Hydrazine derivatives or their salts, pharmaceutical drug, aminoethylpiperazine or their salts

 

(57) Abstract:

Usage: in medicine as having the property of inhibiting the action of the enzyme HIV - protease and anti-virus activity. The essence of the invention: derivatives of hydrazine of General formula 1: R1R2N - C(R3R4) - C(R5R6- N(R7)N(R8R9) , where R1and R9independently from each other hydrogen, lower alkanoyl, phenyl(ness.) alkanoyl, phenyl(NISS). alkanoyl, in which the remainder of the lower alkanoyl replaced by carbamoyl, morpholino(ness.) alkanoyl, thiomorpholine(ness.) alkanoyl, pyridyl(ness.) alkanoyl, chinolin(ness.) alkanoyl, tetrazolyl(NISS. ) alkanoyl, amino(NISS. ) alkanoyl, substituted at the amino nitrogen of the N-th morpholino - or N-thiomorpholine - yl, halogen(ness.) alkanoyl containing up to three halogen atoms, 2-(N-morpholino(ness.) allylcarbamate) lowest alkanoyl, 2-(N-pyridyl(NISS. ) allylcarbamate) lowest alkanoyl, lower alkoxycarbonyl, phenyl(NISS. ) alkoxycarbonyl, tetrahydrofuranyl(ness.) alkylsulphonyl, lower alkylsulfonyl, N-pyridyl(ness.) alkyl-N-(ness.) allylcarbamate, or the acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the>provided that at least one of the residues R1and R9means hydrogen, R2, R4, R6and R8mean hydrogen; R3- lower alkyl, cyclohexyl(ness.) alkyl or phenyl(ness.) alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano; R5means a hydroxyl group; R7- lower alkyl, cyclohexyl(ness.) alkyl, or phenyl(NISS. ) alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano, or their salt, if salt-forming groups, the pharmaceutical preparation containing an effective amount of compounds of formula I, as well as hydrazine derivative of the formula II: H2N - HC(R3) - CH(OH) - N(R7)NH2intermediate products in the synthesis of I. 2 C. and 8 C.p. f-crystals, 3 tables.

The invention relates to a new class of neytralizuya analogues, split by aspartates peptides, namely derivatives of hydrazine and their pharmacologically acceptable salts, having the properties to inhibit the activity of the enzyme HIV-protease and anti-virus activity; pharmaceutical agent based on them, are suitable for combating viral diseases, as well as to new AMINOETHYLPIPERAZINE intermediate products gladeville"), we are talking about the disease with a fatal outcome. This disease is distributed worldwide increasingly, primarily within the known risk groups, and through these high-risk groups. It has already affected millions of people, and fighting his cause is one of the most important goals of modern medicine. Still were able to identify the retroviruses HIV-1 and HIV-2 (HIV stands for "virus human immunodeficiency") as causes of disease and to describe them from the point of view of molecular biology. For therapy among all hitherto existing funds to relieve symptoms of AIDS and known safety means of particular interest is the search for drugs that inhibit reproduction of the virus without damaging the intact cells and tissues of the patients.

As the latter is especially promising are compounds that prevent the formation biosynthesized in human cells protein structural elements of the virus and the combination of these structural elements in full, infectious virions.

HIV-1 and HIV-2, depending on the circumstances, in its genome have a region which encodes a "gag-protease". This "gag-protease" promotion is C coding "group specific antigens (gag) segments (segments) of the genome. This frees the structural proteins of the nucleus of the virus (in English "Core" core, core). "gag-Protease" itself is part encoded by segment pol-genome of HIV-1 and HIV-2 protein precursor that also contains segments (segments) for "reverse transcriptase and integrase, and in all probability split autoproteolytic.

"gag-Protease" breaks down the major protein core (Major Core Protein") p24 HIV-1 and HIV-2, preferably N-terminal prolinnova residues, for example, divalent radicals Phe-Pro, Leu-Pro or Tyr-Pro. We are talking about a protease with a catalytically active aspartate residue in the active center, the so-called aspirinplease.

If you had the ability to interfere with the action "gag-protease", the virus would not be in the possession of necessary protein to build viral core. This would limit or even prevent the virus from replicating. Thus there is a need for inhibitors "gag-protease" for use as antiviral drugs against AIDS and other retroviral diseases.

Already synthesized a number of inhibitors "gag-protease", which contain groups which are not proteoliticheskie be found suitable for use for people inhibitor aspartates for AIDS most infected. For this purpose, decisive are primarily pharmacodynamic properties. In addition, most known so far inhibitors "gag-protease" contain more than two asymmetric carbon atoms in the specified Central structural element that causes the need for relatively expensive stereospecific syntheses for the separation of isomers.

The present invention is the finding available new class of compounds, inhibitors of viral aspartates with the new Central structural element in the molecule. The synthesis of this Central structural element, in addition, it should be possible steric simple. As a new structural element with two ends contains an amino group in the selection of substituents can be used, for example, similar to the retro-inverse peptide structure.

According to the invention offers the hydrazine derivatives of the General formula I.

< / BR>
where

R1and R9independently from each other hydrogen, lower alkanoyl, phenyl-ness. alkanoyl, phenyl-ness. alkanoyl, in which the remainder of the lower alkanoyl replaced by carbamoyl, morpholino-ness. alkanoyl, thiomorpholine-ness. alkanoyl, pyridyl-ness. alonline - or N-thiomorpholine, halogen-ness. alkanoyl containing up to three halogen atoms, 2-(N-morpholino-ness.allylcarbamate)- ness. alkoxycarbonyl, lower alkylsulfonyl, N-pyridyl-ness. alkyl-N-ness.allylcarbamate, or the acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of (D), (L)- or (D,L), where the amino group is not substituted or allerban one of the above-mentioned residues R1or R9provided that at least one of the residues R1and R9means hydrogen;

R2, R4, R6and R8mean hydrogen;

R3lower alkyl, cyclohexyl-ness. alkyl or phenyl-ness. alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano;

R5means a hydroxyl group;

R7lower alkyl, cyclohexyl-ness. alkyl, or phenyl-ness. alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano, or their salt, if salt-forming groups.

Preferred compounds of formula I, in which

R1lowest alkoxycarbonyl, phenyl-ness. alkoxycarbonyl, linked through a carboxyl group, a monovalent radical of aliphatic amino acids selected from valine is it from residues - phenyl-(lower alkanoyl), morpholino-(lower alkanoyl), thiomorpholine(lower alkanoyl), pyridyl-(lower alkanoyl), lower alkoxycarbonyl or phenyl-(lower alkoxycarbonyl) a radical of the above aliphatic amino acids, and those amino acids are represented in the form (D)- (L) - or (D,L);

R2hydrogen;

R3phenyl-(lower alkyl);

R4hydrogen;

R5hydroxyl group;

R6hydrogen;

R7lower alkyl, cyclohexyl-ness. alkyl or phenyl-ness. alkyl;

R8hydrogen; and one of the values R1and the remains of R3and R5the asymmetric carbon atoms are in the S-configuration, and pharmacologically acceptable salts of these compounds.

In particular, preferred compounds of formula I, where

R1tert.-butoxycarbonyl, benzyloxycarbonyl, linked through a carboxyl group, a monovalent radical of the amino acids valine, or linked through the carboxyl group residue of alanine, N-acylated on the amino group of one of the remnants of phenylacetyl, 3-pyridylacetic, morpholinoethyl, thiomorpholine, tert.-butoxycarbonyl or benzyloxycarbonyl;

R2hydrogen;

R3benzyl;

R4
R8hydrogen; and

R9one of the values R1and

the remains of R3and R5the asymmetric carbon atoms are in the S-configuration, and pharmacologically acceptable salts of these compounds.

Especially preferred compounds of formula I, where

R1and R9accordingly linked through a carboxyl group, a N-acylated on the amino group by benzyloxycarbonyl monovalent radical amino-(L)-valine;

R2and R8hydrogen;

R3benzyl;

R4hydrogen;

R5hydroxyl group;

R6hydrogen;

R7benzyl; and

the remains of R3and R5the asymmetric carbon atoms are in the S-configuration, and pharmacologically acceptable salts of these compounds and the compounds of formula I, where

R1and R9accordingly linked through a carboxyl group, a N-acylated on the amino group of 4-thiomorpholine monovalent radical of an amino acid (L)-valine;

R2and R8hydrogen;

R3benzyl;

R4hydrogen;

R5hydroxyl group;

R6hydrogen;

R7isobutyl;

and the remains of R3and R5asymme is.

In particular, preferred compounds of formula I are compounds selected from:

Boc-[PheNNPhe]-Boc;

Boc-(L)-Val-[PheNNPhe] (L)-Val-Boc;

Boc-[PheNNCha]-Boc;

H-(L)-Val-[PheNNPhe] J (L)-Val-H;

N-thiomorpholine-(L)-Val-[PheNNPhe] J (N - thiomorpholine-(L)-Val);

N-morpholinoethyl-(L)-Val-[PheNNPhe] J (N - morpholinomethyl-(L)-Val);

phenylacetyl-(L)-Val-[PheNNPhe] J (N-phenylacetyl-(L)-Val);

N-(3-pyridylethyl)-(L)-Val-[PheNNPhe] J (N-(3 - pyridylethyl)-(L)-Val);

Boc-(L)-Val-[PheNNCha] J -(L)-Val-Boc;

Z-(L)-Val-[PheNNCha] J -(L)-Val-Z;

Boc-[PheNNLeu]-Boc;

Z-(L)-Val-[PheNNLeu] J -(L)-Val-Z, H-(L)-Val-[PheNNCha] J (L)-Val)-H and

N-(3-pyridylethyl)-(L)-Val-[PheNNLeu] J (N-(3 - pyridylethyl)-(L)-Val) or their salts, where

Boc means tert.-butoxycarbonyl,

Z benzyloxycarbonyl,

the remainder of [PheNNPhe] means the divalent radical 3(S)-amino-4-phenyl-1- (N-benzylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNCha] means the divalent radical 3(S)-amino-4-phenyl-

1-(N-cyclohexylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNLeu] means the divalent radical 3(S)-amino-4-phenyl-1-(N-isobutylpyrazine)-butanolato, moreover, amino left - and right carboxy; and the compounds of formula I, selected from

Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J (N-(N-(2-pyridylmethyl)-N - methylaminomethyl)-(L)-Val);

Z-(L) -Val- [(p-F)PheNN(p-F)Phe] J (N-(2(R,S) -carbarnoyl-3-phenyl-propionyl)-(L)-Val);

acetyl-(L)-Val-[PheNNCha] J (N-acetyl-(L)-Val);

acetyl-Ile- [PheNNCha] J (N-acetyl-Ile);

N-(2-pyridylmethyl)-N-methylaminomethyl-(L)-Val-[PheNN(p-F)Phe] J (N-(N-(2-pyridylmethyl)-N-methylaminomethyl)-(L)-Val);

Z-(L)-Val-[PheNN(p-F)Phe] J ((L)-Val)-Z;

Z-(L)-Val-[PheNN(p-CN)Phe] J ((L)-Val)-Z;

Z-(L)-Ile-[PheNNLeu] J ((L)-Ile)-Z;

isobutoxide-(L)-Val-[PheNNLeu] J (N - isobutoxide-(L)-Val);

acetyl-Val-[PheNNLeu] J (N-(2(R,S)-carbarnoyl-3 - phenylpropionyl)-Val;

N-TRIFLUOROACETYL-[PheNNLeu] J (N-(2(R,S)-carbarnoyl-3 - phenylpropionyl)-(L)-Val);

Z-(L)-Val-[PheNNNle] J (N-(2(R,S)-(N-(2-morpholinomethyl)- carbarnoyl)-3-methyl)-butyryl);

Z-(L)-Val-[PheNNNle] J (N-(2(R, S)-(N-(2-pyridylmethyl)- carbarnoyl)-3-methyl)-butyryl);

methoxycarbonyl-(L)-Val-[PheNNLeu] J (N-methoxycarbonyl- (L)-Val);

methoxycarbonyl-(L)-Val-[PheNN(p-F)Phe] J (N - methoxycarbonyl)-(L)-Val);

methoxycarbonyl-(L)-Val-[PheNN(p-CH)Phe] <-- (N - methoxycarbonyl-(L)-Val) or their salts, where Z benzyloxycarbonyl,

formula

< / BR>
where the balance of [PheNNCha] means the divalent radical 3(S)-amino-4-phenyl-1-(N-cyclohexylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNLeu] means the divalent radical 3(S)-amino-4-phenyl-1-(N-isobutylpyrazine)-butane-2(S)-ol and has the formula

< / BR>
the remainder of [PheNNNle] means the radical 3(S)-amino-4-phenyl-1-(N-n-butylhydrazine)-butane-2(S)-ol and has the formula

< / BR>
the remainder of [PheNN(p-F)Phe] means the divalent radical 3(s)-amino-4-phenyl-1-(N-(p-performer)-hydrazino)-butane-2(S)-ol and has the formula

< / BR>
the remainder of [(p-F)PheNN(p-F)Phe] means the divalent radical 3(S)-amino-4-(p-forfinal)-1-(N-(p-performer)-hydrazino)- butane-2-(S)-ol and has the formula

< / BR>
the remainder of [PheNN(p-CN)Phe] means the divalent radical 3(S)-amino-4-phenyl-1-(N-(p-cyanovinylene)-hydrazino)-butane-2(S)-ol and has the formula

< / BR>
and arrow "<--" means rotation due to the deviation from the usual items peptide, and amino left - and right carboxy.

All the compounds of formula 1 have the property to inhibit the activity of the enzyme HIV protease.

The expression "lower" signifies that in this way certain groups or residues, unless otherwise specified, contain plateno, R5and R6the carbon atoms in the compounds of the formula I, if they are asymmetric, as available, if necessary, other asymmetric carbon atoms may be in the (R)-, (S)- or (R,S)-configuration. Thus these compounds may be in the form of mixtures of isomers or as pure isomers, especially in the form of mixtures of diastereomers, pairs of enantiomers or pure enantiomers. Preferred compounds of formula I, where R3and R5is (S)- configuration, and others may be available the asymmetric carbon atoms, independently of one another, are (R)-, (s)- or (R,S)- configuration.

Used in the description of the present invention common expressions and symbols preferably have the following meanings, in different areas of the definitions above and the following residues can be any combination or individual residues instead of the common definitions:

Acyl R1or R9is primarily an acyl group of the carboxylic acid, incomplete complex ester of carbonic acid.

Preferred acyl groups R1and R9carboxylic acids are lower alkanoyl as: formyl, acetyl, propionyl, butoxy)-acetyl or (lower alkoxy)- propionyl, as methoxyacetyl, ethoxyacetic or 3-methoxypropanol; eminently alkanoyl means, for example, 2-aminoacetyl or 2-amino-3-propionyl.

Preferred acyl groups R1and R9incomplete complex ester of carbonic acid are (lower alkoxy)-carbonyl, for example, methoxy, ethoxy, isopropoxy, isobutoxy - or tert. -(lower alkoxy)- carbonyl, as tert. -butoxycarbonyl or isobutoxide: 2-halogen (lower alkoxy)-carbonyl, 2-chloro-, 2-bromo-, 2-iodine - or 2, 2, 2 - trichlorocyanuric.

Preferred acyl groups, R1and R9unsubstituted or substituted carbamino acid, along with suitable, already mentioned as preferred acyl residues R1and R9residues are:

unsubstituted or substituted N-heterocyclyl N-allylcarbamate where heterocyclyl preferably pyridyl, 2-, 3 - or 4-pyridyl, primarily in the N-heterocyclyl(lower alkyl)-N-(lower alkyl)-carbamoyl, for example, as N-pyridyl(lower alkyl)-N-(lower alkyl)-carbarnoyl as N-(2-, 3 - or 4-pyridylmethyl)-N-methylcarbamoyl, or N-heterocyclyl-(lower alkyl)-carbarnoyl, as for example, 2 -, or 3-pyridyl(lower alkyl)- aminocarbonyl as 2 - or 3-pyridine)-carbarnoyl] -3-methylbutyryl, or 2-(N-[pyridyl-(lower alkyl)]-carbarnoyl)-(lower alkanoyl), or (2-(R, S)-(N-(2-pyridylmethyl)-carbarnoyl)-3-methyl)-butyryl; halogen ness. alkanoyl, which preferably contains up to 3 halogen atoms, represents, for example, halogenoacetyl as a fluorine, a chlorine, a bromine-, a -, iodine-, a,, -Cryptor - or a,- trichloroacetyl-or halogenation as b-chloro - or b-bromopropionyl;

alkylsulfonyl as methyl or ethylsulfonyl;

phenyl-lower alkoxycarbonyl represents, preferably, benzyloxycarbonyl.

Preferred acyl groups R1and R9unsubstituted or substituted amino acids are formed by amino acid residues of a - or --amino acids, in particular:

natural amino acids with the L configuration, which is usually a protein, or ephemera such amino acids, that is, with the unnatural D-configuration, or D,L-isomeric mixture.

R2, R4, R6K and R8denote hydrogen.

R3and R7denote lower alkyl, such as isobutyl or n-butyl; represent cyclohexyl(lower alkyl) or vanillasky alkyl, unsubstituted or substituted lower alkoxy, halogen or cyano.

R5indicates hydroxilase phenyl-(lower alkyl), which is unsubstituted or substituted by these substituents is benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano-, 4-methoxy, or its salt, if a salt-forming group.

Salts of compounds of formula I are in particular salts of joining acids, salts with bases or in the presence of several salt-forming groups, if necessary mixed or internal salts.

Salts are primarily the pharmaceutically applicable non-toxic salts of compounds of formula I.

Such salts are formed, for example, compounds of formula I with an acid group and represents, for example, salts with suitable bases, salts with non-toxic metals. The periodic system of elements, salts of metals of groups IA, IB, IIA and IIB; the first is of salts of alkaline metals such as lithium salts, sodium, or potassium, or salts of alkaline earth metals such as magnesium or calcium; further, zinc salts or ammonium, such salts which are formed with organic amines, if necessary substituted by hydroxyl mono-, di - or trialkylamine, in particular mono-, di - or tri-(lower alkyl)-amines, or Quaternary ammonium compounds, for example, with N-marked Tris-(2-oxyethyl)-amine, 2-hydroxy-tert.-butylamine, or Tris-(oxymethyl)-methylamine: N, N-di-(lower alkyl)-N-(hydroxy-(lower alkyl)-amines like N, N-dimethyl-N-(2-oxyethyl)- amine or tri-(2-oxyethyl)-amine, N-methyl-D-glucamine, or Quaternary ammonium salts, as tetrabutylammonium salt. The compounds of formula I with a basic group, for example, the amino group may form a salt accession acids, for example, with inorganic acids, such as halogen acid as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfo-, sulfonic or phosphonic acids or N-substituted sulfamic acids, such as acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, ximalayasha acid, methylmaleimide acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glogarova acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2 - acetoxybenzoic acid, albanova acid, nicotinic acid, or isonicotinoyl acid; then, with amino acids, such as, for example, the following Sultonova, econsultations, 2-oxetanemethanol, ethane-1,2-disulfonate, benzosulfimide, 4-methylbenzenesulfonate, naphthalene-2-acid, 2 - or 3 - phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with formation of cyclamates) or with other acidic organic compounds, such as ascorbic acid. The compounds of formula I with the acid and basic groups can also form internal salts.

For isolation or purification can also find application pharmaceutically unsuitable salts.

Compounds of the present invention have inhibitory effect on viral aspartates, particularly suppressing the gag-protease activity. First proposed connection when tested in the following test at a concentration of 10-610-9mol/l inhibit the action of the gag-protease HIV-1 and HIV-2 and is therefore suitable as a remedy against induced by these or used by retroviruses diseases, such as AIDS.

The ability of the compounds of formula I to inhibit proteolytic activity, for example, HIV-1 protease, can be demonstrated, for example, according to the method described by J. Hansen et al. The EMBO Journal, 7 areny E. coli, fused protein of the gag-precursor protein and MS-2. The substrate and the products of fission separated by polyacrylamide-gel electrophoresis and shown by Western blot turns with monoclonal antibodies against MS-2.

Even more simply carried out the test, which makes possible accurate quantitative readings, as a substrate for gag-protease used a synthetic peptide that corresponds to the location of the cleavage of the gag-precursor protein. This substrate and its cleavage products can be measured using liquid chromatography high pressure (ghvd).

For example, as a substrate for recombinant HIV-1 protease [see Billich S et al, J. Biol Chem. 263(34), 17905 17908 (1990)] use a synthetic chromophore peptide(e.g., HKARLV (NO2FEANLES (Bachem, Switzerland) or Icosa-peptide, as RRSNQVSQNYPQNIQGRR (derived peptide synthesis according to the method), which corresponds to the location of the cleavage of the gag-precursor protein. This substrate and the products of fission can be measured using ghvd.

For this purpose, the test inhibitor of the formula I are dissolved in dimethyl sulfoxide; enzymatic test carried out by the addition of suitable dilutions of the inhibitor in the Chida in 0.3 M sodium acetate, 0.1 m NaCl, pH 7,4, or 122 μm above Icosa-peptide in 20 mm MES buffer with a pH of 6.0. The volume of the mixture is 100 ál. The reaction is initiated by adding in the first case, 2 ál, in the second case, 10 μl of HIV-1 protease and ends in the first case, after 15 min by adding 100 μl of 0.3 M HClO4in the second case, after an hour incubation at 37oC by adding 10 ál of 0.3 M HClO4. The reaction products after centrifuging the samples for 5 min at 10000 g in 100 ál (mixture of chromophore peptide), respectively, 20 μl (mixture with Icosa-peptide) obtained supernatant, after application to the column size 125x4,6 mm NucleosilC 18 5 MK(ghvd) (Macherey and Nagel, D ren) and elution determine quantitatively driven by the peak height of the product of cleavage at 280 nm (a mixture of chromophore peptide) or 215 nm (mixture with Icosa-peptide). Gradient: 100% E 1.1 50% E 1.1 (50% E 1.2 E 1.1:50% acetonitrile, 90% H2O, 0,1% triperoxonane acid (TFA); E 1.2: 75% acetonitrile, 25% H2O, and 0.08% TFA for 15 minutes; the transmission rate of 1 ml/min

For the compounds of formula I are defined preferably IC50values (IC50this concentration, which reduces the activity of HIV-1 protease in comparison with the control without inhibitor at 50%)m test can show the compounds of the present invention protects the cell, which usually become infected with HIV from such infection or at least slow down this infection. The human cell line YT-2 T-cell leukemia [Science, 229, 563 (1985)] which is extremely sensitive to cytopathogenic effect of HIV incubated with one HIV or living with HIV in the presence of the proposed invention compounds and a few days later to assess the viability of the thus treated cells.

For this purpose MT-2 cells incubated at 37oC in humid air with 5% CO2in RPMI-1640 medium (Gibco, Switzerland: RPMI-1640 contains a mixture of amino acids without L-Gln), which is supplemented with 10% activated L-glutamine when heated fetal calf serum, Hepes [2-(4-(2-oxyethyl)-1-piperazine derivatives)-econsultation] and the standard antibiotic. 50 μl of each of the test compounds in culture medium and 100 μl of HIV-1 in culture medium (800 TCID 50/ml) (TCID 50 Tissue Culture Infections 50 dose that infects 50% of MT-2 cells) are added to 4103exponentially growing MT-2 cells in 50 μl of culture medium on the indentation on the microtiter plate with 96-gage holes.

Parallel mixture on another microtiter tablet days in 100 ál of supra-cellular fluid determine the activity (RT) reverse transcriptase. RT-activity is determined in 50 mM Tris ,, -Tris(oxymethyl) -methylamine, ultra-pure, Merck, Germany; pH 7.8; 75 mM KCl, 2 mM dithiothreitol, 5 mM MgCl2; of 0.05% Nonidet P-40 detergent, Sigma, Switzerland); 50 μg/ml polyadenylic acid (pharmacy, Switzerland); 1,6 µg/ml dT (12 18) (Sigma, Switzerland). The mixture is filtered through a 0.45 Micron Acrodisc filter (Gellman Science Inc. Ann Arbor) and stored at 20oC. aliquot To share this solution add 0.1% (by volume) [alpha32P]dTTP to achieve radioactive finite activity 10 MX/ml 10 ál of culture supernatant transferred to a new 96-gage hole microtiter tablet and there is added 30 μl of the indicated RT-"cocktail". After mixing plate (tablet) is incubated for 1.5 to 3 h at 37oC. 5 μl of this reaction mixture is transferred onto the paper Whatman DE 81 (Whatman). The dried filters are washed 3 times for 5 min with 300 mM NaCl/25 mM triacrylate 1 and once with 95% ethanol and again dried in air. Assessment is carried out in a Matrix Packard 96 Well Counter (Packard). The values of the ED90achieved and defined as the lowest concentration of the respective test compound that reduces the RT-activity by 90% compared to untreated test connection cell mixtures. RT-activity in this SUB> about 10-510-8M, preferably about 510-7510-8.

Data showing the activity of the claimed compounds.

Inhibition of in vitro HIV-protease.

By analogy with the method described by F. D. Richards et al. J. Biol. Chem. 265(14), 7733 7736, determined the ability of the following compounds according to the examples on the inhibition of HIV-1 protease (obtained according to the method of S. Billich et al. J. Biol. Chem. 263(34), 17905 17908 (1990) in the presence of a substance similar to the Icosa-peptide RRSNQVSQNYPIVQNIQGRR (substrate of HIV-1 protease derived peptide synthesis by known methods: J. Schneider et al. Cell 54, 363 368 (1988)), which corresponds to the location of the cleavage of the gag-precursor protein. This substrate analogue and product of its cleavage was analyzed quantitatively using liquid chromatography high pressure (ghvd).

The corresponding test substance was dissolved in dimethyl sulfoxide. Enzyme test was carried out by adding suitable solvents tested substance in 20 mM b-morpholinepropanesulfonic acid (MES) buffer, pH 6,0 to the test mixture, which contained the above Icosa-peptide (122 mm) in 20 mM MES buffer, pH of 6.0. The test volume for all components was 100 µl. The reaction was started in resulte add 10 ál Of 3 M CHlO4. After centrifuging the samples for 5 min at g. 20 µl of the resulting sludge was received onNucleosil C-18-MC-ehvd-column (Machery Nagel, Duren, Germany). Nerazdelennyi Icosa-peptides, as well as the fission products after the column was loirevalley using the following gradient: 100% eluent 1 > 50% eluent 1 + 50% eluent 2 (eluent 1: 10% acetonitrile, 90% H2O, 0,1% triperoxonane acid; eluent 2: 75% acetonitrile, 25% H2O, 0,08% triperoxonane acid) for 15 min, flow rate 1 ml/min After elution of the reaction products were quantitatively analyzed using the peak height of the products of cleavage at 215 nm.

The following results were obtained (table. 1).

The value of the IC50shows the concentrations of the tested compounds in which these compounds exhibit a half maximal inhibition.

Inhibition of in vitro HIV in MT-2 cells cultures

MT-2 cells were used as described above, but using the ED100, i.e. the concentration of test substance at which no longer detected activity and the balance of reserves transcriptase in the sediment of infected cells. Thus the following data were obtained for inhibition of VI is from the blood of mice on the content of the tested compounds.

The title compound according to example 55 was dissolved in dimethyl sulfoxide at a concentration of 240 mg/ml of the resulting solution was dissolved in 20% (wt. /volume) solution of hydroxypropyl--cyclodextrin (in water) to obtain the concentration of the test compounds 12 mg/ml of This solution with the help of the probe was injected females mice at a dose of 120 mg/kg, 30 min after the injection of the solution of the mice were killed and their blood was collected. Investigated 3 or 4 animals. Blood was Gaprindashvili and prepared for analysis according to the following methods: blood was deproteinisation by mixing 1 volume part of blood with 1 part of acetonitrile; after centrifugation the precipitate was studied by using the standby phase jhud: analysis was conducted on theNucleosil C-18-ehvd-column(5 MK; Machery Nagel, Duren, Germany), filled with the mobile phase of the 47% of acetonitrile in water/0.1% of triperoxonane acid. Flow velocity of 1 ml/min, detection was at 215 nm. Standards for the title compound in example 55 was developed similarly and used to obtain a calibration curve, which was used to determine concentrations of compounds in vivo. Was established the following concentration:

Concentration (μm) in the blood title coedine for the following examples (table. 3).

Data on the toxicity of compounds

Tested compounds showed the following:

a) test for mutagenesis by AMC mutagenesis were observed,

b) in experiments on cells with MT-2 cells cytotoxicity was not observed,

in experiments on mice with the tested compounds toxicity was not observed.

Activity and lack of toxicity of the claimed compounds derived from the presented data. These data suggest that the compounds inhibit in vitro HIV-protease viruses causing AIDS, prevent the development of infection caused by a virus in cells and in mice, give satisfactory results of blood tests.

The compounds of formula I and salts of compounds of at least one salt-forming group are obtained in a known manner, for example:

a) a hydrazine derivative of the formula (III):

< / BR>
where the residues have the above meanings, is subjected to the interaction with the epoxide of formula (IV)

< / BR>
where the residues have the above values, and free functional groups, with the exception of participating in the reaction, if necessary, protected and, if necessary, otscheplaut; or

b) for compounds of formula I, where R1and the data values.

R2and R8denote hydrogen,

aminosidine formula (V)

< / BR>
where the residues have the above values, condensed with an acid of formula (VI):

R9OH

or a reactive derivative of this acid, where R9have the above values, and free functional groups, with the exception of participating in the reaction, if necessary, are in protected form, and, if necessary, then otscheplaut, or

to obtain compounds of the formula I, where R1and R9denote alkanoyl, sulfonyl, sulfamoyl, which is unsubstituted or substituted on the nitrogen with the above values,

R2denotes hydrogen, R3unsubstituted or substituted alkyl, and the remaining residues have the above values,

aminosidine formula (VII)

< / BR>
where the residues have the above values, is condensed with an acid of the formula (VIII):

R1HE

or a reactive derivative of this acid, where R1have the above values, and free functional groups, with the exception of participating in the reaction, if necessary, are in protected form, and, if necessary, these ZVA the same residue, choose from alkanoyl; sulfamoyl that nitrogen is not substituted or substituted, sulfonyl having the above meanings;

R2denotes hydrogen, R3unsubstituted or substituted alkyl, and the remaining residues have the above values,

diaminododecane formula (IX):

< / BR>
where the residues have the above values, condense with suitable for the introduction of identical residues R1and R9acid or a reactive derivative of this acid, where R1and R9have the above values, and free functional groups, with the exception of participating in the reaction, if necessary, are in protected form, and, if necessary, these protective groups otscheplaut: or

d) to obtain the compounds of formula I, where instead of R7is the remainder , which represents unsubstituted or substituted alkyl,

in the compound of formula (I'):

< / BR>
where

denotes hydrogen, and the remaining residues have the above values, enter the remainder of the non-hydrogen interaction with the compound of the formula (XII):

< / BR>
where X denotes tsepliaeva group, and denotes unsubstituted or substituted alkyl, with the available functional, who, if necessary, these protective groups otscheplaut; or

(e) compound of formula I where the substituents have the abovementioned meanings, with the proviso that in the corresponding compound of formula I at least one functional group protected by a protective group, otscheplaut existing protective group,

and if you want, get one of the above methods a) to (e) compound of formula I with at least one salt-forming group is transferred to its salt or obtained Sol was transferred into the free compound or into another salt, and/or, if necessary, divide the resulting mixture of isomers and/or proposed in the invention, the compound of the formula I is converted into another, proposed in the invention, the compound of formula I.

The above methods are described below more:

Method a) Attaching an amine to the epoxide.

Participating in the reaction of the amino group of hydrazine derivatives of formula III, depending on the values of R7contains preferably at least one free hydrogen atom; however, she can be derivatization to increase the reactivity of the derivative of hydrazine.

The epoxide of formula IV is in odnogo of hydrazine.

The functional group in the raw materials, their conversion should be avoided, particularly carboxy-, amino-, hydroxy-, can be protected with suitable protective groups, which are usually used for the synthesis of peptide compounds, or cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars. These protective groups can be introduced at the preliminary stages and must protect the respective functional group from undesired side reactions, such as acylation, esterification to esters and ethers, okislenii, solvolysis, etc., In certain cases, protective groups, moreover, may contribute to selective, for example, stereoselective course transformations. Typical protective groups is that they are easily, i.e. without undesired side reactions, hatshepsuts, for example, by solvolysis, restoration, or enzymatic proteolysis, for example, in physiological solutions. Similar protective groups remains, however, may also be present in the final (target) substances. The compounds of formula I with protected functional groups may have increased metabolic stability or other superior farmacodinamica is in a more narrow sense discussed above and below when the respective balances are no longer present in the target substances.

Protection of functional groups such protective groups are themselves protective group and the reaction of their removal are described, for example, in standard works, as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and new York, 1973; Th.W.Greene, "Protective Groups in Organic Synthesis", Wiley, new York, 1981; "The Peptides, vol. 3 (E. Gross and J. Meienhofer, Herausg.), Academic Press, London and new York, 1981; "Methods of organic chemistry", Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart, 1974; H.-D. Jakubke, H. Jescheit, "Aminos uren, Peptide, Proteine", ed. Chemie, Weinheim, Deerfield Beach und Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart, 1974.

Carboxypropyl protected, for example, in the form of ester groups, which is selectively cleaved under mild conditions. Protected in ester form carboxypropyl etherification first lower alkyl group, which is preferably branched in the 1-position a lower alkyl group or a substituted 1 - or 2-position a lower alkyl group, suitable substituents.

Protected carboxypropyl that etherification lower alkyl group is, for example, methoxycarbonyl or etoxycarbonyl.

Protected carb group, is, for example, tert.-(lower alkoxy)-carbonyl, for example, tert. butoxycarbonyl.

Protected carboxypropyl that etherification lower alkyl group which is substituted in the 1 - or 2-position a lower alkyl group, suitable substituents, represents, for example, arylethoxysilanes with one or two aryl residues, where the aryl is not substituted or denotes, for example, phenyl, mono-, di - or tizamidine lower alkyl, for example tert.-lower alkyl as tert.-butyl, lower alkoxyl, for example, methoxy, hydroxyl, halogen, for example chlorine, and/or nitro-group; for example, benzyloxycarbonyl, substituted specified by the Vice benzyloxycarbonyl, for example, 4-nitrobenzenesulfonyl or 4-methoxybenzeneboronic, diphenylmethylene or substituted by the mentioned substituents, diphenylcarbinol, for example, di-(4-methoxyphenyl)-methoxycarbonyl further esterified with a lower alkyl group carboxyl, the lower alkyl group substituted in the 1-or 2-position suitable substituents as 1-[(lower alkoxy)-(lower alkoxy)]-carbonyl, for example, methoxyethoxymethyl, 1-methoxyethoxymethyl or 1-ethoxyacetylene, 1-(lower alkyl)-thio-(lower de arolina group is an if necessary substituted, for example, halogen, such as bromide, benzoyl, for example, ventilatsioonil, 2-halogen-(lower alkoxy)-carbonyl, for example, 2,2,2-trichlorocyanuric, 2-pomatoceros or 2 - iodoxybenzoic, and 2-(tizamidine silyl)-(lower alkoxy)- carbonyl, where the substituents, independently of one another, represent aliphatic, analiticeskimu, cycloaliphatic or aromatic hydrocarbon residue, substituted if necessary, for example, lower alkyl, lower alkoxyl, aryl, halogen and/or nitro-group, as, for example, if necessary substituted as indicated above, lower alkyl, phenyl-(lower alkyl), cycloalkyl or phenyl, for example 2-tri-(lower alkyl)-silyl-(lower alkoxy)-carbonyl, 2-tri-(lower alkyl)-silyl-etoxycarbonyl, for example, 2-trimethylsilylethynyl or 2-(di-n-butyl-methylsilyl)-etoxycarbonyl, or 2-triarylsulfonium as trivinylcyclohexane.

Carboxypropyl can also be protected in the form of organic siliconvalley group. Organic similarcaterpillar group represents, for example, tri-(lower alkyl)-silicatecarbon group, for example, trimethylsilylacetamide. Silicon atom by similarseeming or carboxypropyl second molecule of formula I. Connection with such protective groups can be obtained, for example, using dimethylchlorosilane as cilleruelo tools.

Protected carboxypropyl represents preferably tert.- (lower alkoxy)-carbonyl, for example, tert.-butoxycarbonyl. benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 9-fluorenylmethoxycarbonyl or diphenylcarbinol.

A protected amino group may be protected by protective for the amino group, for example, be in the form of acylamino-, aryl-methylamino-etherified to simple ester mercaptamine-, 2-acyl-(lower ALK-1-enyl)-amino - or silylamine or sidegroup.

In appropriate acylamino group, acyl is, for example, acyl residue of an organic carboxylic acid, for example, with the number of carbon atoms up to 18, in particular in case of need substituted, e.g. by halogen or aryl, lower alkenylboronic acid or, if necessary, substituted, e.g. by halogen, lower alkoxyl or nitro-group of benzoic acid, or preferably an incomplete complex ester of carbonic acid. Such acyl groups are, for example, the lowest alkanoyl as formyl,,2,2 trifter - or 2,2,2-trichloroacetyl; if necessary substituted, e.g. by halogen, lower alkoxyl or nitrogroup benzoyl as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4 - nitrobenzoyl; lower alkoxycarbonyl, preferably branched in the 1 - position a lower alkyl residue or suitable way of substituted 1 - or 2-position (lower alkoxy)-carbonyl, for example, tert. -(lower alkoxy)-carbonyl, as tert. -butoxycarbonyl, arylethoxysilanes with one, two or three aryl residues, which represent one or multiply substituted, if necessary, for example, lower alkyl, especially tert.-lower alkyl as tert.-butyl, lower alkoxyl as methoxy, hydroxyl, halogen such as chlorine, and/or nitro-phenyl group, for example, benzyloxycarbonyl, 4-nitrobenzenesulfonyl, diphenylcarbinol, 9-fluorenylmethoxycarbonyl or di-(4-methoxyphenyl)- methoxycarbonyl, roulettecasino where arolina group represents preferably if necessary substituted, e.g. by halogen, such as bromide, benzoyl, for example, fencelineecology; 2-halogen(lower alkoxy)-carbonyl, for example, 2,2,2-trichlorocyanuric, 2 - pomatoceros or 2-iodoxybenzoic; 2-(triamese silicatecarbon or 2-(di-n-butylmethylether)-etoxycarbonyl, or triarylmethyl-(lower alkoxy)-carbonyl, for example, 2-trivinylcyclohexane.

In kilmacanogue, which represents, for example, mono-, di - or especially triarylmethane group, aryl residues are particularly, if necessary, substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl - or especially triphenylethylene.

In esterified to a simple broadcast to mercaptoamines mercaptopropyl is primarily in the form substituted aaltio or aryl(lower alkyl)-thio, where aryl is, for example, substituted if necessary, for example, lower alkyl like methyl or tert.-butyl, lower alkoxy like methoxy, halogen such as chlorine, and/or nitro-group is phenyl, for example 4-nitrophenylthio.

Used as protection for the amino group of the 2-acyl(lower ALK-1-analnyj) residue is an acyl, for example, the appropriate balance lower alkenylboronic acid; substituted if necessary, for example, lower alkyl like methyl or tert.-butyl, lower alkoxyl as methoxy, halogen such as chlorine, and/or nitrogroup benzoic acid, or vlei acid. Suitable protective groups are primarily 1-(lower alkanoyl)-(lower ALK-2-EN-2-yl), for example, 1-(lower alkanoyl)-prop-1 - EN-2-yl, 1-actipro-1-EN-2-yl, or (lower alkoxy)-carbonyl(lower ALK-1-EN-2-yl), for example, (lower alkoxy)-carbonyl-prop-1-EN-2 - yl, as 1-etoxycarbonyl-prop-1-EN-2-yl.

Silylamine is, for example, tri-(lower alkyl)-silylamine group, for example, trimethylsilane - or tert. -butyl-dimethylbenzylamine group. Silicon atom of silylamines may also be substituted by two lower alkyl groups such as methyl groups, and an amino group or carboxypropyl second molecule of formula 1. Connection with such protective groups can be obtained, for example, using CHLOROSILANES, as dimethylchlorosilane, as cilleruelo tools.

The amino group can also be protected by transfer in protonated form; as appropriate anions in the first place take into account such inorganic acids such as sulfuric, phosphoric acid or halogen acids, for example, chlorine - or bromanion, or organic sulfonic acids as p-toluensulfonate.

Preferred protective for the XI)-carbonyl, 2-(lower alkanoyl)-(lower ALK-1-EN-2-yl)- or (lower alkoxy)-carbonyl-(lower ALK-1-EN-2-yl).

The hydroxyl group may be protected, for example, acyl group, for example substituted by halogen such as chlorine, lower alkanoyl as 2,2 - dichloroacetyl, or particularly specified for a protected amino acyl residue of incomplete complex ester of carbonic acid.

Preferred protective for the hydroxyl group of a group is, for example, 2,2,2-trichlorocyanuric, 4-nitrobenzenesulfonyl, diphenylmethylene or triphenylmethyl. Hydroxyl group, then, may be protected by tri-(lower alkyl)-Sillam, for example, as trimethylsilyl, triisopropylsilyl or tert. -butyldimethylsilyl; easy useplease, tarifitsiruemih to simple ester group, for example, alkyl group as tert.-lower alkyl, for example tert.-butyl; oxa - or thia-aliphatic or-cycloaliphatic, in particular 2-oxa - or 2 - cualificaciones or-cycloaliphatic hydrocarbon residue, for example, 1-(lower alkoxy)-(lower alkyl) or 1-(lower alkyl)-thio(lower alkyl), as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa - or 2-Cilag, and 1-phenyl-(lower alkyl) benzyl, diphenylmethyl or triphenylmethyl, and phenyl residues can be substituted, e.g. by halogen such as chlorine, lower alkoxyl as methoxy, and/or nitrogroup.

Two present in the molecule, in particular the neighboring hydroxyl group or neighboring hydroxy - and amino group may be protected, for example, divalent protective group, preferably as, for example, is protected by one or two lower alkyl residues or oxopropoxy methylene group, for example, unsubstituted or substituted by alkylidene, for example, the lower alkylidene as isopropylidene, cycloalkylation as cyclohexylidene, carbonyl group or benzylidene.

As a protective group, for example, protective for carboxypropyl group, in the present invention, should also be considered in a certain way related and easily tseplyalsya with protected functional group, for example, carboxypropyl, polymeric media, which is suitable for the synthesis Merrifield'y. Such suitable polymer carrier is, for example, weakly crosslinked by copolymerization with divinylbenzene polystyrene resin, which has a corresponding montichiello in the normal connection of nucleophiles to epoxides conditions.

Accession shall be effected in particular in aqueous solution and/or in the presence of polar solvents, such as alcohols, e.g. methanol, ethanol or ethylene glycol, ethers like dioxane, amides, as dimethylformamide, or phenols as phenol, in anhydrous conditions in apolar solvents like benzene and toluene, or in emulsions of benzene with water, if necessary in the presence of acidic or basic catalysts, for example alkali as sodium hydroxide solution or in the presence of treated with hydrazine solid-phase catalysts as aluminum oxide, in ethers, for example, diethyl ether, in General at temperatures from about 0oC up to the boiling temperature of the corresponding reaction mixture, preferably at 20-130oC, if necessary at reflux distilled at high pressure, for example, a refractory tube, the temperature may exceed the boiling point, and/or in the atmosphere of inert gas, as nitrogen or argon, and each of the two compounds of formulae III and IV may be in excess, for example in a molar ratio of 1: 1-1: 100, preferably in a molar ratio of 1:1-1:10, particularly preferably in a ratio of 1:1-1:3.

Removal of protected groups>Method b) obtaining the amide bond.

In the source compounds of formulas V and VI functional groups, with the exception of groups that should not react or not to react under reaction conditions, independently of each protected specified in method (a) protective groups.

The compounds of formula VI contain free carboxypropyl or reactive acid derivatives, for example, activated derivatives of esters or reactive anhydrides, next, reactive cyclic amides. Reactive acid derivatives can also be formed in situ.

Activated esters of compounds of the formula VI with carboxypropyl are particularly unsaturated esters, such as vinyl ester, as a complex vinyl esters (obtained, for example, by transesterification of the corresponding complex ester with vinyl acetate; the method of activated vinyl ester); complex carbamoyl esters (obtained, for example, by treatment of the appropriate acid isoxazolin reagent; 1,2-oxazolium method, or a method of Woodward); or 1-(lower alkoxy)-vinyl complex EF the and-acetylene method), or complex amicinemici new type as N-N-disubstituted amidinov esters (obtained, for example, by treatment of the corresponding acid with a suitable N,N-disubstituted carbodiimide. for example, N,N-dicyclohexylcarbodiimide (carbodiimide method), or N,N-disubstituted complex amidinov esters (obtained, for example, by treatment of the corresponding acid with N,N-disubstituted cyanamide (cyanamide method); suitable complex aryl esters, in particular appropriately substituted electroepitaxy substituents complex phenolic esters (obtained, for example, by treating the appropriate acid appropriately substituted phenol, such as 4-NITROPHENOL, 4-methylsulfinylphenyl, 2,4,5 - trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-finaldestiny, in the presence of a condensing means, as N,N-dicyclohexylcarbodiimide; (method activated complex kilowog ether); complex cannetille esters (obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base (method canotilho ether complex); complex thioesters, in particular substituted if necessary, for example, a nitrogroup, kamesennin, for example, a nitrogroup, thiophenols, in particular, with anhydrite or carbodiimide method; the method of the activated complex tiefer), or especially amino or aminosilane esters (obtained, for example, by treatment of the corresponding acid with N-oxyamino, respectively, N-acetamidomalonate, for example, N-oxysuccinimide, N-oxopiperidine, N-acceptability. imide N-hydroxy-5 - norbornene-2,3-dicarboxylic acid, 1-oxybenzoates or Z-hydroxy-3,4 - dihydro-1,2,3-benzotriazin-4-it is, for example, anhydrous or carbodiimide method; the method of the activated complex N-oxyethira). Also used internal esters, for example, gamma-lactones.

Anhydrides of acids may be symmetric or preferably mixed anhydrides of these acids, as, for example anhydrides with inorganic acids, as galodamadruga acids, especially acid chlorides (obtained, for example, by treating the corresponding acid with thionyl chloride, pentachloride phosphorus, phosgene or oxalylamino; method of obtaining the acid chlorides of the acids; azides (obtained, for example, from the corresponding complex ester acids via the corresponding hydrazide and treatment with nitrous acid is Chille alkalemia) esters of carbonic acid (obtained for example, by treating the corresponding acid with a lower alilovic esters of Harborview acid or 1-(lower alkoxy)-carbonyl-2- (lower alkoxy)-1,2-dihydroquinoline; method of mixed esters of O - alkylphenol acid), or anhydrides with dihalogenoalkane, especially deklarirovannoe phosphoric acid (obtained, for example, by treating the corresponding acid with phosphorus oxychloride; phosphoroxychloride method), anhydrides with other derivatives of phosphoric acid, such which can be obtained with phenyl-N-phenyltetrahydropyridine or by transformation of amides alkylphosphoric acid in the presence of anhydrides of sulfonic acids and/or reduce racemization additives, as the N-oxybenzoates, or in the presence of a complex of diethyl ether cyanophosphonate acid or derivatives of phosphorous acid, or anhydrides with organic acids, as mixed anhydrides with organic carboxylic acids (obtained, for example, by treating the appropriate acid with assistance if necessary substituted galodamadruga (lower alkane - or phenyl-(lower alkane) carboxylic acids, for example, the acid chloride phenylacetic acid, pavlinovoi facilitate (work, for example, by treating the salts, such as alkali metal salt of the corresponding acid with a suitable organic galodamadruga sulfonic acids as the acid chloride (lower alkane - or aryl-, for example methane - or p-toluenesulfonic acid; method of mixed anhydrides of sulfonic acids); and symmetric anhydrides (obtained, for example, by condensing the corresponding acid in the presence of a carbodiimide or 1 - diethylaminopropyl; method of obtaining symmetrical anhydrides).

Suitable cyclic inorganic salts are especially amides with five-membered deathcycle aromatic character as amides with imidazoles, for example imidazole (obtained, for example, by treatment of the corresponding acid with N,N-carbonyldiimidazole: imidazole method), or pyrazole, for example, 3,5-dimethylpyrazole (obtained, for example, through the acid hydrazide by treatment with acetylacetone; pyrazolidine method).

As mentioned, derivatives of carboxylic acids, which are used as Alliluyeva means can also be formed in situ. So, for example, N, N-disubstituted amidinothiourea esters can be obtained in situ, so that the mixture of the source compounds of formula V and used the th carbodiimide, for example, N,N-cyclohexylcarbodiimide. Amino - or amido-(esters) used as Alliluyeva funds acids can be obtained in the presence of ciclismo starting compound of formula V, the fact that the mixture of the corresponding acid and amino compounds as starting substances injected into the interaction in the presence of N,N-disubstituted carbodiimide, for example N,N-cyclohexylcarbodiimide, and N-oxyamino or N-acetamide, for example, N-oxysuccinimide, if necessary in the presence of a suitable base, for example, 4 - dimethylaminopyridine. The activation can be conducted in situ by transformation with N,N,N',N'-tetraalkylammonium compounds, such as O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-hexaphosphate, (1,2-dihydro 2-oxo -1 pyridyl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate or O-(3,4-dihydro-4 - oxo-1,2,3-benzotriazole-3-yl)-N, N,N',N'-tetramethyluronium-tetrafluoroborate. Finally, the anhydrides of phosphoric acid, carboxylic acids of formula VI or VII can be obtained in situ, the fact that amide alkylphosphoric acid, as hexamethylphosphorotriamide, in the presence of sulfonic anhydride as the anhydride of 4-toluenesulfonic acid, administered in cooperation with the salt, as tetrafluoroborate, for example, tetrafluoroborate sodium, or other proizvoditelno in the presence of reducing racemization supplements as the N-oxybenzoates.

The amino group in the compound of formula V, which takes part in the reaction, preferably contains at least one reactionnary a hydrogen atom, particularly when reacting with carboxypropyl is in reactive form; however, the amino group may be derivatisation, for example, by reaction with postiton as diethylphosphate, 1,2-phenylenecarbonyl, ethyldichlorosilane, ativanklonopin or tetraethylpyrophosphate. The derivative of such a compound with amino group is, for example, galoyanized carbamino acid or isocyanate, and participating in the reaction of the amino group substituted by halogenocarboxylic, for example, chlorocarbonyl, or respectively, changed its predecessor, such as isocyanate group, and in the latter case are only the compounds of formula 1 which contain a hydrogen atom on the nitrogen atom, is obtained by reaction of amide groups.

If the compound of formula V once substituted on the amino group, lower alkyl or aryl-(lower alkyl), we also obtained the corresponding urea compound in the form of a reactive derivative. For example, sooty with the compound of the formula VI or VIII with a free carboxyl group.

Condensation to obtain the amide bond can be accomplished by itself in a known manner, for example as described in standard works, as Houben-Weyl, Methods of organic chemistry", 4th ed. volume 15/11 (1974), IX (1955), volume E 11 (1985), Georg Thieme Verlag Stuttgart: "The Peptides" (E. Cross and J. Meienhofer, Hg.), volume 1 and 2, Academic Press, London and new York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin, 1984.

The condensation of a free carboxylic acid with the appropriate amine preferably can be performed in the presence of a conventional condensing means, or applying anhydrous or golodnikov as carboxylic acid anhydrides or activated esters of carboxylic acids as p-nitrophenolate esters. The usual condensing means are, for example, carbodiimide, for example, diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)- carbodiimide or especially dicyclohexylcarbodiimide, then suitable carbonyl compounds, for example, carbonyldiimidazole. 1,2-oxazoline connection, for example, 2-ethyl-5-phenyl-1,2-oxazole-3'-sulfonate and 2-tert. - butyl-5-methylisoxazole, or a suitable acylamino connection, for example, 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, N,N,N',N'- tetraol the derivatives of phosphoric acid, for example, diphenylphosphoryl, diethylphosphoramidite, phenyl-N-phenylphosphonothioic, the acid chloride of bis-(2-oxo-3 - oxazolidinyl)phosphinic acid or 1-benzotriazolyl-Tris(dimethylamino)phosphonium-hexaphosphate.

In the desirable case, add an organic base, preferably a tertiary amine, for example, tri-(lower alkyl)-amine with bulky residues, for example, ethyldiethanolamine, or triethylamine, and/or heterocyclic base, for example, 4-dimethylaminopyridine or preferably N-methylmorpholine, or pyridine.

Condensation of activated esters, reactive anhydrides or reactive cyclic amides to the corresponding amines is carried out usually in the presence of organic bases, for example, a simple three-(lower alkyl)-amines, such as triethylamine or tributylamine, or one of the above-mentioned organic bases. In the desirable case, the additional use of the condensing means, as described for the free carboxylic acids.

The condensation of acid anhydrides with amines can be accomplished, for example, in the presence of inorganic carbonates, for example, carbonates or bicarbonates of ammonium).

The carboxylic acid anhydrides, for example, derivatives harpalinae acid produced from the acid of formula VI, or the anhydrides of sulfonic acids are condensed with the appropriate amines, preferably in the presence of an organic amine, for example, the above three-(lower alkyl)-amine, or heterocyclic bases, if necessary in the presence of hydrosulfate.

The condensation is carried out preferably in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example, in amide carboxylic acid, for example, as formamide or dimethylformamide; halogenated hydrocarbon, such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, such as acetone; cyclic simple ether, such as tetrahydrofuran; complex ester, such as ethyl acetate; or a nitrile, such as acetonitrile; or a mixture thereof, if necessary, at reduced or elevated temperature, for example, in the temperature range from about -40oC to approximately +100oC, preferably from approximately -10oC to about +50oC, in the case of the use of complex arylsulfonate esters also at about +100oC +200oC, and the possible water, for example, an alcohol, e.g. ethanol, or an aromatic solvents such as benzene or toluene. In the presence of hydroxides of alkali metals as grounds if necessary, you can add acetone.

Condensation can also be performed by a solid phase method and R. Merrifield'y described, for example, in Angew. Chem. 97. 801-812 (1985), Sciences) 71, 252-258 (1984) or in R. A. Houghten, Proc. Natl. Acad. Aci. USA 82,5131-5135 (1985).

Depending on the starting compounds residues R1and R9in the resulting compounds of formula 1 may be the same or different from each other.

The release of protected groups is carried out, if necessary, as described below in method (e) (removal of protective groups) methods.

Method) obtaining the amide bond.

In the source compounds of formulas VII and VIII functional groups, except groups that should participate in the reaction or which must not react with the reaction conditions, independently from each other, protected specified in method (a) protective groups.

The method is completely analogous to the one specified in the method (b) method, if instead of the compounds of formula V using the compounds of formula VII, and instead soedenenyi formula VII instead of the compounds of formula V.

Depending on the starting compounds residues R1and R9in the resulting compounds of formula 1 may be the same or different from each other.

The release of protected groups is carried out, if necessary, as described in method e) (removal of protective groups) methods.

Method g) obtaining the amide bond.

In the source compounds of the formula IX and suitable for the introduction of identical residues R1and R9acid or its reactive derivatives of functional groups that should not react or not to react under reaction conditions, independently from each other, protected by one of the above in method (a) protective groups.

Suitable for the introduction of identical residues R1and R9the acid preferably corresponds to one of formulas VI or VIII.

If necessary, as protected by the protective groups of the starting compounds of formula IX preferred compounds of formula II, which are described below in the section about the original compounds.

The method is completely analogous to that specified in paragraph (b) method, and instead of compounds of formula V use connections Tsennykh groups is carried out, if necessary, described in method e) below (removal of protective groups) methods.

Method d) Alkylation of the secondary nitrogen atom.

In the source compounds of the formula I' and suitable for introduction of the residue R7" the compound of the formula XII or its reactive derivative functional groups that should not participate in the reaction or that do not have to react under reaction conditions, independently from each other, protected specified in method (a) protective groups.

Remove the group X in particular represents a nucleophilic delete a group selected from hydroxyl, esterified to complex ester with a strong inorganic or organic acids, such as, for example, esterified with an inorganic acid, for example, halogen acids as hydrochloric, Hydrobromic or uudistoodetena acid, or with strong organic sulphonic acids, for example, if necessary substituted, e.g. by halogen like fluorine, (lower alkane-sulfonic acids or aromatic sulfonic acids, for example, in case of need, substituted lower alkyl, like methyl, halogen, such as bromide, and/or nitrogroup of benzoylacetate, for example, metasolv-, p-bromatological or toluensulfonate hydrox is the substance under conditions of nucleophilic substitution of the first or second order.

For example, one of the compounds of formula VIII-XIII, where X denotes the group that you want with a high polarizability of the electron shell, for example, iodine, in a polar aprotic solvent, for example acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimethylformamide. The reaction may be conducted in water, to which is added, if necessary, as agent for dissolving organic solvent, such as ethanol, tetrahydrofuran or acetone. The substitution reaction is carried out, if necessary, at reduced or elevated temperature, for example, in the temperature range from about -40oC to approximately +100oC, preferably from approximately -10oC to about 50oC, and, if necessary, in the atmosphere of inert gas, for example, in an atmosphere of nitrogen or argon.

The release of protected groups is carried out, if necessary, described in method e) (removal of protective groups) methods.

Method e)- Removal of protective groups.

Cleavage of the protective groups that are not an integral part of the desired target products of formula 1, for example, protective for carboxy-, amino-, exigrep is carried out in a known manner, for example, by analisa or chemical recovery as well as photolysis, if necessary, proceeding stepwise or simultaneously, and can also be used enzymatic methods. Cleavage of the protective groups, for example, described in the above in the beginning of the section on "protective groups" standard works.

So, for example, protected carboxyl, for example, tert.-(lower alkoxy)-carbonyl; substituted in 2-position tizamidine silyl group or in the 1-position of the lower alkoxyl or lower alkylthio lower alkoxycarbonyl or, if necessary, substituted diphenylmethylene, you can translate free carboxy by treatment with suitable acids, as formic acid, hydrochloric acid or triperoxonane acid, if necessary with the addition of nucleophilic compounds as phenol or anisole. From lower alkoxycarbonyl you can also release carboxyl through the grounds as hydroxyl, for example, hydroxides of alkali metals, such as NaOH or KOH. If necessary substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, as a catalyst based on palladium. Next, soudry carboxyl through recovery for example, by treatment with an alkali metal, as dithionite sodium, or with a reducing metal, for example zinc, or a reducing metal salt, such as salts of chromium-(II), for example, chloride, chromium(II), usually in the presence of the giver hydrogen funds, which together with the metal can give atomic hydrogen, or in the presence of acids, primarily suitable carboxylic acids, for example, if necessary substituted, e.g. by hydroxyl, (lower alkane) carboxylic acids, for example acetic acid, formic acid, glycolic acid, diphenylpyraline acid, lactic acid, almond acid, 4-harmondale acid or tartaric acid, or in the presence of an alcohol or thiol, preferably water is added. Thanks to the treatment with a reducing metal or metal salt, as described above, can also be converted into free carboxyl 2-halogen-(lower alkoxy)-carbonyl (if necessary after the conversion of 2-bromo-(lower alkoxy)-carbonyl group to the corresponding 2-iodine-(lower alkoxy)-carbonyl group) or roulettecasino. Roulettecasino can also be split by treatment with nuclei the ilil) -(lower alkoxy)-carbonyl, as 2-tri-(lower alkyl)-silyl-(lower alkoxy)-carbonyl, can also translate into a free carboxyl by treatments with giving fluoride anion salt of hydrofluoric acid, as a fluoride of an alkali metal, e.g. sodium fluoride or potassium, if necessary in the presence of a macrocyclic polyether ("crownether") or by using a fluoride of an organic Quaternary base, as Tetra-(lower alkyl)-unmonitored or tri-(lower alkyl)-aryl-(lower alkyl)-unmonitored, for example, tetraethylammonium or tetrabutylammonium, in the presence of an aprotic, polar solvent like dimethylsulfoxide or N,N-dimethylacetamide. Protected in the form of organic siliconserver as tri-(lower alkyl)-siliconserver, for example, trimethylsilylacetamide, carboxyl to be released in the usual manner by means of solvolysis, for example by treatment with water, alcohol or acid, or addition of fluoride, as described above. Esterificated carboxyl you can free enzymatic also, for example, by esterases or suitable peptidases, such as esterified arginine or lysine as the methyl ester of lysine, using trypsin.

Protected and with the help of solvolysis or recovery. (Lower alkoxy)-carbylamine. as tert.- butoxycarbonylamino, it is possible to decompose in the presence of acids such as inorganic acids, for example, galgenwaard. as the chloride or bromoiodide, or sulfuric or phosphoric acid, preferably hydrogen chloride, or strong organic acids, as trigalogenmetany acid, for example, triperoxonane acid, or formic acid, in a polar solvent, such as water, or ethers, preferably cyclic ethers like dioxane; 2-halogen-(lower alkoxy)- carbylamine (if necessary after the conversion of 2-bromo-(lower alkoxy)-carbylamine-group 2-iodine-(lower alkoxy)-carbonylation) you can split by direct dissolution in a liquid organic carboxylic acid as formic acid; kolmetsooniline or 4 nitrobenzisoxazole can be split, for example, by treatment with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid as aqueous acetic acid. Kolmetsooniline can also be split by treatment with a nucleophilic, preferably salt-forming reagent, as thiophenolate sodium, and 4 - nitrobenzyloxy if necessary, diphenylethylenediamine, tert. -(lower alkoxy)- carbylamine or 2-(tizamidine silyl)-(lower alkoxy)- carbylamine as 2-tri-(lower alkyl)-silyl-(lower alkoxy)- carbylamine, can be freed by treatment with suitable acids, for example formic or triperoxonane acid: if necessary, replaced benzyloxycarbonylamino you can release, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, a catalyst based on platinum or palladium; if necessary, replaced triarylmethane or formylamino can be freed, for example, by treatment with acid as an inorganic acid, e.g. hydrochloric acid, or organic acids, for example formic, acetic or triperoxonane acid, if necessary in the presence of water, and is protected in the form of silylamine the amino group can be freed, for example, by hydrolysis or alcoholysis. Protected 2-halogenation, for example, 2-chloroacetyl. the amino group can be freed by treatment with thiourea in the presence of a base, or by using tyaletnoi salt, as tiolet alkali metal, thiourea, and the last is PPI amino group is released, for example, by hydrogenolysis using reason as the hydroxides or carbonates of alkali metals like Na2CO3or K2CO3in polar solvents, such as alcohols, like methanol, at temperatures of 0-100oC, in particular at 40-80oC. Protected 2- (tizamidine silyl)-(lower alkoxy)-carbonyl, 2-tri-(lower alkyl)-silyl- (lower alkoxy)-carbonyl, amino group can be converted to a free amino group by treatment with giving peridinian salt of hydrofluoric acid, as mentioned in the release respectively secured carboxypropyl. You can also split directly associated with heteroatoms as nitrogen, silyl as trimethylsilyl, using a fluoride ion.

Protected in the form of sidegroup the amino group can be converted to a free amino group, for example, by restoring, for example, by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst as platinum oxide, palladium or Raney Nickel, by restoring using mercapto-compounds, as dithiothreitol or mercaptoethanol, or by treatment with zinc in the presence of acid, as acetic acid. Catalytic is an example, in methylene chloride, or water, or a mixture of water with an organic solvent, such as alcohol or dioxane, at about the 20oC-25oC, or when cooling or heating.

Protected by a suitable acyl group, a tri-(lower alkyl)- silyl group or, if necessary, substituted 1-phenyl-(lower alkyl) hydroxyl or mercapto group release likewise correspondingly protected amino group. Protected 2,2-dichloroacetyl hydroxyl, respectively mercapto group, released, for example, by basic hydrolysis, protected tert.-lower alkyl or 2-oxa - or 2-cualificaciones or cycloaliphatic hydrocarbon residue hydroxyl, respectively mercaptopropyl, released by acidolysis, for example, by treatment with an inorganic acid or a strong carboxylic acid, for example, triperoxonane acid.

If there are several protected functional groups, if desired, the protective group can be chosen so that at the same time it was possible to split more than one such group, for example, acidolysis, for example, by treatment with triperoxonane acid, or with hydrogen and a catalyst Hydra all at the same time, and in the desired sequence, and get the corresponding intermediate products.

Additional measures methods.

In case of additional measures in ways that are desirable in the case, the functional group of the parent compounds, which should not participate in the reaction, can be exposed or to be in a protected form, for example, by one or more of the above in method (a) protective groups. The protective group can be stored in the target products have been completely or partially chipped off as specified in the method (e) methods.

Salts of compounds of formula 1 with at least one salt-forming group can be obtained in itself known. Thus, salts of compounds of formula 1 with the acid groups are formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example, sodium salt of 2-ethylhexanoic acid, with organic compounds of alkali or alkaline earth metals, as the corresponding hydroxides, carbonates or bicarbonates, as the hydroxide, carbonate or bicarbonate of sodium and potassium, using the appropriate qualities amounts or only a small excess of the salt-forming means. Salt accession acid compounds of formula 1 are as in the usual manner, for example by treatment with acid or a suitable anion exchange reagent. Internal salts of compounds of formula 1, which contain acidic and basic soleobrazutaya group, for example, a free carboxyl group and a free amino group can be obtained, for example, by neutralising salts, as salts accession acids, isoelectric point, for example with weak bases, or by treatment with ion exchangers.

Salt can be translated into the free compounds in the usual manner; metal salts and ammonium, for example, by treatment with suitable acids, and salts of joining acids, for example, by treatment with suitable asset.

Mixture of stereoisomers, i.e., mixture of diastereomers and/or enantiomers, such as racemic mixtures, in a known manner can be separated through suitable methods of separation of the corresponding isomers. Thus, a mixture of diastereoisomers can be separated into the individual diastereomers by fractional crystallization, chromatography, distribution between solvents, etc. of the Racemates can be separated after transferring optimi, for example, optically active acids or bases, by column chromatography sorbents coated with optically active compounds, or by enzymatic methods, for example, by selective engagement of only one of the two enantiomers. This separation can be performed both on stage one of the initial products, and in the case of the compounds of formula 1.

On a separate centers of chirality in the compound of formula 1 can be targeted to pay the configuration. For example, you can pay the configuration of asymmetric carbon atoms, which contain nucleophilic substituents, such as amino or hydroxyl, by nucleophilic substitution of the second order, if necessary after you put a linked nucleophilic substituent in a suitable nucleophilic remove the group and reaction with introducing the original Vice reagent, or you can change the configuration at the carbon atoms with hydroxyl groups, as for example, a carbon atom with a group R5in the compound of formula 1, by oxidation and reduction of compounds of formula 1, as described below.

The remains of the hydroxyl R5and hydrogen R6in the compound of formula 1 can acylates is the SCP in the keto-group, for example, chromic acid or its derivatives, as pyridinium or tert.-buildroot, dichromate/sulfuric acid, sulfur trioxide, in the presence of heterocyclic bases as pyridine/SO3, further nitric acid, pyrolusite or selenium dioxide, or dimethylsulfoxide in the presence of oxalicacid, water, aqueous or organic solvents, such as halogenated solvents such as methylene chloride, amido carboxylic acids, such as dimethylformamide, or di-(lower alkyl) -sulfoxidov as dimethyl sulfoxide, in the presence or in the absence of basic amines, for example tri-(lower alkyl)-amines as triethylamine, at temperatures from -50oC to 100oC, preferably at -10oC +50oC, for example as described in European patent application EP-A-0 236 734.

On the contrary, in the thus obtained compounds of formula 1 in which R5and R6together form an oxo-group, oxo group can be restored to the hydroxy group. To restore the oxo-group in the compound of formula 1 is suitable reducing agents which, under the reaction conditions of the method to restore an isolated keto-group selectively, or faster than existing in the compounds of formula 1 amide group.

Recovery can be carried out using hydrogen in the presence of suitable catalysts based on heavy metals, such as Raney Nickel or platinum or palladium catalysts, for example platinum or palladium on active charcoal, or according to Meerwein-Ponndorf-Verley using alkanoates aluminum, preferably 2-propenoate aluminum or 2-ethanolate aluminum.

Recovery can be carried out preferably with stoichiometric amounts or reasonably measured by the excess of reducing agent in an inert solvent at temperatures of from -80oC to the boiling point of the solvent, for example, at -20oC +100oC, if necessary, in the atmosphere of inert gas such as nitrogen or argon. The excess of reducing agent necessary especially when it also reacts with the solvent, for example, protons proton solvent.

When using sodium borohydride suitable polar, proton solvent, n is Italy, for example, tetrahydrofuran.

In the compound of formula 1 in which R1and R9do not contain any or contain very reactive aryl residues, available in R7and R3aryl residue, in particular phenyl residue can be gidrirovanii, for example, by catalytic hydrogenation, in particular in the presence of oxides of heavy metals, as mixed rhodium/platinum oxides, for example, Nishimura catalyst, preferably in a polar solvent, such as alcohol, e.g. methanol or ethanol, at temperatures 0-80oC, in particular at 10-40oC, and under a hydrogen pressure of 1-10 ATM, preferably, for example, at normal pressure.

In the resulting compound of formula 1, you can replace the amino - or carboxamido, atrificial to complex ester or lidirovat in a free or reactive form carboxypropyl, respectively, translate esterified or amidinophenoxy carboxypropyl free carboxypropyl.

Substitution carboxamide group, or another primary or secondary amino groups, for example, for the introduction of the residues, as unsubstituted or substituted alkyl, alkenyl or quinil, aryl-(lower alkyl9in the compounds of formula 1, in which one or more of these balances represent hydrogen, is carried out, for example, by alkylation.

Suitable means for alkylation carboxyamide group in the compound of formula 1 are, for example, diazocompounds, for example, diazomethane. Diazomethane can be disposed of in an inert solvent, and formed the free methylene reacts with carboxamide group in the compound of formula 1. Decomposition of diazomethane is preferably catalytically, for example, in the presence of a noble metal in finely dispersed form, for example, copper, or salt of a noble metal, for example, chloride, copper(I) or sulphate of copper(II).

Alkylating agent has also indicated to the Federal Republic of Germany patent 2331133, for example, alkylhalogenide, esters of sulfonic acids, salts of Meerwein or 1-substituted 3-alltrista, which under specified reaction conditions may interact with a compound of formula 1 with carboxamide group.

Other alkylating means are selected from compounds of the formula:

R1-X (X)

R2-X (XI)

R8-X (XIII)and

R9-X (XIV)

where X denotes a group to delete, and the remaining residues have Go as indicated above phosphoryla. The deleted group is a particularly nucleophilic delete a group selected from etherification with a strong inorganic or organic acid hydroxyl how to use inorganic acids, for example, halogen acids as hydrochloric, Hydrobromic or uudistoodetena acid, or with strong organic sulfonic acids, as, if necessary, substituted, e.g. by halogen like fluorine, lower alkanesulfonyl, or aromatic sulfonic acids, for example, how, if necessary, substituted lower alkyl, like methyl, halogen, such as bromide, and/or nitrogroup benzosulfimide; for example, esterified by methansulfonate, trimethylsulfonium or p-toluensulfonate hydroxyl or esterified with attestations acid hydroxyl.

The reaction may proceed in the conditions of a nucleophilic substitution of the first or second order.

For example, one of the compounds of formula VIII-XIII, where X denotes the group that you want with a high polarizability of the electron shell, for example, iodine, in a polar aprotic solvent, for example acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimetane organic solvent, for example, ethanol, tetrahydrofuran or acetone. The substitution reaction is carried out, if necessary, at reduced or elevated temperature, for example, in the temperature range of about -40oC to about 100oC, preferably from approximately -10oC to about 50oC, and, if necessary, in the atmosphere of inert gas, for example, in an atmosphere of nitrogen or argon.

For the esterification or amidation of carboxypropyl in the compound of formula 1 can, if desired, to apply the free acid or translate free acid in one of the above-mentioned reactive derivatives and to enter into interaction with alcohol, ammonia, primary or secondary amine, or for the esterification of the free acid or reactive salt, for example, cesium salt, to enter into an interaction with a reactive derivative of the alcohol. For example, the cesium salt of carboxylic acid can be administered during the interaction with the corresponding alcohol by halide or a complex ester of sulfonic acids. The etherification of carboxypropyl can also be implemented using other conventional alkylating agents, e.g. using diazomethane, alkylhalogenide, esters of sulfonic acids, salts of Meerwein or 1 - free carboxypropyl you can apply one of the above when removal is protective for carboxypropyl groups of methods or in the desirable case, alkaline saponification according to Organikum, 17,ed. VEB Deutscher Verlag der Wissenschaften, Berlin (Ost) 1988, the reaction conditions.

In the compound of formula 1 is esterified with carboxypropyl by aminolysis with ammonia or primary or secondary amine to transfer in substituted if necessary carboxamido group. Aminals can proceed at normal, as specified in Organikum, 15th ed. VEB Deutscher Verlag der Wissenschaften, Berlin (Ost), 1976, for such reactions, the reaction conditions.

In the compound of formula 1 can be allievate available free amino group, for example, to introduce one of these for R1or R9residues: acyl. The acylation proceeds according to the methods outlined in methods b), C) or d) for condensations, or on one of the following security groups methods or, for example, by the method specified in Organicum, 17th ed. VEB Deutscher Verlag der Wissenschaften, Berlin (Ost), 1988.

In the resulting compound of formula 1, where the substituents have the above values and with at least one free hydroxyl group and the other functional groups are in protected form of free hydroxyl group can be allievate or atrificial of metodov, specified in the methods (b)-g), one of these protective groups methods or by the method specified in Organikum, 17th ed. VEB Deutscher Verlag der Wissenschaften, Berlin (Ost), 1988.

Etherification to simple ester can be carried out using the above-mentioned alkylating means and under the same reaction conditions, for example, using diazomethane, alkylhalogenide, esters of sulfonic acids, salts of Meerwein, 1-substituted 3-alltrista etc.

In the compound of formula 1 existing protective group or suitable residues R1or R9then there are those who represent acyl, sulfo, replaced sulfo, phosphono or substituted phosphoryl, otscheplaut for any of the above in method (e) methods, in particular by hydrolysis, for example, in the presence of bases as the hydroxides of alkali or alkaline earth metals such as sodium hydroxide, or acids, organic acids or inorganic acids, for example, halogenation as chlorodrol. The hydrolysis is carried out under normal conditions, for example in aqueous solution or in anhydrous solvents, especially ethers like dioxane, at temperatures from -50oC to the boiling temperature under reflux corresponding reaction">

All the above mentioned stages of the method may be performed at a known, preferably called the specific reaction conditions, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents and dissolve them, in the absence or in the presence of catalysts, condensing means or neutralizing agents, for example ion exchangers, as cationogenic, for example, in the H+form, depending on the type of reaction and/or components of the reaction, under reduced, normal or elevated temperature, for example, in the temperature range from about 100oC to about 190oC, preferably from approximately -80oC to approximately 150oC, for example, at -80oC 60oC, at room temperature, at -20oC-40oC, or at the boiling point of the used solvent, at atmospheric pressure or in a closed vessel, if necessary under pressure, and/or in an inert atmosphere, for example, in an atmosphere of argon or nitrogen.

In the case of all initial and intermediate compounds can be used either to form salts, if there soleobrazutaya group. Salt can obrazovyvalas isomers may be separated into individual isomers, for example, diastereoisomers or enantiomers or any mixture of isomers, for example racemates or mixtures of diastereoisomers, for example, similarly to the methods described under the name of "Additional measures".

In some cases, for example, the hydrogenation can be achieved stereoselectivity of reactions that facilitates obtaining the individual isomers.

To solvents corresponding reaction is referred, for example, water, esters, (lower alkyl)-(lower alkanoate), for example, diethyl ether acetic acid; ethers, as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons as benzene or toluene; alcohols, like methanol, ethanol or 1 - or 2-propanol: NITRILES like acetonitrile; kalogeropoulou as methylene chloride; acid amides as dimethylformamide; grounds as heterocyclic nitrogen bases, for example, pyridine: the anhydrides of the acids, as anhydrides of lower alkanovykh acids, for example, acetanhydride; cyclic, linear or branched hydrocarbons like cyclohexane, hexane or isopentane, or mixtures of these solvents, e.g. aqueous solutions, if in the description of the method of the example, when chromatography or dispersion.

It is also possible such embodiments of the method, under which extend from the obtained at any stage as an intermediate product of the connection and provide the missing stage or a way to interrupt at any stage, or a starting material is obtained in the reaction conditions or is used in the form of a reactive derivative or salt, or received by one of the proposed invention means a compound obtained when the conditions and further processed in situ. Thus preferably extend from such starting substances, which lead to the compounds described above as preferred, particularly as particularly preferred, first of all preferred and/or, above all, preferred.

The pharmaceutical agent.

Proposed according to this invention the pharmaceutical agent contains an effective amount of a derivative of hydrazine of formula 1 or pharmaceutically acceptable salt of this compound with at least one salt-forming group with at least one pharmaceutically acceptable carrier, is able to inhibit HIV protease and has AntiVir is whether organic, solid or liquid pharmaceutically acceptable carriers.

The invention relates to pharmaceutical agent, which is suitable for introduction of warm-blooded animals, especially humans, for the treatment or prevention of disease, which is designed for inhibiting retroviral proteases, in particular retroviral aspartates as HIV-1 or HIV-II-gag-protease, for example, retroviral diseases, such as AIDS, including effective for inhibiting retroviral proteases amount of the compounds of formula 1 or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier.

The proposed tool can be used by introducing warm-blooded humans and animals enterline, for example, through the nose, rectally, orally, or parenterally, e.g. intramuscularly or intravenously, the effective dose of the pharmacologically active substances individually or together with a significant amount of pharmaceutically applicable carrier. The dose of the biologically active substance depends on the species of warm-blooded animals, body weight, age and individual condition, individual pharmacodynamic data, treatable disease, and how will introduce a therapeutically effective amount proposed in the invention compounds of formula 1 warm-blooded, for example, people with the disease, especially AIDS, requires such treatment. For warm-blooded animals, e.g. humans weighing approximately 70 kg, the dose is about 3 mg to about 3 g, preferably from approximately 10 mg to approximately 1.5 g, for example, about 300-1000 mg per person per day, divided preferably 1 to 3 single doses. who, for example, can be the same size. Children usually receive half the adult dose.

The pharmaceutical agents contain about 1-95%, preferably about 20-90% of the biologically active substances. Proposed in the invention the pharmaceutical agents can be, for example, in a unit dosage forms, such as ampoules, vials, suppositories, pills, tablets or capsules.

The pharmaceutical agents of the present invention receive a known manner, for example, using conventional methods of dissolution, freeze-drying, mixing, granulating or drazhirovanija.

Preferably apply solutions of biologically active substances, especially isotonic aqueous solutions or suspensions, and, for example, in the application of lyophilised preparations which contain the biologically active substance individually or together with territory and/or may contain auxiliary substances, for example, preservatives, stabilizers, wetting and/or emulsifying agents, agents, dissolution, salts for regulating osmotic pressure and/or buffers, and are prepared in the usual manner, for example, using conventional methods, dissolution or lyophilization. These solutions or suspensions can include increasing the viscosity of the substance, as carboxymethylcellulose sodium, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain as oil components customary for injection purposes, vegetable, synthetic or semi-synthetic oils. As such, should be especially liquid esters of fatty acids as acid components contain long-chain fatty acid with 8-22, especially 12-22, carbon atoms, such as lauric acid, traditiona acid, myristic acid, pentadactyla acid, palmitic acid, margaric acid, stearic acid, orhideea acid, Bekenova acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, rukanova acid, brasavola acid or linoleic acid, if necessary Ananta these esters of fatty acids contains a maximum of 6 C atoms and is a one - or polyhydric, for example, one-, two -, or trivalent alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol, or their isomers, primarily glycols and glycerin. As esters of fatty sour so preferably you need to specify: etiloleat, isopropylmyristate, isopropyl, "Labrafil M 2375" (polyoxyethyleneglycol company Gattefosse, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with long chains of C8-CR12the company Huls AG, Germany), particularly preferred vegetable oil, as oil seeds, cotton, almond oil, olive oil, castor oil, semasa, soybean oil and especially peanut butter.

Preparation of injectable preparations carried out in the usual manner under sterile conditions, in the same way by filling in ampoules or vials (vials), and capping of containers.

Pharmaceutical preparations for oral administration can be obtained by a combination of biologically active substances with solid carriers, the resulting mixture granularit and the mixture, if desired or necessary, after adding suitable auxiliaries, processed into tablets, pills or capsules. Thus they can be administered in synthetic nosit.

Suitable carriers are, for example, fillers like sugar, for example lactose, saccharose, mannitol or sorbitol; cellulose additives, and/or calcium phosphates, for example, tribalistic or calcium phosphate; binders, as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragant, methylcellulose, oksipropilmetiltselljuloza, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, extenders, as the abovementioned starches, further, carboximetilkrahmala, transversely crosslinked polyvinylpyrrolidone, agar, alginic acid or its salt, as sodium alginate. AIDS are primarily the fluidity regulators and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium and/or polyethylene glycol. Tablets are supplied suitable, if necessary resistant to gastric juice coatings, and apply, in particular, concentrated sugar solutions, which, if necessary, contain gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic px substances, as ethylcellulose or oksipropilmetiltselljuloza. Capsules are detachable capsule of gelatin, and also soft, sealed capsules of gelatin and a plasticizer, as glycerol or sorbitol. Detachable capsules can contain a biologically active substance in the form of a granulate, for example, fillers, such as lactose, binders, as starches, and/or softeners (lubricants), as talc or magnesium stearate, and, if necessary, with stabilizers. In soft capsules the active substance is preferably dissolved or suspended in a suitable oil auxiliary substances, such as fatty oils, paraffin oil or liquid polyethylene glycols, and also can be added stabilizers and/or antibacterial agents. In tablets or dragee coatings and shell capsules can add dyes or pigments, for example, to identify or to mark different doses of biologically active substances.

Intermediate compounds.

The object of the present invention are new intermediate compounds to obtain the hydrazine derivatives of the General formula II

< / BR>
where R3, R7mean lower alkyl, cyclohexyl-lower aliadiere, if they have soleobrazutaya group.

Upon receipt of all original materials free of functional groups that should not participate in the relevant reactions are not protected or are in protected form, for example, protected above in method (a) protective groups. These protective groups can be released at suitable points in time due to described in method e) reactions.

Source materials used in method (a) known or, if they are new, can be obtained in a known manner, for example, hydrazine or its corresponding derivatives of compounds of formula III, from the appropriate amino acids or their analogues, for example, with one or two specified values of R3and R4, compounds of formula IV.

The compounds of formula III, for example, are obtained from compounds of formula XV:

H2N-NH-R11< / BR>
where R11denotes hydrogen or protection for the amino group described above in method b), in particular (tert.-lower alkoxy)-carbonyl, as tert. butoxycarbonyl, aryl-(lower alkoxy)-carbonyl, as benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl, or one of the above aceraminophen groups. The way Zack is ewenny or substituted alkyl, with the introduction of the compound XV last alkylate using the compounds of formula XII as described above in method d), or the remainder R7introduced by reaction of the corresponding carbonyl compounds with free amino group of the compounds of formula XV or its acylated derivatives with subsequent recovery of the resulting hydrazone to the hydrazine derivatives of the formula XVI:

R7-NH-NH-R11< / BR>
and remains in all of these compounds have the above values and functional groups in the participating agents, which should not participate in the reaction, if necessary protected; if necessary, the protective group R11if it does not match one of the residues R9in the compounds of formula I, and/or other protective groups otscheplaut, and enter the remains of R9except for hydrogen, by condensation of the above conditions (b) interaction with acids of formula VI, or by alkylation of compounds of formula XIII or formula XV as defined above.

Used to obtain the compounds of formula XVI, suitable for introduction R7carbonyl compounds are aldehydes or ketones, reactive carbonyl group to azannyh residues R7; preferred aldehydes which are suitable for introduction of lower alkyl, cyclohexyl-(lower alkyl) or phenyl-(lower alkyl).

The reaction of carbonyl compounds with compounds of formula XVI with the corresponding hydrazones is carried out in the usual reactions of carbonyl compounds with amines conditions, preferably in a polar organic solvents such as ethers, like tetrahydrofuran or diethyl ether, alcohols, like methanol or ethanol, amido carboxylic acids as dimethylformamide, or esters as ethyl acetate, or in an aqueous solution, preferably in methanol, then in the presence or in the absence of acidic catalysts, for example, carboxylic acids, as formic acid or acetic acid, or sulfonic acids as n-toluensulfonate, at temperatures from 0oC to the boiling temperature under reflux the reaction mixture, preferably at temperatures from 20oC to the boiling temperature under reflux the reaction mixture.

Recovery of the resulting hydrazone is carried out preferably by hydrogenation in the presence of a suitable catalyst. As suitable for hydrogenation catalysis their oxides, as palladium or rhodium, respectively, their oxides; if necessary, for example, deposited on suitable carriers, as barium sulfate, aluminum oxide or active charcoal, or in the form of skeletal catalysts as Raney Nickel. Used solvents for the catalytic hydrogenation are, for example, water, alcohols like methanol or ethanol, esters like ethyl acetate, ethers like dioxane; chlorinated hydrocarbons like dichloromethane, amides of carboxylic acids as dimethylformamide, or carboxylic acids, as glacial acetic acid, or mixtures of these solvents. The hydrogenation is carried out at temperatures 10 250oC, preferably from room temperature to 100oC, and under a hydrogen pressure of 1 to 200 bar, preferably 1 to 10 bar, with the usual instruments.

Especially preferred for producing compounds of formula XV are the reaction conditions are similar to those described in J. Chem. Soc. Perkin I, 1712 (1975).

The compounds of formula XV, for example, obtained by recovery of the amino acids of the formula:

< / BR>
where R10denotes hydrogen or one of the above in method (a) for protective amino group, especially tert.-(lower alkoxy)-carbonyl, as tert. the bout is mentioned there acyl-aminosidine groups; R3and R4have the above for compounds of formula I values, preferably amino acids of the formula:

< / BR>
in which the residues have the above values, to obtain the aldehyde of the formula:

< / BR>
where the residues have the above values, preferably aldehydes of the formula:

< / BR>
where the residues have the specified values (obtained, for example, from compounds of the formula XVIII), followed by the introduction in the interaction of these aldehydes with ylides connection, preferably with thio-ylides connection with obtaining epoxide of the formula:

< / BR>
where the residues have the above values, preferably compounds of the formula:

< / BR>
(so, for example, from compounds of formula XIX (A), where the residues have the above values,

and, if necessary, by removal of the protective group R11if it does not match one of the residues R8or R9in the compounds of formula 1, and the remains have specified values, and alkylation of the amino group of the obtained compound with the nucleophilic reagents removed by the groups of formulae X or XI, where the residues have the above meanings, in the conditions described for additional measures methods.

Recovery of amino acids of formula XVIII or XVIIIA prior to and subsequent oxidation to these aldehydes.

The recovery of alcohols is carried out, for example, by hydrogenation of golodnikov acids or other specified in method b), activated derivatives of carboxylic acids under specified for the hydrogenation derived from compounds of formula XVI hydrazones conditions, or with complex hydrides, such as sodium borohydride. Subsequent oxidation of the resulting alcohols may, for example, the conditions for the oxidation of compounds of formula 1 in which R5denotes hydroxyl and R6denotes hydrogen, such that R5and R6together denote an oxo group, as described in additional measures, methods, or by oxidation of the hydroxyl group using a sulfoxide as dimethyl sulfoxide, in the presence of activating the hydroxyl group of the reagent, as acid chloride of the carboxylic acid, for example, oxanilide, in an inert solvent, for example, halogenated hydrocarbon like dichloromethane, and/or acyclic or cyclic simple ether like tetrahydrofuran at -80oC-0oC, for example, from 78oC to -50oC.

It is also possible to direct the recovery of amino acids into aldehydes, for example, by hydrogenation in the presence of partially poisoned PSSA alilovic esters, as ethyl ether, using complex hydrides, for example sodium borohydride, or preferably aluminum hydrides, for example, sociallyengaged, lithium tri-(tert.-butoxy)-aluminiumhydride or particularly diisobutylaluminium, in apolar solvents, for example hydrocarbons or aromatic solvents, such as toluene, at -100oC-0oC, preferably at -70oC -30oC, and subsequent conversion into the corresponding semicarbazone, for example) with the corresponding salts of semicarbazones as semicarbazide, in an aqueous solvent system, such as alcohol/water, for example, ethanol/water, at temperatures from 20oC to 60oC, preferably at 10-30oC, and the introduction of the interaction obtained semicarbazones with reactive aldehyde, for example formaldehyde, in an inert solvent, for example, polar organic solvent, for example, amide carboxylic acid as dimethylformamide, at temperatures from -30oC to 60oC, preferably at 0-30oC, and then enter into interaction with the acid, for example, with strong inorganic acid, as galgenwaard, in aqueous solution, if necessary in the presence of the previouslyC., the Corresponding esters are obtained by the interaction of amino acids with the corresponding alcohols, for example ethanol, is similar to that used in the condensation in the way b) the conditions of, for example, by reacting with inorganic halogenide acids, as thionyl chloride in mixtures of organic solvents, such as mixtures of aromatic and alcoholic solvents such as toluene and ethanol, at temperatures from 50oC to 50oC, preferably at -10oC-20oC.

Obtaining compounds of formula XIX and formula XIXA is particularly preferably in the same terms as specified in J. Org. Chem. 47 3016 (1982) or J. Org. Chem. 43 3624 (1978).

Suitable for the conversion of compounds of formula XIX or XIXA in the epoxides of formula XX or settle down under thio-ridom is, for example, dialkylaminomethyl, for example, dimethylsulfonium, alkyl - or phenyldimethylchlorosilane, for example, methyl - or phenyldimethylchlorosilane, or dialkylaminomethyl, for example, dimethyl - or diethylsulfoxide.

Appropriate thiolene connection it is better to obtain in situ from the corresponding sulfonato or sulfoxonium salts and bases, naprimer, tetrahydrofuran or 1,2 - dimethoxyethane and then entered into an interaction with compounds of formula XIX or XIXA. Interaction usually occurs at room temperature, while cooling, for example, up to -20oC, or under mild heating, for example, up to the 40oC. Simultaneously formed sulfide, sulfonamide, respectively, sulfoxide is removed during subsequent processing water.

Interaction with tailyda is preferably in the same terms as in J. Org. Chem. 50, 4615 (1985).

The compound of formula XX (preferably settle down under) is obtained from the compounds of formula XIX (preferably XIXA), as described above, by introducing it in interaction with three- (lower alkyl) -silymarine connection Grignard reagent, for example, prepared from the corresponding kaleidocycle as chloromethyl-trimethylsilane, in an inert solvent, for example ether, as dioxane or diethyl ether, at temperatures of 0-50oC, for example, from room temperature to approximately 40oC; subsequent elimination when removing silyl residue and the formation of a double bond, for example, by using a Lewis acid as BF3preferably also cleaved prisutstyovie ether, or halogenougljovodonika as dichloromethane, or mixtures thereof, at temperatures from -50oC to the boiling temperature under reflux, especially when 0-30oC and, if necessary, by acylation with the introduction of protective for the amino group, such as R10as described above, and oxidizing the obtained double bond to oxirane, preferably using nagkalat, for example, m-chlormadinone acid, in an inert solvent, for example, halogenated hydrocarbon, as dichloromethane, at temperatures between -20oC to the boiling point of the mixture under reflux, for example, 10-30oC.

The original connection methods, b), C) and d) are known or, if they are new, can be obtained by known methods, for example, the compound of formula V can be obtained from the corresponding hydrazine powered derivative of the formula III in which R9denotes hydrogen, and the remaining residues have the above for compounds of formula V values, and suitable epoxides of the formula IV, where the residues have the above for compounds of formula V values (method b)); a compound of formula VII can be obtained from the corresponding hydrazine powered derivative of the formula III, in which the remains are specified for soybeans is diversified residues are indicated for compounds of formula VII values (method)); and the compound of formula IX can be obtained from the corresponding hydrazine powered derivative of the formula III in which R9denotes hydrogen, and the remaining residues have the above for compounds of formula IX values (method d) and the corresponding epoxides of formula IV, where R1denotes hydrogen, and the remaining residues have the above for compounds of formula IX values (method d) ), by analogy with the method and, if necessary, during the application and removal of protective groups.

The compounds of formula I', in which the substituents have the above values can be obtained, for example, from compounds of the formula III':

< / BR>
where the residues have the above for compounds of formula 1 values, as described in method b), by entering into interaction with the compound of the formula IV, and the available functional groups that should not participate in the reaction, as there are protected and after the reaction can be released.

Preferred method g) are the starting compounds of the formula:

< / BR>
where R3denotes unsubstituted or substituted alkyl or cyclohexylethyl; phenyl-lower alkyl, unsubstituted or substituted; and R7denotes unsubstituted or substituted alkyl or cyclohex is the quiet are intermediate compounds according to the invention.

These connections can be protected in particular by one or both amino groups, and in the case of two protective for amino groups can be identical or different from each other.

As protection for the amino group, for example, are used above in method (a) for protective amino group. Specified for compounds of formula II residues R3and R7have the values specified above for compounds of formula 1 when determining residues R3and R7.

Very preferred compounds of formula II, where R3denotes cyclohexyl-(lower alkyl), phenyl-(lower alkyl) or n-forfinal(lower alkyl) and R7denotes lower alkyl, cyclohexyl-(lower alkyl), phenyl-(lower alkyl), n-cyanophenyl-(lower alkyl) or n-forfinal(lower alkyl) as well as salts of these compounds, if any soleobrazutaya group.

Very particularly preferred compounds of formula II, where R3denotes a phenyl-(lower alkyl) and R7denotes lower alkyl, cyclohexyl(lower alkyl) or phenyl-(lower alkyl), and salts of these compounds, if any soleobrazutaya group.

First of all predpochetaet n-butyl, isobutyl, cyclohexylmethyl, benzyl, p-terbisil or p-cyanobenzyl, as well as salts of these compounds, if any soleobrazutaya group.

In a first particularly preferred compounds of formula II, where R3denotes benzyl and R7represents isobutyl, cyclohexylmethyl or benzyl, as well as salts of these compounds, if any soleobrazutaya group.

First of all, these preferred examples of the compounds of formula II.

The compounds of formula II, where the substituents have the abovementioned meanings, or their salts, if there are soleobrazutaya groups receive, for example, the fact that hydrazine derivative of the formula:

R7-NH-NH-R11< / BR>
where R11means for protective amino group attached to an epoxide of the formula:

< / BR>
where R10means for protective amino group, and, if necessary, obtained by the above method a) compound of formula II with at least one salt-forming group is transferred to its salt or obtained Sol was transferred into the free compound or into another salt and/or, if necessary, the resulting mixture of isomers share and/or the protective group in the compound of formula II Otway, the compound of formula II.

Receiving and converting salts, separation of mixtures of isomers, cleavage of protective groups and the transformation of compounds of formula II are similar to those described above for compounds of formula I by the way.

Particularly preferably, the initial product of the formula II, in which the substituents have the values specified by removal of the protective group from compounds of formula II in which one or both of an amino group protected by a protective for amino groups, in particular when the conditions for hydrolysis of compounds of formula I, as described in additional measures methods.

Methods of attaching the compounds of formula XVI to those formulas settle down under described above in method (a) upon receipt of the compounds of formula I.

Obtaining protective compounds of the formula I is carried out, for example, any of the hitherto known methods, in particular of the compounds of formulas III and IV, and functional groups in these compounds, if necessary, protected by a protective group, as described in method a).

Acid of formula VI, VIII, XVII, and XXI, as well as connections with the nucleophilic groups of the formulae X, XI, XII, XIII, XIV and XV are known or, if they are new, work itself, they do not limit the scope of protection.

Temperatures are indicated in degrees centigrade (oC). If there are no temperature data, then the reaction proceeds at room temperature, Rf- values, which indicate the ratio of the distance travelled by the relevant substance to the distance traveled front of the solvent, is determined on the plates with a thin layer of silica gel by thin-layer chromatography (TLC) in the following solvent system (table.4).

The abbreviation "Rf(A)" denotes, for example, that Rfthe value is defined in the solvent system A. the proportion of solvents to one another is always stated in volume fractions (table.5).

Column (g,6 mm), filled with material "reversible phase" C18- Nucleosil(5 μm average grain size; covalently linked octadecylsilane, derivationally silica gel, Macherey Nagel, Duren, Germany). Definition via UV absorbance at 215 nm. The retention times (tRet) are specified in minutes. The flow rate 1 ml/min

To denote systems of liquids (Fliessmittel) when the pulse chromatography and chromatography medium pressure apply the same reduction.

Other commonly used names short and reducing the ACC-spectrometry, or FAB-MS method (method of "fast atom bombardment"). Mass spectral data are in the first case to deprotonirovannym molecules (M)+or protonated molecules (M+H)+.

Values obtained using spectroscopy proton nuclear resonance (1H-NMR) are reported in ppm (parts per million) per tetramethylsilane was as an internal standard. s singlet, d doublet, t - triplet, k Quartet, m-multiplet, dd = double doublet, br. wide.

Values in IR spectroscopy indicated in cm-1in parentheses is indicated the corresponding solvent. If specified, s is strong, m denotes the average and w denotes the weak intensity of the corresponding bands.

The remainder in the value of [PheNNPhe] denotes the divalent residue of 3(S)-amino-4-phenyl-1-(N-benzylpiperazine)-butane-2(S)-ol and has the formula:

< / BR>
The remainder with the designation of [PheNNCha] denotes the divalent residue of 3(S)-amino-4-phenyl-1(N-cyclohexylpiperazine)-butane-2(S)-ol and has the formula:

< / BR>
The remainder with the designation of [PheNNLeu] denotes the divalent residue of 3(S)-amino-4-phenyl-1-(N-isobutylpyrazine)-butane-2(S)-ol and has the formula:

< / BR>
The balance Zn is/BR>< / BR>
The balance value -[PheNN(p-F)Phe] denotes the divalent residue of 3(S)-amino-4-phenyl-1-(N-(p-performer)-hydrazino)-butane-2-(S)-ol and has the formula:

< / BR>
The balance value-[(p-F)PheNN(p-F)Phe] denotes the divalent residue of 3(S)-amino-4-(p-forfinal)-1-(N- (p-performer)-hydrazino)-butane-2(S)-ol and has the formula:

< / BR>
Balance with a value of [PheNN(p-CN)Phe] denotes the divalent residue of 3(S) -amino-4-phenyl-1-(N-(p-cyanovinylene)-hydrazine)-butane-2(S)-ol and has the formula:

< / BR>
The balance value is[ChaNNLeu] denotes the divalent residue of 3(S)-amino-4-cyclohexyl-1-(N-isobutyl-hydrazino)-butane-2(S)-ol and has the formula:

< / BR>
To denote a divalent radical of a natural alpha-amino acids used conventional in the chemistry of peptides reduction. However, amino acids that are in the name of the connection to the right of the radicals-[PheNNPhe]-[PheNNCha]-[PheNNLeu] -[PheNNNle,-[PheNN(p-F)Phe]-[(p-F)PheNN(h-F)Phe] -[PheNN(p-CN)Phe] or[ChaNNLeu] in contrast to the usual nomenclature of peptides, where on the left is the amino-end and right-carboxy-end linking the carboxy group is to the left, as indicated by the arrow () represents the inverse voltage is L) or (D). Esterified to ethers on the phenolic hydroxyl group residue R the tyrosine radicals are indicated by Tyr(OR). Nle denotes the radical of norleucine.

Example 1: Boc-[PheNNPhe]-Boc:

A solution of 300 mg (1,14 mmol) of (2R)-[1'(S)-BOC-amino-2'-penile-til]oxirane (J. Org. Chem. , 4615 (1985)) and 253 mg (1,14 mmol) tert.-butyl-3-benzylmorphine (J. Chem. Soc. Perkin, 1, 1712, (1975)) in 4 ml of methanol for 12 h refluxed. After cooling the reaction mixture to 0oC a large part of the connection specified in the header, is deposited. The mother liquor is evaporated and the residue is dissolved in a small amount of methylene chloride. After addition of hexane precipitated a further quantity of the title compound in the form of a white precipitate. FAB-MS: (M+H)+486, tRet(I) of 26.8 minutes Rf(E) 0,70.

Example 2: Z-(L)-Val-[PheNNPhe] J (L)-Val-Z):

191 mg (from 0.76 mmol) of Z-(L-valine, 336 mg (from 0.76 mmol) is a THIEF and 103 mg (from 0.76 mmol) of HOBt are dissolved in 5 ml of a 0.3m solution of NMM in DMF after 10 minutes, add 100 mg (0.25 mmol) of H-[PheNNPhe]-H3l and stirred for 2 h at room temperature in a nitrogen atmosphere. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and washed us twice, sodium bicarbonate solution. Organically is methylene chloride/ether (1: 1). After lyophilization containing the product fractions from dioxane get mentioned in the title compound in the form of a solid white color. FAB MS: (M+H)+752, tRet(I) of 27.8 minutes Rf(E) of 0.45.

The source material is prepared as follows.

a) H-[PheNNPhe]-H3l

A solution of 280 mg (of 0.58 mmol) Boc-[PheNNPhe]-Boc from example 1 in 10 ml of 4n of hydrogen chloride in dioxane is stirred for 2 h at room temperature and under nitrogen atmosphere and then lyophilized. New lyophilization from a mixture of dioxane with tert.-butanol gives the title compound in the form of flocculent solid. FAB-MS: (M+H)+286; tRRet(I) of 23.1 minutes Rf(C) 0,17.

Example 3: Boc-(L)-Val- [PheNNPhe] J ((L)-Val-Boc):

In a similar manner as described in example 2, from 50 mg (0.13 mmol) of H-[PheNNPhe] -H3HCI, 83 mg (0.83 mmol) of Boc-(L)-valine, 168 mg (0.38 mmol) THIEF, 51 mg (0.38 mmol) NEW and 2.5 ml of 0.3m NMM in DMF after chromatographic purification on silica gel with a mixture of chloroform with methanol (95:5) and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+684; tRet(l) a 27.4 minutes Rf(E) 0,38.

Example 4: Boc-[PheNNCha]-Boc:

Analogously to example 1, from 232 mg (0.88 mmol) of (2R,3S)-1-[3-BOC-amino-2-phenylethyl] oxirane and 200 mg (0.88 to Malta from hexane. FAB-MS: (M+H)+492; tRet(l) a 30.4 min; Rf(E) 0,78.

The source material was obtained as follows:

a) tert.-butyl-3-cyclohexylmethyl-carbazate:

10.2 g (45,1 mmol) cyclohexylcarbonyl-tert.-butoxycarbonyl - nishikata dissolved in 400 ml of methanol, hydronaut in the presence of 5.1 g of 5-Noah platinum-on-coal at room temperature and under hydrogen pressure of 4 ATM. After the reaction is filtered from the catalyst and the filtrate is evaporated. The residue is dissolved in methylene chloride and washed with water. After evaporation of the organic phase receive specified in the title compound as a colourless resin.

1NMR (200 MHz, CDCI3): 6,1 (s, br, 1H); 3.9 to (s, br, 1H); to 2.65 (d, 2H); 1,8-of 0.75 (m, 11H); 1,45 (s, 9H); tRet(I) of 32.0 minutes Rf(E) of 0.75.

b) cyclohexylcarbonyl-tert.-butoxycarbonylamino:

A solution of 10.8 g (81.2 mmol) of tert.-BUTYLCARBAMATE and 10.1 g (90 mmol) of cyclohexanecarboxaldehyde in 400 ml of ethanol is refluxed for 2 hours. Then distilled off half of the solvent and by adding water precipitated specified in the header connection. It directly applies hereinafter in paragraph (A).

Example 5: H-(L)-Val-[PheNNPhe] J ((L)-Val)-H3HCI:

A solution of 40 mg (0.06 mmol) of Boc-(L)-Val-[PheNNPhe] J((L)- diluted with dioxane and after lyophilization get mentioned in the title compound as hydrochloride. FAB-MS: (M+H)+484; tRet(II) to 25.8 min RfA) of 0.45.

Example 6: N-thiomorpholine-(L)-Val_[PheNNPhe] J (N-thiomorpholine-carbonyl-(L) -Val):

A solution of 20 mg (0.03 mmol) of H-(L)-Val-[PheNNPhe] J ((L)-Val)-H3l from example 5 in 0.5 ml of DMF are mixed at room temperature sequentially with 35 μl (0.25 mmol) of triethylamine and 16 mg (0.1 mmol) of 4 - dimorpholinyldiethyl and stirred for 1 hour at room temperature. The reaction mixture was diluted with chloroform and washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and the residue chromatographic on silica gel using a gradient chloroform/methanol (15: 1->8: 1). Fraction of the product is evaporated and precipitated using a mixture of methylene chloride with DIPE. After lyophilization from dioxane they give specified in the title compound in the form of flocculent solid. FAB-MS: (M+H)+742. tRet(l) to 21.6 min Rf(D) 0,54.

The source material was obtained as follows:

a) (4-thiomorpholine)-chloride:

To a solution of 85 ml (165 mmol) in 20-s of phosgene in toluene at 0oC was added dropwise a solution of 10 g (97 mmol) thiomorpholine in 200 ml of toluene and stirred suspension of white for 1 hour at room temp is. what are square mentioned in the title compound as a yellow oil. IR-spectrum (CH2Cl2cm-1): 1735, 1450, 1440, 1405, 1370, 1180.

Example 7: N-morpholinopropan-(L)-Val-[PheNNPhe] J (N-morpholino-carbonyl-(L)-Val):

A solution of 100 mg (0.25 mmol) of H-[PheNNPhe]-H3HCI from example 2A, 163 mg (from 0.76 mmol) N-morpholinoethyl-(L)-valine and 288 mg (from 0.76 mmol) HBTU in 2 ml of DMF is mixed with 210 μl (of 1.52 mmol) of triethylamine and stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture is evaporated completely, the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and chromatographic on silica gel with a mixture of methylene chloride/methanol (15: 1). Specified in the title compound precipitated from methylene chloride-hexane and after lyophilization from dioxane with tert.-butanol receive in the form of a flocculent solid.

FAB-MS: (M+H)+710; tRet(I) of 16.3 min Rf(E) 0,16.

The source material was obtained as follows:

a) N-morpholinoethyl-(L)-valine:

2.7 g (8.4 mmol) of N-morpholinoethyl-(L)-valine benzyl ether complex is dissolved in 75 ml of acetic ether and in the presence of 500 mg 10 TB of palladium-on-coal under Yes the e evaporation of the solvent receive specified in the title compound as a colourless oil.1H NMR (300 MHz, CD3OD: is 4.15 (m, 1H); the 3.65 (m, 4H); 3.40 in (m, 4H); 2,12 (m, 1H), 0,95 (2d, 6N).

b) N-morpholinoethyl-(L)-valine benzyl ester:

A solution of 4 g (10.5 mmol) of 4-toluensulfonate complex (L)-valine benzyl ester in 560 ml of methylene chloride is mixed with 0.8 ml (8.1 mmol) (morpholinomethyl)-chloride (receiving: J. Med. Chem. 31, 2277 (1988)) and 4.1 ml (24,1 mmol) of N-ethyldiethanolamine and stirred for 24 h at room temperature. The reaction mixture is diluted with acetic ether and washed sequentially with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic phase is dried over sodium sulfate and evaporated. After chromatography on silica gel with acetic ether it gives a complex N-morpholinoethyl-(L)-valine benzyl ester as colorless oil. Ester immediately applied later in a).

Example 8: Phenylacetyl-(L)-Val-[PheNNPhe] J (N-phenylacetyl-(L)-Val:

Analogously to example 7, from 100 mg (0.25 mmol) of H-[PheNNPhe]-H3HCI from example 2A, 143 mg (0.61 mmol) phenylacetyl-L-valine (receive: Mem. Tokyo Univ. Agric. 20, 51 (1978)), 230 mg (0.61 mmol) HBTU and 200 ál (of 1.42 mmol) of triethylamine, after chromatographic purification using a mixture of methylene chloride/ether/methanol (20:20:1) and lyophilisation from f(G) of 0.21.

Example 9: N-(3-pyridylethyl)-(L)-Val-[PheNNPhe] J (N-3-pyridylacetic)-(L)-Val:

Analogously to example 7, from 100 mg (0.25 mmol) of H-[PheNNPhe]-H3HCI from example 2A, 576 mg (of 1.52 mmol) HBTU, 358 mg (of 1.52 mmol) of N-(3 - pyridylethyl)-(L-valine and 316 μl (2.3 mmol) of triethylamine, after chromatographic purification using a mixture of chloroform/methanol (5:1) and lyophilized from a mixture of dioxane with tert.-butanol, get mentioned in the title compound in the form of a solid white color. FAB-MS: (M+H)+722. tRet(II) of 27.9 min Rf(A) to 0.71.

The source material was obtained as follows:

a) N-(3-pyridylethyl)-(L)-valine:

3.4 g of N-(3-pyridylethyl)-(L)-valine-tert.-butyl ether complex was dissolved in 20 ml triperoxonane acid with methylene chloride (1:1) and stirred for 16 h at room temperature. The reaction solution is completely evaporated and the residue insist with DIPE. Get listed in the title compound as amorphous solid white.1H-NMR (200 MHz, CD3OD): a 8.9 and 8.6 (m, br, 1H); and-8.5 (m, 1H), 7,95 (m, 1H); to 4.33 (m, 1H); 3,93 (s, 2H); 2,2 (m, 1H); and 0.98 (2d, 6H).

b) N-(3-pyridylethyl)-(L)-valine-tert.-butyl ester:

The solution to 3.36 g (16 mmol) of tert.-butyl ether (L)-valine in the form of hydrochloride, 2 g ( 0°C was added dropwise to 4.2 ml of triethylamine. The reaction mixture was stirred for 48 h at room temperature, then diluted with methylene chloride and washed with 10 citric acid, and saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and after evaporation of the solvent it gives tert.-butyl ether N-(3-pyridylethyl)-(L)-valine, which immediately apply hereinafter in (a).

Example 10: Boc-(L)-Val-[PheNNCha] J (L)-Val)-Boc:

Analogously to example 7, from 500 mg (1.25 mmol) of H-[PheNNPhe]-H3HCI, 1.08 g (4,98 thought) Boc-(L-valine, 1.89 g (to 4.98 mmol) HBTU and 1.39 ml (9,96 thought) of triethylamine after chromatographic purification on silica gel using a mixture of methylene chloride and ether (1:1) and lyophilisation from dioxane, get mentioned in the title compound in the form of a flocculent solid. FAB-MS: (M+H)+690; tRet(I) to 29.3 minutes Rf(H) of 0.48.

The source material was obtained as follows:

a) H-[PheNNPhe]-H3l

1.10 g (2.2 mmol) of Boc-[PheNNCha]-Boc from example 4 was dissolved in 20 ml of 4n of hydrogen chloride in dioxane and stirred at room temperature for 3 hours After freeze-drying the reaction solution is get mentioned in the title compound as hydrochloride. FAB-MS: (M+H)+292; tRet(II) in 27.3 minutes

Prong (from 0.37 mmol) of Z-(L)-valine, 165 mg (from 0.37 mmol) THIEF, 51 mg (from 0.37 mmol) HOBt and 2.5 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using a mixture of methylene chloride and ether (1:1) and lyophilisation from dioxane, receive specified in the header connection. FAB-MS: (M+H)+758; tRet(I) of 29.1 minutes Rf*(H) 0,55.

Example 12: Boc-[PheNNLeu]-Boc:

Analogously to example 1, on the basis of 1.0 g (3.8 mmol) of (2R)-[1'(S)-Boc-amino-2'-phenylethyl] oxirane and 715 mg (3.8 mmol) of tert.-butyl-3-isobutylpyrazine (receiving: J. Chem. Soc. Perkin I, 1712 (1975)), get mentioned in the title compound as a precipitate from hexane. FAB-MS: (M+H)+452; tRet(I) of 27.2 minutes Rf(I) of 0.55.

Example 13: Z-(L)-Val-[PheNNLeu] J ((L)-Val)-Z:

Analogously to example 2, from 60 mg (0,17 mmol) of H-[PheNNLeu]-H3l, 125 mg (0.50 mmol) of Z-(L)-poured, 221 mg (0.50 mmol) THIEF, 67 mg (0.50 mmol) of HOBt and 3.3 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using a mixture of methylene chloride and ether (1:1) and lyophilisation from dioxane receive specified in the header connection. FAB - MS: (M+H)+718, tRet(I) of 26.8 min, Rf(H) 0,38.

The source material was obtained as follows:

a) H-[PheNNLeu]-H3l:

Analogously to example 10a, 1,21 g (2.48 mmol) of Boc-[PheNNLeu]-Boc from example 12, receive specified in the header SUP>NNCha] J ((L)-Val)-H3HCI:

Analogously to example 10a, 632 mg (of 0.91 mmol) Boc-(L)-Val- [PheNNCha] J ((L)-Val)-Boc from example 10, after lyophilization get mentioned in the title compound as hydrochloride. FAB-MS: (M+H)+490, tRet(II) of 29.4 min, Rf(K) of 0.23.

Example 15: N-(3-pyridylethyl)-(L)-Val-[PheNNLeu] J -(3-pyridylethyl)-(L)-Val:

Analogously to example 9, from 90 mg (0.25 mmol) of H-[PheNNLeu]-H3HCI from example 13A, 358 mg (of 1.52 mmol) of N-(3-pyridylethyl)-(L)-poured, 576 mg (of 1.52 mmol) and HBTU 316 μl (2.5 mmol) of triethylamine, after chromatographic purification using a mixture of methylene chloride with methanol (5:1) and lyophilisation from dioxane with tert.-butanol and water, get listed in the header connection. FAB-MS: (M+H)+688, tRet(IV) 15.5 min, Rf(D) 0,37.

Example 16: N-TRIFLUOROACETYL-[PheNN(p-F)Phe]-Boc:

A solution of 4.0 g (15,4 mmol) 2-(R)-[1'(S)-(triptorelin)-2'-phenylethyl] oxirane and the 3.89 g (16.2 mmol) of tert. -butyl-3-(p-forfinal-methyl)carbazate in 35 ml of methanol is heated for about 20 hours in a refractory tube at 80oC. the Reaction mixture is evaporated, the residue is dissolved in a small amount of dichloromethane, this solution of hexane precipitated specified in the header connection (refrigerator). Then the product is subjected to column is x2">

The source material was obtained as follows: a) N-3(S)-(Boc-amino)-2 (R,S) -hydroxy-4-aenil-1-trimethylsilylmethyl:

In an atmosphere of nitrogen was placed a pre-24,7 g (of 1.02 mol) of magnesium in 100 ml of abs. ether and 35 min mix with a small amount of iodine and at the same time with 132,5 ml (0.95 mol) of chlorotetracycline and 300 ml of ether, and the temperature is maintained at 38oC using an ice bath.

The reaction mixture is then stirred for 1.5 h at room temperature. After cooling down to-60oC is mixed with the suspension to 48.6 g (of € 0.195 mol) of N-BOC-phenylalanine (receiving: D. J. Kempf, J. Org. Chem. 51, 3921(1986)) in 1.1 l of ether for 40 minutes at 90 min, the reaction mixture is heated to room temperature and the following 90 min it is stirred at this temperature. Then poured into 2 l of ice water and 1.5 l of 10 aqueous solution of citric acid. The separated aqueous phase is extracted twice with 500 ml of ether. All extracts are washed with 500 ml of 10 citric acid and twice with brine. After drying over sodium sulfate concentrated in vacuo and the resulting specified in the header, the connection is used further without any additional purification.

TCX: Rf(L) of 0.6. FAB-MS: (M+N)+338.

b) 1 ml of methylene chloride at 5oC for 10 min mix from 35.6 ml (0.28 mol) of approximately 48-aqueous solution of boron TRIFLUORIDE in ether. The reaction mixture is then stirred for 16 h at room temperature, cooled to 10oC for 20 min, mixed with 270 ml of a 4n solution of sodium hydroxide. The aqueous phase is separated and extracted twice with 400 ml methylene chloride. The combined organic extracts washed with brine and dried over sodium sulfate. Specified in the header of the product is to be used further without additional purification. TLC: Rf(C) 0,15; IR.-spectrum (methylene chloride) (cm-1): 3370, 3020, 2920, 1640, 1605.

in) N-TRIFLUOROACETYL-1-phenyl-3-Bud-2 (S)-amine:

Dissolved in 210 ml of methylene chloride and 70 ml of pyridine, 11.9 g (81 mmol) of 1-phenyl-3-butene-2(S)-amine at 0oC dropwise mix from 17.0 ml (121 mmol) of anhydride triperoxonane acid. After stirring for half an hour at 0oC is extracted 2 times with diluted HCl, water and brine. The aqueous phase is washed 2 more times with methylene chloride, dried over sodium sulfate and evaporated. TCX: Rf(M) 0,4.

g) 2(R)-1'(S)-(TRIFLUOROACETYL-amino)-2'-phenylethyl]oxirane:

A solution of 14.5 g (60 mmol) of N-TRIFLUOROACETYL-1-phenyl-3-butene-2(S)-amine in 600 ml of chloroform is mixed with 54,28 g (314 mmol) of m-chlormadinone of castor sodium sulfite, 2 times with saturated sodium carbonate solution, water and brine. The aqueous phase is extracted 2 more times with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated, giving specified in the title compound, which without further purification used in the nearest stage. TCX: Rf(N) 0,6.

d) p-fortunelounge-tert.-butoxycarbonylamino:

Analogously to example 4B), 32 g (242 mmol) of tert.-BUTYLCARBAMATE and 30 g (242 mmol) of p-forventelige in 300 ml of ethanol is injected into the interaction within 3 h at 80oC to obtain the title compound, which after cooling and dilution with distilled water: TCX Rand(N) to 0.48; tRet(I) to 19.4 minutes

e) tert.-butyl-3-(p-performer)carbazate:

Analogously to example 4A), 55 g (231 mmol) of p-fortunelounge - tert. -butoxy-carbohydrazone in 500 ml of THF hydronaut using palladium (5%)-on-coal with obtaining specified in the connection header. 1H-NMR (200 MHz, CD3OD: to 7.35 (dd, 8 and 6 Hz, 2H); 7,05 (t, 8 Hz, 2H); 3.9 to (s, 2H); 1,45 (s, N).

Example 17: N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe]-Boc:

A mixture of 185 mg (0.80 mmol) of N-morpholinoethyl-(L)-valine (receipt: see example 7a), 270 mg (0.67 mmol) of H-[Pheamerivault 5 h at room temperature. The reaction mixture is evaporated on a rotary evaporator and the residue is distributed between the four portions of methylene chloride, the two portions of sodium carbonate solution, water and brine. Dried over sodium sulfate, the combined organic phases are evaporated and purified by column chromatography (SiO2, ethyl acetate). TCX Rf(O) 0,38; tRet(l) to 21.8 min, FAB-MS: (M+N)+616.

The source material was obtained as follows:

a) H-[PheNN(p-F)Phe]-Boc:

If 70oC to a solution of 0.3 g (0.6 mmol) of N-TRIFLUOROACETYL-[PheNN(p-F)Phe]-Boc (receipt see Example 16) in 50 ml of methanol in a nitrogen atmosphere pin 15 ml of 1M aqueous potassium carbonate solution and additionally stirred for 25 h at this temperature. The reaction mixture is evaporated on a rotary evaporator, the residue is mixed with methylene chloride and washed 2 times with water and brine. The aqueous phase is extracted with methylene chloride, the organic phase is dried over sodium sulfate and evaporated. The crude product is used in the nearest stage without further purification: tRetRet(l) of 16.2 minutes

Example 18: N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe] J ((L)-Val)-Z:

A solution of 86 mg (0.34 mmol) of Z-(L)-Val and 160 mg (0.31 mmol) of N - morpholinoethyl-(L)-Val-[PheNN(p-F)Phe]-H in 2.7 ml of 0.25 M NMM in AUC between the three portions of methylene chloride, the two portions of saturated sodium bicarbonate solution and brine. Drying the organic phase over sodium sulfate and evaporation gives specified in the title compound, which after infusion obtained pure from methylene chloride ether in the ratio 1:1. TCX Rf(P) 0,4; tRet(l) of 22.4 min; FAB-MS: (M+H)+749.

The source material was obtained as follows:

a) N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe]-H:

210 mg (0.34 mmol) of N-morpholinol-(L)-Val-[PheNN(p-F)Phe]- Boc (example 17) dissolved in 105 ml of formic acid and stirred for 4 h at room temperature. Then evaporated, the residue is treated with methylene chloride and the solution washed with saturated sodium bicarbonate solution and brine. Extraction of aqueous phase with two portions of methylene chloride, drying the organic phases over sodium sulfate and evaporation gives specified in the title compound, which without further purification used in the nearest stage, tRet(I) of 12.9 minutes

Example 19: N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe] J ((L)-Val)-h:

At normal pressure of 160 mg (0.21 mmol) of N-morpholinoethyl-L-Val-[PheNN(p-F)Phe] J ((L)-Val)-Z (example 18) in ethanol hydronaut using 40 mg of palladium (10%) on coal. After filtra and lyophilization from dioxane receive specified in the header connection: tRet(hydrochloride (I) and 13.4 min; FAB-MS: (M+H)+615.

Example 20: N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe] <-- ((L)-Val-morpholinoethyl-Gly):

A solution of 26.9 mg (0,143 mmol) N-morpholinoethyl-glycine and 80 mg (0,130 mmol) N-morpholinoethyl-(L)-Val-[PheNN(p-F)Phe] <-- ((L)-Val)-H 1.1 ml of NMM/CH3CN 0.25 M are mixed with 54 mg (0,143 mmol) HBTU and stirred for 16 h at room temperature. Is evaporated and the residue distributed between the three portions of ethyl acetate, water, two portions of saturated sodium bicarbonate solution, water and brine. Drying the organic phase over sodium sulfate and evaporation gives specified in the title compound, which after dissolution in a small amount of DMF and precipitation from DIPE, get clean: tRet(l) 15 min; FAB-MS: (M+H)+785.

The source material was obtained as follows:

a) N-morpholinoethyl-glycine benzyl ester:

Analogously to example 7b), of 7.69 g (of 22.8 mmol) of 4-toluensulfonate complex benzyl ester of glycine and 2.8 g (19 mmol) (morpholinomethyl)- Chlorella in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiethanolamine enter into interaction within 18 hours Specified in the title compound precipitates net of hexane, after extraction with methylene chloride and nysl) complex benzyl ester of N-morpholinosydnonimine in 100 ml of ethyl acetate hydronaut with 1 g of palladium (10%) on coal to obtain specified in the connection header.1H - NMR (300 MHz, CDCl3): 3,88 (s, 2H); to 3.64 (s, 4H); 3.50 for each (s, 2H), 3,35 (s, 4H).

Example 21: Z-(L)-Val-[PheNN(p-F)Phe]-Boc:

A solution of 335 mg (1,33 mmol) of Z-(L)-Val and 448 mg (1.11 mol) of H-[PheNN(p-F)Phe] -Boc (receipt see example 17A) 9.4 ml of 0.25 M NMM CH3CN mixed with 463 mg (1,22 mmol) of HBTU. After stirring for 16 h at room temperature, evaporated and the residue distributed between the three portions of methylene chloride, the two portions of saturated sodium bicarbonate solution and brine. Drying the organic phase over sodium sulfate and evaporation gives specified in the title compound, which is purified by column chromatography (SiO2, hexane/ethyl acetate 4:1 L 1:1): tRet(I) to 26.6 min; FAB-MS: (M+H)+637.

Example 22: Z-(L)-Val-[PheNN(p-F)Phe]<--((L)-Val)-Boc:NN
(p-F)Phe] -H in 6 ml of NMM/CH3CN, 0.25 M, enter into interaction with 289 mg (0,76 thought) HBTU obtaining specified in the connection header, which can directly from the reaction medium yet to crystallize and filtered: tRet(I) to 27.2 min; FAB-MS: (M+H)+=736.

The source material was obtained as follows:

a) Z-(L)-Val[PheNN(p-F)Phe]-H:

Analogously to example 18a, 440 mg (0,69/P> Example 23: Z-(L)-Val-[PheNN(p-F)Phe]<-- ((L)-Val)-H:

Analogously to example 18a, 250 mg (0.34 mmol) of Z-(L)-Val-[PheNN(p-F)Phe] <--((L)-Val)-Boc (example 22) using 50 ml of formic acid removes the protection for this in the header connection: tRet(l) 18,0 min; FAB-MS: (M+N)+636.

Example 24: Z-(L)-Val-[PheNN(p-F)Phe]<-- (L)-Val)<-- (N-morpholinomethyl-Gly):

Analogously to example 20, 32 mg (0,17 mmol) of N-morpholinosydnonimine (example 206) and 99 mg (0.16 mmol) of Z-(L)-Val-[PheNN(p-F)Phe] L ((L)-Val)-H 1.3 ml of NMM/CH3CN, 0.25 M, enter into interaction with 65 mg (0,17 mmol) HBTU obtaining specified in the title compound, which crystallized directly from the reaction solution is: tRet(l) to 21.1 min; FAB-MS: (M+H)+806.

Example 25: Z-(L)-Asn-[PheNN(p-F)Phe]-Boc:

To a solution of 2.09 g (5.2 mmol) of H-[PheNN(p-F)Phe]-Boc (receipt see example 17A) in 68 ml of DMF and 2.7 ml (16 mmol) of N-ethyl-Diisopropylamine add 3.0 g (7.8 mmol) of Z-(L)-asparagine-p-nitrophenylamino of ester (Bachem, Bubendorf, Switzerland). After stirring for 16 h at room temperature and evaporated on a rotary evaporator, the residue is treated a large number of methylene chloride (poorly soluble) and washed with two portions of 5-aqueous potassium carbonate solution. The aqueous phase extragere is evaporated. After dissolving the crude product in small amount of methanol and precipitating by adding toluene at -20oC get the specified header connection: tRet(I) to 21.2 min; FAB-MS: (M+H)+652.

Example 26: H-(L)-Asn-[PheNN(p-F)Phe]-Boc:

Analogously to example 19, 0.40 g (0.61 mmol) of Z-(L)-Asn-[PheNN(p-F)Phe]-Boc in 20 ml of methanol hydronaut to the specified in the connection header: tRet(I) of 14.9 min; FAB-MS: (M+H)+518.

Example 27: quinoline-2-carbonyl-(L)-Asn-[PheNN(p-F)Phe]-Boc:

Analogously to example 17,134 mg (0.78 mmol) quinoline-2-carboxylic acid (Fluka, Buchs, Switzerland) in 4 ml of NMM/DMF, 0.3 M, enter into interaction with 344 mg (0.78 mmol) THIEF, 105 mg (0.78 mmol) t and 268 mg (0.52 mmol) of H-(L)-Asn-[PheNN(p-F)Phe] -Boc. Because according Ehud after 16 hours at room temperature there is H-(L)-Asn-[PheNN(p-P)Phe]-Vos, then again add 299 mg THIEF, 70 mg of HOBt, 89 mg gialdino acid and 113 μl of NMM. After following 16 h, evaporated and the residue distributed between the three portions of methylene chloride, the two portions of saturated sodium bicarbonate solution and brine. The combined organic phases are dried over sodium sulfate and evaporated. Dissolving the crude product in small amount of DMF, the deposition using DIPE and cooling to-20oN(p-F)Phe] J ((L)-Val)-Z:

88 mg (0.35 mmol) of Z-(L)-Val 3.8 ml of NMM/DMF, 0,3 N, activate with 153 mg (0.35 mmol) is a THIEF and 47 mg (0.35 mmol) of HOBt and after 15 min, mixed with 144 mg (0.23 mmol) of Z-(L)-Asn-[PheNN(p-F)Phe]-H2l. After stirring for 14 h at room temperature, the reaction mixture is evaporated, the residue is dissolved in 2 ml of methanol and distributed among the three portions of methylene chloride and the two portions of 1M sodium carbonate solution, the organic phase is dried over sodium sulfate and evaporated. Re-dissolving the crude product in small amount of DMF and precipitation using DIPA network specified in the header connection: tRet(I) 22,2 min; FAB-MS: (M+H)+785.

The source material was obtained as follows:

a) Z-(L)-Asn-PheNN(p-F)Phe]-H2l:

Under nitrogen atmosphere a solution of 150 mg (0.23 mmol) of Z-(L)-Asn- [PheNN(p - F)Phe] -Howl (example 25) in 1 ml of dioxane is mixed with 2 ml of HCl/dioxane, 4N (Fluka, Buchs, Switzerland). After stirring for 1.5 hours at room temperature, the reaction mixture lyophilized and lyophilized immediately enter into interaction next.

Example 29: TRIFLUOROACETYL-[PheNN(p-F)Phe] J ((L)-Val)-Z:

Analogously to example 17, for 15 hours to enter into interaction 239 mg (0.95 mmol) of Z-(L)-Val 10.5 ml of NMM/DMF, 0,3 N, Sion (SiO2, methylene chloride/ether 10:1) in precipitation from DMF solution using DIPA network specified in the header connection: TCX Rf(O) 0,15; tRet(l) 25,9 min; FAB-MS: (M+H)+633.

The source material was obtained as follows: a) N-TRIFLUOROACETYL- [PheNN(p-F)Phe] -H: At 0oC 0.20 g (0.40 mmol) of N-TRIFLUOROACETYL-[PheNN(p-F)Phe] -Boc (receipt see example 16) in 5 ml of methylene chloride is mixed with 5 ml triperoxonane acid. After stirring 4 h at 0oC and 2 h at room temperature, the reaction mixture is evaporated. Lyophilization of the residue from dioxane gives specified in the title compound, which without treatment is introduced in the interaction then: tRet(l) of 14.7 minutes

Example 30: Z-(L)-Asn-[PheNNPhe]-Boc:

Analogously to example 25, 167 mg (0.34 mmol) of [PheNN(p-F)Phe]-Boc 3.6 ml DMF) and 0.18 ml (1 mmol) N-ethyl-Diisopropylamine enter into interaction with 0.20 g (0.52 mmol) of p-nitrophenylamino of ester of Z-(L)-asparagine with obtaining specified in the title compound, which after column chromatography (SiO2, ethyl acetate) is obtained pure: TCX Rf(O) to 0.19; tRet(l) of 20.9 minutes

The source material was obtained as follows:

a) N-TRIFLUOROACETYL-[PheNNPhe]-Boc:

Analogously to example 16,1,82 g (7.0 mmol) of 2(R erkin, 1,1712, (1975)) in 15 ml of methanol is injected into the interaction in a refractory tube with obtaining specified in the title compound, which is excreted by column chromatography (SiO2, methylene chloride/ether 50:1): TCX Rf(J) 0,38; tRet(l) to 24.5 minutes

b) H-[PheNNPhe]-Boc:

Analogously to example 17A, 258 mg (of 0.53 mmol) of N-TRIFLUOROACETYL-[PheNNPhe] -Boc in 60 ml of methanol is injected into the interaction of 10.7 ml of 1M potassium carbonate solution with obtaining specified in the connection header.

Example 31: Z-(L)-Val-[(p-F)PheNN(p-F)Phe]-Boc:

Analogously to example 21,18 mg (0,070 mmol) of Z-(L)-Val and 27 mg (0,064 mmol) H-[(p-F)PheNN(p-F)Phe]-Boc 0.6 ml of NMM/CH3CN, 0.25 M, enter into interaction with 26.6 mg (0,070 mmol) HBTU obtaining specified in the title compound, which after dissolution in a small amount of methylene chloride and precipitation with DIPE cleared: FAB-MS: (M+H)+655, Rf(CH2CI2/(C2H5)20

0,54.

The source material was obtained as follows:

a) N-Boc-(p-forfinally):

0.4 l of a mixture of dioxane with water in the ratio 1:1 is injected into the interaction 20 mg (109 mmol) of p-pertanyaannya (Fluka, Buchs, Switzerland) with 35.5 g (163 mmol) of Boc-anhydride and 150 g (of 1.09 mol) of potassium carbonate. Later icesee phases are washed with 10 citric acid, water and brine, dried over sodium sulfate and evaporated. Dissolution of the residue in a small amount of methylene chloride and crystallization by adding hexane gives specified in the header connection: tRet(I) to 16.9 minutes

b) N-Boc-(p-pertanyaannya):

Under-5oC -10oC solution of 17.9 g (63 mmol) of N-BOC-(p-ftoheia-Lanina) in 73 ml of abs. THF is mixed from 9.66 ml (69 mmol) of triethylamine was added dropwise and the solution 9,05 ml (69 mmol) of isobutyl ether of Harborview acid in 44 ml of abs. THF. After stirring for half an hour at room temperature the precipitate is sucked off. The filtrate upon cooling pin to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. After stirring for half an hour at room temperature, acidified with 10 citric acid, THF is evaporated on a rotary evaporator part and the remainder distributed among the three portions of ethyl acetate, the two portions of 2n sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine. Dried over sodium sulfate and evaporated organic phases yield, after dissolving in a small amount of methylene chloride and crystallization due to the additive hexane specified in the header is connected to 5 Hz, 2H); is 2.88 (dd, 13 and 6 Hz, 1H); 2,62 (dd, 13 and 8 Hz, 1H); of 1.36 (s, N).

b) N-Boc-(p-forgeneral):

In a nitrogen atmosphere to a cooled to -60oC to a solution of 4.0 ml (46.8 mmol) of oxalicacid in 44 ml of methylene chloride pin of 4.44 ml (of 62.4 mmol) of DMSO dissolved in 76 ml of methylene chloride. After stirring for 15 min add to the clear reaction solution of 8.4 g (% 31.2 mmol) N-BOC-(p-pertanyaannya) in the form of a solution in 185 ml of methylene chloride/THF (1:1) ( J sedimentation) and further stirred for 25 minutes Then add the 17.3 ml (of 124.8 mmol) of triethylamine, dissolved in 38 ml of methylene chloride. After stirring for 30 min pin 278 20 ml aqueous solution of potassium hydrosulfate, and then adding 220 ml of hexane. Leave to warm to room temperature, the aqueous phase is separated and extracted it with two portions of ether. The organic phase after washing with saturated sodium bicarbonate solution, water and brine, drying over sodium sulfate and evaporation, give specified in the title compound, which without further purification used in the nearest stage.1H-NMR (200 MHz, CDCI3): 9,63 (s, 1H); 6,9-7,2 (2m, 4H); 5,04 (m, 1H); was 4.42 (m, 1H); 3,10 (m, 2H); 1,43 (s, N).

g)N-3(S)-(Boc-amino)-2(R, S)-hydroxy-4-(p-perforative from 8.3 ml (60 mmol) of chlorotetracycline getting Grignard compounds, which, after reaction with 13 mmol N-Boc-(p-pertanyaannya), extraction and column chromatography (SiO2, hexane/ethyl acetate 5: 1 J 4:1) gives a mixture of diastereomers specified in the header connection: TCX Rf(L) 0,32; tRet(L) 24,9 min (22%)/25,5 min (78%); FAB-MS: (M+H)+356.

d) 1-(p-forfinal)-3-butene-2 (S)-amine:

Analogously to example 16 b, 1.1 g (3.1 mmol) of N-3(S)-(Boc-amino)-2(R,S)- hydroxy-4-(p-forfinal)-1-(trimethylsilyl)-butane in 22 ml of methylene chloride is injected into the interaction with 1.9 ml (15,5 mmol) approximately 48-aqueous solution of boron TRIFLUORIDE in ether to obtain specified in the connection header:1H-NMR (300 MHz, CDCI3): 7,2-7,10 and 7,05-6,9 (2m, 2H); 5.9 to about 5.8 (m, 1H); 5,2-5,0 (m, 2H); 3,57 (m, 1H); and 2.79 (dd, 12 and 6 Hz, 1H); 2,62 (dd, 12 and 8 Hz, 1H); 1,7 (s, br, 2H).

e) N-TRIFLUOROACETYL-1-(a-forfinal)-3-Bud-2(S)-amine:

Analogously to example 16B, 364 mg (2.2 mmol) of 1-(p-forfinal)-3-butene-2(S)-amine in 1.8 ml of methylene chloride and 5.4 ml of pyridine enter into interaction with 460 μl (3.3 mmol) of anhydride triperoxonane acid with obtaining specified in the title compound, which after soaking in hexane obtained pure: TCX Rf(F) 0,58; MS (M)+261.

W) 2 (R)-[1' (S)-(TRIFLUOROACETYL-amino)-2'- (p-forfinal)ethyl] oxirane:

Analogously to example 16g, 359 mg (1.37 mmol) of N-Tr is Oh acid with obtaining specified in the header connection: TCX Rf(R) of 0.45.

C) N-TRIFLUOROACETYL-[(p-F)PheNN(p-F)Phe]-Boc:

Analogously to example 16, 415 mg (1,49 mmol) of 2(R)-[1'(S)-(TRIFLUOROACETYL-amino)-2'-(p-forfinal)ethyl]oxirane enter into interaction with 377 mg (1.57 mmol) of tert. -butyl-3-(p-forfinal-methyl)carbonate in 9 ml of methanol to obtain specified in the connection header. TCX Rf(*S) 0,53; FAB-MS: (M+H)+518;1H-NMR (300 MHz, CD3OD): between 7.4 to 7.3 and 7.3 to 7.2 (2m, 2H); 7,05-6,9 (m, 4H);to 4.23 (m, 1H); 3,90-the 3.65 (m, 3H); 3,03-2,78 and 2,74-2,60 (2m, 2H); of 1.30 (s, N).

and) H-[(p-F)PheNN(p-F)Phe]-Boc:

Analogously to example 17A, 285 mg (0.55 mmol) of N-TRIFLUOROACETYL-[(p-F)PheNN(p-F)Phe] -Boc in 45 ml of methanol is injected into the interaction with 14 ml of 1M potassium carbonate solution with obtaining specified in the connection header: tRet(l) to 16.4 minutes

Example 32: Z-(L)-Val-[(p-F)PheNN(p-F)Phe]-H:

Analogously to example 18a, 215 mg (0.33 mmol) of Z-(L)-Val-[(p-F)PheNN(p-F)Phe] -Vos remove protection using 100 ml of formic acid with obtaining specified in the title compound: FAB-MS: (M+H)+555', tRet(I) 18 minutes

Example 33: Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J (N-(N-(2-pyridylmethyl)-N-methylaminomethyl)- (L)-Val):

Analogously to example 18, to 23.6 mg (0,089 mmol) N-(N-(2-pyridylmethyl)- N-methylaminomethyl)-(L)-poured (see getting in EP 402646 A1, 19 December 1990. ) and 45 mg (of 0.081 is the group specified in the connection header and recrystallized it from DMF/DIPA: TCX Rf(O) TO 0.39; FAB-MS: (M+H)+802.

Example 34: Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J (N-2(R,S)-carbarnoyl-3-phenylpropionyl) (L) -Val):

Analogously to example 18, to 26.0 mg (0,089 mmol) N-2((R,S)-carbarnoyl-3 - phenylpropionyl)-(L)-poured (receive: Synth. struct. Fund. Proc. Am. Pept. Symp. 7th, 85, (1981))and 45 mg (of 0.081 mmol) of Z-(L)-Val-[(p-F)PheNN(p - F)Phe] -H (example 32) being in engagement with and 33.8 mg (0,089 mmol) HBTU in 0,76 ml of NMM/CH3CN 0.25 M to education specified in the connection header and recrystallized it from DMF/DEPA: Rf(P) 0,64; FAB-MS: (M+H)+829.

Example 35: Acetyl-Val-[PheNNPhe] J (N-acetyl-Val):

Analogously to example 7, from 100 mg (0.25 mmol) of H-[PheNNPhe]-H-3HCI from example 2A, 121 mg (from 0.76 mmol) of N-acetyl-(L)-valine, 288 mg (from 0.76 mmol) and HBTU 0,211 ml (of 1.52 mmol) of triethylamine in DMF receive specified in the title compound after lyophilization from dioxane. FAB-MS: (M+H)+568, tRet(I) 15,0 min, Rf(C) 0,46.

Example 36: Z-(D)-Val-[PheNNPhe] J ((D)-Val)-Z:

Analogously to example 2, from 50 mg (0,123 mmol)of H-[PheNNPhe] -H3HCl from example 2A, 95 mg (0.38 mmol) of Z-(D)-poured, 168 mg (0.38 mmol) THIEF, 51 mg (0.38 mmol) and HOBt 2,53 ml of 0.3m NMM in DMF, get mentioned in the title compound after lyophilization from dioxane. FAB-MS: (M+H)+752; tRet(I) of 26.4 min, Rf(H) of 0.21.

Example 37: quinoline-2-Karl) is a THIEF and 72 mg (of 0.53 mmol), HOBt dissolved in 3.5 ml of a 0.3m solution of NMM in DMF, after 10 min add 70 mg (0.18 mmol) of H-[PheNNPhe]-HHCI (example 2A) and stirred for 5 h at room temperature in a nitrogen atmosphere. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution, once with 10% citric acid solution and once again with a saturated solution of sodium bicarbonate. The organic phases are filtered through cotton wool, evaporated and the residue precipitated twice from methylene chloride with methanol by adding DIPA. After lyophilization from dioxane get mentioned in the title compound in the form of a solid white color (mixture of two different jhud of diastereomers). FAB-MS: (M+H)+794; tRet(A) of 29.1 and 29,3 min; Rf(C) 0,81.

a) N-(quinoline-2-carbonyl)-(L)-valine:

A solution of 2.5 g (14.5 mmol) of (L)-poured-tert.-butyl of ester and 2.5 g (14.5 mmol) of quinoline-2-carbolic acid in 100 ml of methylene chloride with THF (10: 1) mixed with 3.28 g (15.9 mmol) of N,N-dicyclohexylcarbodiimide and 2.0 ml (14.5 mmol) of triethylamine and stirred for 18 h at room temperature. The reaction mixture was cooled to -18oC and filtered from urea. The filtrate is evaporated, the residue is dissolved in methylene chloride and washed one after chromatographic purification on silica gel using mixtures of hexane/ethyl acetate (2:1) to obtain N-(quinoline-2-carbonyl)-(L)-poured-tert. -butyl ether. 2,59 g (12.2 mmol) leave it for 4.5 h at room temperature in a mixture of methylene chloride/TFA (1:1). After evaporation the residue is purified by chromatography on silica gel using mixtures of hexane/ethyl acetate (2:1). Containing the product fraction is evaporated, dissolved again in methylene chloride and by rinsing with 1N-sodium hydroxide solution and 1N hydrochloric acid the title compound was transferred into the hydrochloride. 1H-NMR (200 MHz, CD3OD: of 1.05 and 1.07 (2d, J=6 Hz, 6N); 2.40 a (m, 1H); with 4.65 (m, 1H); of 7.70 (m, 1H); a 7.85 (m, 1H), 8,00 (dxd, 1H); to 8.20 (m, 2H); 8,48 (d, 1H).

Example 38: acetyl-(L)-Val-[PheNNCha] <-- (N-acetyl-(L)-Val):

Analogously to example 37, from 160 mg (0.40 mmol) of H-[PheNNCha]-H3HCI from example 10A, 190 mg (1,19 mmol) N-acetyl-(L)-roller, 525 mg (1,19 mmol) THIEF, 160 mg (1,19 mmol) HOBt and 7.9 ml of 0.3m NMM in DMF receive, after deposition of a mixture of chloroform with methanol using DIPE and lyophilization from dioxane specified in the header connection. FAB-MS: (M+H)+574, tRet(I) to 18.1 min, RfB) 0,30.

Example 39: N-(3-pyridylethyl)-(L)-Val-[PheNNCha] <-- (N-(3-pyridylethyl)-(L)-Val)3HCI.

Analogously to example 7, from 100 mg (0.25 mmol) of H-[PheNNCha]-H3l from example 10A, 358 mg (of 1.52 mmol) of N-(3-pyridylethyl)-(L)-valine from example 9a, 576 mg (of 1.52 mmol) and HBTU 0,316 ml (2.28 mmol) of triethylamine in DMF, telengard/methanol (15:1) and liofilizatsii containing the product fractions from dioxane. FAB-MS: (M+H)+728, tRet(I) to 11.3 min, Rf(U) 0,21.

Example 40: acetyl-I1e-[PheNNCha] <-- (N-acetyl-I1e):

Analogously to example 37, from 160 mg (0.40 mmol) of H-[PheNNCha]-H3HCI from example 10A, 206 mg (1,19 mmol) N-acetyl-(L)-isoleucine, 525 mg (1,19 mmol) THIEF, 160 mg (1,19 mmol) HOBt and 7.9 ml of 0.3m NMM in DMF after precipitation from methylene chloride with methanol by adding DIPA and definitely from a mixture of dioxane/tert. -butanol get mentioned in the title compound (mixture of different HPLC of two diastereomers); FAB-MS: (M+H)+602, tRet(I) to 20.4 and 20.7 min, Rf(D) 0,33.

Example 41: thiomorpholine-(L)-Val-[PheNNCha] <-- (N-thiomorpholine-(L)-Val):

Analogously to example 6, on the basis of 70 mg (0.12 mmol) of H-(L)-Val-[PheNNCha] <-- (N-(L)-Val)-H3HCI from example 14, 58 mg (0.35 mmol) (4-thiomorpholine)-chloride from example 6A and to 0.127 ml of triethylamine in 2 ml of DMF after chromatographic purification on silica gel using a mixture of methylene chloride/methanol (95: 5) and lyophilization containing the product fractions from dioxane, receive specified in the header connection. FAB-MS: (M+H)+748; tRet(I) 24,0 min, Rf(C) 0,70.

Example 42: Z-(L)-Glu-[PheNN(p-F)Phe] <-- (L-Glu)-Z:

A solution of 130 mg (0.14 mmol) of Z-(L)-GIu(O-tert.-butyl)-[PheNN(p-F)Phe] <-- ((L)-Glu(O-tert.-butyl)-the terms radical glutamic acid] in 8 ml of a mixture of methylene chloride (TFA/1:1) is stirred for 3 h at room temperature. The solvent is evaporated under reduced pressure and the residue precipitated from methylene chloride by adding DIPA. Get listed in the title compound after lyophilization from a mixture of dioxane with tert.-butanol. FAB-MS: (M+H)+830; tRet(I) a 19.6 min; Rf(B) 0,32.

a) Z-(L)-Glu(O-tert. -butyl)-[PheNN(p-F)Phe] ((L)-Glu(O-tert. -butyl))-Z:

Analogously to example 37, from 100 mg (0.24 mmol) of H-[PheNN(p-F)Phe]-H3l, 245 mg (0.73 mmol) of tert.-butyl ester of Z-(L)-glutamic acid, 321 mg (0.73 mmol) THIEF, 98 mg (0.73 mmol) of HOBt and 4.8 ml of 0.3m NMM in DMF, get mentioned in the title compound, after chromatographic purification on silica gel using a mixture of methylene chloride and ether (1:1), tRet(I) 30,2 min, Rf(H) 0,17.

b) H-[PheNN(p-F)Phe]-H3l:

Analogously to example 2A, on the basis of 1.77 g (3,51 mmol) Boc-[PheNN(p-F)Phe] -Boc, after lyophilization, get mentioned in the title compound, FAB-MS: (M+H)+304; Rf(K) 0,19.

C) Boc-[PheNN(p-F)Phe]-Boc:

Analogously to example 1, from 2.0 g (7,60 mmol) of (2R)-[1'(S)- BOC-amino-2'-phenylethyl] oxirane and 2.17 g (9,04 mmol) tert.-butyl-3-(4-performer)carbazate example e), get mentioned in the title compound, after chromatographic purification on silica gel using mixtures of hexane with this is aminocarbonyl-(L)-Val-[PheNN(p-F)Phe] J (N-(N-(2-pyridylmethyl)-N-methylaminomethyl)-(L)-Val):

Analogously to example 37, from 70 mg (0,17 mmol) of H-[PheNN(p-F)Phe]-H3l from example 42B, 135 mg (0.51 mmol) of N-(N-(2-pyridylmethyl)-N-methylaminomethyl)-(L)-roller (receipt as described in European patent EP 0402646 A1 dated December 19, 1990), 225 mg (0.51 mmol) THIEF, 69 mg (0.51 mmol) of HOBt and 3.4 ml (0.3 M) of NMM in DMF, after chromatography on silica gel using a mixture of methylene chloride with methanol (15:1) and lyophilized containing the product fractions from dioxane, get mentioned in the title compound, FAB-MS: (M+H)+798, tRet(IV) 35 min, Rf(U) 0,21.

Example 44: N-(3-tetrazol-1-yl)propionyl)-(L)-Val-[PheNN(p-F)Phe] J-(N-(3-tetrazol-1-yl) -propionyl)-Val:

Analogously to example 37, from 100 mg (0.24 mmol) of H- [PheNN(p-P)Phe]-H3l (from example 42B), 146 mg (0.61 mmol) of (N-(3-tetrazol-1-yl)-(L)-valine, 268 mg (0.061 mmol) THIEF, 82 mg (0.61 mmol) of HOBt and 4 ml of 0.3m NMM in DMF after precipitation from methylene chloride by the addition of DIPE and lyophilization from dioxane (HPLC differ 4 diastereoisomer) will be specified in the header connection. FAB-MS: (M+H)+750; tRet(III) 30,8 min, to 31.4 min, 32,4 min and 32,8 min; Rf(K) of 0.5.

Example 44a: N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine:

Analogously to example 9b, on the basis of 4 g (16.4 mmol) of the hydrochloride is December 27, 1988), 2.4 ml of diethyl ether cyanophosphonate acid and 4.4 ml of triethylamine in DMF after chromatographic purification on silica gel using a mixture of methylene chloride with methanol (30: 1), receive benzyl ester of N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine. 2.66 g (8,03 mmol) in a mixture of methanol-water (9:1) hydronaut in the presence of 530 mg 10-aqueous palladium-on-coal under hydrogen pressure of 1 ATM and after precipitation from methanol with DIPE receive specified in the header of the connection.1H-NMR (200 MHz, CD3OD): 0,9 (d, J=7 Hz, 6N); 2,1 (m, 1H); 2.95 and (m, 2H); 4,29 (d, J=6 Hz, 1H); 4,78 (m, 2H); to 9.15 (s, 1H).

Example 45: Z-(L)-Val-[PheNNN(p-F)Phe] J ((L)-Val)-Z:

Analogously to example 37, from 100 mg (0.24 mmol) of H-[PheNN(p-F) Phe]-H3HCI (from example 42B), 182 mg (0.38 mmol) of Z-(L)-valine, 321 mg (0.73 mmol) THIEF, 98 mg (0.73 mmol) of HOBt and 4.8 ml of 0.3m NMM in DMF after precipitation from methylene chloride by the addition of DIPE and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+770; tRet(I) to 26.3 min, Rf(H) 0,25.

Example 46: acetyl-Val-[PheNN(p-F)Phe] J (N-acetyl-Val):

Analogously to example 37, from 80 mg (0,19 mmol) of H-[PheNN(p-F)Phe]-H3HCl from example 42B, 124 mg (0.78 mmol) of N-acetyl-(L)-valine, 344 mg (0.78 mmol) THIEF, 105 mg (from 0.76 mmol) HOBt and 4.5 ml of 0.3m NMM in DMF after double resultant deposition rates of CME is asanee in the header connection. FAB-MS: (M+H)+586, tRet(I) to 15.8 min, Rf(E) 0,32.

Example 47: acetyl-Val-[PheNN(p-CN)Phe] J (N-acetyl-Val):

Analogously to example 37, from 80 mg (0,19 mmol) of H-[PheNN(p-CN)Phe]-H3HCl, 124 mg (0.78 mmol) of N-acetyl-(L)-valine, 344 mg (0.78 mmol) THIEF, 105 mg (0.78 mmol) of HOBt and 4.5 ml of 0.3m NMM in DMF after precipitation from a mixture of methylene chloride with methanol due to additive DIPA and lyophilization from dioxane, get mentioned in the title compound as a mixture of two different HPLC diastereomers. FAB-MS: (M+H)+593; tRet(l) to 14.4 and 14.6 min; Rf(D) to 0.39.

a) H-[PheNN(p-CN)Phe]-H3HCl:

Analogously to example 2A, based on 2,69 g (5,27 mmol) Boc-[PheNN(p-CN)Phe] -Boc, after lyophilization, receive specified in the header connection. FAB-MS: (M+H)+311; Rf(K) 0,16.

b) Boc-[PheNN(p-CN)Phe]-Boc:

Analogously to example 1, from 2.0 g (7,60 mmol) of (2R)-[1'(S)-Boc - amino-2'-phenylethyl] oxirane and of 1.87 g (7.6 mmol) of tert.-butyl-3-(4 - cyanovinylene)-carbazate obtain, after crystallization from a mixture of methanol with DIPE specified in the header connection. FAB-MS: (M+H)+511; tRet(I) 25 min; Rf(Y) 0,19.

C) tert.-butyl-3-(4-cyanophenyl-methyl)-carbazate:

Analogously to example 4B, 10 g (76,3 mmol) of 4-cyanobenzaldehyde enter into interaction with 10 g (76,3 IMO is this compound in 150 ml of THF hydronaut in the presence of 2 g of palladium-on-coal (10-s) under hydrogen pressure of 2 ATM and get listed at the beginning of the connection.1H-NMR (200 MHz, CDCI3): the 7.65 (d, J=8 Hz, 2H); was 7.45 (d, J=8 Hz, 2H); between 6.08 (s, br, 1H); 4,3 (s, br, m), was 4.02 (s, 2H); 1,45 (s, 9H).

Example 48: Z-(L)-Val-[PheNN(p-CN)Phe] J ((L)-Val)-Z:

Analogously to example 37, from 70 mg (0,17 mmol) of H-[PheNN(p-CN)Phe]-H3HCl (from example 47A), 125 mg (0.5 mmol) of 2-(L)-valine, 221 mg (0.5 mmol) THIEF, 68 mg (0.5 mmol) of HOBt and 3.33 ml of 0.3m NMM in DMF after precipitation from methylene chloride by the addition of hexane and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+777; tRet(l) to 25.3 min; Rf(D) to 0.69.

Example 49: Z-(L)-Ile-[PheNNLeu] J ( (L)-Ile)-Z:

Analogously to example 37, from 70 mg (0,19 mmol) of H-[PheNNLeu] -H3HCI (from example 13A), 154 mg (of 0.58 mmol) of Z-(L)-isoleucine, 257 mg (of 0.58 mmol) THIEF, 79 mg (of 0.58 mmol) and HOBt 3,88 ml of 0.3m NMM in DMF after chromatography on silica gel using a mixture of methylene chloride with ether (3:1) and precipitation containing product fractions from methylene chloride using DIPE and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+746; tRet(I) of 28.2 min; Rf(H) to 0.39.

Example 50: isobutoxide-(L)-Val-[PheNNLeu] J (N-isobutoxide-(L)-Val):

Analogously to example 37, from 70 mg (0,19 mmol) of H-[PheNNLeu]-H3HCI (from example 13A), 130 mg (of 0.58 mmol) N-(isobutoxide)-(L)-valine, 256 mg (of 0.58 mmol) THIEF, 78 M1) and lyophilization containing the product fractions from dioxane, get listed in the header connection. FAB-MS: (M+H)+650; tRet(I) 26,4 min; Rf(H) 0,38.

a) N-(isobutoxide)-(L)-valine:

A solution of 10 g (85,3 mmol) of (L)-we bring in 100 ml of 2n sodium hydroxide solution is mixed with 11.2 ml (85,3 mmol) isobutylphthalate and stirred at room temperature for 18 hours. The reaction solution is washed with methylene chloride, acidified with 4n hydrochloric acid and extracted with methylene chloride. The organic extracts washed with brine, filtered through cotton wool and after evaporation receive specified in the title compound as a colourless resin. 1H-NMR (200 MHz, CD3OD): 0,95 (m, N); 1,9 (m, 1H); to 2.15 (m, 1H); of 3.85 (d, J=7 Hz, 2H); of 4.05 (d, br, 1H).

Example 51: N-(3-(tetrazol-1-yl)-propionyl)-(L)-Val-[PheNNLeu] J (N-3-(tetrazol-1-yl) -propionyl L)-Val):

Analogously to example 37, from 150 mg (0.42 mmol) of H-[PheNNLeu]-H3HCI (from example 13A), 251 mg (1.04 mmol) of N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine from example 44a), 460 mg (1.04 mmol) THIEF, 140 mg (1.04 mmol) of HOBt and 6.9 ml of 0.3 M N-methylmorpholine in DMF after precipitation from methylene chloride by using DIPE and lyophilization from dioxane with tert.-butanol and water, get listed in the header connection. FAB-MS: (M+H)+689; tRet(l) of 14.7 min; Rf(K) of 0.36.

Example 52: a), 184 mg (1,16 mmol) N-acetyl-(L)-valine, 512 mg (1,16 mmol) THIEF, 156 mg (1,16 mmol) HOBt and 7.8 ml of 0.3m NMM in DMF after precipitation from a mixture of methylene chloride with methanol by adding DIPA and lyophilization from dioxane with tert.-butanol and water, get specified header connection (according to HPLC differ diastereoisomer 2). FAB-MS: (M+H)+534; tRet(I) of 14.7 and 15.1 min; Rf(D) 0,35.

Example 53: Boc-(L)-Val-[PheNNLeu] J ((L)-Val)-Boc:

Analogously to example 7, from 300 mg (0.83 mmol) of H-[PheNNLeu]-H3HCI (For example), 722 mg of 3.33 mmol) Boc-(L)-poured, 1,262 g of 3.33 mmol) and HBTU 0,927 ml (6,66 mmol) of triethylamine in DMF after chromatographic purification on silica gel using a mixture of methylene chloride and ether (1:1), deposition containing the product fractions and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+650; tRet(I) to 26.3 min; Rf(H) of 0.64.

Example 54: H-(L)-Val-[PheNNLeu] J ((L)-Val)-H3HCI:

Analogously to example 5, from 396 mg (0.61 mmol) of Boc-(L)-Val-[PheNNLeu] J ((L)-Val)-Boc (example 53) and 10 ml of hydrogen chloride in dioxane, after freeze-drying the reaction solution, get listed in the header connection. FAB-MS:(M+H)+450; tRet(II) 24,1 min; Rf(K) of 0.25.

Example 55: N-thiomorpholine-(L)-Val-[PheNNLeu] J (N-timehole the l) (4-timehole-ylcarbonyl) -chloride (from example 6A) and 0,172 ml of triethylamine in DMF, after chromatographic purification on silica gel using a mixture of methylene chloride with methanol (95: 5), deposition containing the product fractions from methylene chloride/hexane and lyophilization from dioxane, get mentioned in the title compound as amorphous solid. FAB-MS: (M+H)+708; tRet(l) 21,4 min; Rf(E) of 0.45.

Example 56: 2(R,S)-tetrahydrofuryl-methoxycarbonyl-(L)-Val-[ChaNN-Leu] J (N-2(R,S)-tetrahydrofuryl-methoxycarbonyl-(L)-Val):

Analogously to example 37, from 80 mg (0.22 mmol) of H-[ChaNNLeu]-H3HCl, 160 mg (of 0.65 mmol) of N-(2(R,S)-tetrahydrofuryl-methoxycarbonyl)-(L)-valine, 289 mg (of 0.65 mmol) THIEF, 88 mg (of 0.65 mmol) HOBt and 4.3 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using ethyl acetate and lyophilized containing the product fractions from dioxane, receive specified in the header connection. FAB-MS: (M+H)+712; tRet(l) of 22.4 min; Rf(E) 0,21.

a) H-[ChaNNLeu]-H3HCl:

Analogously to example 5, from 150 mg (0.33 mmol) of Boc-[ChaNNLeu]-Boc and 10 ml of 4n of hydrogen chloride in dioxane, after freeze-drying the reaction solution, get 100 mg (83%) specified in the connection header. Rf(K) 0,26.

b) Boc-[ChaNNLeu]-Boc:

A solution of 200 mg (0.24 mmol) of Boc-[PheNNLeu]-Boc (example 12) in 15 ml of methanol hydronaut in PR is of 4 hours. The catalyst is filtered off, the solvent is completely evaporated and get listed in the title compound after crystallization from methylene chloride with hexane. tRet(l) to 26.7 min; Rf(V) to 0.21.

C) N-(2(R,S)- (tetrahydrofuran-methoxycarbonyl)-(L)-Aplin:

Analogously to example 50, from 7 g (60 mmol) of (L)-valine and 9.8 g (60 mmol) of 2(R, S)-tetrahydropyrimidin-chloroformiate (Heterocycles 27, 1155 (1988)) in 100 ml of 2n sodium hydroxide solution and 30 ml of dioxane get mentioned in the title compound as a mixture of two diastereomers. tRet(II) to 23.5 and 23.8 minutes

Example 57: Z-Val-[PheNNLeu] J (N-(3-tetrazol-1-yl)-propionyl)-Val):

Analogously to example 37, from 100 mg (0.21 mmol) of Z-(L)-Val-[PheNNLeu]-H, 75 mg (0.31 mmol) of N-(3-(tetrazol-1-yl)-propionyl(L)-valine from example 44a, 137 mg (0.31 mmol) THIEF, 42 mg (0.31 mmol) of HOBt and 2 ml of 0.3m NMM in DMF after precipitation from methylene chloride/hexane and drying of a mixture of dioxane with tert.-butanol, get mentioned in the title compound (HPLC differ diastereoisomer 2). FAB-MS: (M+H)+708; tRet(I) to 21.1 and 21.1 min; Rf(D) of 0.45.

a) Z-(L)-Val-[PheNNLeu]-H:

A solution of 250 mg (0.43 mol) of Z-(L)-Val-[PheNNLeu]-Boc in 5 ml of formic acid is stirred for 7.5 hours at room temperature. After this time, when HPLC. The residue is dissolved in chloroform and washed with saturated sodium bicarbonate solution. The chloroform phase was filtered through cotton wool and obtain, after evaporation of the solvent specified in the header of the junction of the red color. tRet(l) of 16.7 min; Rf(K) of 0.21.

b) Z-(L)-Val-[PheNNLeu]-Boc:

Analogously to example 37, from 230 mg (0,653 mmol) of H-[PheNNLeu]-Boc, 247 mg (0.98 mmol) of Z-(L)-valine, 434 mg (0.98 mmol) THIEF, 133 mg (0.98 mmol) of HOBt and 6.5 ml of 0.3 M NMM in DMF after precipitation from methylene chloride/methanol by adding DIPA receive specified in the header connection. FAB-MS: (M+H)+585; tRet(I) of 27.5 min; Rf(C) to 0.71.

in) H-[PheNNLeu]-Boc:

Analogously to example 17A, on the basis of 1.27 g (2,84 mmol) of N-TRIFLUOROACETYL- [PheNNLeu] -Boc and 24 ml of 1N aqueous solution of sodium carbonate in 90 ml of methanol, get mentioned in the title compound, which is precipitated from methylene chloride by the addition of DIPE. tRet(I) of 14.9 min; Rf(K) 0,38.

g) N-TRIFLUOROACETYL-[PheNNLeu]-Boc:

Analogously to example 16, from 3 g (11,57 mmol) of 2(R)-[1'(S)-(TRIFLUOROACETYL-amino)-2'-phenylethyl] oxirane (from example 16g) and 2.3 g (12,15 mmol) tert.-butyl-3-isobutyl-carbazate (receiving: J. Chem. Soc. Perkin 1, 1712 (1975)) after chromatographic purification on silicagel thef(W) of 0.36.

Example 58: acetyl-Val-[PheNNLeu] J (N-2(R,S)-carbarnoyl-3-phenylpropionyl)-Val):

Analogously to example 37, from 140 mg (0.3 mmol) acetyl-(L)-Val- [PheNNLeu] -H2HCI, 132 mg (0.45 mmol) of N-(2(R,S)-carbarnoyl-3-phenyl - propionyl)-(L)-valine (receive: Synth.Struct.Funct. The OEWG. Am. Pept. Symp. 7th, 85, (1981)), 199 mg (0.45 mmol) THIEF, 61 mg (0.45 mmol) of HOBt and 3.5 ml of 0.3 M NMM in DMF after precipitation from methylene chloride by using DIPE and lyophilization from dioxane, get the title compound (HPLC to distinguish between two diastereoisomer). FAB-MS: (M+H)+= 667; tRet(l) and 17,9 18,4 min; Rf(D) 0,33.

a) acetyl-Val-[PheNNLeu]-HHCI:

Analogously to example 2A, on the basis of 230 mg (0.46 mmol) acetyl-(L)- Val-[PheNNLeu] -Boc, after lyophilization get mentioned in the title compound, tRet(I) to 10.5 min; Rf(D) 0,38.

b) acetyl-Val-[PheNNLeu]-Boc:

Analogously to example 37, from 250 mg (0.71 mmol) of H-[PheNNLeu]-Boc (from example 57b), 170 mg (1.07 mmol) of N-acetyl-(L)-valine, 471 mg (1.07 mmol) THIEF, 144 mg (1.07 mmol) of HOBt and 7.1 ml of 0.3m NMM in DMF after precipitation from methylene chloride by the addition of DIPE and lyophilization from dioxane, receive specified in the header connection. FAB-MS: (M+H)+493; tRet(I) of 20.5 min; Rf(D) 0,59.

Example 59: N-morpholinoethyl-(L)-Val-[PheNNLeu] J (N-(3-tens, 67 mg (0.38 mmol) of N-(3-(tetrazol-1-yl)- propionyl)-(L)-valine from example 44a), 124 mg (0.28 mmol) THIEF, 38 mg (0.28 mmol) of HOBt and 2.1 ml of 0.3m NMM in DMF after precipitation from methylene chloride by the addition of DIPE and lyophilization from dioxane, get mentioned in the title compound (HPLC differ diastereoisomer 2). FAB-MS: (M+H)+687; tRet(I) of 15.2 and 15.4 min; Rf(D) of 0.25.

a) N-morpholinoethyl-(L)-Val-[PheNNLeu]-H2HCl:

Analogously to example 2A, on the basis of 279 mg (0.49 mmol) of N-morpholinoethyl-(L)-Val-[PheNNLeu] -Boc, after lyophilization, receive specified in the header connection. FAB-MS: (M+H)+464; tRet(ll) 30,3 min; Rf(D) 0,46.

b) N-morpholinoethyl-(L)-Val-[PheNNLeu]-Boc:

Analogously to example 37, from 250 mg (0.71 mmol) of H-[PheNNLeu]-Boc (from example 57b), 265 mg (1.07 mmol) of N-morpholinoethyl-(L)-valine from example 7a), 471 mg (1.07 mmol) THIEF, 144 mg (1.07 mmol) of HOBt and 7.1 ml of 0.3m NMM in DMF after precipitation from methylene chloride with hexane and lyophilization from dioxane, receive specified in the header connection. F-MS: (M+H)+564; tRet(I) a 21.5 min; Rf(K) to 0.69.

Example 60: N-TRIFLUOROACETYL-[PheNNLeu] J (N-2(R,S)-carbarnoyl-3 - phenylpropionyl)-(L)-Val):

Analogously to example 37, 136 mg (0.32 mmol) of N-TRIFLUOROACETYL-[PheNNLeu] -H2HCI, 142 mg (0,0,49 mmol) THIEF 66 mg (0.49 mmol) of HOBt and 5 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using chloroform with methanol (15: 1), deposition containing the product fractions from methylene chloride using DIPE and lyophilization from dioxane with tert.-butanol, get mentioned in the title compound (HPLC differ diastereoisomer 2). FAB-MS: (M+H)+622; tRet(l) to 21.6 and 22.0 Rf(K) 0,26.

a) N-TRIFLUOROACETYL-[PheNNLeu]-H2HCl:

Analogously to example 2A, on the basis of 300 mg (0.67 mmol) of N-TRIFLUOROACETYL-[PheNNLeu] -Boc (example g), after lyophilization receive specified in the header connection. Rf(w) <0,1.NNNle] J N-(2(R,S)-(N-(2-morpholinoethyl)-carbarnoyl)-3-methyl) -butyryl)

Analogously to example 37, from 100 mg (0,17 mmol) of Z-(L)-Val-[PheNNNle]-H2HCl, 69 mg (0.27 mmol) of 2(R,S)-(N-(2-morpholinoethyl)-carbarnoyl)-3-methylmalonic acid (N-(2-morpholinoethyl)-mononitratebuy acid), 119 mg (0.27 mmol) THIEF, 36 mg (0.27 mmol) of HOBt and 2.1 ml of 0.3m NMM in DMF after precipitation from methylene chloride by using DIPE and lyophilization from dioxane, get mentioned in the title compound (HPLC differ diastereoisomer 2). FAB-MS: (M+H)+725; tRet(I) to 17.2 and 17.6 min; Rf(D) of 0.56.

a) Z-(L)-Val-[PheNNNle]-H2HCl:

Analogously to example 2A, and theRet(I) to 16.4 min; Rf(U) of 0.25.

b) Z-(L)-Val-[PheNNNle]-Boc:

Analogously to example 37, from 250 mg (0.71 mmol) of H-[PheNNNle]-Boc, 268 mg (1.07 mmol) of Z-(L)-roller 472 mg (1.07 mmol) THIEF, 144 mg (1.07 mmol) of HOBt and 7.1 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using a mixture of methylene chloride with methanol (40:1) and precipitation containing product fractions from methylene chloride using DIPA get mentioned in the title compound, tRet(I) 25.6 min; Rf(X) 0,17.

in) H-[PheNNNle]-Boc:

Analogously to example 17A, on the basis of 830 mg (of 1.85 mmol) of N-TRIFLUOROACETYL- [PheNNNle] -Boc, after precipitation from methylene chloride by using DIPA receive specified in the header connection. tRet(l) to 15.4 min; Rf(X) of 0.54.

g) N-TRIFLUOROACETYL-[PheNNNle]-Boc:

Analogously to example 16, from 1 g (3,86 mmol) of 2(R)-[1'(S)-triptoreline)-2'-phenylethyl] -oxirane (from example 16g) and 720 mg (3,86 mmol) tert. -butyl-carbazate, after chromatographic purification on silica gel using a mixture of methylene chloride with ether (20:1) receive specified in the header connection. tRet(I) to 25.3 min; Rf(Q) 0,43.

d) tert.-butyl-3-butyl-carbazate:

Analogously to example 4B, 18.0 g (136,2 mmol) tert.-BUTYLCARBAMATE and 12.3 ml (136,2 mmol) n-butanol in example 4A, hydronaut in the presence of 10 g of 5-Noah platinum-on-coal, and under hydrogen pressure of 4 ATM. Chromatographic purification of the crude product on silica gel using mixtures of hexane/ethyl acetate (1:1) is specified in the header connection. Rf(N) 0,44;1H-NMR (200 MHz, CD3OD): to 0.92 (t, J=7 Hz, 3H); 1,43 (s, N); 1,30-1,50 (m, 4H); a 2.75 (t, J=7 Hz, 2H).

(e) 2(R,S)-(N-(2-morpholinoethyl)-carbarnoyl)-3-matlakala acid

Analogously to example 9b, from 7 g (43,7 mmol) of racemic nanometrology ether isopropylmalonic acid (Chem. Ber. 119,1196 (1986)), 6.3 ml (48.1 mmol) aminoacylation, and 6.6 ml (43,7 mmol) diethyl ether cyanophosphonate acid and 12.8 ml (91,8 mmol) of triethylamine in DMF receive methyl ester 2(R, S)-(N-(2-morpholinoethyl)-carbarnoyl)-3-methylmalonic acid (methyl ester of N-morpholinoethyl isopropylmalonic acid). Within 5 min it was stirred at room temperature in a mixture of 28 ml of 2n sodium hydroxide solution and 28 ml of dioxane, acidified with 2n hydrochloric acid and is completely evaporated. The remainder insist with ethanol, filtered off and get after evaporation of the filtrate indicated in the header of the connection.1H-NMR (200 MHz, CD3OD): of 0.95 and 1.00 (2d, J=7 Hz, 6N); to 2.25 (m, 4H); 2,70 (m, 6N); 2,75 (d, J=8 Hz, 1H); to 3.45 (m, 2H); 3.75 to (m, 4H).

Example 62: Z-(L)-Val-[PheHCl (from example 61A), 65 mg (0.27 mmol) of N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine from example 44a), 119 mg (0.27 mmol) THIEF, 36 mg (0.27 mmol) of HOBt and 2.1 ml of 0.3 M N-methylmorpholine in DMF after precipitation from methylene chloride by using DIPE and lyophilization from dioxane with tert.-butanol, get mentioned in the title compound (HPLC distinguishable diastereoisomer 2). FAB-MS: (M+H)+708; tRetof 20.3 and 20.6 min; Rf(D) 0,43.

Example 63: Z-(L)-Val-[PheNNNle] J (N-2(R,S)-(N-(2-pyridylmethyl)-carbarnoyl)-3-methyl)-butyryl) (dibenzalacetone):

Analogously to example 37, from 95 mg (0,17 mmol) of Z-(L)-Val-[PheNNNle]-H2HCl (from example 61A), 60 mg (0.26 mmol) of N-(2-picolyl)-monoamide-(R,S)-isopropylmalonic acid, 113 mg (0.26 mmol) THIEF, 35 mg (0.26 mmol) of HOBt and 2.0 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using a mixture of methylene chloride/methanol (15:1) is specified in the title compound as the free amine. It is dissolved in methylene chloride, mixed with two equivalents of benzosulfimide and precipitated by adding DIPA. The lyophilisation from tert.-butanol gives dibenzoylmethanato salt (HPLC distinguishable diastereoisomer 2). FAB-MS: (M+H)+703: tRet(l) and 17,7 18,0 min; Rf(D) 0,54.

a) N-(2-picolyl)-monoamide isopropylmalonic acid:

A solution of 15 g (93,6 mmol) mol) N-methylmorpholine and then dropwise with 13.5 ml (103 mmol) of isobutylacetate. After 30 minutes add 15.3 ml (150 mmol) of 2-picolylamine and stir the resulting suspension for 2 hours. The reaction mixture is diluted with methylene chloride, washed with 1N-sodium hydroxide solution and water, the organic phase is filtered through cotton and evaporated. Crystallization of the residue gives N-(2-picolylamine)-methyl ether of isopropylmalonic acid, which, as described in example 6E, hydrolyzing in a 2n solution of sodium hydroxide and dioxane. tRet(ll) 16,0 min

Example 64: Z-(L)-Val-[PheNN(p-F)Phe] J (N-(3-(tetrazol-1-yl)-propionyl)-(L)-Val) (bansilalpet).

Analogously to example 37, from 100 mg (0.16 mmol) of Z-(L)-Val-[PheNN(p-F)Phe] -H (from example 22A), 59 mg (0.25 mmol) of N-(3-tetrazol-1-yl)-propionyl)-(L)-valine from example 44a), 109 mg (0.25 mmol) THIEF, 33 mg (0.25 mmol) t and 1,19 ml of 0.3 M N-methylmorpholine in DMF after precipitation from methylene chloride by using DIPA get mentioned in the title compound as the free amine. It dissolved in a mixture of methylene chloride with water, mixed with 1 equivalent of benzosulfimide and precipitated by adding hexane. The lyophilisation from tert. -butanol gives specified in the title compound in the form of benzosulfimide. FAB-MS: (M+H)+760; tRet(l) to 21.6 min; Rf(B) 0,49.

Example 65: m is a rule example 7, enter into interaction with 197 mg (0.84 mmol) of N-phenylacetyl-(L)-valine (receive: Mem. Tokyo Univ. Agric. 20, 51 (1978)), 317 mg (0.84 mmol) of HBTU and 0.23 ml (1,67 mmol) of triethylamine in DMF after precipitation from methanol by the addition of ether, receive specified in the header connection. FAB-MS: (M+H)+581; tRet(I) a 20.2 min; Rf(B) of 0.64.

a) methylsulphonyl-[PheNNPhe]-H2HCl:

Analogously to example 2A, on the basis of 130 mg (0.28 mmol) methylsulphonyl- [PheNNPhe]-Boc, after lyophilization, receive specified in the header connection. FAB-MS: (M+H)+364; tRet(ll) of 28.5 min, Rf(K) of 0.56.

b) methylsulphonyl-[PheNNPhe]-Boc:

Analogously to example 16A, on the basis of 1.1 g (4,56 mmol) of 2(R)-[1'(S)- (methylsulfonylamino)-2'-phenylethyl-oxirane and 1,11 g (5,02 mmol) tert.- butyl-3-benzylmorphine (receiving: J. Chem. Soc. Perkin 1,1712 (1975)), get mentioned in the title compound as a mixture of diastereoisomers in the ratio of 4:1. By crystallization from methylene chloride with hexane ratio improves in favor of the 25-diastereoisomer to 10:1. FAB-MS: (M+H)+464; tRet(I) 21,3 min; Rf(N) 0,26.

in) 2(R)-[1'(S)-(methylsulfonylamino) -2'-phenylethyl]oxirane:

A solution of 1 g (6.8 mmol) of 1-phenyl-3-butene-2(S)-amine (from example 16B) in 10 ml of methylene chloride at 0oC is mixed with a 2.36 g of the mixture was washed with water and saturated sodium bicarbonate solution, the organic phase is filtered through cotton and evaporated and get 2(S)-methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of this crude product is dissolved in 30 ml of methylene chloride, mixed at room temperature from 3.05 g (17,7 mmol) 4-chlormadinone acid and stirred for 18 hours the Reaction solution is washed 5 times with 10-naked aqueous solution of sodium sulfite, filtered through cotton wool and completely evaporated. The crude product, according to1H-NMR, contains both (2R)-and (2S)-epimer in the ratio of 4: 1.1H-NMR (200 MHz, CD3OD): 2,30 and 2.52 (s, together 3H); 2,6-3,2 (m, 5H); 3,55 (m, 1H); 7,32 (m, 5H).

Example 66: methoxycarbonyl-(L)-Val-[PheNNLeu] J (N-methoxycarbonyl-(L)-Val):

Analogously to example 37, from 200 mg (0.55 mmol) of H-[PheNNLeu]-H-H3HCl (from example 13A), 291 mg (from 1.66 mmol) N-methoxycarbonyl-(L)-poured (receive: Chem. Lett. 705, (1980)), 735 mg (from 1.66 mmol) THIEF, 225 mg (from 1.66 mmol) HOBt and 11 ml of 0.3m NMM in DMF receive, after precipitation from methylene chloride by using DIPE and lyophilization from dioxane specified in the header connection. FAB-MS: (M+H)+566; tRet(I) to 18.6 min; Rf(U) 0,33.

Example 67: methoxycarbonyl-(L)-Val-[PheNN(p-F)Phe] J (N-methoxy-carbonyl-(L)-Val):

Analogously to example 37, from 200 mg (0.48 mmol) of H-[PheNN(p-F)Phe]- H3HCl (from example 42B), 255 mg (1,45 mm is f get after precipitation from methylene chloride by using DIPE and lyophilization from dioxane specified in the header connection. FAB-MS: (M+H)+618; tRet(I) of 19.5 min; Rf(U) 0,22.

Example 68: methoxycarbonyl-(L)-Val-[PheNN(p-CN)Phe] J (N-methoxy-carbonyl- (L)-Val):

Analogously to example 37, from 200 mg (0.48 mmol) of H-[PheNN(p-CN)Phe]-H3HCl (from example 47A), 250 mg (1,43 mmol) N-methoxycarbonyl-(L)-valine (receive: Chem. Lett. 705, (1980)), 631 mg (1,43 mmol) THIEF, 193 mg (1,43 mmol) HOBt and 9.5 ml of 0.3m NMM in DMF after chromatographic purification on silica gel using a mixture of methylene chloride/methanol (15:1) and lyophilized containing the product fractions from dioxane, receive specified in the header connection. FAB-MS: (M+H)+625; tRet(I) 18 min; Rf(U) 0,31.

Example 69: Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J (N-2(R,S)-(N-(2-morpholinoethyl)-carbarnoyl)- 3-methyl)-butyryl):

Analogously to example 18, 23,0 mg (0,089 mmol) of 2(R,S)-(N-(2-morpholinoethyl)-carbarnoyl)-3-methylmalonic acid (example e) and 45 mg (of 0.081 mmol) of Z-(L)-Val-[(p-F)PheNN(p-F)Phe]-H (example 32) being in engagement with and 33.8 mg (0,089 mmol) HBTU in 0,76 ml of NMM/CH3CN (0.25 M) to obtain specified in the connection header and perioada it using DMF/DIPE. TLC Rf(P) 0,42; FAB-MS: (M+H)+795.

Example 70: Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J N-(2(R,S)-(N-(2-PI-amide isopropylmalonic acid (example 63A) and 45 mg (of 0.081 mmol) of Z-(L)-Val-[(p-F)PheNN(p-F)Phe] -H (example 32) being in engagement with and 33.8 mg (0,089 mmol) HBTU in 0,76 ml of 0.25 M NMM in CH3CN to obtain specified in the connection header and periostat of DMF with DIPE. TCX Rf(P) 0,53; FAB-MS: (M+H)+773.

Example 71:

Similarly, the above method can be obtained the following compounds:

a) Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J ((L)-Val) J (N-morpholinomethyl-Gly);

b) N-morpholinylcarbonyl-(L)-Val-[(p-F)PheNN(p-F)Phe] J ((L)-Val) J (N - morpholinomethyl-Gly);

C) N-(quinoline-2-carbonyl)-(L)-Asn-[PheNN(p-F)Phe] <-- ((L)-Val)-Z;

g) N-(morpholinomethyl)-(L)-Val-[PheNNLeu] <-- (N-(morpholinomethyl)- (L)-Val).

Example 72: gelatin solution:

Sterile-filtered aqueous solution with 20% cyclodextrin as an agent of the dissolution of one of the previous examples of compounds of the formula I as biologically active substances when heated, mixed with a sterile gelatin solution as preservative contains phenol, under aseptic conditions, so that 1.0 ml of solution has the following composition:

Biologically active substance 3 mg

Gelatin 150,mg

Phenol 4,7 mg

Distilled water with 20% cyclodextrin as the agent of dissolution

Example 74 spray for nose (aerosol):

In a mixture of 3.5 ml of Myglyol 812and 0.08 g of benzyl alcohol are suspended 500 mg of finely milled powder (<5.0 µm) one of the specified in the above examples, the compounds of formula 1 as biologically active substances. This suspension is poured into a container with a dispensing valve. Fill 5.0 freon 12under pressure through the valve into the container. By shaking "freon" is dissolved in a mixture of Myglyol with benzyl alcohol. This capacity-atomizer contains approximately 100 single doses that can be entered separately.

Example 75: lacquered tablets:

For the preparation of 10,000 tablets, each containing 100 mg of biologically active substance, process the following components:

Biologically active R>
Stearic acid 50 g

Carboximetilkrahmal sodium 250 g

Water quantum satis

A mixture of one of these in the above examples, the compounds of the formula I as biologically active substances, 50 g of corn starch and colloidal silicic acid with starch paste 250 g of corn starch and 2.2 kg demineralizing water is processed in a wet mass. This mass is forced through a sieve with apertures of 3 mm and dried at 45oC for 30 min in a fluidized bed dryer. The dried granulate is forced through a sieve with openings of 1 mm, mixed with a previously sieved mixture (sieve hole size 1 mm) 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl amylum and pressed into weakly convex tablets.

1. Hydrazine derivatives of General formula

< / BR>
where R1and R9independently from each other hydrogen, lower alkanoyl, phenyl-ness. alkanoyl, phenyl-ness.alkanoyl, in which the remainder of the lower alkanoyl replaced by carbamoyl, morpholino-ness.alkanoyl, thiomorpholine-ness.alkanoyl, pyridyl-ness. alkanoyl, chinolin-ness.alkanoyl, tetrazolyl-ness.alkanoyl, amino ness. alkanoyl, zamestnanosti, 2-(N-morpholino-ness. allylcarbamate) lowest alkanoyl, 2-(N-pyridyl-ness.allylcarbamate) lowest alkanoyl, lower alkoxycarbonyl, phenyl-ness.alkoxycarbonyl, tetrahydrofuranyl-ness. alkoxycarbonyl, lower alkylsulfonyl, N-pyridyl-ness.alkyl - N-ness.allylcarbamate, or the acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of (D), (L)- or (D,L), where the amino group not substituted or allerban one of these residues R1or R9provided that at least one of the residues R1and R9hydrogen;

R2, R4, R6and R8hydrogen;

R3lower alkyl, cyclohexyl-ness.alkyl or phenyl-ness.alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano;

+R5hydroxyl group;

R7lower alkyl, cyclohexyl-ness.alkyl or phenyl-ness.alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano,

or their salts in the presence of salt-forming groups.

2. The compounds of formula I on p. 1, where R1lowest alkoxycarbonyl, phenyl-ness. alkoxycarbonyl, linked through a carboxyl group, a monovalent aliphatic radical of amino the pot on the amino group of one of the residues phenyl-(lower alkanoyl), morpholino-(lower alkanoyl), thiomorpholine-(lower alkanoyl), pyridyl-(lower alkanoyl), lower alkoxycarbonyl or phenyl-(lower alkoxycarbonyl) is the radical of a specified aliphatic amino acids, and those amino acids are represented in the form (D), (L)- or (D,L)-; R2hydrogen; R3phenyl-(lower alkyl); R4hydrogen; R5hydroxyl group; R6is hydrogen; R7lower alkyl, cyclohexyl-ness.alkyl or phenyl-ness.alkyl; R8hydrogen; R9one of the values R1and the remains of R3and R5the asymmetric carbon atoms are in the S-configuration,

as well as pharmacologically acceptable salts of these compounds.

3. The compounds of formula I on p. 1, where R1tert-butoxycarbonyl, benzyloxycarbonyl, linked through a carboxyl group, a monovalent radical of the amino acids valine, or linked through the carboxyl group residue of alanine, N-acylated on the amino group of one of the remnants of phenylacetyl, 3-pyridylacetic, morpholinoethyl, thiomorpholine, tert-butoxycarbonyl or benzyloxycarbonyl; R2hydrogen; R3benzyl; R4is hydrogen; R5hydroxyl group; R6hydrogen; R7- isobutyl, cyclohexylmethyl or without the carbon are in the S - configuration,

as well as pharmacologically acceptable salts of these compounds.

4. The compounds of formula I on p. 1, where R1and R9respectively linked through a carboxyl group, a N-acylated on the amino group by benzyloxycarbonyl monovalent radical of aminokisloty-(L)-valine; R2and R8hydrogen; R3benzyl; R4hydrogen; R5gidroksila group; R6hydrogen; R7benzyl, and the remains of R3and R5the asymmetric carbon atoms are in the S-configuration,

as well as pharmacologically acceptable salts of these compounds.

5. The compounds of formula I on p. 1, where R1and R9respectively linked through a carboxyl group of the N-acylated on the amino group of 4-thiomorpholine monovalent radical amino-(L)-valine; R2and R8hydrogen; R3benzyl; R4hydrogen; R5hydroxyl group; R6hydrogen; R7isobutyl, and the remains of R3and R5the asymmetric carbon atoms are in the S-configuration,

as well as pharmacologically acceptable salts of these compounds.

6. The compounds of formula I on p. 1, chosen from:

Vos-[PheNNPhe] -Boc; Boc-(L)-Val- [PheNNPhe](L)-Val-Vos; Vos-[PheNNCha] -Boc; H-(L-(L)-Val-[PheNNPhe] J(N-morpholinoethyl-- (L)-Val); phenylacetyl-(L)-Val-[PheNNPhe] J(N-phenylacetyl-(L)-Val); N-(3-pyridylethyl)-(L)-Val-[PheNNPhe] J(N-(3-pyridylethyl)- -(L)-Val); BOC-(L)-Val-[PheNNCha] J(L)-Val-Vos; Z-(L)-Val-[PheNNCha]J(L)-Val-Z; Vos-[PheNNLeu]-BOC; Z-(L)-Val-[PheNNLeu)J(L)-Val-Z, H-(L)-Val-[PheNNCha] J(L)- Val)- N-(3-pyridylethyl)-(L)-Val-[PheNNLeu]J(N-(3-pyridylethyl)-(L)-Val)

or their salts,

where BOC means tert-butoxycarbonyl,

Z benzyloxycarbonyl,

the remainder of [PheNNPhe] means the divalent radical 3(S)-amino-4-phenyl-1-(N-benzylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNCha] means the divalent radical 3(S)-amino-4-phenyl-1-(N-cyclohexylpiperazine)-butane-2(S)-ol and has the formula

1 where the remainder of [PheNNLeu] means the divalent radical 3(S)-amino-4-phenyl-1-(N-isobutylpyrazine)-butane-2-(S)-ol and has the formula

< / BR>
and "" means rotation due to the deviation from the usual items peptide, and amino left and right carboxy.

7. The compounds of formula I on p. 1, selected from Z-(L)-Val-[(p-F)PheNN(p-F)Phe] (N-(N-(2-pyridylmethyl)-N - methylaminomethyl)-(L)-Val); Z-(L)-Val-[(p-F)PheNN(p-F)Phe] J(N-(2(R, S)-carbarnoyl-3 - phenylpropionyl)-(L)-Val); acetyl-(L)-Val-[PheNNCha] J(N-acetamidomethyl)-N-methylaminomethyl)-(L)-Val); Z-(L)-Val-[PheNN(p-F)Phe] J(L)-Val)-Z; Z-(L)-Val-[PheNN(p-CN)Phe] J(L)-Val)-Z; Z-(L)-Jle-[PheNNLeu] J(L)-Jle)-Z; isobutoxide-(L)-Val-[PheNNLeu]J(N-isobutoxide (- L)-Val); acetyl-Val-[PheNNLeu] J(N-(2(R, S)-carbarnoyl-3-phenylpropionyl) -Val; N-TRIFLUOROACETYL-[PheNNJ(N-(2(R,S)-carbarnoyl-3 - phenylpropionyl)-(L)-Val); Z-(L)-Val-[PheNNNle]J(N-(2(R,S)-(N-(2-morpholinomethyl)- carbarnoyl)-3-methyl)-butyryl); Z-(L)-Val-[PheNNNle]J(N-(2(R,S)-(N-(2-pyridylmethyl)- carbarnoyl)-3-methyl)-butyryl); methoxycarbonyl-(L)-Val-[PheNNLeu]J(N-methoxycarbonyl-(L)-Val); methoxycarbonyl-(L)-Val-[PheNN(p-F)Phe] J(N-methoxycarbonyl) -(L)-Val); methoxycarbonyl-(L)-Val-[PheNN(p-CN)Phe]J(N-methoxycarbonyl- (L)-Val -

or their salts, where Z benzyloxycarbonyl, the remainder of [PheNNPhe] means the divalent radical 3(S)-amino-4-phenyl-1-(N-benzylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNCh] means the divalent radical 3(S)-amino-4-phenyl-(N-cyclohexylpiperazine)-butane-2(S)-ol and has the formula

< / BR>
where the balance of [PheNNLeu] means the divalent radical 3(S)-amino-4-phenyl-1-(N-isobutylpyrazine)-butane -2(S)-ol and has the formula

< / BR>
the remainder of [PheNNNIe] means the radical 3(S)-amino-4-phenyl-1-(N-n-butylhydrazine)-butane-2(S)-ol and has the formula

< / BR>
steet formula

< / BR>
the remainder of [(p-F)PheNN(p-F)Phe] means the divalent radical 3(S)-amino-4-phenyl-(p-forfinal)-1-(N-(p-performer)-hydrazino)-butane - 2(S)-ol and has the formula

< / BR>
the remainder of [PheNN(p-CN)Phe] means the divalent radical 3(S)-amino-4-phenyl-1-(N-(p - cyanovinylene)-hydrazino)-butane-2(S)-ol and has the formula

< / BR>
and "" means rotation due to the deviation from the usual items peptide, and amino left and right carboxy.

8. The compounds of formula I under item 1, with the properties to inhibit the activity of the enzyme HIV protease.

9. Pharmacologically-active composition, inhibiting HIV protease and possessing antiviral activity, containing the active principle and a pharmaceutically acceptable carrier, characterized in that the active agent contains an effective amount of the compounds of formula I on PP.1 7 or its pharmaceutically acceptable salt.

10. AMINOETHYLPIPERAZINE formula II

< / BR>
where R3and R7lower alkyl, cyclohexyl-lower alkyl, or phenyl-lower alkyl, unsubstituted or substituted with halogen, lower alkoxy or cyano, or their salts, if they have soleobrazutaya group.

 

Same patents:

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: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: medicine.

SUBSTANCE: peptide of the following formula: X-Pro-Gly-P, where X = Thr-Lys-Pro-Arg-; Lys-pro-Arg-; pro-Arg-; Arg-, being of untiulcerous activity. They should be applied at intraperitoneal injection at the dosage of 0.58-3.20 mcM g/kg for preventing and treating ulcers of gastro-intestinal tract.

EFFECT: higher efficiency and prophylaxis.

4 dwg, 5 ex

FIELD: medicine, chemistry of peptides, amino acids.

SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).

EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.

4 cl, 16 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: method involves applying composition based on receptor antagonist P substance and magnesium salt.

EFFECT: reduced hematoencephalic barrier permeability; reduced risk of vasogenic brain edema; prevented water accumulation in brain; smoothing consequences caused by reduced cognitive abilities.

23 cl, 2 dwg, 3 tbl

FIELD: medicine, peptides.

SUBSTANCE: invention relates to osteogenic growth oligopeptides used as stimulators of hemopoiesis. Invention proposes using an oligopeptide of molecular mass in the range from 200 to 1000 Da, comprising one of the following sequence: Tyr-Gly-Phe-Gly-Gly, Met-Tyr-Gly-Phe-Gly-Gly used in preparing a pharmaceutical composition and enhancing mobilization of hemopoietic stem cells from many differentiation line into peripheral blood, in particular, CD34-positive hemopoietic stem cells. Advantage of the invention involves expanding field in using oligopeptides used in stimulation of hemopoiesis.

EFFECT: enhanced and valuable properties of oligopeptides.

34 cl, 2 tbl, 7 dwg, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: releasing peptides of growth hormone are described with formula (I): R112345-R2, where:А1 designates Aib, Apc or Inp; А2 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Тrp; А3 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp; А4 designates 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); А5 designates Apc, Dab, Dap, Lys, Orn or deleted; R1 designates hydrogen; and R2 designates NH2; and their pharmaceutically acceptable salts.

EFFECT: pharmaceutical compositions and the methods of their application are presented.

25 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention can be used for medical treatment of secondary hypothyroid state accompanied by low synthesis of thyrotrophic hormone by hypophysis and of iodine hormone by thyroid gland. Substance of invention implies application of peptide Lys-Glu-Asp-Gly as a medicine stimulating synthesis of thyrotrophic hormone by hypophysis and of thyroid hormone by thyroid gland.

EFFECT: high specific activity of introduced peptide and decrease of side effect risk.

4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to compounds of Formula II and to methods of immune response suppression, e.g. by inhibition of indirect MHC type II of T-cells activation. Compounds under invention can be applied to treatment or prevention of derangements, such as rheumatoid arthritis and/or multiple sclerosis.

EFFECT: production of compounds which can be used for immune response suppression.

25 cl, 19 dwg, 4 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, namely to medicated products normalising cardiac function, particularly being perspective for treatment of coronary heart disease (CHD). Peptide of general formula CH3CO-Lys-Lys-Arg-Arg-NH2 is disclosed as an anti-ischemic and antihypoxic agent.

EFFECT: declared invention ensures apparent anti-ischemic, antihypoxic and adaptive action and is being available in medical practice.

1 cl, 3 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: invention relates to peptides of general formula , and to their cosmetically or dermopharmaceutically acceptable salts, where: X is chosen from the group formed by cysteinyl, seryl, threonyl and aminobutyryl; R1 is chosen from the group formed by H or a saturated linear C2-C24 acyl group; R2 is chosen from the group formed by an amino group optionally substituted with C1-C24 alkyl, or a hydroxy group. Besides the invention covers a method for making said peptides, their cosmetic or dermopharmaceutical compositions intended for reducing or eliminating baggy lower eyelids.

EFFECT: higher effectiveness.

12 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of biologically active substances of peptide nature, having cartilage-derived morphogenetic protein CDMP-1 activity on chondrocyte proliferation. Through in silico construction, an oligopeptide of general formula I is obtained: X1-X2-X3-X4 (I), where X1 denotes M; X2 denotes A or G; X3 denotes W; X4 denotes W or is absent.

EFFECT: invention enables to obtain an oligopeptide having cartilage-derived morphogenetic protein CDMP-1 activity on chondrocyte proliferation, thereby widening the range of effective therapeutic agents which accelerate regeneration of cartilage tissue of joints.

5 dwg, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in claim described are organic compounds of formula I where radicals are given in description, which are applicable for elimination, prevention or alleviation of one or more symptoms, associated with HCV disorders.

EFFECT: obtaining pharmaceutical composition which possesses inhibiting activity with respect to NS3-4 HCV serinprotease, including formula I compound and pharmaceutically acceptable carrier.

30 cl, 25 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds possessing high activity targeted on modulating NMDA-receptor activity and using the same for treating diseases and disorders, such as learning disorder, cognitive disorders and analgesia, and particularly for relieving and/or eliminating neuropathic pain.

EFFECT: producing compounds possessing high activity targeted on modulating NMDA-receptor activity.

9 cl, 13 dwg, 2 tbl, 11 ex

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