, 2H); 3,23 (m, 2H); to 3.89 (m, 2H); 4,13-of 4.25 (m, 2H); was 4.42 (d, 5 Hz, 2H); 7,02 (d, 8 Hz, 2H); 7,13-to 7.32 (m, 10H); 7,69-7,81 (m, 4H).

P R I m e R 46. N,N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-dicyclohexylmethane-3S,4S-diol.

200 mg of N, N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol was dissolved in 25 ml of glacial acetic acid and was carried out by hydrogenation for 18 h at 60oC and 120 bar in the presence of 100 mg dioc the STATCOM recrystallized from a mixture of ethanol and water.

The output 150 mg.

Mass spectrum (FAB): 535 (M+Na)+, 513 (M+H)+, 413.

MR (270 MHz, DMCO <D>): 0,75 (m, 2H); 0,94 (m, 2H); 1,03-1,32 (m, 1OH); to 1.38 (s, N); the 1.44 (m, 2H); 1,50-of 1.73 (m, 8H); of 1.80 (m, 2H); up 3.22 (m, 2H); of 3.53 (m, 2H); 4,28 (d, 6 Hz, 2H); 6.48 in (d, 9 Hz, 2H).

P R I m e R 47. N,N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-dicyclohexylmethane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 46 by the way.

Mass spectrum (FAB): 513 (M+H)+, 413.

NMR (270 MHz, DMCO <D>): 0,65-to 0.96 (m, 4H); 1,03 of 1.28 (m, O); 1,30-1,45 (m, 2HE); 1,54 is 1.70 (m, 8H); to 1.82 (m, 2H); 3,11 (m, 2H); to 3.89 (m, 2H); 4,22 (m, 2H); 5,88 (d, 9 Hz, 2H).

P R I m e R 48. N,N'bis-(tertbutoxycarbonyl)-2S, 5S-diamino-1,6-dicyclohexylmethane-3R, 4S-diol.

The synthesis was carried out similar to that described in example 46 by the way.

Mass spectrum (FAB): 513 (M+H)+, 413.

P R I m e R 49. N,N'bis-(4Z-aminocyclohexanecarboxylic) -L-i.e. phenylalanyl-L-felled)-2S, 5S-diamino-1,6-diphenyl-3S, 5S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16, respectively 6.

Mass spectrum (FAB): 1043 (M+H)+, 1025.

P R I m e R 50. N,N'bis-(4Z-N-tertbutoxycarbonyl)- cyclohexanecarbonyl-L-i.e. phenylalanyl-L-Vali the way.

Mass spectrum (FAB): 1243 (M+H)+, 1143, 1043.

P R I m e R 51. N,N'bis-(2S-(1,1-dimethylaminocarbonylmethyl-3-(1-naphthyl)-propionyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol

The synthesis was carried out similar to that described in example 13 by the way.

Mass spectrum (FAB): 1131 (M+H)+, 716.

NMR (270 MHz, DMCO <D>): 0,77 (d, 7 Hz, 6N), 0,80 (d, 7 Hz, 6N), 1,12 (s, N), to 1.87 (m, 2H), 2,75 (m, 2H), and 2.83 (m, 2H), 2,92-3,03 (m, 2H), 3,10-up 3.22 (m, 2H), approximately 3.27 to to 3.49 (m, 6N), 3,54-to 3.67 (m, 2H), was 4.02-to 4.15 (m, 4H), of 4.66 (d, 6 Hz, 2H), 7,01 - to 7.09 (m, 2H), 7,10-7,25 (m, 8H), 7,28-the 7.43 (m, 4H), of 7.48-to 7.68 (m, 6N), 7,79 (d, 8 Hz, 2H), 7,88-to 7.95 (m, 2H), 8,15-of 8.25 (m, 4H).

P R I m e R 52 N,N'bis-<(2S-(1,1-dimethylaminocarbonylmethyl)-3 - phenyl-propionyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 13 by the way.

Mass spectrum (FAB): 1053 (M+Na)+, 1031 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,72 (d, 7 Hz, 6N); 0,78 (d, 7 Hz, 6N); 1,14 (s, N); of 1.85 (m, 2H); 2,62-2.94 (m, 8H); approximately 3,20-to 3.35 (m, about 4H); 3,53 (double d, 10 Hz, 14 Hz, 2H); as 4.02 is 4.13 (m, 2H); 4,50 (m, 2H); with 4.64 (m, 2H); 7,01-7,10 (m, 2H); 7,12-7,39 (m, 22N); with 8.05 (d, 8 Hz, 2H).

P R I m e R 53. N,N'bis-<(3-(1,1-dimethylaminophenyl)- propionyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis of the/SUP>:

NMR (270 MHz, DMCO <D>): 0.69 (d, 6 Hz, 6N); 0,73 (d, 6 Hz, 6N); of 1.33 (s, N); of 1.84 (m, 2H); 2,54 at 2.59 (m, 6N); to 2.67 (m, 2H); about 3,15-3,30 (m, 6N); 4,05 (double d, 7 Hz, 9 Hz, 2H); 4,47 (m, 2H), 4,63 (m, 2H); 7,06-7,21 (m, 10H); 7,30 (d, 9 Hz, 2H); 7,94 (d, 8 Hz, 2H).

P R I m e R 54. N,N'bis-<(2R-(1,1-dimethylaminocarbonylmethyl) -3-(2-thionyl)-propionyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 13 by the way.

Mass spectrum (FAB), 1065 (M+Na)+, 1049 (M+Li)+.

NMR (270 MHz, DMCO <D>): 0,51 (d, 7 Hz, 6N); 0,56 (d, 7 Hz, 6N); 1.28 (in C, N); of 1.85 (m, 2H); 2.95 and-3,19 (m, 8H); 3,30-of 3.60 (m, 8H); 3,95 (double d, 8 Hz, 5.2 Hz, 2H); 4,06 (m, 2H); to 4.62 (d, 7 Hz, 2H); 6,93 (l, 3,2 Hz, 4H); 7,08-7,25 (m, 10H); 7,34 (m, 2H); the 7.43 (d, a 8.4 Hz, 2H); to 8.14 (d, 8 Hz, 2H).

P R I m e R 55. N,N'bis-<L-i.e. phenylalanyl-L-felled)-4S, 7S-diamino-2,9-dimethyl-Dean-5,6-diol dihydrochloride.

The synthesis was carried out similar to that described in example 56 way.

Mass spectrum (FAB): 725 (M+H)+.

P R I m e R 56. N,N'bis-<(tertbutoxycarbonyl-L - i.e. phenylalanyl-L-felled)-4S, 7S-diamino-2,9-dimethylbutan-5,6-diol dihydrochloride.

The synthesis was carried out similar to that described in example 6, respectively, in examples 3-5, the way.

Mass spectrum (FAB): 925 74 (double d, 10 Hz, 13 Hz, 2H); 2.95 for (double d, 4 Hz, 13 Hz, 2H); 3,23 (m, 2H); 3,88 (m, 2H); 4,13-to 4.28 (m, 4H); of 4.45 (d, 5 Hz, 2H); 7,02 (8, 8 Hz, 2H); 7,13-7,33 (m, 10H); 7,76 (d, 8 Hz, 2H); 7,80 (d, 8 Hz, 2H).

P R I m e R 57. N,N'bis-<(2S-(1,1-dimethylaminocarbonylmethyl) -3-phenyl-propionyl)-L-poured>-4S, 7S-diamino-2,9-dimethylbutan-3,4-diol.

The synthesis was carried out similar to that described in example 13, respectively, in examples 3-5, by the way.

Mass spectrum (FAB): 985 (M+Na)+, 963 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,78 (d, 7 Hz, 6N), 0,80-0,93 (m, N) and 1.15 (s, N), 1,20 by 1.68 (m, 6N), to 1.98 (m, 2H), 2,58 (double d, 10 Hz, 14 Hz, 2H), 2,73 (double d, 14 Hz, 3 Hz, 2H), 2,98 (double d, 14 Hz, 4 Hz, 2H), 3,23 (m, 2H), about to 3.33 (m, 2H), 3,47-3,61 (m, 2H), 2,85 (m, 2H), 4,14 (m, 2H), of 4.44 (d, 5 Hz,2H), 7,15-7,33 (m, 10H), 7,69 (d, 9 Hz, 2H), by 8.22 (d, 9 Hz, 2H).

P R I m e R 58. N,N'bis-<(2-pyridyl)-acetyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

74 mg of 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride and 68 mg of the hydrochloride of 2-pyridyloxy acid was dissolved in 2 ml of dimethylformamide and then mixed prepared solution of 53 mg of hydroxybenzotriazole, 125 mg TBTU and 0,221 ml diisopropylethylamine. The mixture was stirred for 2 h at room temperature and then processed in the usual way. After the chromatograph is"ptx2">

Mass spectrum (FAB): 759 (M+Na)+, 737 (M+H).

NMR (270 MHz, DMCO <D>): 0,70 (2D, N); of 1.88 (m, 2H); 2,62 (double d, 14 Hz, 5 Hz, 2H); 2,77 (double d, 14 Hz, 10 Hz, 2H); and 3.72 (m, 4H); 4,13 (double d, 6 Hz, 9 Hz, 2H); to 4.46 (m, 2H), 7,05-of 7.23 (m, 10H); 7,28-7,40 (m, 4H); of 7.48 (d, 9 Hz, 2H); 7,82 (double t, 8 Hz, 2 Hz, 2H); 7,97 (d, 9 Hz, 2H); 8,54 (m, 2H).

P R I m e R 59. N,N'bis-<4 pyridylthio-acetyl-L-felled)-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

74 mg of 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride and 66 mg of 4-pyridinecarboxylic acid was dissolved in 2 ml of dimethylformamide and mixed prepared solution of 53 mg HE-benzotriazole, 125 TBTU 0,177 ml Diisopropylamine. The mixture was stirred for 2 h at room temperature, drove the solvent in vacuo and the residue was mixed for 30 min with ethyl acetate and the solution of NaHCO3. Nerastvorim part was filtered and washed with ethyl acetate and water. The crude product was dissolved in warm dimethylformamide, the solution was filtered and mixed with ethyl acetate. The precipitate was aspirated and dried.

The output 76 mg.

Mass spectrum (FAB): 801 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,68 (2D, N); of 1.84 (m, 2H); 2,62 (double d, 14 Hz, 5 Hz, 2H); 2,78 (double d, 14 Hz, 9 Hz, 2H); or 3.28 (m, 2H); to 3.73 (d, 15 Hz, 2H); 3,90 (d,N); a 8.34 (m, 4H).

P R I m e R 60. N,N'bis-<L-i.e. phenylalanyl-D-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol-dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 793 (M+H)+.

P R I m e R 61. N,N'bis-<D-i.e. phenylalanyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 793 (M+H)+.

P R I m e R 62. N,N'bis-<tertbutoxycarbonyl-L-i.e. phenylalanyl-D-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 993 (M+H)+, 893, 793.

NMR (270 MHz, DMCO <D>): 0,42 (d, 7 Hz, 6N); 0,47 (d, GC, 6N); of 1.26 (s, N); of 2.58 (m, 2H); 2,73 (m, 2H); 2,98 (double d, 13 Hz, 5 Hz, 2H); and 3.16 (m, 2H); 3.40 in (m, 2H); 4,00-4,32 (m, 6N); 4,85 (d, 5 Hz, 2H); 6,86 (d, 9 Hz, 2H); 7,07-7,30 (m, 2HE); 7,74 (d, 9 Hz, 2H); 8,19 (d, 9 Hz, 2H).

P R I m e R 63. N,N'-bis-<tertbutoxycarbonyl-D-i.e. phenylalanyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1015 (M+Na)+, 993 (M+H)+, 893, 793.

P R I m e R 64. N,N'bis-< L-phenylalaninol>-2S, 5S-diamino-1,6-diphenylhexane-2S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 709 (M+H)+.

P R I m e R 65. N,N'bis-<L-i.e. phenylalanyl-L-isoleucyl>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 821 (M+H)+.

P R I m e R 66. N,N'bis-<L-latingirl>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 20 method.

Mass spectrum (FAB): 641 (M+H)+.

P R I m e R 67. N,N'bis-<tertbutoxycarbonyl-L - phenylalaninol>2S, 5S-diamino-1,6-phenylhexa-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 931 (M+Na)+; 909 (M+N)+; 809, 709.

NMR (270 MHz, DMCO <D>): 1.38kg (with, IN); 2,58-2,78 (m, 4H); 2,92-to 3.09 (m, 4H); 3.43 points-3,62 (m, 4H); 3,78 (double d, 16 Hz, 5 Hz, 2H); of 4.05 (m, 2H); 4,19 (m, 2H); a 4.83 (d, 5 Hz, 2H); 6,92 (d, 9 Hz, 2H); 7,10-7,29 (m, 10H) - Rev.>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1021 (M+ H)+, 921, 821.

NMR (270 MHz, DMCO <D>): 0,70-0,85 (m, N); of 1.03 (m, 2H); 1,29 (c, 18 H); to 1.37 (m, 2H); of 1.65 (m, 2H); 2,68 is 2.80 (m, 4H); 2,84 totaling 3.04 (m, 4H); 3,39 (m, 2H); 4,00-4,13 (m, 4H); 4,20 (m, 2H); with 4.64 (d, 7 Hz, 2H); 7,02 (d, 9 Hz, 2H); 7,05-7,33 (m, 20N); 7,62-7,73 (m, 4H).

P R I m e R 69. N,N'bis-<tertbutoxycarbonyl-L - latingirl>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 863 (M+Na)+, 841 (M+H)+, 741, 641.

NMR (270 MHz, DMCO <D>): 0,83 (d, 6 Hz, 6N); of 0.87 (d, 6 Hz, 6N); 1,38 (C. N); about to 1.42 (m, 4H) and 1.60 (m, 2H); 2,62 (double d, 14 Hz, 2H); 3,03 (double m, 14 Hz, 2H); 3,44 (m, 2H); 3,52 (double d, 16 Hz, 5 Hz, 2H); 3.72 points (double d, 16 Hz, 5 Hz, 2H); 3,90-4,08 (m, 4H), 4,79 (D, 5 Hz, 2H); 6,93 (d, 9 Hz, 2H); 7,10-7,28 (m, 10H); 7,78-of 7.90 (m, 4H).

P R I m e R 70. N,N'-bis-<L-i.e. phenylalanyl-L-seryl>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 769 (M+H)+.

P R I m e R 71. N,N'bis-<5S-amino-4S-hydroxy-7-methyl-2R - propiolactones-2S, 5S-diamino-1,6-WPPT is 34 mg N-tertbutoxycarbonyl-5S-amino-methyl-2R - propyl-4S-(tertBUTYLPEROXY)-octanoic acid was dissolved in 3 ml of dimethylformamide and the prepared solution was mixed with 43 mg bt, 101 mg TBTU and 155 mg of diisopropylethylamine. The mixture was stirred for 4 h at room temperature, solvent was removed in vacuum and distributed the residue between dichloromethane and water. The organic phase was subjected to extraction solutions KHSO4, NaHCO3and water. After drying over anhydrous sodium sulfate the organic phase was concentrated and the residue was subjected to chromatography on silica gel (mobile phase: a mixture of cyclohexane and ethyl acetate at a ratio of 3: 1). As a result received 157 mg of N,N'bis-<N-tertbutoxycarbonyl-5S-amino-7-methyl-2R - propyl-4S-(tertBUTYLPEROXY)-octanoyl>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride. The processing of Hcl in dioxane in the same manner as described in example 16, received the target connection.

N-tertbutoxycarbonyl-5S-amino-7-methyl-2R-propyl-4S- (tributyltinhydride)-octanoic acid, the second component of combination reaction, was obtained similar to that described in example 27 by the way.

For this purpose, the original connection (5S)-5-<(1S)-1-(N-Boc-amino) -3-methylbutyl>dihydrofuran-2(3H)-it is additionally alkilirovanie allylbromide and then was first made (in the same way as when the connection 11, described Fray and others).

P R I m e R 72. N,N'bis-<L-i.e. phenylalanyl-L - cyclohexylglycine>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 873 (M+H)+.

P R I m e R 73. N,N'bis-<tertbutoxycarbonyl-L-i.e. phenylalanyl-L-cyclohexylglycine>2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1073 (M+H)+, 973, 873.

NMR (270 MHz, DMCO<D>): 0,82-of 1.66 (m, approximately 22N); of 1.29 (s, N); 2,56-of 2.97 (m, 8H); about 3.30 (m, 2H); 4,08-4,22 (m, 4H); 4,50 (m, 2H); 4,63 (m, 2H); 7,02 (d, 9 Hz, 2H);? 7.04 baby mortality-to 7.32 (m, 2HE); 7,47 (d, 9 Hz, 2H); 7,56 (d, 9 Hz, 2H).

P R I m e R 74. N,N'bis-<L-methionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 761 (M+H)+.

P R I m e R 75. N,N'bis-<tertbutoxycarbonyl-L-methionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in primer); to 1.38 (s, N); 1,70-1,90 (m, 6N); 2,02 (C, 6N); about 2,37-2,5 (m, 4H); about of 3.32 (m, 2H); 3,94-4,10 (m, 6N); 4,63 (d, 7 Hz, 2H);? 7.04 baby mortality-7,20 (m, N); 7,49-to 7.59 (m, 4H).

P R I m e R 76. N,N'bis-<(0-methyltyrosine)-L-poured>2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 853 (M+H)+.

P R I m e R 77. N,N'bis-<tertbutoxycarbonyl- (0-methyltyrosine)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out as described in example 16 by the way.

Mass spectrum (FAB): 1053 (M+H)+, 953, 853.

NMR (270 MHz, DMCO <D>): 0,73-0,83 (m, N); of 1.29 (m, N); of 1.84 (m, 2H); 2,60-to 3.02 (m, 8H); to 3.36 (m, 2H); 3,70 (s, 6N); 3,99-4,18 (m, 6N); with 4.64 (d, 6N, 2H); PC 6.82 (d, 9 Hz, 4H); 6,98 (d, 9 Hz, 2H); 7,05-7,22 (m, 14N); to 7.59 (d, 9 Hz, 2H); the 7.65 (d, 9 Hz, 2H).

P R I m e R 78. N,N'bis-<L-tyrosyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 825 (M+H)+.

P R I m e R 79. N,N'bis-<(N-tertbutoxycarbonyl-0-tertbutyl-L-tyrosyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to OPI is 6>): 0,72-0,85 (m, N); 1,25 (s, N); 1.28 (in C, N); of 1.85 (m, 2H); 2,62-2,82 (m, 4H); 2,84-a 3.01 (m, 4H); to 3.36 (m, 2H); 3,98-4,12 (m, 4H); 4,19 (m, 2H); with 4.64 (m, 7 Hz, 2H); 6,85 (d, 8 Hz, 4H); 7,02 (d, 9 Hz, 2H); 7,05-7,21 (m, 18 H); 7,60 (d, 8 Hz, 2H); 7,66 (d, 9 Hz, 2H).

P R e m a R 80. N,N'bis-<N-benzyloxycarbonyl-N2- tertbutoxycarbonyl-L-lysyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB/LiI): 1229 (M+H)+.

P R I m e R 81. N,N'bis-<N-benzyloxycarbonyl-N2(tertbutoxycarbonyl-L-i.e. phenylalanyl)-L-lysyl>-2S, 5S-diamino-1,6 - diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1319 (M+H)+; 1219, 1185.

NMR (270 MHz, DMCO <D>): 1,08 to 1.47 (m, N); 2,60-2,82 (m, 6N); 2,87-3,00 (m, 6N); 3,23 (m, 2H); 4,08-to 4.23 (m, 4H); 4,36 (m, 2H); 4,69 (m, 2H); 4,99 (s, 4H); 6,94 (d, 9 Hz, 2H);? 7.04 baby mortality-7,40 (m, N); 7,46 (d, 8 Hz, 2H); of 7.69 (d, 9 Hz, 2H).

P R I m e R 82. N,N'bis-<L-glutamyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-bildegalleri.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FA/LiI): 763 (M+Li)+, 757 (M+H)+.

NMR (270 MHz, DMCO <D>: 0, N); and 4.68 (d, 7 Hz, 2H); 7,06-7,21 (m, 10H); to 7.68 (d, 8 Hz, 2H); by 8.22 (m, 6N); 8,46 (d, 9 Hz, 2H).

P R I m e R 83. N,N'bis-<tertbutoxycarbonyl-L - glutamyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out using as starting material the compound according to example 84, by catalytic hydrogenation on palladium catalyst with coal in a mixture of glacial acetic acid and water at a ratio of 9:1.

Mass spectrum (FAB): 979 (M+Na)+, 958 (M+H)+.

NMR (270 MHz, DMCO <D>): 0.70 to about 0.82 (m, N); to 1.38 (s, N); 1,62-of 1.93 (m, 6N); 2,17-to 2.29 (m, 4H); to 2.74 (m, 2H); 2.95 points (double m, 13 Hz, 2H); about the 3.35 (m, 2H); 3,90-4.09 to (m, 6N); 4,12 (m, 2H); 7,00-7,20 (m, N); of 7.48 to 7.62 (m, 4H).

P R I m e R 84. N,N'bis-<(N-tertbutoxycarbonyl-0-benzyl-L-glutamyl)-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diode.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1159 (M+Na)+, 1137 (M+H)+, 1037.

NMR (270 MHz, DMCO <D>): 0.75 in (d, 6 Hz, N); to 1.37 (s, N); 1.70 to to 1.98 (m, 6N); 2,33 at 2.45 (m, 2H); was 2.76 (m, 2H); of 2.93 (m, 2H); about 3.3 (m, 2H); 3,94-4,08 (m, 6N); 4,60 (C, 7 Hz, 2H); to 5.08 (s, 4H); 7,03-7,17 (m, N); 7,30-of 7.48 (m, 10H); 7,50 (d, 8 Hz, 2H); 7,58 (d, 9 Hz, 2H).

P R I m e R 85. N,N'bis-<glycyl-L-poured>-2S, 5S-dia is e 16 way.

Mass spectrum (FAB): 635 (M+Na)+, 613 (M+H)+.

P R I m e R 86. N,N'bis-<tertbutoxycarbonyl-L - poured>2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 835 (M+Na)+; 813 (M+N)+.

NMR (270 MHz, DMCO <D>): 0,70 (d, 7 Hz, N); to 1.38 (s, N); of 1.84 (m, 2H); 2,62 (double d, 14 Hz, 4 Hz, 2H); 2,87 (double d, 14 Hz, 10 Hz, 2H); 3,26 (m, 2H); 3,52 (d, 6 Hz, 4H); 4,13 (m, 2H); was 4.42 (m, 2H); 4,69 (m, 2H); 7.03 is (m, 2H); 7,08-7,21 (m, 10H); 7,38 (d, 9 Hz, 2H); 7,50 (d, 9 Hz, 2H).

P R I m e R 87. N,N'bis-<L-leucyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 747 (M+Na)+, 725 (M+H)+.

P R I m e R 88. N,N'bis-<tertbutoxycarbonyl-L-leucyl-L - poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 947 (M+Na)+; 925 (M+N)+; 825, 725.

NMR (270 MHz, DMCO <D>): 0,72-0,80 (m, N); 0,85 (d, 7 Hz, 6N); 0,89 (d, 7 Hz, 6N); 1,28-and 1.54 (m, 22N) and 1.60 (m, 2H); is 1.81 (m, 2H); was 2.76 (double d, 13 Hz, 9 Hz, 2H); 2,93 (double d, 13 Hz, 4 Hz, 2H); about to 3.33 (m, 2H); 3,92-methionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-4R, 4R-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 847 (M+PA)+, 825(M+H)+< / BR>
P R I m e R 90. N,N'bis-<tertbutoxycarbonyl-L-(S-dioxo) methionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 6 by the way.

Mass spectrum (FAB): 1074 (M+Na)+.

NMR (270 MHz, DO <D>): 0,65-0,78 (m, N); of 1.39 (s, N); 1,74-2,07 (m, 6N); 2,63 (m, 2H); of 3.07 (m, 4H); 2,78 (m, 2H); 3,26 (m, 2H); 3,98-4,17 (m, 4H); of 4.44 (m, 2H); of 4.67 (m, 2H); 7,07-of 7.23 (m, N); 7,49 (d, 9 Hz, 2H); 7,53 (d, 9 Hz, 2H).

P R I m e R 91. N,N'bis-<[2S-(1,1-dimethylaminocarbonylmethyl) -3-phenylpropionyl] -L-tertbutylphenyl>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 13 by the way.

Mass spectrum (FAB): 1081 (M+Na)+, 1059 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,83 (s, N); 1,12 (s, N); 2,39 (double d, 11 Hz, 14 Hz, 2H); 2,56-of 2.72 (m, 4H); 2,73-2,90 (m, 4H); about 3.25 to 3.40 in (m, about 4H); 3,53 (double d, 10 Hz, 14 Hz, 2H); 4.20 (d, 9 Hz, 2H), 4,54 (m, 2H); 6,98 (m, 2H); 7,07 and 7.36 (m, N); 7,47 (d, 9 Hz, 2H); 7,98 (d, 9 Hz, 2H).

P R I m e R 92. N,N'bis-<[2S-(1,1-dimethylaminocarbonylmethyl) -3-panovicin described in example 13 by the way.

Mass spectrum (FAB): 1109 (M+Na)+, 1087 (M+N)+.

NMR (270 MHz, DCl3), 0,86 (s, N); 1,08 (double, d, 8 Hz, 14 Hz, 2H); to 1.35 (s, N); 1,58 (double d, 14 Hz, 2H); 2,75 is-3.45 (m, about 8H); of 3.80 (m, 2H); 4,12 (m, 2H); 5,80 (d, 8 Hz, 2H); 6,27 (d, 8 Hz, 2H); 7,10 and 7.36 (m, about 10H).

P R I m e R 93. N,N'bis-<(2-S-hydroxy-3-phenylpropionyl) -L-poured>-2S, 5S-diamino-1,6-diphenylhexane-2S, 4S-diol.

To 0,065 mmol N,N'bis-<-L-poured>-2S, 3S-diamino-1,6-diphenylhexane-3S, 4S-diol hydrochloride and 33 mg of S-phenylmalonic acid in 4 ml of dimethylformamide was added 27 mg HE-bt, 64 mg TBTU and then slowly 0,088 ml diisopropylaniline. After 15 min was removed in vacuum at room temperature, the dimethylformamide, the residue was dissolved in ethyl acetate and was carried out by extraction solutions KHSO4and NaHCO3and water. The organic phase was dried MgSO4and concentrated, the residue is triturated with ether and was sucked out. The output 43 mg.

Mass spectrum (FAB): 795 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,63 (d, 7 Hz, 6N); 0,67 (d, 7 Hz, 6N); to 1.82 (m, 2H); 2,64-and 2.79 (m, 4H); 2.91 in totaling 3.04 (m, 4H); to 3.38 (m, 2H); a 3.87-4,17 (m, 6N); 4.72 in (d, 6 Hz, 2H); 5,77 (d, 6 Hz, 2H); 7,08-7,29 (m, 20N); 7,38 (d, 9 Hz, 2H); a 7.85 (d, 8 Hz, 2H).

P R I m e R 94. N,N'bis-<(2S-hydroxy-4-phenylbutyl) -L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol.

+, 323 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,73 (d, 5 Hz, 6N); 0,76 (d, 5 Hz, 6N); 1,76 is 2.00 (m, 6N); 2,55-2,78 (m, 6N); 2,98 (double m, 14 Hz, 2H); 3,39 (m, 2H); to 3.89 (m, 2H); 4,00-4,18 (m, 4H); at 4.75 (d, 6 Hz, 2H); 5,88 (d, 6 Hz, 2H); 7,05-7,32 (m, 20N); 7,45 (d, 9 Hz, 2H); 7,88 (d, 8 Hz, 2H).

P R I m e R 95. N,N'bis-<[2-(1-imidazolidinyl)-3 - phenylpropionyl]-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol (based on "diastereoisomer 1").

35,8 mg 2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol dihydrochloride and 90 mg of 2-(1-imidazolidinyl)-3-phenylpropionyl-L - valine (diastereoisomer 1) was dissolved in 2 ml of dimethylformamide and mixed the prepared solution at room temperature with 32 mg OH-bt, 77 mg TBTU and then 0,163 ml diisopropylethylamine. The mixture was stirred for 3 h, the solvent was removed in vacuum and the residue was distributed between ethyl acetate and a solution of NaHCO3. The organic phase was washed policecontributing NaCl, dried and concentrated. The residue is triturated with diethyl ether, was aspirated and subjected to chromatography on silica gel (podvodnaya phase: a mixture of HER and MeOH in a ratio of 85:15). The result obtained 57 mg of the target compound.

Mass spectrum (FAB): 923 (M+H)+.

2(1-imidazolidinyl)-3-phenylprop-IMT-L-valine was obtained with the config solution in an argon atmosphere at room temperature with 40 mg of NaH. After 7 days the reaction solution was poured in 50 ml KH2PO4and thrice were extracted with 50 ml of methyl tertiary butyl ether. From the organic phase twice held the extraction NaHSO4, the aqueous phase was podslushivaet K2CO3and twice again subjected to extraction with 50 ml of methyl tertiary butyl ether. As a result, when the concentration was received 390 mg of ethyl ester of 2-benzene-3-(1-imidazolyl)propanoic acid, which omilami NaOH and then was subjected to combined with valintatalo ether through ACE. The diastereomers were separated using a mixture of ethyl acetate and MeOH in a ratio of 10: 1. 0,34 = diastereoisomer 1 0,18 = diastereoisomer 2

When the saponification with NaOH in a mixture of dioxane and water received components for the reaction combinations used in examples 95 and 96.

P R I m e R 96. N,N'bis-<[2-(1-imidazolidinyl)-3 - phenylpropionyl]-L-poured->2S, 5S-diamino-1,6-diphenylhexane-3S, 4S-diol (based on "diastereoisomer 2"). Getting see example 95.

Mass spectrum (FAB): 923 (M+H)+.

P R I m e R 97. N,N'bis-<3-(4-amino-1-piperidinophenyl) -2-benzoylpropionic-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out similar to that described in example 16 by the way.

Macc-spectrum (FAB is of IMT-propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

57 mg of N,N'bis-<L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride and 129 mg of 2-benzyl-3(4-tert.-butoxycarbonylamino - but-1-piperidinophenyl)-propionic acid was dissolved in 1 ml of dimethylformamide and the resulting solution was mixed with 41 mg of HObt, 96 mg TBTU and 135 μl of diisopropylethylamine. After 20 min the solvent was removed in vacuo, the residue was dissolved in DCM and spent extraction solution KHSO4and KHCO3and water. After drying and concentrating the organic phase and the viscous residue was dissolved in a small amount of a mixture of DCM and MeOH and put a product out of solution in diethyl ether. The output 64 mg.

Mass spectrum (FAB): 1337 (M+Na)+, 1315 (M+H)+, 1237, 1215, 1137, 1115.

2-benzyl-3(4-tertbutoxycarbonyl - Mino-1-piperidinophenyl)- propionic acid was synthesized similar to that described in example 13 by the way. At the intermediate stage by the interaction of the ether benzylacrylamide acid teoksessa acid was obtained benzyl ether of 3-acetyl-thio-2-benzoylpropionic acid. Subsequent oxidation with chlorine resulted in the formation of benzyl ether of 2-benzyl-3-chlorosulfonylbenzoic acid, which by combining with 4-tertbutoxide.

P R I m e R 99. N,N'bis-<3-(4-amino-1-piperidinylcarbonyl) -2R-benzoylpropionic-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride.

The synthesis was carried out similar to that described in example 16 by the way.

Mass spectrum (FAB): 1043 (M+H)+.

P R I m e R 100. N,N'bis-<2R-benzyl-3-(4 - tertbutoxycarbonyl-1-piperidinylcarbonyl)-propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride.

57 mg of N,N'bis-<L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride and 129 mg 2R-benzyl-3-(4-tert.-butoxycarbonyl - Mino-1-piperidinylcarbonyl)- propionic acid, synthesized by the combination of 4-tertbutoxycarbonyl and benzyl ester 2-R-benzyl-3-carboxypropanoyl acid, was dissolved in 1 ml of dimethylformamide and mixed, the resulting solution with 41 mg HE-bt 96 mg TBTU and then slowly add is 0.135 ml diethylethanolamine. After 20 min the solvent was removed in vacuo, the residue was dissolved in IT and spent extraction solution KHSO4and NaHCO3and water. The organic phase was dried over MgSO4and concentrated. The residue was dissolved in a small amount of DCM, were planted by the product in diethyl ether and was filtered. Visil-3-carboxyl)- propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

The synthesis was carried out on the basis of the connection in accordance with example 102 by processing it triperoxonane acid.

Mass spectrum (FAB): 901 (M+Na)+, 879 (M+H)+.

P R I m e R 102. N,N'bis-<(2R-benzyl-3 - tertbutoxycarbonyl)-propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

45 mg of N,N'bis-<L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride img 2R-benzyl-3-tertbutoxycarbonyl acid was dissolved in 2 ml of dimethylformamide and the resulting solution was mixed with 37 mg HE-bt, 87 mg TBTU and 112 μl of ethyldiethanolamine. The mixture was stirred for 15 min at room temperature, the dimethylformamide was removed in vacuo, the residue was dissolved in ethyl acetate and extraction was performed with solutions of KHSO4, NaHCO3and water. The organic phase was dried over MgSO4and concentrated. The residue is triturated with diethyl ether and was filtered. The output 44 mg.

Mass spectrum (FAB): 1013 (M+Na)+, 991 (M+H)+.

NMR (270 MHz, DMCO <D>): 0,69 (d, 6 Hz, 6N); 0,74 (d, 6 Hz, 6N); 1,31 (s, N); to 1.83 (m, 2H); 1,95 (m, 2H); 2,32-2,47 (m, 4H); 2,60-2,87 (m, 6N); 2,98 (m, 2H); 3,29 (m, 2H); 4.09 to (double d, 8 Hz, 7 Hz, 2H); to 4.46 (m, 2H); with 4.64 (m, 2H); 7,02-7,31 (m, 10H); 7,38 (d, 9 ,6-diphenylhexane-3R, 4R-diol dihydrochloride (based on "diastereoisomer 1")

The synthesis was carried out similar to that described in example 16 by way of the compounds according to example 105.

Mass spectrum (FAB): 843 (M+Na)+, 821 (M+N)+.

P R I m e R 104. N,N'bis-<(3-amino-2-benzyl)-propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride (based on "stereoisomer 2").

The synthesis was carried out similar to that described in example 16 by way of the connection in accordance with example 106.

Mass spectrum (FAB): 843 (M+Na)+, 821 (M+H)+.

P R I m e R 105. N,N'bis-<(2-benzyl-3 - tertbutoxycarbonyl)-propionyl L-poured>-2S, 5S-diamino-1,6 - diphenylhexane-3R, 4R-diol (based on "diastereoisomer 1").

37 mg of 2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol dihydrochloride combined with 98 mg of N,N'bis-<(2-benzyl-3-tert - butoxycarbonylamino)-propionyl L-valine by TBTU method. After conventional treatment and chromatography (mobile phase: a mixture of DCM and methanol at a ratio of(98:2)-(95:5) received 28 mg of the target compound.

Mass spectrum (FAB): 1043 (M+Na)+, 1021, (M+H)+, 921, 821.

Component N,N'bis-<(2-benzyl-3-tertbutoxycarbonyl) -propionyl L-valine was prepared as obslete. With stirring, was added to the mixture dropwise 11.5 ml of benzylchloride. The solution was left to stand overnight at room temperature, after which the precipitate was filtered NaCl and drove the solvent. The residue was dissolved in ethyl acetate and subjected him to have it subjected to extraction with water. The organic phase was concentrated and the residue was distilled under vacuum (0.5 mm RT. Art., 120-125oC). Output, 8,1

The obtained ethyl ester benzylcarbamoyl acid was dissolved in 200 ml EtOH and was first made in the presence of Raney Nickel. After extraction of the catalyst and concentration was obtained 8.2 g of the oily liquid and after chromatography on silica gel (ethyl acetate after a mixture of ethyl acetate and MeOH in a ratio of 5: 1) 5.5 g of ethyl ester of 3-amino-2-benzoylpropionic acid. The compound obtained was subjected to interaction with Vos2O with the formation of the ethyl ester of 2-benzyl-3-(tertbutoxycarbonyl)- propionic acid, which omilami and subjected to a combination of H-Val-OMe in the ACE method. The resulting diastereomers were separated using chromatography (mobile phase: a mixture of toluene and diisopropyl ether in the ratio 1: 1).

Rf= 0,140 = diastereoisomer 1

Rf= 0,097 = diastereoisomer 2

Emile is este parent compounds in examples 105 and 106.

P R I m e R 106. N,N'bis-<(2R-benzyl-3 - tertbutoxycarbonyl)-propionyl L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol (based on the diastereoisomer 2).

The synthesis was carried out similar to that described in example 105 way.

Mass spectrum (FAB): 1043 (M+Na)+, 1021 (M+H)+, 921, 821.

P R I m e R 107. N,N'bis-<0-(D-mannopyranosyl)-2S-hydroxy-3 - phenylpropionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

20 mg of the compounds according to example 108 was stirred for 30 min at room temperature with methanol solution of hydrochloric acid. Volatile components are then kept in vacuum, the residue was insisted with diethyl ether, was aspirated and dried. Exit 13 mg.

NMR (270 MHz, DMCO <D>): 0,58 (d, 6 Hz, 6N); 0,62 (d, 6 Hz, 6N); to 1.82 (m, 2H); 2,60 (double d, 4 Hz, 14 Hz, 2H); 2.71 to 2,82 (m, 4H); 2,98 (double d, 14 Hz, 3 Hz, 2H); about of 3.25 (m, 2H); 3,30-to 3.49 (m, 6N); to 3.58 (m, 2H); 3,67 (double d, 11 Hz, 3 Hz, 2H); about 3,70-4,30 (m, about N); 4,43 (m, 2H); 4,49 (d, 2 Hz, 2H); 7,05-7,29 (m, 20N); to 7.35 (d, 9 Hz, 2H); to 7.67 (d, 9 Hz, 2H).

P R I m e R 107a. N,N'bis-<-0-(2,3-5,6-diisopropylidene-D - mannopyranosyl-2S-hydroxy-3-phenylpropionyl-L-poured>-2S, 5S-diamino-1,6-diphenylhexane-3R, 4R-diol.

57 mg of N,N'bis-<L-poured>-2S, 5S-diami pianoboy acid was dissolved in 1 ml of dimethylformamide and spent the reaction mix on TBTU method. The output 60 mg.

Mass spectrum (FAB): 1279 (M+H)+, 1261, 1221.

NMR (270 MHz, DMCO <D>): 0,63 (d, 6 Hz, 6N); 0.69 (d, 6 Hz, 6N); 1,19 (C, 6N); 1,21 (C, 6N); of 1.30 (s, N); to 1.79 (m, 2H); 2,60-2,82 (m, 8H); 3,29 (m, 2H); to 3.73 (double d, 8 Hz, 6 Hz, 2H); 3,85-3,98 (m, 4H); 4,23 (double d, 8 Hz, 3 Hz, 2H); however, 4.40 (d, 6 Hz, 2H); of 4.45 (m, 2H); to 4.62-4.72 in (m, 4H); 7,03-7,32 (m, approximately 22N); 7,40 (d, 9 Hz, 2H); to 7.59 (d, 9 Hz, 2H).

405 mg (0-)-2,3-5,6-diisopropylidene-D-mannopyranosyl of trichloroacetimidate and 194 mg of ethyl ester phenylalkanoic acid was dissolved in 15 ml of absolute CH2CL2. The solution was cooled to 0oC and was added 100 μl of 1M solution of BF3 epirate in CH2CL2. The solution was stirred for one hour at 0oC, was poured into 100 ml NaHCO3and was extracted with CH2CL2. The organic phase was dried Na2SO4and concentrated. After chromatography on silica gel "mobile phase" (a mixture of methyl tertiary butyl ether and heptane at a ratio of 1:1) received 195 mg of the target compound.

P R I m e R 108. N,N'bis-(L-i.e. phenylalanyl-L-felled)-3S, 6S-diamino-1,8-di-(4-pyridyl)-octane-4R, 5R-diol tetrahydrochloride.

The synthesis was carried out similar to that described in example 16 by way of the connection in accordance with example 27.

Mass-Spa l = 0 or 1;

m = 1;

A is a radical of the formula

D - (E)n- (F)o(G)p;

and A*is a radical of the formula

D*-(E*)n*-(F*)o* - (G*)p*

where D is the radical R1or a radical of the above formula;

D*the radical R*1or a radical of the General formula

< / BR>
< / BR>
n, n*, o, o*, p, p*independently from each other 0 or 1;

E, E*, F, F*, G, G*independently from each other - amino group of Val, Lys, Lys (Z), Phe, Chg, Ser, Asn, Gly, Jle, Tbg, Nva;

or R1and R*1independently from each other hydrogen, carboxyl, methylsulphonyl, tert-butylsulfonyl, tert-butoxycarbonyl, 2-hydroxyarylalkyl, 1,2,3-trihydroxypropane, 1,2,3-triacetoxy, benzyloxycarbonyl, 4-methylphenylsulfonyl, 4-chlorobenzylthio, bansilalpet, 4-chlorobenzenesulfonyl, hexadecacarbonyl, 4-amino-1-piperidinyl-sulfonyl, N-tert-butoxycarbonyl-4-amino-1-piperidinemethanol, 4-amino-1-piperidinylcarbonyl, N-tert-butoxycarbonyl-4-amino-1-piperidinylcarbonyl, 2-amino-3-phenyl-propyl, N-tert-butoxycarbonyl-2-amino-3-phenylpropyl, 2-amino-1-hydroxy-4-methylpentyl, deoxyribosyl-1, mannopyranosyl, 4-aminocyclohexanol, 2-pyridylethyl, 4-pyridylthio aloperidin), tert-butylthio, 4-Z-N. tert-butoxycarbonyl, aminocyclohexanone, 4-pyridyl, deletion, phenyl, amino or tert-butoxycarbonylamino;

R2and R*2independently from each other hydrogen, 2-(4-pyridyl)-ethyl, isopropyl, isobutyl, N. of pentyl, benzyl, 3,4-methylenedioxybenzyl, 2,4-dimethoxybenzyl, 4-tert-butylbenzyl, 2-phenylethyl or cyclohexylmethyl;

R3and R*3R4and R*4R6and R*6R7, R10, R*10is hydrogen;

R5and R*5independently of one another is hydrogen or hydroxyl;

R8and R*8is hydrogen or together with R9or R*9/and related atoms form a 1,2,3,4-tetrahydroquinoline-3,4;

R9and R*9independently from each other hydrogen, hydroxyl, acetoxy, N. propyl, isopropyl, isobutyl, aminomethyl, 4-aminobutyl, hydroxymethyl, tert-butoxymethyl, aminocarbonylmethyl, 2-benzyloxycarbonylation, tert-butoxycarbonylamino, Z-naphthylmethyl, tert-butylthioethyl, 4-benzyloxycarbonylamino, N,N0di(benzyloxycarbonyl)-guanidinopropionic, cyclohexyl, cyclohexylmethyl, benzyl, 2-phenylethyl, 4-hydroxybenzyl, 4-meth is, -(N-oxidability)-methyl, 2-methylthioethyl, 2-methylsulfonylmethyl, tert-butylsulfonyl or 2-carboxyethyl;

R11and R*11independently from each other hydrogen, hydroxyl, acetoxy,

moreover, in the General formula I, one or more amide groups (-CONH-) in the main chain may be replaced by-CH2NH - or-CH(OH)CH2-,

or a physiologically tolerated salts of these compounds.

 

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3 ex

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2 ex

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10 cl, 3 ex

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2 ex

FIELD: pharmaceutical chemistry.

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

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

14 cl, 4 dwg, 3 tbl, 9 ex

FIELD: veterinary science.

SUBSTANCE: one should collect summer colostrums in cows to be filtered, poured into sterile tanks per 1-1.5 l and frozen in freezing chambers at -20 - -22 C. In winter-spring period colostrums should be gradually defrosted while calves are being calved. To remove casein in raw material one should apply abomasal enzyme - pepsin (4-6 g pepsin/l colostrum). This enzyme should be added into colostrums heated up to 38 C. After casein precipitation on should filter the whey to be conserved with potassium sorbate (1 g potassium sorbate/l whey). The method is very simple and enables to obtain high-quality preparation.

EFFECT: higher efficiency.

1 dwg, 1 ex, 1 tbl

FIELD: medicine, pediatrics.

SUBSTANCE: the present innovation deals with treating motor-autonomic disorders in children associated with affected function of central nervous system. For this purpose one should puncture perineural areas in the region of the main nervous trunks with alfetin dissolved in cerebrolysine. Additionally, one should puncture in projection area of cervical and lumbar spinal thickenings and areas that correspond to segmentary innervation of organs with affected function and, also, in scalp areas depending upon the character of patient's disorders. The method suggested provides improved autonomic-trophic impact of nervous system.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, hematology, pharmacy.

SUBSTANCE: invention relates to the composition of factor VIII composed without addition of albumin and comprising the following excipients of composition in addition to factor VIII: from 4% to 10% of filling agent taken among group consisting of mannitol, glycine and alanine; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance about between 6 and 8. Alternatively, the composition can comprise from 2% to 6% of hydroxyethylstarch; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance between 6 and 8. In additional variant of realization of invention the composition can comprise: from 300 mM to 500 mM of NaCl, from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose and arginine; from 1 mM to 5 mM of calcium salt, and buffer agent. The composition provides stability in the absence of albumin or other proteins.

EFFECT: valuable properties of compositions.

35 cl, 11 tbl, 7 ex

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

FIELD: pharmaceutical chemistry.

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

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

14 cl, 4 dwg, 3 tbl, 9 ex

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