Derivatives of 5-amino-4-oxohexanoate acid and method of production thereof

 

(57) Abstract:

Usage: in medicine and biochemistry. Essence: derivatives of 5-amino-4-oxohexanoate acid f-ly I: R1-B1-NH-CH(CH2R2)-CH(OH)-CH2-CH(CH2R3)-CO-A1-A2-N(R4,R5with certain literal values, the method of production thereof and derivatives of 5-amino-4-oxohexanoate acid, active in suppressing SP-protease from HIV-1. 3 table.

The invention relates to neytralizuya analogues fissionable aspirinplease peptides, namely derivatives of 5-amino-4-oxohexanoate acid active during the suppression of the protease of HIV-1, and the way they are received.

AIDS, as we know currently, is a caused by the retrovirus HIV (human immunodeficiency virus) disease of the immune system. This disease, according to who estimates, struck about 10 million people and covers everything. The disease almost always leads to death of the patient. For therapy, beyond the still limited capacity to relieve symptoms of AIDS and known safety features are of special interest in the search for drugs themselves ven the fast connection, which block the replication of the virus in that they prevent the Association of the infectious viral particles.

HIV-1 and HIV-2, depending on the circumstances, in its genome have a region which encodes a "gag-protease". This "gag-protease" responsible for the proper proteoliticescoe cleavage of protein precursors that originate from coding "Group Specific Antigens" (gag) segments of the genome. This frees the structural proteins of the viral core, in English "e". Itself "gag-protease" is an integral part of the encoded segment of the pol-genome of HIV-1 and HIV-2 protein precursor that also contains segments "reverse transcriptase and integrase and cleaved likely autoproteolytic. "Gag-protease" breaks down the major protein core ("jor 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.

Based on the Central role of "gag-protease" while processing the specified "With e-proteins" ("protein Central part"), based on the fact that the effective ingibirovany be used therapeutically.

A prerequisite for therapeutic efficacy in vivo is to achieve good opportunities Leopoldovna, for example, a high level in the blood, in order thus to achieve in infected cells is sufficiently high concentrations.

Already synthesized a number of "gag-protease" inhibitors that contain a core group representing neprotekayuschy cleaved peptide-soapery. Still, despite intensive surveys have not yet found suitable for use in humans inhibitors aspartates for AIDS for the most part positive. In this case, the most important are primarily pharmacodynamic problems.

The aim of the invention is to find new inhibitors of HIV-1 aspartates.

According to the invention offers derivatives of 5-amino-4-oxohexanoate acid of General formula:

< / BR>
where R1means hydrogen, lower alkoxycarbonyl, benzofuranyl, pyridylcarbonyl, morpholinylcarbonyl, tetrahydroisoquinoline, morpholinomethyl or N-(pyridylmethyl)-N-methylaminomethyl, IN1means bond or a divalent radical of the amino acid poured, N-end of which is connected with R1a C-checkout cyclohexyl or phenyl, the latter may be unsubstituted or substituted in p-position by halogen, trifluoromethyl, cyano or lower alkoxygroup, A1and A2together represent the bivalent radical of a dipeptide selected from the group of Val-Phe, Val-Cha, Val-(p-F)Phe, Val-(p-CH3Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe and Val-Tyr, N-end of which is connected to the group-C= O and C-end with a group NR4R5and R4and R5together with the associated nitrogen atom signify thiomorpholine or morpholinopropan or protected lower alkanoyl on the hydroxy-group derivatives of these compounds.

In the description of the invention used to determine the groups or residues, for example lower alkoxy, lower alkoxycarbonyl, the expression "lower" means that unless nothing else, these groups contain up to (and including) 7 and preferably 4 C-atoms.

If necessary, the existing asymmetric C-atoms in the substituents R1B1, R2, R3, A1and/or A2may be (R), (S) or (R, S)-configuration. Thus, the proposed connection can be in the form of mixtures of isomers or as pure isomers, especially in the form of mixtures of diastereomers, enantiomeric pairs or pure enantiomers.


Lowest alkoxycarbonyl R1contains preferably branched lower alkyl residue, in particular Deut. or tert.-the lower alkyl residue, and represents, for example, butoxycarbonyl as tert.-butoxycarbonyl or isobutoxide. Especially preferred tert.-butoxycarbonyl.

Pyridylcarbonyl represents, for example, pyridyl-3-carbonyl, morpholinylcarbonyl, such as morpholinomethyl; benzofuranol is, for example, this 3-benzofuranol, tetrahydroisoquinolinium is, for example tetrahydroisoquinoline-3-carbonyl, preferably tetrahydroisoquinoline-3-carbonyl.

The compound of formula I, where R1means morpholinomethyl, and the remaining residues have the above values, is particularly preferred.

N-(pyridylmethyl)-N-methylaminomethyl represents, for example, N-(2-pyridylmethyl)-N-methylaminoethanol. The compounds of formula I, where R1denotes N-(pyridylmethyl)-N-methylaminomethyl, and other residues have the above values, the definition of compounds of the formula I, especially, prepact the end associated with the amino group bearing R2-CH2-carbon atom, preferably valine (Val) is a D-, L - or (D,L)-, preferably in an L-shape, and in particular is connected with the remnants of R1selected from lower alkoxy)-carbonyl, for example tert.-butoxycarbonyl, or geterotsiklicheskikh as morpholinoethyl.

If B1means a connection, R1directly linked to the amine nitrogen of the linking carbon atom bearing residue R2-CH2in formula I.

Especially preferred are combinations of R2and R3in which at least one of the residues R2or R3is phenyl, which is substituted by a residue selected from halogen, in particular fluorine, trifloromethyl, and ceanography, preferably Deputy selected from fluorine or ceanography.

Even more preferred is R2selected from phenyl, 4-methoxyphenyl, 4-ftoheia, cyclohexyl and 4-trifloromethyl, while R3selected from phenyl, 4-methoxyphenyl, cyclohexyl, 4-ftoheia, 4-tryptophanyl and 4-cianfanelli.

First of all R2is selected from phenyl, 4-ftoheia and cyclohexyl, while R3is selected from phenyl, cyclohexyl, 4-ftoheia R2cyclohexyl and R34 cyanophenyl; R2cyclohexyl and R34-forfinal; R2and R3depending on the circumstances, cyclohexyl. Alternative or additionally also mostly preferred combination: R2phenyl and R34-forfinal; R2phenyl and R34 cyanophenyl; R24-forfinal and R34-triptoreline; R24-triptoreline and R3phenyl; R24-triptoreline and R34-forfinal; R24-triptoreline and R34-triptoreline.

Hydroxyl group in compounds of formula I, the carbon atom that is adjacent to the carbon atom bearing the remainder R2CH2- can be free or protected form, and as protection for the hydroxyl groups take into account the lower alkanoyloxy as the atomic charges.

Formed from A1and A2the bivalent radical of a dipeptide, the Central peptide bond which restored and N-end associated with the group-C=O and C-end is associated with a group NR4R5is preferably of the two above-mentioned hydrophobic a-amino acids, particularly N-terminal amino acid radical selected from Gly (reset.), Val (VA, n-methoxyphenylalanine.

These values of A1and A2, which together form a bivalent radical of a dipeptide of the formula selected from the group of Val-Phe, Ile-Phe, Val-Cha, Val-Gly, Val-(n-F-Phe), Val-(n-CH3O-Phe)- Val-Tyr, Ile-Gly, or Val-Val, where amino acids are in the (D)- or (L), especially (L)-form, except (L)-Val-Phe, where Phe is (L)- or (D) of the form.

The preferred form of the invention refers to those compounds of formula I, where B1indicates the relationship B1and A2depending on the circumstances, represent one of the divalent radicals --amino acids or together represent one of the mentioned bivalent radical of a dipeptide with the restored Central amide bond.

Preferred compounds where R4and R5form together with the linking nitrogen atom of the unsubstituted morpholinopropan.

Thus, preferred are the compounds of formula I in which R1denote hydrogen, tert.-butoxycarbonyl, pyridine-3-carbonyl, morpholinoethyl, 3-benzofuranyl or 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, B1means of communication, R2and R3independently of one another denote phenyl or cyclohexyl, and phenyl is ANO, A1and A2together represent the bivalent radical of a dipeptide selected from the group of Val-Phe, Val-Cha, Val-(PR-F)Phe, Val-(PR-CH3O)Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe and Val-Tyr, N-end of which is connected to the group-C=O and C-end with a group NR4R5and R4and R5together with the associated with the associated nitrogen atom signify thiomorpholine or morpholino.

Most preferred is a compound of formula I, in which R1means tert.-butoxycarbonyl, R2and R3accordingly, phenyl, A1and A2the bivalent radical of a dipeptide (L)-Val-(L)-Phe, N-end of which is connected to the group-C=O and C-end with a group NR4R5a R4and R5together with the associated nitrogen atom signify morpholino.

Also preferred is a compound of formula I of Boc-Phe[C](PR-CH3O)Phe-(L)-Val-(L)-Phe-morpholin-4-alamid, in which R1means tert.-butoxycarbonyl, R2phenyl, R3- p-methoxyphenyl, A1and A2together denote the radical peptide (L)-Val-(L)-Phe, N-end of which is connected to the group-C=O and C-end is connected with a group NR4R5, a R4and R5together with the associated nitrogen atom signify morpholino.

Especially important is the compound of formula I, where R1the convoy is'alene; A2phenylalanine and R4and R5together with the linking nitrogen atom denote morpholino.

Also especially important compound of formula I, where R1tert.-butoxycarbonyl, B1bond; R2cyclohexyl; R3p-forfinal; A1valine; A2p-forfinally and R4and R5together with the linking nitrogen atom denote morpholino.

Also especially important compound of formula I, where R1denotes tert.-butoxycarbonyl, B1bond; R2cyclohexyl; R3p-forfinal; A1valine; A2p-methoxyphenylalanine; and R4and R5together with the linking nitrogen atom signify morpholino.

Also of particular importance is the compound of formula I, where R1tert.-butoxycarbonyl, B1bond; R2cyclohexyl; R3p-forfinal; A1valine; A2cyclohexylamine; and R4and R5together with the linking nitrogen atom denote morpholino.

Also of particular importance is the compound of formula I, where R1denotes tert. -butoxycarbonyl, B1bond; R2cyclohexyl; R3p-forfinal; A1valine; A2phenylalanine; and R4and R5together with the linking nitrogen atom of bonil, B1bond; R2cyclohexyl; R3p-forfinal; A1isoleucine; A2phenylalanine; and R4and R5together with the linking nitrogen atom denote morpholino.

Especially important is the compound of formula I, where R1tert.-butoxycarbonyl, B1bond; R2phenyl; R3p-forfinal; A1valine; A2phenylalanine; and R4and R5together with the linking nitrogen atom denote morpholino.

Also of particular importance is the compound of formula I, where R1denotes tert. -butoxycarbonyl, B1bond; R2p-forfinal; R3p-forfinal; A1valine; A2phenylalanine; and R4and R5together with the linking nitrogen atom denote morpholino.

Particularly important is the compound of formula I, where R1tert.-butoxycarbonyl, B1bond; R2p-forfinal; R3p-forfinal; A1valine; A2p-forfinally; and R4and R5together with the linking nitrogen atom denote morpholino.

Especially important is the compound of formula I, where R1tert.-butoxycarbonyl, B1bond; R3p-cyanophenyl; A1valine; A2phenylalanine; and R4and Runity formula I, where R1tert.-butoxycarbonyl. B1bond; R2and R3phenyl; A1valine; A2phenylalanine; and R4and R5together with the linking nitrogen atom provide thiomorpholine.

Compounds of the invention possess inhibitory activity against retroviral aspartate, particularly suppressing the gag-protease activity. First of all they inhibit in the following test at a concentration of 10-6-109M the action of the gag-protease HIV-1 and are therefore suitable means against induced by these or related retroviruses diseases, such as AIDS.

I. the ability of the compounds of the formula to inhibit proteolytic activity, for example, HIV-1 protease, can be demonstrated, for example, as described by J. Hansen and others, The EMBO Journal 7, 1785 1791 (1988) method. Thus the suppression of the action of HIV-1 protease is measured on the substrate, which is exponirovanya in E. coli fused protein of gag-protein precursor and MS-2. The substrate and the products of fission separated by polyacrylamide gel electrophoresis and show by immunoablative with monoclonal antibodies against MS-2.

Even more have gag-protease using a synthetic peptide which corresponds to one of the places cleavage of gag-protein precursor. This substrate and the products of fission can be measured by liquid chromatography high pressure (LC). For example, as a substrate for recombinante HIV-1 protease (getting under Billich, S. and others, J. Biol. Chem, 263 (34), 18905 17908. 1990) use synthetic chromophore peptide (for example, HKARVL/NO2/FEANles (Bachem, Switzerland) or Imazapic as RRSNQVSNYPIBQNIQGRR (obtained by peptide synthesis by known methods), which corresponds to one of the places cleavage of gag-protein precursor. This substrate and the products of fission can be measured by liquid chromatography high pressure (LO).

For this purpose, the test inhibitor of the formula I are dissolved in dimethyl sulfoxide; enzymatic test exercise that is suitable dilution of the inhibitor in 20 mm-morpholinobutyrophenone, (ES) buffer, pH 6.0 is added to the mixture for analysis of 67,2 mM above chloroform peptide in 0.3 M sodium acetate, 0.1 M NaCl, pH 7,4; or 122 M above Icosapentate 20 mm S buffer, pH 6.0; the amount of the mixture is 100 μm. The reaction is initiated due to the additives in the first case, 2 ál, in the second case, 10 μl of HIV-1 protease and PE> in the second case, after an hour incubation at 37oC the reaction is stopped by adding 10 μl of 0.3 M lO4. The reaction products after centrifuging the samples for 5 min at 10,000 x g in 100 μl of reaction mixture with chloroform peptide), respectively, 20 μl (mixture with Ecosuperior) obtained supernatant, and after making LC-column 125 x 4.6 mm with Nucleosil.

C18-5 (Macherey and Nagel, Duren) and elution determine quantitatively driven by the peak height of the product of cleavage at 280 nm (a mixture with chloroform peptide) or 215 nm (mixture with Ecosuperior); gradient: 100 EI. 1 > 50 EI.1/50 EI.2/E1.1: 10 acetonitrile, 90 water, 0,1 cryptanalyses acid (TFA); EI1.2: 75 acetonitrile, 25 water 0,08 TFA for 15 min; the transmission rate of 1 ml / min (EI. eluent).

For compounds of formula I preferably are determined by the IC50values (IC50this concentration, which reduces the activity of HIV-1 protease in comparison with the control without inhibitor 50) approximately 10-6-10-9M, in particular 10-7-10-8M.

II. In another test it was shown that the compounds of the invention protect cells that are normal infected by HIV from such infection or what if c HIV-1 in the presence of one 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 in RPMI 1640 medium (Gibco, Switzerland; RPMI 1640 contains a mixture of amino acids without L-Gbn), which added 10 is activated when heated embryonic calf serum, 1-glutamine, Hepec (2-[4-(2-oxyethyl)-1-piperazine derivatives] -econsultation) and the standard antibiotic, and incubated at 37oC in humidified air with 5 CO25 μl of each test compound in culture medium and 100 μl of HIV-1 in culture medium and 100 μl of HIV-1 in culture medium (800 ID 50/ml) (IL 50 infectious dose of cell culture 50 dose that infects 50 MT-2-cells) contribute 4 x 103exponentially growing MT-2 cells in 50 μl of culture medium on deepening tablets for microtitre with 96-Yu holes. Parallel mixture on another tablet for microtitre cells and test compound contain 100 μl of culture medium without virus. After incubation for 4 days determined in 10 µl of the supernatant of cells the activity of reverse transcriptase (RT). RT activity is determined in 50 mm Tris (a, a, a-Tris(oxymethyl)-methylamine, ultra-pure, Merck, Germany), pH 7.8; 75 mm KCl, 2 mm dithiothreitol, 5 mm MgCl2; 0,05 Nonedet P-40 (detergent; Sigma, Switzerland); 50 μg/ml polyadenylic acid (pharmacy, Switzerland); 1.6 m is wound at -20oC. the aliquot of this solution add 0.1 (by volume) /alpha32P/dTTP to achieve radioactive finite activity 10 Ci/ml 10 ál of culture supernatant transferred to a new plate with 96-Yu holes microtitre and there add 30 µl of the indicated RT-"cocktail". After mixing the tablet incubated for 1.5 to 3 h at 37oC. 5 μl of this reaction mixture is transferred onto Whatman DEE81 (Whatman). The dried filters are washed three times for 5 min with 300 mm NaCl/25 mm Tris/citrate/ and 1 time with 95-aqueous ethanol and again dried in air. Assessment is carried out in a Matrix Packard 96 well coumter (Packard). ED90values calculated as the lowest concentration of the respective test compounds determined such that RT reduces activity by 90 compared with untreated cell mixtures test substances. RT activity is a measure of the propagation of HIV-1.

Proposed according to the invention the connection at this show ED90about 10-5-10-8M, preferably about 10-7-10-8M

Compounds of the invention are preferred pharmacokinetic properties and it can be expected that in vivo they have the decree, the mice 20 mg/kg of the compounds of formula I after 10 min after injection equal to 4 µg/ml of blood and above. Further, by oral administration of 120 mg/kg of the compounds of formula I concentration after 90 min is about the same high or higher than the above-mentioned ED90.

Determining the level in blood is carried out, for example, as follows: the compounds are dissolved in an organic solvent like dimethyl sulfoxide (DMSO). The solution oksipropil-b-cyclodextrin (20 wt./volume) in water is added up to obtain the desired concentration of biologically active substances (for example, 2 mg/ml for parenteral injection, 12 mg/ml for oral administration) at the same time establishing a DMSO concentration of 5 (by volume). Compounds that, under these conditions, insoluble, parenteral entered only intraperitonal; soluble compounds additionally intravenously. After the introduction of compounds (for example, 20 mg/kg intravenously or intraperitoneally, or 120 mg/kg orally) at different points in time, for example after 10 min, parenteral or after 90 min when administered orally, take away the blood. At the time use the blood of three mice and either for each mouse individually, any of the three United blood samples of three mice, after the addition of solvent, for example Azevedo substance is determined using LC, for example, on a column of Nucleosil5C18length of 120 mm and a diameter of 4.6 mm using a mixture or 60 acetonitrile (40 water) 0,05 triperoxonane acid (by volume), or 50 acetonitrile (40 water) 0,05 triperoxonane acid (by volume) as the eluting means when the speed of the expiration of 1 ml/min and the detection and quantification at 200 nm.

Another object of this invention is a method of obtaining the compounds of formula I consists in the fact that the carboxylic acid of the formula:

< / BR>
or its reactive derivative,

where R1denotes hydrogen, (lower alkoxy)-carbonyl, benzofuranyl, pyridylcarbonyl, morpholinylcarbonyl, tetrahydroisoquinoline, morpholinomethyl or N-(pyridylmethyl)-N-methylaminoethanol;

B1means a connection or a divalent radical of the amino acids valine, N-end of which is connected with R1, a C-end amino group on the carbon atom bearing R2CH2-; R2and R3independently of one another denote phenyl or cyclohexyl, and phenyl may be substituted in p-position Deputy, selected from lower alkoxyl, halogen, trifloromethyl and ceanography, condenses with the amino compound of the formula:

< / BR>
3
O)Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe and Val-Tyr, N-end associated with the group-C=O and C-end with a group NR4R5and R4and R5together with the connecting nitrogen atom denote thiomorpholine or morpholino, and free functional groups in the source compounds of formulas VI and VII, with the exception of participating in the reaction, if necessary, are in protected form, and, if desired otscheplaut existing protection group.

The compounds of formula I or derivatives thereof with a protected hydroxyl group, and salts of such compounds with at least one salt-forming group can be obtained by other known methods, for example:

a) to obtain compounds of the formula:

< / BR>
where R1is specified for compounds of the formula I R1besides hydrogen; hydroxyl group on the carbon atom which is adjacent to the carbon atom bearing the remainder R2-CH2- free or in protected form, and the remaining residues have the above for compounds of formula I values

carboxylic acid of the formula: R'1OH (II);

or a reactive derivative of this acid, where R'1has the same meaning as R1in the m derivative, where the residues have the above for compounds of formula I values, and the source compounds of formulas II and III free functional groups, with the exception of participating in the reaction are protected, if necessary, form, and desirable in the case of having a protective group otscheplaut, or

b) to obtain compounds of the formula:

< / BR>
where B'1refers to the same residues as B1in the compounds of the formula I, in addition to communication; a hydroxyl group at the C-atom which is adjacent to the carbon atom bearing the remainder R2-CH2- free or in protected form, and the remaining residues have the above for compounds of formula I values

carboxylic acid of the formula: R1-B'1-OH (IV) or its reactive derivative of this formula, where R1is specified for compounds of formula I value, and B'1first of all these last values condense with aminoguanidinium formula:

< / BR>
or its reactive derivative, where the residues have the above for compounds of formula I value, with free functional groups in the original materials of the formulae IV and V, except for participating in the reaction, by whom or

to obtain compounds of the formula:

< / BR>
where A'1and A'2have the value of A1and A2in the compounds of formula I, where A'1not , however, indicates no relationship and a peptide bond between A'1and A'2is not restored in the form of; a hydroxyl group at the C-atom which is adjacent to the bearing residue R2-CH2the carbon atom in free or protected form, and the other residues have the above for compounds of formula I value carboxylic acid of the formula:

< / BR>
or its reactive derivative, where the residues have the above values, condense with aminoguanidinium formula:

< / BR>
or its reactive derivative, where the residues have the above values, and free functional groups in the original materials of formulas VIII and IX, with the exception of participating in the reaction, are in protected form, and desirable in the case of existing protective group otscheplaut, or

d) a carboxylic acid of the formula:

< / BR>
or its reactive derivative, where the residues have the above for compounds of formula I value condense with aminoguanidinium formula:

< / BR>
or its reactive progroup in the source materials of formulas X and XI, except for participating in the reaction, if necessary, are in protected form, and desirable in the case of existing protective group otscheplaut; or

d) the compound of the 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/or, if desired, from one of the presented methods a) and b) compound of the formula I with at least one salt-forming group is transferred to its salt and/or obtained Sol was transferred into the free compound or into another salt and/or, if necessary, the mixture of isomers of compounds of formula I are separated and/or proposed according to the invention the compound of formula I is converted into another, according to the invention, the compound of formula I.

The above methods are described in more detail below.

Method (a) (Obtaining amide bond).

In the original materials of formulas II and III functional groups, except groups that should take part in the reaction or no reaction in the reaction conditions, independently of each protected by a protective group. Prov. to avoid in a particularly carboxy-, amino - and hydroxy-groups are in particular such protective groups, which are usually used for the synthesis of peptide compounds, and also of cephalosporins, penicillins and derivatives of nucleic acids and sugars. These protective groups can be present already in the previous stages and must protect the respective functional group from undesired side reactions, such as acylation, esterification to esters and ethers, oxidation, solvolysis, etc., In certain cases, moreover, the protective group is called selective, for example, stereoselective, the course of interactions. Typical protective groups is that they are easily, i.e. without undesired side reactions, hatshepsuts, for example, by solvolysis, recovery, photolysis or enzyme, for example, under physiological conditions. Protective groups, however, can also exist in the target substances. The compounds of formula I with protected functional groups may have a higher metabolic stability, or improved pharmacological properties than the corresponding compounds with free functional groups. Appropriate connections with the protected groups, napaea due to enzymatic degradation, for example, by esterases.

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. "Prorective Groups in Organic Chemistry" Plenum Press. London and new York. 1973; Th. W. Greene, "Protectice Groups in Organic Synthesis". Wiley. New York. 1981; "The Pepdides" so 3 (E. Gross and J. Meienhofer, Herausg), Academic Press. London and new York, 1981; in the "Methods of organic chemistry". Houben-Weyl, 4th ed. so 15/1 ed. Georg Thime Stuttgart, 1974, N.-D. Jakubre and N. Jescheit "Aminosauren, Peptide, Proteice" ed. Chemie Weinheim, Deerfield Basel 1982; and Jochen Lehmann "Chemie der Kohlenhydrate: Monosaccharide und Derivate ed. Georg Thieme. Stuttgart, 1974.

The carboxyl group is, for example, is protected in the form of ester groups, which under mild conditions selectively cleaved. To protect the carboxyl group in the first place tarifitsiruetsya to ester thanks a lower alkyl group, in which 1-position of the lower alkyl groups or branched in the 1 - or 2-position a lower alkyl group substituted by suitable substituents.

Protected carboxyl group, which etherification to ester due to the lower alkyl group represents, for example, methoxycarbonyl or etoxycarbonyl.

Protected carboxylase branched alkyl groups, represents, for example, tert.-(lower alkoxy)-carbonyl, for example tert-butoxycarbonyl.

Protected carboxyl group, which etherification to ester at the expense of lower alkyl groups, which in 1 - or 2-position a lower alkyl group substituted by suitable substituents and represents, for example, arylethoxysilanes with one or two aryl residues, where aryl represents unsubstituted or mono-, di - or tizamidine, for example, by lower alkyl, for example tert.-(lower alkyl) as tert.-butyl, lower alkoxyl, for example, methoxy; hydroxyl; halogen, for example chlorine, and/or nitro-group is phenyl; 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; then esterified to complex ester of a lower alkyl group carboxyl, the lower alkyl group in the 1 - or 2-position is substituted by suitable substituents, 1-lower alkoxy-lower alkoxycarbonyl, such as methoxyethoxymethyl, 1-methoxyethoxide the l or 1-ethyldiethanolamine, roulettecasino, where the aryl group is an if necessary substituted, e.g. by 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, each, if necessary substituted, for example lower alkyl, lower alkoxyl, aryl, halogen and/or nitro-group, aliphatic, analiticheskii, cycloaliphatic or aromatic hydrocarbon residue, 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)-cillatokiohotel, for example 2-trimethylsilylethynyl or 2-(di-n-butyl-methyl-silyl)-etoxycarbonyl or 2-triarylsulfonium as trivinylcyclohexane.

The carboxyl group can be protected in the form of organic siliconecable group. Organic similarcaterpillar group, for example, is a tri-(lower alkyl)-C which may also be substituted by two lower alkyl groups, for example methyl groups, and amino - or carboxypropyl second molecule of formula I. Compounds with such protective groups can be obtained, for example, using dimethylchlorosilane as cilleruelo tools.

The carboxyl group is protected in the form of internal complex ester with a suitable distance, for example --in position to the carboxyl group in the molecule a hydroxyl group, i.e., in the form of a lactone, preferably --lactone.

Protected carboxyl group preferably represents a tert. -(lower alkoxy)-carbonyl, for example tert.-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 9-fluorenylmethyl or diphenylmethylene, or protected in the form of a lactone, in particular-lactone, carboxyl group.

Protected amino group protected by a protective for the amino group, for example, in the form of acylamino, arylmethylidene-etherified to simple ester mercaptamine-, 2-acyl-(lower ALK-1-enyl)-amino - or silylamine or sidegroup.

In alluminare acyl is, for example, acyl residue of an organic carboxylic acid, for example, with the number of C-atoms by plateu acid or, if necessary, replaced, for example, by halogen, lower alkoxyl or nitrogroup, benzoic acid, or preferably an incomplete complex ester of carbonic acid. Such acyl groups are preferably lower alkanoyl as formyl, acetyl, propionyl or pivaloyl; halogen-(lower alkanoyl); for example, 2-halogenoacetyl as 2-chloro-, 2-bromo-, 2 -, iodine-, 2,2,2-Cryptor 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 a substituted 1 - or 2-position suitable way lower alkoxycarbonyl, for example tert.-(lower alkoxy)-carbonyl, as tert.-butoxycarbonyl; arylethoxysilanes with one, two or three aryl residues, which, if necessary, represent mono - or polyamidine, for example, lower alkyl, especially tert.-lower alkyl as tert.-butyl, lower alkyl as methoxy, hydroxyl, halogen such as chlorine, and/or nitro-group is phenyl, for example, benzyloxycarbonyl, 4-nitrobenzenesulfonyl diphenylcarbinol, 9-fluorenylmethoxycarbonyl, or di-Oh substituted if necessary, 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, 2-(tizamidine silyl)-(lower alkoxy)-carbonyl, for example 2-tri-(lower alkyl)-silyl-(lower alkoxy)-carbonyl, 2-trimethylsilylethynyl, or 2-(di-n-butyl-methyl-silyl)-etoxycarbonyl, or triallelic-(lower alkoxy)-carbonyl, for example 2-trivinylcyclohexane.

In kilmacanogue, for example mono-, di - or, in particular, triarylmethane, aryl residues are, in particular, if necessary substituted phenyl residues. Such groups are, for example, benzyl, diphenylmethyl - or, in particular, triphenylethylene.

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

As used in kachestvennymi the remainder of the lower alkenylboronic acid, if necessary substituted, for example, lower alkyl like methyl or tert.-butyl, lower alkoxyl as methoxy, halogen such as chlorine, and/or nitrogroup, benzoic acid, or, in particular, incomplete complex ester of carbonic acid, as a part of the lower alkilany ester of carbonic acid. Suitable protective groups are primarily 1-(lower alkanoyl)-(lower ALK-1-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)-carbonero-1-EN-2-yl, as 1-ethoxycarbonyl-1-EN-2-yl.

Silylamine is, for example, tri-(lower alkyl)-silylamines, for example, trimethylsilane or tert.-butyldimethylsilyl. Silicon atom of silylamines may also be substituted by two lower alkyl groups such as methyl groups, and the amino group or carboxyl group of the second molecule of formula I. Compounds with such protective groups can be obtained, for example, using the corresponding CHLOROSILANES, as dimethylchlorosilane.

The amino group can be protected by transfer in protonated form; as appropriate anions take in halogenation acids, for example, chlorine - or bromanion, or organic sulphonic acids, such as p-toluenesulfonic acid.

Preferred protective for amino groups groups are lower alkoxycarbonyl, phenyl-(lower alkoxy)-carbonyl, fluorenyl-(lower alkoxy)-carbonyl, 2-(lower alkanoyl)-lower ALK-1-EN-2-yl, or lower alkoxy-(carbonyl-lower ALK-1-EN-2-yl), particularly preferably tert.-butoxycarbonyl or benzyloxycarbonyl.

The hydroxyl group may be protected, for example, acyl group, for example unsubstituted or substituted with halogen such as chlorine, lower alkanoyl as acetyl or 2,2-dichloroacetyl, or, in particular, specified for a protected amino acyl residue of incomplete complex ester of carbonic acid. Preferred protective for hydroxyl group is, for example, 2,2,2-trichlorocyanuric, 4-nitrobenzenesulfonyl, diphenylmethylene or triphenylmethyl. Hydroxyl group, then, may be protected by tri-(lower alkyl)-Sillam, such as trimethylsilyl, triisopropylsilyl or tert.-butyldimethylsilyl; easy useplease simple ether group, such as alkyl group as tert.-lower alkyl, for example tert.-butyl; in particular, 2-oxa - or 2-teamocil, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa - or 2-thiacyclohexane from 5 to 7 atoms in the cycle, as 2-tetrahydrofuranyl or 2-tetrahydropyranyl, or appropriate thioanalogues, and 1-phenyl-(lower alkyl) benzyl, diphenylmethyl or triphenylmethyl, and phenyl residues can be substituted, e.g. by halogen such as chlorine, lower alkoxyl, for example, methoxy, and/or nitrogroup.

Two available in the molecule, in particular, neighboring hydroxyl group or a neighboring hydroxyl and amino groups can be protected, for example by 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 lower alkylidene as isopropylidene, cycloalkylation as cyclohexylidene, carboxylic group or benzylidene.

In the neighboring position to the carboxyl group, hydroxyl group can be protected by forming a complex internal ester (lactone), in particular-lactone.

Preferably protected hydroxyl group protected tri-(lower alkyl)-silicom or group for example, carboxyl can be used easily derived from the protected functional groups, for example carboxyl groups, which are suitable, for example, for the synthesis of Merrifield. Such suitable polymer carrier is, in particular, weakly crosslinked by copolymerization with divinylbenzene polistirolnoj resin, which is suitable for reversible binding bridge group.

Carboxylic acids of formula II are either with a free carboxyl group, or its reactive derivative, for example, as derived from the free carboxyl compounds of the activated complex of the ether, in the form of a reactive anhydride, or, further, in the form of a reactive cyclic amide. Reactive derivatives can also be formed in situ.

Activated esters of compounds of the formula II c a carboxyl group are particularly unsaturated at the linking carbon atom tarifitsiruemih balance esters, such as vinyl ester, as a complex vinyl ether (obtained, for example, by transesterification of the corresponding complex ester with vinyl acetate; method Akti is testwuide acid using isoxazolines reagent; 1,2-oxazole or Woodward method) or 1-(lower alkoxy)-vinyl ester is obtained by treatment of the appropriate acid (lower alkoxy)-acetylene; ethoxyacetylene method (or esters amidnogo type as N,N'-disubstituted amicinemici) by treatment of the corresponding acid to the corresponding N,N'-disubstituted by a carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbodiimide method (or N,N'-disubstituted amidinov esters (obtained, for example, by treating the appropriate acid, N, N'-disubstituted-cyanamide; cyanamide method); suitable complex aryl esters, in particular substituted electroanatomic substituents difficult phenyl esters (obtained, for example, by treating the appropriate acid corresponding suitable substituted phenol, for example 4-NITROPHENOL, 4-methylsulfinylphenyl, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazonium, in the presence of a condensing means, as N,N'-dicyclohexylcarbodiimide; the method of the activated complex aryl ether); cyanomethylene esters (obtained, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a base; method canotilho is, is false the phenyl thioethers (obtained, for example, by treating the appropriate acid with the assistance, if necessary, replaced, for example, a nitrogroup, thiophenols, among other things, with anhydrite or carbodiimide method; the method of the activated complex Colnago ether (or, in particular, complex amines or amidoamine) are obtained, for example, by treating the appropriate acid N-oxyamino - or N-acetamidocinnamic, for example, as N-oxysuccinimide, N-oxopiperidine, N-acceptilation, imide, N-hydroxy-5-norbornene-2.3-dicarboxylic acid, 1-oxybenzoates or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example, anhydrous or carbodiimide method; the method of the activated complex N-oxyethira). Also used internal esters, for example --lactones.

Anhydrides of acids may be a symmetric or preferably mixed anhydrides of these acids, for example anhydrides with unlimited acids, as galodamadruga acids, especially acid chlorides (obtained, for example, by treating the corresponding acid with thionyl chloride, pentachloride phosphorus or oxalylamino; method carboxylic acid); azides (obtained, for example, and the; azide method), anhydrides with partial esters of carbonic acid, for example lower alkyl partial esters of carbonic acid (obtained, for example, by treating the appropriate acid complex lower alkilany ether Harborview acid or 1-(lower alkoxy)-carbonyl-2-(lower alkoxy)-1,2-dihydroquinoline; method of mixed anhydrides O-alkylphenol acids (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 (for example, those that can be obtained with phenyl-N-phenyltetrahydropyridine or by transformation of amides alkylphosphoric acid in the presence of anhydrides of sulfonic acids and/or reducing racemization additives, as the N-oxybenzoates, or in the presence 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, if necessary, substituted halogenate, pavlinovoi acid or triperoxonane acid; method of mixed anhydrides of carboxylic acids, or with organic sulfonic acids (obtained, for example, by treating a salt, such as alkali metal salt, of the corresponding acid with a suitable organic halogenerator sulfonic acids as the acid chloride (lower alkane - or aryl-sulfonic acids, for example, metanil p-toluene-sulfo-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 symmetrical anhydrides).

Suitable cyclic inorganic salts are, in particular, amides with five-membered deathcycle aromatic character as amides with imidazoles, for example imidazole (obtained, for example, by treating the corresponding acid with N,N'-carbodiimide; imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtained, for example, via acid hydrazide due to the treatment with acetylacetone; pyrazolidine method).

As mentioned, derivatives of carboxylic acids, which are used as Alliluyeva funds may also be processed in situ. So is ormula III and used as Alliluyeva funds acid of formula II is administered in the interaction in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N'-cyclohexylcarbodiimide, for example, in the presence of a suitable base, like triethylamine. Complex amino - or amidoamine using as Alliluyeva funds acids can be obtained in the presence of Alliluyeva starting material of formula III thus a mixture of the corresponding starting compounds acids and amino compounds injected into the interaction in the presence of N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, and N-oxyamino or N-acetamide, for example N-oxysuccinimide, if necessary in the presence of a suitable base, for example 4-dimethylaminopyridine. Further, activation in situ can be achieved by introducing into the interaction with N,N, N', N'-tetraalkylammonium compounds, such as O-benzotriazol-1-yl-N,N,N', N'-tetramethylpropylenediamine. Finally, the anhydrides of phosphoric acid, carboxylic acids of formula II in situ, you can get what 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, such as tetrafluoroborate sodium, or other derivative hexamethylphosphorotriamide as benzotriazol-1-yloxytris-(demethylases.

The amino compounds of formula III, which takes part in the reaction, preferably contains at least one reactive hydrogen atom, particularly when reacting the carboxyl group is in reactive form; however, it also can be derivatisation, for example, by reaction with postiton as diethylphosphate, 1,2-phenylenecarbonyl, ethyldichloroarsine, ativanklonopin or tetraethylpyrophosphate. Derivatives of such compounds with amino group is, for example, galoyanized carbamino acid, and participating in the reaction of the amino group substituted by halogenocarboxylic, such as chlorocarbonyl.

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

The concentration of free carboxylic acid with the corresponding amine can be performed preferably in the presence of a conventional condensing means. Normal andproper)-carbodiimide or especially dicyclohexylcarbodiimide, next, suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazole-3'-sulfonate and 2-tert.-butyl-5-methylisoxazole, or suitable acylaminorhodanines, for example 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, N, N,N',N'-tetraalkylammonium compounds as O-benzotriazole-N, N,N, N'-Tetra-methylenedioxyphenethyl, then activated derivatives of phosphoric acid, for example diphenylphosphoryl, diethylphosphoramidite, phenyl-N-phenyltetrazole, the acid chloride of bis-(2-oxo-3-oxazolidinyl)-phosphinic acid or 1-benzotriazolyl-Tris-(dimethylamino)-fosfodiesterasa.

Similarly, as in the case called for the condensation of carboxylic acids of the formula II type reactions, also sulfonic acids of the formula II c end sulfonyloxy group by condensation with compounds of formula III can be converted to the corresponding sulfonamides of formula IB.

For example, you can use the activated esters of sulfonic acids, for example, relevant, especially substituted by nitro groups, aryl complex esters, as difficult phenyl esters, and amine component of the formula IB can also be used in the form and what about the metal nitrogen-containing heterocycles, for example pyrrole potassium.

Further it is possible to use reactive anhydrides, such as, for example, corresponding to the symmetric (obtained, for example, by reaction alkylsulfonyl silver salts with alkylsulfonamides) or preferably asymmetric anhydrides of the acids, for example anhydrides with inorganic acids, as sulphonylchloride, especially sulphonylchloride (obtained, for example, by reacting the corresponding sulfonic acids with inorganic acid chlorides of the acids, for example thionyl chloride, sulfurylchloride or pentachloride phosphorus), organic carboxylic acids (obtained, for example, by processing guledagudda sulfonic salt of carboxylic acid, as a salt of an alkali metal, similar to the above described method of obtaining the mixed anhydrides of acids) or azides (obtained, for example, from the corresponding carboxylic acid and of sodium azide or via the corresponding hydrazide and by treatment with nitrous acid, the same as the above azide method).

If desired, add organic base, such as tri-(lower Alcide)-amine with bulky residues such as ethyldiethanolamine, and/or geterotsiklicheskikh activated esters, reactive anhydrides or reactive cyclic amides to the corresponding amines is carried out usually in the presence of an organic base, 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 also apply 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, such as carbonates, ammonium or alkali metal or ammonium bicarbonates or alkali metals, such as sodium carbonate or potassium or sodium bicarbonate or potassium (usually together with a sulfate); the reaction of golodnikov sulfonic acids as the acid chlorides of sulfonic acids can be carried out in the presence of hydroxides such as hydroxides of alkali metals such as sodium hydroxide or potassium.

The carboxylic acid anhydrides, for example, produced by acid of formula II, in particular derivatives harpalinae acid, is condensed with the appropriate amines, preferably in the presence of an organic amine, for example the above three(SS="ptx2">

The condensation is carried out preferably in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example in amide carboxylic acids, such as formamide or dimethylformamide; halogenated hydrocarbon, such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic simple ether, for example tetrahydrofuran, complex ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures of them, if necessary, at reduced or elevated temperature, for example in the temperature range from about -40oWith approximately 100oC, preferably at about -10 +50oWith and without inert gas or in an atmosphere of inert gas, for example nitrogen or argon.

You can also use 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 the basis, if necessary, you can also add acetone.

The condensation can be carried out according to known for solid-phase synthesis method, which is carried out by R. Merrifield, which is described, for example, in Angew. Chem. 97, 801 812 (1985), Naturw functional groups in the resulting compounds of the formula I with protected functions if necessary, carry one or more, specified in method e) methods.

Method b). Getting amide bond.

In the original materials of the formula IV and formula V functional groups except groups that should participate in the reaction or no reaction in the reaction conditions, independently from each other, protected by a protective group.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactive derivatives and used for condensation methods are completely similar to those described in option (a) to obtain the amide bond, based on the compounds of formulas II and III, if, instead of the specified carboxylic acids of formula II using the compounds of formula IV and instead of the amino compounds of formula III using the compounds of formula V.

The release is protected by protective groups for functional groups in obtaining the compounds of formula I with protected functions carried out if necessary by one or more specified in option e) methods.

The way in). Getting amide bond.

In the original materials of the formula VI and VII functional groups, except groups that should take part in the reaction or do not respond free carboxylic acids and their reactive derivatives, free amines and their reactive derivatives and used for condensation methods are completely similar to those described in method a) to obtain the amide bond, based on the compounds of formulas II and III, if, instead of the specified carboxylic acids of the formula II used such formulas VI and instead of the amino compounds of formula III using any formula VII.

The release is protected by protective groups for functional groups in the resulting compounds of the formula I with protected functions carried out if necessary by one or more specified in option e) methods.

Method g). Getting amide bond.

In the original materials of the formulae VIII and IX functional groups, except groups that should take part in the reaction or no reaction in the reaction conditions, independently from each other, protected by a protective group.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactive derivatives and used for condensation methods similar to those described in method a) to obtain the amide bond of the compounds of formulas II and III, if, instead of the specified carboxylic acids of the formula IItx2">

The release is protected by protective groups for functional groups in the resulting compounds of the formula I with protected functions carried out, if necessary, for one or more specified in option e) methods.

Method d). Getting amide bond.

In the original materials of formulas X and XI functional groups, except groups that should take part in the reaction or no reaction in the reaction conditions, independently from each other, protected by a protective group.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactive derivatives and used for condensation methods are completely similar to those described in method a) to obtain the amide bond, based on the compounds of formulas II and III, if, instead of the specified carboxylic acids of formula II using the compounds of formula X and instead of the amino compounds of formula III using the compounds of formula XI.

Reactive derivatives of such compounds of formula XI with the amino group are its predecessors, such as isocyanate, which is involved in the reaction of the amino group converted into isocyanate group, and the last is th groups have a hydrogen atom.

The release is protected by protective groups for functional groups in the resulting compounds of the formula I with protected functions carried out if necessary by one or more specified in option e) methods.

Method e). Cleavage of the protective groups.

Cleavage of the protective groups that are not an integral part of the desired target product of the formula I, for example, protective for carboxyl, amino and/or hydroxyl groups is in itself known, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by recovery, especially hydrogenolysis or by recovery, especially hydrogenolysis or with other reducing agents, as well as photolysis, if necessary Paladino or simultaneously. Cleavage of the protective groups, such as described in the above in the beginning of section "Protective group" standard works.

So, for example, protected carboxyl, for example tert.-(lower alkoxy)-carbonyl, 2-position is protected tizamidine silyl group or in the 1-position substituted lower alkoxyl or lower alkylthio-(lower alkoxy)-carbonyl or if necessary samisen Ravina, salt or triperoxonane acid, if necessary with the addition of nucleophilic compounds as phenol or anisole. If necessary substituted benzyloxycarbonyl you can release, for example, by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, like palladium catalyst. Further suitable manner substituted benzyloxycarbonyl as 4-nitrobenzenesulfonyl, you can translate free carboxyl by restoring, for example, by treatment with an alkaline metal, as ditional sodium, or regenerating metal, for example zinc, or by using a reducing metal salt, as salt of chromium (II), for example, chloride, chromium (II), usually in the presence emit hydrogen funds, which together with the metal can give atomic hydrogen as acids, primarily suitable carboxylic acid, if necessary substituted, e.g. by hydroxyl, (lower alkane)-carboxylic acid, for example acetic, formic, glycolic, diphenylpyraline, milk, almond, 4-chloro-almond or tartaric acid, or an alcohol or thiol, preferably water is added. By processing through the reduction of the 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 be split by treatment with a nucleophilic, preferably salt-forming reagent, as thiophenolate sodium or sodium iodide. 2-(Tizamidine silyl) (lower alkoxy)-carbonyl you can translate free carboxy by treatment with giving fluoride anion salt of hydrofluoric acid, as a fluoride of an alkali metal such as sodium fluoride or potassium, if necessary, in the presence of a macrocyclic polyether ("crown ether"), or by using a fluoride of an organic Quaternary base, as Tetra-(lower alkyl)-unmonitored or tri-(lower alkyl)-aryl-(lower alkyl)-monitored, such as 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, such as trimethylsilylacetamide, carboxyl to be released in the usual way convolutions, for example by treatment with water, alcohol or acid or, alternatively, fluoride, as described above. Protected internal of ester, in the form of lactone, carboxyl can wysw the metal, for example NaOH, KOH or LiOH, especially LiOH, and simultaneously released, respectively, a protected hydroxyl group.

Protected amino group known release and depending on the kind of protected groups in a variety of ways, preferably by means of solvolysis or recovery. (Lower alkoxy)-carbylamine as tert.-butoxycarbonylamino, it is possible to decompose in the presence of acids, for example inorganic acids, such as galgenwaard as florodora or Pomodoro, or phosphoric acid, preferably of florodora, in polar solvents, such as water, or carboxylic acids, as acetic acid or ethers like dioxane; 2-halogen-(lower alkoxy)-carbylamine-group), 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. Rolecontroller can also be split by treatment with a nucleophilic, preferably salt-forming reagent, as thiophenolate sodium, and 4 nitrobenzisoxazole by processing dithionite alkaline IU the s alkoxy)-carbylamine or 2-(tizamidine silyl)-(lower alkoxy)-carbylamine, as 2-tri-(lower alkoxy)-silyl-(lower alkoxy)-carbylamine, can be freed by treatment with suitable acids, for example formic or triperoxonane acid; and, if necessary, replaced benzyloxycarbonylamino, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, as paradiesvogel catalyst, preferably in polar solvents, such as di-(lower alkyl)-(lower alkanoyl)-amides, for example dimethylformamide, ethers, as cyclic ethers, for example dioxane, or alcohols, as methanol, ethanol or propanol, and particularly preferred methanol; if necessary, replaced triarylmethane or formylamino, for example, by treatment with acids, for example inorganic acids, for example chlorotalonil acid, or organic acids, for example formic, acetic or triperoxonane acid, if necessary in the presence of water; and protected in the form of silylamine the amino group, for example, by means of hydrolysis or alcoholysis. Protected 2-halogenation, for example 2-chloroacetyl, the amino group can be freed by treatment with thiourea in the presence of osmoles or hydrolysis, the resulting product substitution. Protected 2-(tizamidine silyl)-(lower alkoxy)-carbonyl, 2-tri-(lower alkyl)-silyl-(lower alkoxy)-carbonyl, amino group also can be converted to a free amino group by treatment with giving floridamiami salt of hydrofluoric acid, as described above in connection with the release, respectively, the protected carboxyl group. Likewise, you can directly associated with heteroatoms as nitrogen, silyl as trimethylsilyl, to split with fluoride ion.

Protected in the form of sidegroup the amino group, for example, by restoring translate into a free amino group, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst as platinum oxide, palladium or Raney Nickel; by restoring using merkaptosoedineny as dithiothreitol or mercaptoethanol, or also by treatment with zinc in the presence of acid, for example acetic acid. The catalytic hydrogenation is carried out preferably in an inert solvent, as a halogenated hydrocarbon, for example methylene chloride, or also in water or mixtures of water with organic solvent, as with alcohol or dioxane group, tri-(lower alkyl)-silyl group or, if necessary, substituted 1-phenyl-(lower alkyl) group, a hydroxyl group released similarly correspondingly protected amino group. Protected 2,2-dichloroacetyl hydroxyl group is released, for example, by basic hydrolysis; protected tert-lower alkyl or 2-okaili 2-thia-aliphatic or-cycloaliphatic hydrocarbon residue hydroxyl group is released by acidolysis, for example by treatment with an inorganic acid or a strong carboxylic acid, for example triperoxonane acid. Two hydroxyl groups or neighboring amino and hydroxyl groups which are secured together by divalent protective group, preferably, for example, one or dvojklicnoliste lower alkyl methylene group as the lowest alkylidene, for example isopropylidene, cycloalkylation, such as cyclohexylidene, or benzylidene, can be released through acid solvolysis, especially in the presence of an inorganic acid or a strong organic acid. Tri-(lower alkyl)-silyl group is also cleaved by acidolysis, for example, with inorganic acid, preferably the through the above restoration, for example, the regenerating metal, as zinc, reducing metal salts, such as salts of chromium (II), or due to sulphur compounds, such as dithionite sodium or preferably the sodium sulfide and carbon disulfide. Esterified to esters of hydroxyl group, for example (lower alkanoyl)-oxypropyl as acetoxy, can also be released by using esterase; acylated amine, for example, through suitable peptidases.

The temperature for the release of protected functional groups are preferably from -80oWith up to 100oS, particularly preferably from -20oC to 50oWith, for example, when 10 35oC, preferably at room temperature.

If there are several protected functional groups, if desired, can be protective group to choose so you can split more than one such group, for example, acidulating by processing triperoxonane acid, or with hydrogen and a hydrogenation catalyst, as the catalyst is palladium-on-charcoal grill. On the contrary, the group may also be selected so that they could be chipped off, not all at the same time and in the desired sequence, and get to meet the R method, which are desirable in the case, the functional group of the parent compounds, which should not participate in the reaction, can be unprotected or protected form, for example by one or more specified above in method (a) protective groups. The protective group can be stored in the target products or fully or partially chipped off according to one of the above in method (e) methods.

Mixtures of stereoisomers, and therefore a mixture of diastereomers and/or enantiomers, such as racemic mixtures, in itself known manner can be divided into the respective isomers by means of suitable methods of separation. Thus, mixtures of diastereomers can be divided by fractional crystallization, chromatography, distribution between solvents, etc., to separate the diastereomers. The racemates after transferring the optical antipodes in the diastereoisomers, for example, by introducing into interaction with optically active compounds, for example, optically active acids or bases, can be divided by chromatography, by selective conversion of only one of the two enantiomers. This separation can be performed both on stage one of the initial products is owned by the group is free and is associated with the C-atom, which is adjacent to the bearing residue R2-CH2-carbon atom, by introducing a protective group as described above in method (a) free hydroxyl group can be converted to esterified to complex ester hydroxyl group type (lower alkanoyl)-hydroxy as acetoxy. The etherification to complex ether is carried out as shown in method a) condensation to amides, and instead amino-components reacting a hydroxyl group. The reaction is preferably carried out under similar conditions as described in method a), in particular in the application (lower alkanoyl)-anhydride, such as acetanhydride, for the formation of the corresponding (lower alkanoyl)-oxypropyl, in an organic solvent, for example a simple cyclic ether like tetrahydrofuran, in the presence of cyclic tertiary amine, as dimethylaminopyridine, and/or tri-(lower alkyl)-amine like triethylamine, at temperatures from 0oWith up to the temperature of the reaction mixture, in particular at 10 30oC.

In the compound of formula I of the existing protective group or suitable residues R1except for hydrogen, can be split for any of the above in method (e) methods, in particular by hydrolysis, e.g. the anhydrous solvents, in particular ethers like dioxane, at temperatures from -50oC to the boiling temperature under reflux respective reaction mixtures, for example at 0 to 59oC, preferably in the presence of inert gas, e.g. argon or nitrogen.

In the compound of formula I in which at least one of the residues R2or R3denotes a phenyl group and/or one or more residues of the B1, A1or A2represents phenylalanine, and phenyl residues also, depending on the circumstances, as described above, can be replaced by the corresponding phenyl residue or the corresponding phenyl residues, for example, can be selectively recovered in the appropriate tsiklogeksilnogo residues, such as gidrirovanii. The hydrogenation carried out preferably in the presence of a catalyst which allows the hydrogenation of double bonds in the presence of peptide bonds, in particular catalyst from heavy metal oxides as catalyst Rh/III/Pt/IV/oxide according to Nishimura (S. Nichimura, Bull. Che, Soc. Japan 33, 566 (1960), in suitable solvents, particularly in water, alcohols like methanol or ethanol, esters like ethyl acetate, or ethers like dioxane, for example is at hydrogen pressures of 1 to 50 bar, for example, at normal pressure.

The exercise of such options, which come from the obtained at any stage in the form of intermediate compounds and implement the missing stage or a way to break off at any stage or initial substance obtained when the reaction conditions or is used in the form of a reactive derivative or salt, or obtained by the proposed in the invention method, the connection will get in terms of method and further processed in situ. Thus preferably extend from such starting substances, which lead to compounds that are described above as preferred.

Pharmaceutical drugs.

The invention allows to obtain pharmaceutical preparations containing the compounds of formula I.

Pharmacological applicable compounds of the invention can be applied, for example, to obtain pharmaceutical preparations which contain an effective amount of biologically active substance together or in mixture with substantial amounts of inorganic or organic, solid or liquid, pharmaceutically applicable carrier.

The pharmaceutical preparations can be Opole, the introduction of warm-blooded animals (humans and animals), which contain an effective dose of pharmacological biologically active substance as such, and with the significant amount of pharmaceutically applicable carrier. The dose of the biologically active substance depends on the state, individual pharmacodynamic data, treatable diseases, and also as a way of introduction.

You can use these pharmaceutical preparations for the treatment caused by the retrovirus diseases, such as AIDS, especially when HIV-1 causes disease. This involves a therapeutically effective amount proposed in the invention compounds of formula I, particularly warm-blooded animals, for example humans, which one of these diseases, particularly AIDS, in need of such treatment. Introduced warm-blooded animals, for example humans weighing approximately 70 kg, the dose is about 3 mg to about 10 g, preferably from about 40 mg to 4 g, for example, from about 300 mg to 1.5 g per individual in a day, dividing the dose is preferably 1 to 3 times, which, for example, can be the same. The child usually gets half adult dose.

The pharmaceutical preparations contain about 1 to 95 site is e preparations can be made, for example, in the form of ampoules, vials, suppositories, pills, tablets or capsules.

Pharmaceutical drugs get in a known manner, for example by conventional methods of dissolution, freeze-drying, mixing, granulating or drazhirovanija.

Preferably apply solutions of biologically active substances, along with them, and also suspensions or dispersions, namely especially isotonic aqueous solutions, dispersions or suspensions, and, for example, in the case of lyophilised preparations which contain the biologically active substance individually or together with a base, for example mannitol, can be prepared before use. The pharmaceutical preparations can be sterilized and/or contain auxiliary substances such as preservatives, stabilizers, wetting and/or emulsifying agents, agents, dissolution, salts for regulating osmotic pressure and/or buffers, and receive them in a known manner, for example by means of conventional dissolving or lyophilization. These solutions or suspensions can include increasing the viscosity of a substance, such as sodium carboxymethyl cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suceska or semi-synthetic oils. As such, should be especially liquid esters of fatty acids as acid components contain long-chain fatty acid with 8 to 22, in particular 12 to 22 carbon atoms, for example lauric, traditiona, myristic, pentadactyla, palmitic, margaric, stearic, arachidonic, Bekenova acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, rukanova acid, brazilina acid or linoleic acid, if necessary with the addition of antioxidants, such as vitamin E, - carotene or 3,5-di-tert. -butyl-4-oxytrol. The alcohol component of these esters of fatty acids has up to 6 C-atoms and represents a one - or polyhydric, for example one-, two -, or trivalent alcohol such as methanol, ethanol, propanol, butanol or pentanol or their isomers, primarily glycol and glycerin. As esters of fatty acids so, for example, you need to call: etiloleat, isopropylmyristate, isopropyl, Labrafil M 2375" (polyoxyethyleneglycol company Gattefossr, Paris), "Miglyol 812" (triglycerin saturated fatty acids with chain length WITH8-C12the company Huls AG, Germany), CCA is continued just peanut butter.

Preparation of drugs for injection carried out in the usual manner under sterile conditions, such as filling in ampoules or vials, as well as closing the containers.

Pharmaceutical preparations for oral administration can be obtained by a combination of biologically active substances with solid fundamentals, the mixture if necessary granularit and, if desirable or necessary, after the addition of suitable excipients, processed into tablets, dragee cores or capsules, or by preparation of dispersions, preferably phospholipids, which is poured into the cups. This biologically active substances can be incorporated in the basis of synthetic material, which give them a metered or allow them to diffuse.

Suitable bases are, in particular, fillers like sugar, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, for example triphosphate calcium or phosphate of calcium, then the binder as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragant, methylcellulose, oksipropilmetiltselljulozy, carboxymethy is s; next, carboxymethyl-starch, cross crosslinked polyvinylpyrrolidone, agar, alginic acid or its salt, as sodium alginate. Auxiliary funds primarily represent 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. The kernel also supplied is suitable, if necessary resistant to gastric juice, coatings, and use concentrated sugar solutions, which, if necessary, contain gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or dioxane titanium, lacquer solutions in suitable organic solvents or, for the preparation of resistant to gastric juice coatings, solutions of suitable cellulose preparations, as ethylcellulose or oksipropilmetiltselljuloza. Capsules are detachable capsules made of gelatin, and also soft, sealed capsules of gelatin and a plasticizer, as glycerol or sorbitol. Split the capsules contain biologically active substance in the form of a granulate, for example, with fillers like lactose, a binder, as starches, and/or softeners, as talc or magnesium stearate, and SL is andirovnu preferably in a suitable oil auxiliary substances, as fatty oils, paraffin oil or liquid polyethylene glycols, and you can also add stabilizers and/or antibacterial agents. Tablets or dragee with coatings and shells of the capsules can be dyes or pigments, for example, for identification or to indicate different doses of biologically active substances.

As pharmaceuticals particularly preferred stabilized phospholipid dispersion of biologically active substances, preferably for oral administration, containing

(a) a phospholipid or more phospholipids of the formula:

< / BR>
where RArepresents C10-20-acyl, RBdenotes hydrogen or C10-20-acyl, Ra, Rband Rcdenote hydrogen or C1-4-alkyl and n denotes an integer of 2 to 4, and if desired

b) another phospholipid or more other phospholipids,

C) a biologically active substance and

d) pharmaceutically applicable liquid-based and optionally other excipients and/or preservatives.

The method of preparation of these dispersions characterized in that the solution or suspension components a) and b) or a), b) and C), preferably (a) and (b) in a weight ratio of leut, for example, by centrifugation, gel filtration, ultrafiltration or features by dialysis, for example tangential dialysis, preferably with removal of water; the resulting dispersion, preferably after the addition of excipients or preservatives, if necessary, when establishing acceptable pH values by adding pharmaceutically acceptable buffers like phosphate salts or organic acid (pure or dissolved in water), as acetic acid or citric acid, preferably pH 3 to 6, for example a pH of 4 to 5; if the variance has no need of the concentration of biologically active substances, concentrate, preferably to a concentration of biologically active substances 2 30 mg/ml, in particular from 10 to 20 mg/ml, and the concentration carried out preferably according to the above methods for removal of organic solvent, in particular by ultrafiltration, for example when using the instrument for the implementation of the tangential dialysis and ultrafiltration.

Obtained in this way, stable phospholipid dispersion is stable at room temperature for at least several hours proved relatively kalijogo use people.

The magnitude of the obtained particles in the dispersion variable and is preferably about 1.0 x 10-8about 1.0 x 10-5m, in particular about 10-7: 2 x 10-6m

The nomenclature of the phospholipids of the formula I and the numbering of atoms is guided by the data in Eur. G. of Buochem. 9,11 21 (1977) "Nomenclature of Lipids", IUPAC-IUB. Commission on biochemical nomenclature (CBN) guidelines (sn-item, stereospecific numbering).

In a phospholipid of the formula And RAand RBmatter10-20-acyl, preferably linear C10-20-alkanol with an even number of C-atoms and linear C10-20-alkanol with a double bond and an even number of C-atoms.

Linear alkanoyl with10-20, RAand RBwith an even number of C-atoms is, for example, n-dodecanoyl, n-deletion, n-hexadecanoyl or n-octadecanoyl.

Linear C10-20-alkanoyl RAand RBwith a double bond and an even number of C-atoms is, for example, 6-CIS, 6-TRANS, 9-CIS-or 9-TRANS-dodecanoyl-tetradecanoyl-hexadecanoyl-octadecenoyl or cosinor, especially 9-CIS-octadecenoyl (oleoyl).

In a phospholipid of the formula And n denotes an integer of Chisleu alkylen, for example, 1,1-ethylene, 1,1-, 1,3 - or 1,2 - or 1,3-propylene or 1,2-, 1,3 - or 1,4-butylene. The preferred 1,2-ethylene (n 2).

The phospholipids of the formula And represents, for example, natural capalini, where Ra, Rband Rcdenote hydrogen, or natural lecithins, where Ra, Rband Rcdenote methyl, for example zevalin or lecithin from soy, brain of cattle, liver cattle or chicken eggs, with different or identical acyl groups, RAand RBor mixtures thereof.

Preferred synthetic, mainly pure phospholipid of formula But with different or identical acyl groups, RAand RB.

The concept of "synthetic phospholipid of the formula And means phospholipids, which are relatively RAand RBhave a uniform composition. Such synthetic phospholipids are preferably below the lecithins and cephaline, acyl group, RAand RBhave a fixed structure and are produced from certain fatty acids with a degree of purity higher than about 95 RAand RBmay be the same or different and unsaturated. Preferably RAsaturated, for example n-hexadecanoyl, is And means phospholipids, relative to RAand RBhave no homogeneous composition. Such natural phospholipids are also lecithins and Catalina, acyl groups which RAand RBstructurally indeterminate and are made from natural mixtures of fatty acids.

The term "essentially pure" phospholipid means the degree of purity of more than 70 wt. the phospholipid of formula A, which is detected by appropriate methods for determining, for example, using paper chromatography.

Particularly preferred synthetic, essentially pure phospholipid of formula A, where RAdenotes linear WITH10-20-alkanol with an even number of C-atoms and RBdenotes linear WITH10-20-alkanol with a double bond and an even number of C-atoms. Ra, Rband Rcdenote methyl and "n" 2.

Particularly preferably the phospholipid of the formula And RAdenotes the n-dodecanoyl, n-deletion, n-hexadecanoyl or n-octadecanoyl and RBrefers to 9-CIS-dodecenyl, 9-CIS-tetradecanoyl, 9-CIS-hexadecenoic, 9-CIS-octadecenoyl or 9-CIS-cosinor. Ra, Rband Rcdenote methyl and n is 2.

Especially preferred phospholipid of the formula And avlocardyl natural, essentially pure phospholipid of the formula And are particularly lecithin (L----phosphatidylcholine from soy and eggs.

For acyl residues in phospholipids of the formula And are also given in parentheses denote: 9-CIS-dodecenyl (lowerlevel), 9-CIS-tetradecanoyl (myristoleic), 9-CIS-hexadecenoic (palmitoleic), 6-CIS-octadecenoyl (petroselic), 6-TRANS-octadecenoyl (petroselinic), 9-CIS-octadecenoyl (oleoyl), 9-TRANS-octadecenoyl (ladol), 11-CIS-octadecenoyl (vaccinal), 9-CIS-cosinor (gadoleic), n-dodecanoyl (lauroyl), n-deletion (myristyl), n-hexadecanol (Palmitoyl), n-octadecanol (stearoyl), n-emosanal (Arachidyl).

Other phospholipids are preferably esters of phosphatidic acid (3-sn-phosphatidic acid) with the specified acyl residues, as phosphatidylserine and phosphatidylethanolamine.

Sparingly soluble biologically active substances can also be in the form of a water-soluble, pharmaceutically acceptable salts, as defined above.

In liquid-based g) components a), b) and C) or a) and C) are in the form of liposomes, so that in the course of time from several days to weeks not formed any solid or twodice preferably orally.

In liquid-based g) may contain pharmaceutically acceptable, non-toxic excipients that are suitable for isotonic conditions, such as ionic additives as sodium chloride, or non-ionic additives (carisoorodol) as sorbitol, mannitol or glucose, or lactose, fructose or sucrose.

In addition to the water-soluble auxiliary substances in the liquid base can be applicable for liquid pharmaceutical forms emulsifiers, wetting or surface-active substances, in particular emulsifiers, as oleic acid, non-ionic surfactants of the type of ester of fatty acid and polyhydric polyxystra as sorbitanoleat, -oleate, -stearate or palmitate; corbettreport or trioleate; polyoxyethylene adducts esters of fatty acids with polyhydric oxyspermum as polyoxyethylenesorbitan, -oleate, -stearate, -palmitate, -tristearate or trioleate; esters of polyethylene glycol and fatty acids, as polyoxyethylene, polyethylene glycol and fatty acids, as polyoxyethylene, polyethylene glycol-400-stearate, polyethylene glycol-2000 stearate, especially copolymers telpochcalli preservatives are, for example, antioxidants, ascorbic acid, or bactericides, as sorbic acid or benzoic acid.

Raw materials

New raw materials and/or intermediates and methods for their preparation are also part of the description. Preferably use such source materials and choose the reaction conditions in such a way that they come to the above as preferred compounds.

Upon receipt of all original materials free of functional groups that should not participate in an appropriate reaction may be unsecured or may be in protected form, for example to protect the above in method (a) protective groups. These protective groups the desired times can be released by means described in method e) reactions. Compounds with salt-forming groups, depending on the circumstances, may also find application in the form of salts, and salts obtained at any stage or again converted into the free compounds.

In formulas, if the stereochemistry of the asymmetric carbon atoms is not specified directly by the adequate choice of symbols of communication, configuration of asymmetric atoms of carbon are known and are commercially available or can be obtained by known methods. For example, they can be obtained from compounds of the formula:

< / BR>
where R2specified for compounds of formula I value and Pa stands for protective amino group, in particular (lower alkoxy)-carbonyl, as tert. -butoxycarbonyl, or phenyl-(lower alkoxy)-carbonyl, as benzyloxycarbonyl that by restoring transferred to the compound of the formula:

< / BR>
where residues are indicated in the last time.

Recovery of amino acid derivatives of the formula XII to the corresponding aldehyde XII is carried out, for example, by restoring to the corresponding alcohol and subsequent oxidation to the aldehyde of formula XIII.

The recovery of alcohols carried out usually by hydrogenation of the corresponding golodnikov acids or other specified in the method (a) activated derivatives of carboxylic acids, or by introducing into the interaction of activated derivatives of carboxylic acids of compounds of formula XII, in particular anhydrides with organic carboxylic acids, preferably esters halogenarenes acid, as isobutyl ether of Harborview acid (which is preferably obtained by transformation of compounds forwardish, as cyclic ethers, for example dioxane, at temperatures from -50oWith up to 80oC, preferably at 0 to 50oC, with complex hydrides, as borhydride alkali metals, e.g. sodium borohydride in aqueous solution in the presence or in the absence of the above apply organic solvent, at temperatures from -50oup to 80oC, preferably at 0 to 50oC. Subsequent oxidation of the resulting alcohols preferably carried out with the help of such oxidizing agents that selectively convert the hydroxyl group to the aldehyde, such as chromic acid or its derivatives, as pyridinium or tert.- buildroot, bichromate (sulfuric acid, sulfur trioxide in the presence of heterocyclic bases as pyridine) SO3, di-(lower alkyl)-sulfoxidov as dimethylsulfoxide, then, nitric acid, pyrolusite or selenium dioxide, in water, aqueous or organic solvents, such as halogenated solvents such as methylene chloride, amides of carboxylic acids as dimethylformamide, and/or simple cyclic ethers like tetrahydrofuran, in the presence or in the absence of basic amines, such as tri-(lower alkyl)-amino, as triethylamine, at the UP>With, for example as described in European patent application EP-A-0 236 734.

It is also possible to direct the restoration of the compounds of formula XII aldehydes, for example, by hydrogenation in the presence of partially poisoned palladium catalyst or by restoring the appropriate esters of amino acids, such as complex lower alilovic esters as complex ethyl ester, using complex hydrides, for example, borhydride as sodium borohydride, or preferably hydrides of aluminum, for example, sociallyengaged, lithium-tri-/tert. -butoxy/-hydride or particularly diisobutylaluminium; in apolar solvents, for example hydrocarbons or aromatic solvents, such as toluene, at 100 0oC, preferably at from -70oC to -30oC, and subsequent conversion into the corresponding semicarbazone, for example, using the corresponding salts of the acids of semicarbazones as semicarbazide, in an aqueous solvent system, such as alcohol/water, for example ethanol/water, at temperatures from -20 to 60oC, preferably at 10 to 30(198>C, and the interaction of the obtained semicarbazone with reactive aldehyde, for example formaldehyde, in an inert solvent, peraturan from -30 to 60oC, preferably at 0, 30oC, and then enter into interaction with the acid, such as a strong inorganic acid, as galgenwaard, in aqueous solution, if necessary in the presence of the above-mentioned solvent, at temperatures from -40 to 50oC, preferably at (-10) (+30)oC.

The corresponding esters are obtained by the interaction of amino acids with the corresponding alcohols, for example ethanol, similarly used by condensation and in method b) conditions, for example by introducing into the interaction with inorganic halogenide acids, as thionyl chloride, in mixtures of organic solvents, such as mixtures of aromatic and alcoholic solvents, such as toluene, ethanol, at temperatures from -50oC to 50oC, preferably at from -10oC to 20oC.

Obtaining compounds of formula XIII carry out a particularly preferred manner, in the same terms as specified in J. Org. Chem. 47, 3016, 1982; J. Org. Chem. 43, 3624. 1978; or J. Org. Chem. 51, 3921 1986, the reaction conditions.

For the synthesis of compounds of formula III obtained compound of formula XIII is injected into the interaction with reactive tetraallylsilane, preferably halogene, as diethyl ether, cyclic simple ether, as dioxane, or a complex ester like ethyl acetate, at temperatures from -100oWith up to 50oC, preferably at -65oWith up to 40oC, and obtain the compounds of formula:

< / BR>
where R6, R7and R8denote lower alkyl, for example methyl, and the remaining residues have the above meanings; the compounds obtained in the presence of a Lewis acid as athirat boron TRIFLUORIDE in an inert solvent, especially a halogenated hydrocarbon like methylene chloride, followed by additional treatment with aqueous base, e.g. sodium hydroxide solution, at temperatures from -30oC to 80oC, in particular at 0, 50oWith the destruction and removal of protective groups, are taken to the olefinic compounds of the formula:

< / BR>
where R2is specified for compounds of formula I value in the corresponding olefin again enter protective for the amino group of the RA, as described in method (a) for the introduction of protective for amino groups, in particular with acid anhydride in a chlorinated hydrocarbon like methylene chloride, at temperatures from -50oC to 80oC, in particular at 0 35oC; and produces the IDE turn in oxiran, preferably stereoselective when using peroxides, in particular nadarbazevi acids, such as halogenating acid as m-chlormadinone acid, in an inert organic solvent, preferably in a halogenated hydrocarbon like methylene chloride, at temperatures from -50oC to 60oWith, in particular at from -10oC to 25oC, and must carry out the separation of the diastereomers, and get the epoxides of the formula:

< / BR>
in which the residues have the above meanings; to the corresponding olefins attach the corresponding complex fluids malonic acid, for example dimethyl malonic acid or diethyl ester of malonic acid, for example, by activating a methylene group complex diapir of malonic acid with an alkali metal, e.g. sodium, in a polar anhydrous solvent such as an alcohol like methanol or ethanol, at temperatures from -50oC to 80oC, in particular at 0 35oC, and the solution is treated with acid, such as carboxylic acid, such as citric acid; and the result is a lactone of the formula:

< / BR>
where R9indicates the lowest alkoxy, for example methoxy or ethoxy, and other estate or substituted as described for compounds of formula I, this residue to restore cyclohexyl, in particular by hydrogenation, preferably in the presence of a catalyst as oxides of noble metals, for example a mixture of oxides Ph (III) Pt (VI) (according Nichimura), preferably in polar solvents, such as alcohols, for example methanol, at normal pressure or up to 5 bar, preferably at normal pressure, at temperatures from -20oC to 50oC, preferably at 10 35oC; directly or after hydrogenation of the compounds of formula XVIII enter into interaction with introducing the remainder R3-CH2-reagent, for example of formula R3-CH2-W, where R3is specified for compounds of formula I value, and W denotes a nucleophilic delete a group selected from esterified by a strong inorganic or organic acid, hydroxyl, for example esterified with an inorganic acid, such as halogen acids, as chlorodane, bromatologia or iododerma acid, or with strong organic sulfonic acids, as, if necessary, substituted, e.g. by halogen like fluorine, (lower alkane)-acid, or aromatic sulfonic acids, supremacist, for example, methanesulfonate, trimethylsulfonium or p-toluenesulfonic acid, hydroxyl, in particular bromide; in an anhydrous polar solvent, such as alcohol, as ethanol, in the presence of an alkali metal such as sodium, at a temperature from -50oWith up to 80oC, preferably at 0 35oC; obtaining compounds of the formula:

< / BR>
where the residues have the above meanings;

the compound of formula XIX hydrolyzing and decarboxylase, for example, by hydrolysis using a base like alkali metal hydroxide such as lithium hydroxide, at temperatures from -50oC to 80oC, preferably at about 0 35oC; in an organic solvent, such as simple air, as dimethoxyethane, and subsequent decarboxylation by heating in an inert solvent, preferably a hydrocarbon such as an aromatic hydrocarbon, like toluene, at temperatures of 40 to 120oWith, preferably 70 100oC, and the obtained compound of the formula:

< / BR>
where the residues have the above meanings;

the obtained (R, S, S)- and (S,S,S)-isomers are separated by column chromatography; (R,S,S)-isomer is used next, and for disclosure lactoovo ring is injected into vzaimode the simple ether, for example dimethoxyethane, obtaining the compounds of formula:

< / BR>
where the residues have the above values,

in the received connection input a security for the hydroxyl group of Ru, for example one of the above in method (a) for protective hydroxyl groups under specified conditions, in particular tri-(lower alkyl) silyl group, with the corresponding halogen-tri-(lower alkyl)-silane, for example tert. butyldimethylchlorosilane, in a polar solvent, such as di-(lower alkyl)-(lower alkanoyl)-amide as dimethylformamide, in the presence of spatially constrained amino compounds, as a cyclic amine such as imidazole, at temperatures of -50oC to 80oC, preferably at 0 35oC, to obtain the compounds of formula:

< / BR>
where the residues have the above values, and the compounds of formula III c specified in the method (a) residues receive, for example, by condensation with the compound of the formula VII, where the remains are specified in the method) the value, if specified in the method and conditions, in particular by reaction in situ in the presence of a condensing means as benzotriazol-1-yl-oxide-(dimethylamino) -phosphodiesterasesamongst or O-benzotriazol-1-yl-N,N,N',N'-tetramethylethylene, as 1-oxybenzoates, in a polar solvent, preferably amide acid, such as di-(lower alkyl)-amino-(lower alkanoyl)-amide as dimethylformamide, at temperatures from -50oC to 80oC, in particular at 0 35oC, and by subsequent removal of the protective groups of RA, as described in method e) if the RA does not denote any corresponding radical of H1- with the above for compounds of formula I other than communication residue; condensation with the compound of the formula H1-OH, where1is specified in the method (b) values, under the above conditions, condensation and, finally, removal of Ru and/or other protective groups as described in method e). To obtain the compounds of formula III may sequential interaction of the compounds of formula XXII with compounds which introduce the radical B1-, -A1-, -A2-, -A1A2-, -A2NR4R5and/or NR4R5in the compound of formula VII.

The above compounds of formula XV also leave the residue-NH2the carbon atom can be in the (R,3)-configuration, instead of the specified (S)-configuration; compounds of formulas XII, XIII, XVI, and in particular of the formula XVII, XVII, XVIII, XIX, XX, XXI and/or leave the remainder of the RA-NH-Etoile mixture of diastereoisomers can be divided at all stages.

The compounds of formula XX, in which the residues have values that are also compounds of the formula XIII, in which the residues have the above values, the fact that aldehydes of formula XIII is administered in cooperation with esters of 2-kalogeropoulou acids, in particular esters of 2-iodopropionic acid as ethyl ester of 2-iodopropionic acid, and obtain the compounds of formula:

where the residues have the above values and where the bearing carbon atom of the residue RA-NH - alternative may be in the (R,S)-configuration.

The interaction is carried out primarily in the formation of homoeopath of ester 2-kalogeropoulou acid in the presence of a mixture of zinc with copper in the di-(lower alkyl)-(lower alkanoyl)-amide, such as dimethylacetamide, at temperatures of 0 100oC, in particular at 20 80oC. In another case, preferably in an atmosphere of inert gas, as nitrogen or argon, Tetra-(lower alkyl)-orthotitanate as tetraisopropyldisiloxane, in an aromatic solvent like toluene or xylene, in the presence of kalogeropoulou as methylene chloride, mixed with tetrachloride titanium, as titanium tetrachloride and stirred at 0 50oC, in particular at 20 to 30oC, the lowest alkylen), in particular trichlorfon-diisopropylate. To him at temperatures from -50o0oC, in particular at from -40oC, -25oC, was added dropwise a solution of homoeopath zinc and then added dropwise to the aldehyde of formula XIII in halogenougljovodonika, such as methylene chloride, and the interaction takes place at from -50o30oC, preferably at about -20oC to 5oWith the formation of ester, in particular a complex of ethyl ether, the compounds of formula XXIII. This ester and then hydrolyzing with obtaining the compounds of formula XIII, as described above, preferably in an organic solvent, as an aromatic hydrocarbon, for example toluene or xylene, in the presence of acid as the carboxylic acid, for example acetic acid, at temperatures from 20oC to the boiling temperature of the reaction mixture, in particular at 70 90oC. If necessary, carries out the separation of the diastereoisomers, for example by chromatography, for example on silica gel, using a mixture of organic solvents as a mixture of alkane with a complex ether, as lower alkane and complex (lower alkyl)-(lower alkanoyl)-ether as hexane/ethyl acetate.

Of the compounds of formula XXIII then by diproton, the carbanion and subsequent nucleophilic substitution of the residue W in the compound of formula R3-CH2-W, where R3and W are defined as above in obtaining compounds of formula XIX, obtain the corresponding compound of formula XX, the reaction preferably stereoselective leads to (R)-configuration leave the remainder R3-CH2-carbon atom in the compound of formula XX. The interaction with a strong base, especially amidon organosilicon alkali metal, for example bis-(tri-lower alkyl)-silyl-amide of alkaline metal, such as bis-(trimethylsilyl)-amide, lithium, or, later, di-(lower alkyl)-amide of alkaline metal, as diisopropylamide lithium, preferably carried out in an inert organic solvent, in particular a simple ether, e.g. a cyclic simple ether like tetrahydrofuran, at temperatures from -100oC and 0oC, preferably at from -78oto -50oC; nucleophilic substitution in situ by adding the compounds of formula R3-CH2-W, in the same solvent, at temperatures from -100oC and 0oC, preferably at from -60oto -40oC.

The compound of formula XV, where the remains have McAskie you can get by what ester of formic acid, for example lower alkilany ester of formic acid as ethyl formate by reaction with allylamine at temperatures 20 70oC, in particular at 50 to 60oC, turn in arylamide formic acid. This amide is then in an atmosphere of inert gas, as nitrogen or argon, dehydration, preferably using galodamadruga acid as phosphorus oxychloride, phosgene or particularly galodamadruga organic sulfonic acids, for example the acid chloride of arylsulfonate as the acid chloride toluenesulfonic acid, in the presence of a base, such as tri-(lower alkyl)-amine like triethylamine, or in particular mono - or bicyclic amine as pyridyl or quinoline at temperatures of 50 100oC, in particular about 80 100oC. thereby forming arylisocyanate, which by interacting with organolithium salt, for example (lower alkyl)-lithium, as n-utility, transferred to the corresponding lithium salt, the reaction is preferably carried out in an inert organic solvent, in particular in a simple ether as dioxane or diethyl ether, or in alkane, for example hexane, or a mixture of these solvents, at temperatures from -120oC to -50o2-CH2-W, where R2is specified for the compounds of formula I values and W have the above for compounds of formula R2-CH2values, preferably bromine; preferably by addition of R2-CH2-W in an organic solvent, for example in a simple ether like tetrahydrofuran, under specified the last time the temperature and subsequent heating up to 0 50oC, preferably up to 20 30oC. When it is formed isocyanate of the formula:

< / BR>
where the residues have the specified values. The compound of formula XXIV is then hydrolyzing, preferably in aqueous solution, to which was added the acid, for example in aqueous halogen acid as hydrochloric acid, in particular in concentrated hydrochloric acid, at temperatures between -20oC to 30oC, in particular at about 0 to 10oC, and obtain the connection formula XV, where the remains defined above and where preferably bearing a group-NH2the carbon atom is (R,S)-configuration.

The compound of the formula IV are known or are obtained by known methods, for example by condensation of carboxylic acids of the formula II or their reactive derivatives with amino compounds of the formula H-B1-OH, where Rwhich in the case of compounds of formula II, where R1denotes N-(heterocyclyl)-(lower alkyl)-N-(lower alkyl)-aminocarbonyl as N-(2-pyridylmethyl)-methylaminomethyl, similarly, European patent N 0 402 646, 1990 (example 218).

The compounds of formula V receive, for example, from compounds of the formula XXII by condensation with the compound of the formula VII or sequential condensation with compounds (for example, H-A1-OH, H-A2-OH; H-A1-A2-OH), or a compound of formula XI, where, depending on the circumstances, the residues have the above values, the elements of which correspond to the compound of formula VII. Condensation conditions similar to those described for preparing compounds of formula III.

The compounds of formula VI receive, for example, from amino compounds of the formula XXII, for example by introducing protective for carboxyl group, as described in method a) and removal of protective groups RA, as described in method e), by condensation with a carboxylic acid of formula R1-B1-OH, where the residues have the above for compounds of formula I values.

The compounds of formula VII receive, for example, from the corresponding amino acids N-AND'1-OH or H-AND'2-OH, or peptides N-A1-A2-OH and aminocompounds formula XI, where residues, depending on the situation the teachings of the compounds from the recovered peptide bond, preferably at the stage of the dipeptide, for example, using hydrogen in the presence of catalysts based on noble and heavy metals, such as platinum or palladium, optionally in the media as active carbon, or by complex hydrides, preferably complex hydrides, such as socialogical or vitaminsforyou, in polar solvents, such as alcohols, for example ethanol, or ethers, as cyclic ethers, for example tetrahydrofuran, at temperatures of 0 to 150oC, preferably at 20oC to the boiling temperature of the corresponding reaction mixture. Amine of the formula XI are known or obtained by the known methods.

The compounds of formula VIII can be obtained, for example, from compounds of formula VI by condensation with introducing the residue AND1the amino acid. The interaction is similar to that described for method a) conditions.

The compounds of formula IX receive, for example, from amino acids N-AND'2-OH, where a'2is specified in method g) value, and an amine of the formula XI, where the residues have the above for compounds of formula I values, by condensation.

The compounds of formula X receive, for example, from compounds of formula VI and the corresponding amino acids N-AND'1-OH is ilstam, have the above meanings, by condensation similar to the way

described in method a). To obtain compounds from the recovered peptide bond between a1and a2restore the peptide bond between a1and a2preferably at the stage of the dipeptide, for example, using hydrogen in the presence of catalysts based on noble and heavy metals, such as platinum or palladium, optionally in the media as active carbon, or by complex hydrides, preferably complex hydrides, such as socialogical or vitaminbody, in polar solvents, such as alcohols, for example ethanol, or ethers, as cyclic ethers, for example tetrahydrofuran, at temperatures of 0 - 150oC, preferably at 20oC to the boiling temperature of the reaction mixture.

The remaining parent compound is known, are obtained by means known or available for sale.

The following examples serve to illustrate the invention, but in no way limit the scope of protection.

Temperatures are given in degrees Celsius (oC). If you have not specified any temperature, the reaction is conducted at room temperature is th distance of the solvent front, determined on plates with silica gel for thin-layer chromatography by thin-layer chromatography (TLC) in the following solvent system:

The solvent system for TLC:

And hexane/ethyl acetate 1 1

B ethyl acetate -

In hexane/ethyl acetate 4 1

G hexane/ethyl acetate 2 1

L hexane/ethyl acetate 3 1

E methylene chloride/methanol 9 1

W chloroform/methanol/water/glacial acetic acid 85 13 1,5 0,5

H ethyl acetate/ethanol 9 1

And hexane/ethyl acetate 1 2

To chloroform/methanol/acetic acid/water 75 27 0,5

L ethyl acetate/acetic acid 19 1

M methylene chloride/methanol 7 3

N methylene chloride/ether 49 1

About methylene chloride/ether 3 1

The abbreviation "Rf/A/ a" denotes, for example, that Rf is the value defined in the solvent system A. the proportion of solvents to one another is always stated in volume percentage (by volume). When determining the solvent system for column chromatography quantitative ratio of the used solvents are given in volumetric proportions (by volume).

Other used as shorthand and abbreviations have the following meanings:

abs. absolute

ATM. physical atmosphere (unit of pressure) 1 ATM. corresponds to the FOP

TCX thin-layer chromatography

DCC dicyclohexylcarbodiimide

DMF dimethylformamide

DMSO dimethyl sulfoxide

acetic ether acetate

the ether is diethyl ether

FAB-MS mass spectroscopy method for the fast atom bombardment

hour. hour (time)

HBTU 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium

Not 1-oxybenzoates

IR infrared spectroscopy

min minute (min)

NMM N-methylmorpholine

org. organic

Pd/C palladium on active coal (catalyst)

KT at room temperature

so pl. melting point

the brine saturated solution of sodium chloride

TBAF tetrabutylammonium (trihydrate)

Z benzyloxycarbonyl

Mass spectroscopy measured values obtain by the method of "fast atom bombardment" (Fast-Atom-Bom-vardment FAB-MS). Mass data refers to the protonated molecules (M + N)+.

Values for the IR spectra are indicated in cm-1in parentheses is indicated the corresponding solvent.

To denote a divalent radicals of natural amino acids used conventional in the chemistry of peptides reduction. The configuration of the u-carbon atom is indicated by the prefix (the ohms; -(p-CH3-Phe)-substituted in p-position of the phenyl ring methoxy group; and -(p-CN-Phe)-substituted in p-position of the phenyl ring, cyano group, i.e. phenylalanyl.

The following shorthand residues are determined by the relevant images, formulas and symbols:

The remainder of the reduction-Phe(C)Phe denotes a divalent radical of 5-(S)-amino-2-(R)-benzyl-4-(S)-hydroxy-6-phenylhexanoic acid and has the formula:

-

The remainder of the reduction-Cha(C) (p-CN)-Phe denotes a divalent radical of 5-(S)-amino-2-(R)-(p-cyanovinylene)-6-cyclohexyl-4-(S) -oxohexanoate acid and has the formula:

< / BR>
The remainder of the reduction-Cha(C)Cha) denotes the divalent residue of 5(S)-amino-2-(R)-6-cyclohexyl-2-(R)-cyclohexylmethyl-4-(S) -oxohexanoate acid and has the formula:

< / BR>
The remainder of the reduction-Cha(C) (p-F)-Phe denotes a divalent radical of 5-(S)-amino-6-cyclohexyl-2-(R)-(p-performer)-4-(S) -oxohexanoate acid and has the formula:

< / BR>
The remainder of the reduction -(p-F)-Phe(C)Phe denotes a divalent radical of 5-(S)-amino-2-(R)-benzyl-6-(p-forfinal)-4-(S)-oxohexanoate acid and has the formula:

< / BR>
Following further image formulas Central units comply with the following reduction of the p-F) Phe - corresponds to the divalent radical 5[S] -amino-2[R] -[p-performer] -4[S] -hydroxy-6-phenylhexanoic acid; -Phe[C] (p-CN)-Phe - corresponds to the divalent radical 5[S]-amino-2[R] -(p-cyanovinylene)-4[S] -hydroxy-6-phenylhexanoic acid; -Phe[C] (p-CH3OPhe - corresponds to the divalent radical 5[S]-amino-4[S]-hydroxy-2[R] -(p-methoxyphenethyl)-6-phenylhexanoic acid; -Phe[C](p-CF3)Phe - corresponds to the divalent radical 5[S] -amino-4[S]-hydroxy-6-phenyl-2[R]-(p-trifluoromethyl)-hexanoic acid; (p-F)Phe[C](p-F)Phe - corresponds to the divalent radical 5[S]-amino-6-(p-forfinal)-2[R]-(p-performer)-4[S] -oxohexanoate acid; a -(p-F)Phe[C](p-CN)Phe - corresponds to the divalent radical 5[S] -amino-2[R]-(p-cyanovinylene)-6-(p-forfinal)-4[S]-oxohexanoate acid; -ha[C] (p-CH3Phe - corresponds to the divalent radical 5[S] -amino-2[R] -(p-methoxyphenethyl)-6-cyclohexyl-4[S] -oxohexanoate acid; -ha[C](p-CF3)Phe - corresponds to the divalent radical 5[S]-amino-6-cyclohexyl-4[S]-hydroxy-2[R] -(p-triftormetilfullerenov)-hexanoic acid (see tab. 2).

< / BR>
Balance -(p-F)Phe[C] (p-CF3)Phe - corresponds to a bivalent radical of 5[S]-amino-4[S]-hydroxy-6-(p-forfinal)-2[R]-(p-triftormetilfullerenov) -hexanoic acid.

The symbol () should Express that remains -(CF3)Phe[C] Phe-, -(CF3)Phe[C] (p-F)Phe - (CF3[C](p-With the OIC acid, 5-amino-2-(p-forfinal)-4-hydroxy-6-(p-triptoreline)-hexanoic acid and 5-amino-2-(p-triptoreline)-4-hydroxy-6-(p-triptoreline)-hexanoic acid, in the respective examples are in the form of a mixture of 2[R] 4[S] 5[S]-isomers of 2[S] 4[R] 5[R]-isomers.

Example 1. Boc-Cha(C) (n-F)Phe-(L)-Val-(L)-Phe-morpholine-4-alamid

A solution of 160 mg 5[S]-BOC-amino-4[S]-tert.butyldimethylsiloxy)-6 - cyclohexyl-2(R)-(n-performer)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-yl-amide 1.8 ml of abs. DMF is mixed with 116 mg TBAF and the reaction mixture is then stirred for 4.5 h at RT. The colorless solution is poured into 50 ml of water and extracted 4 times with acetic ester. The combined extracts, depending on the circumstances, washed twice with water and once with brine and then dried over sodium sulfate. After evaporation of the solvent the residue is crystallized from diisopropyl ether and receive the title compound.

TLC Rf (AND) 0,14; FAB-MS (M + H)+753.

The source material was obtained as follows.

1 (a) N-3-[S]-(Boc-amino)-2-(R,S)-hydroxy-4-phenyl-1-trimethylsilylmethyl.

of 24.7 g of magnesium contribute in 100 ml of abs. ether and within 35 min mix with a small amount of iodine and at the same time with 132,5 ml of chlorotetracycline and 300 ml of ether, and the temperature TF is th to 48.6 g of N-Boc-phenylalanine (receiving: D. J, Kempf. J. Org. Chem, 51, 3921. 1986) in 1.1 l of ether. After 90 min the reaction mixture is heated to CT and mix the following 90 min at this temperature. Then poured into 2 l of ice water and 1.5 l of 10-Noah aqueous citric acid. The separated aqueous phase is extracted with twice 500 ml of ether. All ether extracts washed with 500 ml of 10 aqueous citric acid solution and twice with brine. After drying over sodium sulfate concentrated in vacuo and the resulting title compound is used further without additional purification.

TLC Rf (B) 0,6; FAB-MS (M + H)+3,38.

1 (b) 1-Phenyl-3-butene-2(S)-amine.

A solution of 18.8 g of n-3(S)-(Boc-amino)-(R,S)-hydroxy-4-phenyl-1-trimethylsilylmethyl in 420 ml of methylene chloride at 5oC for 10 min mix 35.6 ml at about 48-aqueous solution of boron TRIFLUORIDE. The reaction mixture is then stirred for 16 h at RT, cooled to 10oWith and within 20 min mix with 276 ml of 4 n sodium hydroxide solution. 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. The title product is used further without additional purification.

TLC Rf (G) 0,15; IR (methylene chloride) (cm-1): 3370, 3020, 2920, milenaria dropwise and mixed with a solution of 38.3 g of Boc-anhydride in 250 ml of methylene chloride. After stirring for 1.5 h at RT concentrated to 100 ml, then diluted with 1.5 liters of ether and successively washed twice with 400 ml of 10 citric acid, once with 400 ml of water, once with 400 ml saturated aqueous sodium bicarbonate solution and twice with brine and dried over sodium sulfate. After evaporation of the solvent is purified by column chromatography (SiO2, hexane/acetic ether 95 5 80/20) and the title compound vykristallizovyvalas from hexane. So pl. 67 68oC.

TLC Rf (B) 0,4; FAB-M (M + H)+248.

1G) 2(R)-[I(S)-(Boc-amino)-2-phenylethyl]-oxiran.

A solution of 1.45 g of N-Boc-1-Phenyl-3-butene-2(S)-amine in 20 ml of methylene chloride for 15 min at 0 to 5oWith mixed with solution 9,74 g m-chlormadinone acid in 50 ml of methylene chloride. After stirring for 18 h at the same temperature, stirred even the next 8 hours when heated to CT and poured into ice 10-cent solution of sodium carbonate. The aqueous phase is shaken out three times with ether. The combined organic phases are washed successively three times 10-s ' solution of sodium sulfate, three times with saturated solution of sodium bicarbonate, sodium thiosulfate solution and brine and dried over sodium sulfate. After conc is first aired: 4/1) and recrystallized from hexane. So pl. 51 52oC.

TLC Rf (B) 0,33; FAB-MS (M + H)+264.

1D) 5(S)-(I(S)-(Boc-amino)-2-phenylethyl-(3-(R,S) -carboalkoxylation-2-(3H)-he.

A solution of 26 ml of diethyl ester of malonic acid in 260 ml of abs. ethanol portions mixed with 3.4 g of sodium. After consumption of sodium (about 1.5 hours) for 10 min was added dropwise a solution of 13 g of 2(R)-(I/S)-(Boc-amino)-2-phenylethyl)-oxirane in 100 ml of ethanol. After stirring for 5 h at RT the reaction mixture is poured into 1.5 l of ice water and with 10 citric acid to establish a pH of 4. After 4-fold extraction with ether, the combined organic phases are successively washed twice with saturated aqueous sodium bicarbonate solution, once with brine, again saturated aqueous sodium bicarbonate, water and once with brine. After concentration of the solvent the title compound is obtained by column chromatography (SiO2, hexane/acetic ether: 4/1).

TCX Rf (B) 0,33; FAB-MS (M + H)+378.

1e) 5(S)-(I(S)-(Boc-amino)-2-cyclohexylethyl)-3(R, S) -carbethoxypsoralen-2-(3H)-he.

10 g of 5(S)-(I/S)-(Boc-amino)-2-phenylethyl)-3-(R,S) -carbethoxypsoralen-2-(3H)-she's in 100 ml of ethanol with 1 g of Nishimura catalyst (oxide Ph (III) and Pt (VI) (ManagerID, Degussa is atomowa earth, Sigma, Switzerland), washed with ethanol and the filtrate is evaporated.

TLC Rf (B) of 0.23.

1G) 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3(R,S) -carbethoxy-3-(p-fluoro-phenylmethyl)-dihydrofuran-2-(3H)-he

10.2 g of 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3(R,S) -carbethoxypsoralen-2-(3H)-it is injected into the interaction of 5.39 g of p-ftorangidridy (Fluka, Buchs, Switzerland) and 0.68 g of sodium in 180 ml of ethanol at RT. Because, according to TLC, after 1.5 h, it was not the whole lactone entered into interaction, add 0.2 g of sodium and 0.7 g of p-ftorangidridy. After 16 h, poured onto a mixture of 10 citric acid and ice and extracted three times with ether. The organic phase is washed twice with water and brine, dried over Na2SO4and evaporated. After adding hexane with acetic ether, distilled oily product under the influence partly of ultrasound in obtaining the title compound (ratio of diastereomers 4 1). Column chromatography (SiO2, hexane/acetic ester 4 1) the mother liquor gives an additional amount of the title compound (ratio of diastereomers approximately 1 to 4).

TCX Rf (B) 0,29; FAB-MS (M + H)+492.

1Z) 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3(R)-(p-performer) -dihydrofuran-2-(3H)-he and 5(S)-(Xilitol)-3(R, S)- carbethoxy-3-(p-performer)-dihydrofuran-2(3H)-she (the ratio of the diastereomers of about 1 1) in 174 ml of 1,2-dimethoxyethane for 5 min on drops mixed with 91 ml of a solution of lithium hydroxide, at RT, and stirred for 15 h at RT. After evaporation of the solvent, the obtained residue was poured into 500 ml of 10 citric acid and extracted three times with ether. The combined ether phases are washed once with brine and dried over sodium sulfate. After evaporation of the solvent to obtain the crude carboxylic acid, which with subsequent decarboxylation by heating for 9 hours at 90oC in 450 ml of toluene was transferred into the mixture of title compounds. Column chromatography (SiO2, hexane/acetic ether 9 1 --> 4:1) gives the first 3(R)-epimer (TCX Rf (D) of 0.45), 3(S)-epimer (TLC Rf (D) 0,41).

1i) 5(S)-(I/S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-performer) -hexanoic acid.

2,05 g 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3(R)-(p-performer) -dihydrofuran-2-(3H)-she's in 78 ml of dimethoxyethane and 39 ml of water at 20 25oC dropwise over 2 min mix 19.6 ml of 1 M solution of lithium hydroxide. After stirring for 3 h at RT concentrated under reduced pressure and the residue is dissolved in 100 ml nasusunog the joint organic phases are washed with brine and dried over sodium sulfate. After concentrating obtain the title compound in the form of foam, which without further purification used in the nearest stage.

1K) 5(S)-(Boc-amino)-4-(S)-(tert. -butyldimethylsiloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoic acid.

The solution 2,01 g 5(S)-(I/S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(p-performer)- hexanoic acid, 6.4 ml of DMF together 2,73 g of imidazole and 3,39 g of tert. butyldimethylchlorosilane stirred for 18 h at RT. Then the reaction mixture was poured into ice water, extracted with 3 portions of acetic ether, washed the combined organic phase with 10 citric acid, water and brine, dried over sodium sulfate and evaporated. Get the oil. This oil is dissolved in 68 ml of methanol and 23 ml of THF is added at RT to a solution of 4.1 g of potassium carbonate in 23 ml of water, stirred for one hour and finally partially evaporated at RT. The aqueous residue was poured into 10-cent citric acid solution and ice, extracted three times with acetic ether, the organic phase is washed twice with water and brine, dried over sodium sulfate and evaporated. Column chromatography (SiO2 hexane/acetic ether 5 1 --> 2 1) gives the title compound.

TCX Rf (L) 0,2; FAB-MS (M is hexanoyl-(L)-Val-(L)Phe-morpholine-4-alamid.

A solution of 102 mg of 5(S)-(Boc-amino)-4(S)-(tert.butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoic acid, 90 mg THIEF and 27 mg Not stirred for 30 min at RT in about 2 ml of DMF and then mixed with 74 mg of N-(L)-VaI-(L)-Phe-morpholine-4-yl-amide (receipt, see 1m) 1P)). After 16 h at RT is evaporated and the residue is partitioned between 3 portions of acetic ether, water, saturated sodium bicarbonate solution, water and brine, dry the organic phase with sodium sulfate and evaporated. Get the title compound in the form of crude product.

TCX Rf (AND) 0,57; FAB-MS (M + H)+867.

1m) Z-(L)-Phe-morpholine-4-alamid.

A solution of 4.49 g of Z-(L)-Phe-HE in 190 ml of methylene chloride cooled to 0oC and mixed with 3,09 g DCC. After stirring for 20 min at 0oC for 15 min was added dropwise a solution of 1.31 ml of the research in 10 ml of methylene chloride. The reaction mixture is stirred for a further 24 h at RT and after filtering off spin-off of dicyclohexylamine washed successively with methylene chloride, aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate and concentrating receive crude title compound, which vykristallizovyvalas from the ether.

T Pd/C in 150 ml of methanol at RT for one hour by using the calculated amount of hydrogen by hydrogenolysis transferred to the title compound. After filtering off the catalyst concentrate and after dilution with acetic ether, the resulting solution washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrate under reduced pressure. After column chromatography (analogously to example 1A)) to obtain the title compound in pure form.

TLC Rf (T) of 0.3.

1o) Z-(L)-VaI-(L)-Phe-morpholine-4-alamid.

A solution of 2.14 g of Z-(L)-VaI-OH in 80 ml of abs. ice of methylene chloride is mixed with 1.75 g DCC and after stirring for 20 min at this temperature, dropwise mixed for 15 min with a solution of 2 g of N-(L)-Phe-morpholine-4-ylamide. The reaction mixture is stirred for a further 24 h at RT and the resulting urea is filtered off. The filtrate is washed successively with an aqueous solution of sodium bicarbonate and brine and after drying over sodium sulfate, concentrated. By trituration with ether and filtering off the insoluble residue receive, after concentration, the title compound, which without additional purification process next.

TLC Rf (E) of 0.7.

1H) N-(L)-VaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 1H) of 3.9 g of Z-(L)-VaI-(L)-Phe-morpholine-4-yl-amide translated by Nochnoi chromatography (SiO2the methylene chloride until the methylene chloride/methanol 97,5 2,5 (by volume).

TLC Rf (E) of 0.4.

Example 2. Boc-Phe(C)Phe-(L)-VaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 1 330,3 mg of 5(S)-Boc-amino-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethyl-hexanoyl-(L)-VaI-(L)-Phe-morpholine-4-yl-amide in 3 ml of abs. DMF with the help of 247.2 mg TBAF translated in the title compound, which crystallizes from hexane. TLC Rf (E) of 0.5. FAB-MS (M + H)+729.

The source material was obtained as follows.

2a) 5(S)-(I/S)-(Boc-amino)-2-phenylethyl)-3(R,S)-carbethoxy-3-fenilmetilketenom-2-(3H)-he

A solution of 23.8 g of 5(S)-(I/S)-(BOC-amino)-2-phenylethyl)-3(R,S)-carbethoxypsoralen-2-(3H)-he's in 410 ml of abs. ethanol and 14.4 ml of benzylbromide added to a solution of 2.76 g of sodium in 410 ml of abs. of ethanol. The reaction mixture was stirred at RT in an argon atmosphere for 18 h and then poured into a mixture of ice with 10 citric acid. After three times of extraction with ether, the combined organic extracts washed with water and brine and dried over sodium sulfate. After concentrating receive the title compound as a colourless oil, which was used without additional purification in the nearest stage.

TLC Rf (B) of 0.4. FAB-MS (teletel)-3(S)-fenilmetilketenom.

A solution of 10 g of 5(S)-(I/S)-(Boc-amino)-2-phenylethyl)-3(R,S)-carbethoxy-3-fenilmetilketenom-2-(3H)-she's in 175 ml of dimethoxyethane dropwise within 5 min mix from 81.4 ml of 1 M aqueous solution of lithium hydroxide, CT. Then stirred for 15 h at RT, and after evaporation of the solvent, the obtained residue was poured into 500 ml of 10 citric acid and extracted three times with ether. The combined ether phases are washed once with brine and dried over sodium sulfate. After evaporation of the solvent gain of 9.8 g of the crude carboxylic acid which decarboxylase to the title compound by heating for 14 hours at 90oC in 450 ml of toluene. The title compound purified by column chromatography (hexane/acetic ether 9/1), and you get 5(S)-(I/S)-BOC-amino)-2-phenylethyl)-3-(R)-phenylmethyl) -dihydrofuran-2-(3H)-he (TLC Rf (B) 0,3; FAB-MS (M + H)+396, then get a 5(S)-(I/S)-(Boc-amino)-2-phenylethyl)-3(S)-fenilmetilketenom-2-(3H)-he.

TLC Rf (B) 0,25; FAB-MS (M + H)+396.

2B) 5(S)-(Boc-amino)-(4/S)-hydroxy-6-phenyl-2(R)-fenilmetilketenom acid.

A solution of 17.6 g of 5(S)-(I/S)-(Boc-amino)-2-phenylethyl-3(R)-fenilmetilketenom-2-(3H)-she 710 ml simple etilenpropilendienovogo ether and 352 ml of water for 10 min at 20oactuarial is evaporated. The residue is poured into 1 l of cold 10 citric acid and the acidic solution is extracted three times with 800 ml of acetic ether. The combined extracts washed first with water (800 ml), then with 800 ml of brine. After drying the organic solution over sodium sulfate, the solvent is distilled off. The crude title compound without further purification used in the nearest stage.

FAB-MS (M + H)+414.

2G) 5(S)-(Boc-amino)-(4/S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R) -fenilmetilketenom acid

A solution of 6.35 g of 5(S)-(Boc-amino)-(4/S)-hydroxy-6-phenyl-2(R)-fenilmetilketenom acid in 90 ml of DMF with stirring, mixed with 8 g of imidazole and 10 g of tert. butyldimethylchlorosilane. After stirring for 18 h at CT yellow clear solution is poured into ice water and extracted three times with 250 ml of acetic anhydride. The combined extracts are washed successively three times with 10 citric acid, once with water and three times with aqueous saturated sodium bicarbonate solution, once with water and finally brine. After drying over sodium sulfate the solvent is evaporated and the thus obtained simple tert.-butyldimethylsilyloxy ester (13.5 g) was dissolved in 53 ml of THF and treated with 53 ml of the UKS the joint ether extracts are washed twice with water and once with brine and dried over sodium sulfate. After concentration the crude product is purified by column chromatography (SiO2, hexane/acetic ester 3,5/1,5) and get the title compound.

TLC Rf (G) 0,37; FAB-MS (M + H)+528.

2D) 5(S)-(Boc-amino)-(4/S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R) -phenylmethanol-(L)-VaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 1l) 250 mg of 5(S)-(BOC-amino)-(4/S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid in 3 ml DMF with the help of 230.5 mg THIEF, 70,4 mg Not, 182,6 ml of N-methylmorpholine and 189,5 mg N-VaI-Phe-morpholine-4-ylamide transferred to the title compound.

TCX Rf (A) 0,24; FAB-MS (M + H)+843.

Example 3. Boc-Cha(C)-(p-CN/Phe-(L)-VaI-(L)-Phe-morpholine-4-yl-amide.

Analogously to example 1 185 mg of 5(S)-(Boc-amino)-(4/S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (n-cyanovinylene)-hexanoyl-(L)-VaI)-(Phe-morpholine-4-ylamide using 13 mg TBAF 2.5 ml of abs. DMF was transferred to the title compound.

TLC Rf (B) 0,33; FAB-MS (M + H)+760.

The source material was obtained as follows.

3a) 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3 - carbomethoxyamino-2-(3H)-he

2.5 g of 5(S)-(I/S)-(BOC-amino)-2-phenylethyl)-3-carbethoxypsoralen-2-(3H)-it (example 1D) in 50 ml of methanol hydronaut in the presence of 250 mg of the ATM). After filtration and additional washing of the catalyst with methanol, concentrated and the title compound by column chromatography (SiO2, hexane/acetic ether 3/1 by volume) are obtained in pure form.

TCX Rf (L) 0,2; FAB-MS (M + H)+370.

3b) 5(S)-(I/S)-(BOC-amino)-2-cyclohexylethyl)-3(R, S)-carbomethoxy-3- (p-cyanovinylene)-dihydrofuran-2-(3H)-he.

Analogously to example 1 g) 2.25 g of 5(S)-(I/S)-(BOC-amino)-2-cyclohexylethyl)-3(R, S)- carbomethoxyamino-2-(3H)-he with the help of 1.32 g of n-cyanobenzaldehyde (Fluka, Buchs Switzerland) and 156 mg of sodium in methanol was transferred to the title compound. After processing get the title compound.

TLC Rf (D) of 0.27.

3b) 5(S)-(I/S)-(BOC-amino)-2-cyclohexylethyl)-3(R)-(p-cyanovinylene) -dihydrofuran-2-(3H)-he and 5(S)-(I/S)-(BOC-amino)-2-cyclohexylethyl)-3(S)-(p-cyanovinylene) -dihydrofuran-2-(3H)-he.

Analogously to example 1H) 2,95 g 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3 - carbomethoxy-(n-cyanovinylene)-dihydrofuran-2-(3H)-she's in 55 ml of 1,2-dimethoxyethane using 24,4 ml of 1 M solution of lithium hydroxide was transferred to the corresponding carboxylic acid and subsequent decarboxylation by heating in 130 ml of toluene was transferred to the title compound. RA is-(R)-form of the title compound, which crystallizes from a mixture of ether and hexane (so pl. 106 108oC. TCX Rf (A) OF 0.53; FAB-MS (M + H)+427) and then gives 3(S)-form of the title compound (TLC Rf (A) 0,47; FAB-MS (M + H)+427).

3G) 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(n-cyanovinylene) -hexanoic acid.

A solution of 550 mg of 5(S)-(I/S)-(Boc-amino)-2-cyclohexylethyl)-3(R)-(p-cyanovinylene) -dihydrofuran-2-(3H)-she in 20 ml of 1,2-dimethoxyethane and 14 ml of water at 20 25oC dropwise over 2 min, mixed with 7 ml of 1 M solution of lithium hydroxide. After stirring for 2 h at RT concentrated under reduced pressure and the residue is dissolved in 100 ml of a saturated aqueous solution of ammonium chloride and 5 ml of 10 citric acid and extracted four times with methylene chloride. The combined organic phases are washed with brine and dried over sodium sulfate. After concentrating obtain the title compound.

TCX Rf (E) of 0.4.

3D) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (n-cyanovinylene)-hexanoic acid

790 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(n-cyanovinylene) -hexanoic acid, about 10 ml of DMF with stirring, mixed with 1.18 g of tert.-butyldimethylchlorosilane and imidazole. After stirring in TECOM. The combined extracts are successively washed three times with 10 citric acid, once with water, three times aqueous saturated sodium bicarbonate solution, once with water and finally brine. After drying over sodium sulfate the solvent is evaporated and the thus obtained simple tert.-butyldimethylsilyloxy ester (13.5 g) was dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After stirring for 3 h at RT poured onto water and extracted three times with ether. The combined ether extracts are washed three times with water and dried over sodium sulfate. After concentration the crude product is subjected to final cleaning. Final purification is performed by column chromatography (SiO2, hexane/acetic ether 3/1 1/1 (by volume)). Get the title compound.

TLC Rf (A) at 0.42; IR (methylene chloride), cm-1: 2856, 2230, 1711, 1609, 1440.

3e) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-cyanovinylene)-hexanoyl-(L)-Val -(L)P-Phe-morpholine-4-alamid

Analogously to example 1l) 138 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-cyanovinylene)-hexanoic acid with 122 mg THIEF, 37 mg Not, 0,069 ml of N-methylmorpholine and 100 mg of H-(L)-Val-(is ecografia (SiO2, hexane/acetic ether 1/1 by volume). Get pure title product.

TCX Rf (A) 0,25; FAB-MS (M + H)+874.

Example 4. H-Phe(C)Phe-(L)-Val(L)-Phe-morpholine-4-alamid.

The solution 1,048 g Boc-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-yl-amide (example 2) in 20 ml of abs. the methylene chloride 5oC for 3 minutes and mixed with 20 ml triperoxonane acid. After following 90 min of stirring at RT, evaporated, the residue is mixed with 150 ml of saturated aqueous sodium bicarbonate solution and extracted three times with acetic ester. The combined extracts are washed successively with 100 ml water, 100 ml saturated sodium bicarbonate solution, 100 ml of water and brine. After drying over sodium sulfate the solvent is evaporated and the crude product purified by column chromatography (SiO2, methylene chloride/methanol/ammonia 95/5/0,1 90/10/0,1 by volume) to give the title compound. TLC Rf (W) 0,33; FAB-MS (M + H)+629.

Example 5. 3-Benzofuranyl-Phe(C)he-(L)-Val-(L)-Phe-morpholine-4-alamid.

A solution of 30.9 g benzofuran-3-carboxylic acid (getting under Chin-Hsing Chou, etc. G. Org. Chem. 51, 4208 4212, 1986) in 3 ml of DMF is mixed successively with 93 mg THIEF, 29 mg Not and 0.044 ml N-methylmorpholine and then stirred for 30 min at RT. After addition of 100 mg of N-Ph. After three times of extraction with 50 ml of acetic ether the combined organic phases are washed successively with 100 ml water, 100 ml saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml brine. After drying over sodium sulfate and evaporation, the residue is soaked in ether and the compound obtained is dried.

TLC Rf (W) 0.73; FAB-MS (M + H)+773.

Example 6. Nicotinoyl-Phe(C)Phe-(L)-Val-(C)-Phe-morpholine-4-alamid.

Analogously to example 5 of 23.5 ml nicotinic acid in 3 ml DMF with 93 mg THIEF, 29 mg Not, 0,044 ml of N-methylmorpholine and 100 mg of H-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-1-ylamide transferred to the title compound. After crystallization from ether and drying of the pure title compound.

TLC Rf (W) 0,57; FAB-MS (M + H)+734.

Example 7. Morpholinoethyl-Val-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 5,44 mg N-morpholinoethyl-(L)-Val in 3 ml of DMF with 93 ml of a THIEF, 29 mg Not, 0,044 ml of N-methylmorpholine and 100 mg of H-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 4) transferred to title compound. Crystallization from ether and drying leads to the title compound.

TLC Rf (W) 0,5; FAB-MS (M + H)+841,5.

7a) N-Chlorocarbonylsulfenyl.

180 ml Adeney to 5 10oC a solution of 18 ml of the research in 180 ml of toluene. White suspension is stirred for 1 h at RT and 2 h in a stream of nitrogen. After the extraction of the solids and the subsequent washing his toluene filtrate is evaporated. Thus obtained the title compound without further purification process further. IR (CH2Cl2): 1730, 1400, 1205 cm-1.

7b) N-Morpholinoethyl-(L)-Val-benzyl ester.

3 ml of N-chlorocarbonylsulfenyl in 210 ml of CH2Cl2mixed with 15 g of p-toluensulfonate salt (L)-valine benzyl ether complex (Fluka, Buchs, Switzerland) and 15.4 ml of n-ethyldiethanolamine. After stirring for 16 h at RT again mixed with 1.5 ml then, after 23 h, again with 0.8 ml of N-chlorocarbonylsulfenyl. Later, in General, 39 h, the reaction mixture was concentrated, diluted with acetic ether and washed successively twice with 1 N. hydrochloric acid, once with water, once with saturated aqueous sodium bicarbonate solution and twice with brine. After drying over sodium sulfate concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, acetic ether) to give the title compound.

TLC Rf (B) of 0.5.

7b) N-Masnago ether hydronaut for 3 h h at RT in the presence of 2 g of 10-aqueous Pd/C under normal pressure. After filtration and additional washing of the catalyst with acetic ether mother liquor concentrate. The residue is treated with acetic ether, filtered through Hyflo Super Cel(kieselguhr, Fluka, Buchs, Switzerland) and concentrate under reduced pressure. Obtained the title compound without further purification processed next.

Example 8. Boc-Cha(C)Cha-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 3A) 100 g of Boc-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 2) in 30 ml of methanol hydronaut in the presence of 40 mg of catalyst Nichimura for 4 h at RT. After adfilternone catalyst and concentration, the residue crystallizes from hexane and purified by column chromatography (SiO2, hexane/acetic ether 1/2 by volume) to obtain the title compound.

TLC Rf (AND) 0,5; FAB-MS (M + H)+747.

Example 9. Boc-Cha(C)(p-F(Phe-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1, 0.18 g of 5(S)-(BOC-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoyl-(L)P-Val-(L)-(p-F-Phe)-morpholine-4-yl-amide with 114 mg TBAF in 1.8 ml DMF was transferred to the title compound.

TLC Rf (B) OF 0.44; FAB-MS (M + H)+771.

The source material was obtained from the NIN (Fluka, Buchs, Switzerland) in 55 ml of THF and 20 ml of N2O add 2 N. NaOH until the pH is about 10. To the resulting suspension was added dropwise of 4.66 g of benzyl ether of Harborview acid and additionally stirred for 4 h at RT, pH-value support by adding 2 N. NaOH is equal to 10. The reaction mixture is evaporated, the residue is distributed between ethyl acetate, 10% citric acid solution and brine and dried over Na2SO4. By column chromatography (SiO2, dichloromethane/methanol 7 3) pure title compound.

TCX Rf (K) of 0.50.

9b) Z-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1m) 9,01 g of Z-(L)-(p-F-Phe)-OH and of 2.38 g of the research in 350 ml of dichloromethane using 5,62 g DCC translated in the title compound, which after column chromatography (SiO2, acetic ether) are obtained in pure form.

TCX Rf (B) 0,6.

9b) H-(L)-(p-F-Phe)-formalin-4-alamid.

Analogously to example 1H) of 0.90 g of Z-(L)-(p-F-Phe)-morpholine-4-ylamide in 50 ml of methanol by hydrogenolysis using 0.2 g of 10-aqueous Pd/C was transferred to the title compound.

TCX Rf (M) 0,4.

9g) Z-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1B) of 1.36 g of N-(L)-(p-F-Phe)-morpholine-4-ylamide and 1.36 g of Z-(L>9D) N-(L)-Val-(L)-(n-F-Phe)-morpholine-4-alamid.

Analogously to example 1H) 2,80 g of Z-(L)-Val-(L)-(n-F-Phe)-morpholine-4-ylamide in 150 ml of methanol by hydrogenolysis using 0.6 g of 10-aqueous PD/C was transferred to the title compound, which after column chromatography (SiO2, dichloromethane methanol 9 1) are obtained in pure form.

TLC Rf (E) of 0.44; FAB-MS (M + H)+352.

9e) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

A solution of 100 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-cyclohexyl--2(R)- (p-performer)-hexanoic acid (example 1) and 70,3 ml N-(L)-Val-(L)-(p-F-Phe)-morpholine-4-ylamide 1.7 ml of NMM/CH3CN, 0.25 M (0.25 M NMM in CH3CN) is mixed with 76 mg of HBTU. After 6 h at RT is evaporated. The distribution of the residue between 3 portions of ethyl acetate, water, 2 portions of 10-aqueous citric acid solution, water, 2 portions of saturated sodium bicarbonate solution, water and finally brine, drying the organic phases over sodium sulfate and evaporation gives the title compound.

TCX Rf (A 0,2; FAB-MS (M + H)+885.

Example 10. Boc-ha-(C)(p-F)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1 0.18 g of 5(S)-(Boc-amino)-4(S) - tert.-BU what omashu 114 mg TBAF in 1.8 ml DMF was transferred to the title compound.

TLC Rf (B) 0,4; FAB-MS (M + H)+783.

The source material was obtained as follows.

10a) Z-(DL)-n-Methoxyphenylalanine.

Analogously to example 9a) 2.5 g of DL-(p-methoxyphenylalanine (Bachem, Bubendorf, Switzerland) in 64 ml of THF and 17.9 ml of N2About enter into interaction with 2.3 g of benzyl ether of Harborview acid, and the pH-value is maintained approximately equal to 10 by adding 1 N. Na2CO3-solution. Evaporation of the reaction mixture and distribution of the residue between ethyl acetate and diluted hydrochloric acid and brine gives the title compound.

TLC Rf (B) is 0.3; IR (CH2Cl2): 1720, 1612, 1513 cm-1.

10B) Z-(DL)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1m) 2.4 g of Z-(DL)-(p-CH3O-Phe)-OH(Z-DL)-p-methoxyphenylalanine in 36 ml of methylene chloride and 0.63 g of the research in 36 ml of methylene chloride is injected into the interaction with 1.5 g DCC to obtain the title compound.

TLC Rf (B) of 0.5; IR (CH2Cl2): 1720, 1641, 1612, 1512 cm-1.

10V) N-(DL)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1 n) 3.8 g of Z-(DL)-(p-CH3O-Phe)-morpholine-4-ylamide in 170 ml of methanol by hydrogenolysis using 0.8 g of 10-aqueous Pd/C is transformed into the title compound, which is IR (CH2Cl2): 1642, 1613, 1514, 1463, 1443 cm-1.

10g) Z-(L)-Val-(DL)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1B) of 1.80 g of Z-(L)-Val-OH in 40 ml of methylene chloride and 1.90 g of N-(DL)-(p-CH3O-Phe)-morpholine-4-ylamide in 40 ml of methylene chloride is injected into the interaction with 1,48 DCC to obtain the title compound.

TLC Rf (B) 0,12; IR (CH2Cl2) 1722, 1674, 1643, 1612, 1512, 1465, 1443.

10D) N-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-elhamid and N-(L)-Val-(D)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1H) 3.6 g of Z-(L)-Val-(DL)-(p-CH3O-Phe)-morpholine-4-ylamide in 150 ml of methanol by hydrogenolysis with 0.6 g of 10-aqueous Pd/C was transferred to a mixture of the title compounds. Column chromatography (SiO2, dichloromethane --> dichloromethane/methanol 19 1 --> dichloromethane/methanol 9 1 gives a first function, which according to amino acid analysis by gel-chromatography (GC) on Herasil-L-Val-column (E. Bayer, Z. Naturforschung, B. 1983, 38, 1281) contains N-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-alamid TLC Rf (E) 0,52; FAB-MS (M + H)+364; GC TRet((p-CH3O-Phe)-derived 27,65 min); then there is the faction with the epimer N-(L)-Val-(D)-(p-CH3O-Phe)-morpholine-4-ylamide TLC Rf (E) 0,37; GC TRet(p-CH3O-(Phe-derived) 27,65 min)

10e) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-example 9F) solution of 100 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoic acid (example 1K) and 72.7 mg of H-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide 1.7 ml of NMM/CH3CN, 0.25 M, and 1 ml of DMF enter into interaction with 76 mg BTU to obtain the title compound.

TCX Rf (A) 0,18; FAB-MS (M + H)+879.

Example 11. Boc-Cha(C)(p-F/Phe-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 1, 0.16 g of 5(S)-(Boc-amino)-4(S) - tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-Cha-morpholine-4-ylamide with 114 mg TBAF in 1.8 ml DMF was transferred to the title compound.

TLC Rf (B) 0,49; FAB-MS (M + H)+759.

The source material was obtained as follows.

11a) H-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 3A) 1.0 g N-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 1H) in 25 ml of methanol hydronaut using 0.15 g of Nishimura catalyst to the title compound, which by column chromatography (SiO2, methylene chloride --> methylene chloride/methanol 40 1) and extracts in hexane obtained pure.

TCX Rf (G) 0,5; FAB-MS (M + H)+340. IR (CH2Cl2): 1645, 1509, 1463, 1449.

11b) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 9F) 100 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)M, enter into interaction with 76 mg TU the title compound.

TCX Rf (A) 0,47; FAB-MS (M + H)+873.

Example 12. 1,2,3,4-Tetrahydroisoquinoline-3(S)-carbonyl-Val-Phe(C)-Phe-(L)-Val-Phe - morpholine-4-alamid.

Analogously to example 4 242 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)- carbonyl-Val-Phe(C)-Phe-(L)-Val/-Phe-morpholine-4-yl-amide in 8 ml of methylene chloride digested with 8 ml triperoxonane acid.

TCX Rf (K) of 0.5; FAB-MS (M + H)+887,5; IR (KBR): 1639, 1531, 1495, 1453.

The source material was obtained as follows.

12a) of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid.

400 ml of a mixture of digoxin water 1 1 for 4 h at RT mix 20 g of 1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid (getting by P. L. Julian, W. J. Karpel, A. Magnani and E. W. Meyer, J. Am. Chem. Soc. 1948, 70, 180, however, based on (L)---- phenylanine), 233,6 g of potassium carbonate and 37 g of Boc-anhydride. The reaction mixture is acidified with diluted Hcl to pH 2 and extracted 3 times using ethyl acetate. After washing the organic phases 1 N. solution of potassium hydrosulfate, water and brine, drying over Na2SO4, evaporation and crystallization from a mixture of methylene chloride with hexane get the title compound.

TCX Rf (B) IS 0.2; ()D= 16(c 1, IU is osphere nitrogen 6,47 g N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid in 70 ml of methylene chloride at 0oC with the help of 4.7 g of 1-chloro-N,N-2-trimethylpropyl-1-enylamine (Haveaux, B. Dekoker, A. Rens, M. Sidani, A. R. Toye, J. Ghoser and L. Org. Synth. 59, 29 and 34) transferred to the corresponding acid chloride of the acid and after 15 min, mixed with 9.0 g of Hunig base and solution 6,83 g L-Val-benzyl complex ether hydrochloride in 54 ml of methylene chloride. After 15 min at 0oC and 16 h at RT, the reaction mixture is washed with 10-aqueous citric acid solution, water, saturated sodium bicarbonate solution, water and brine. The aqueous phase is extracted with two portions of methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated. Because according to the1H-NMR in this Boc-protective group is partly removed, the crude product is again injected into the interaction with 6.8 g of Boc-anhydride in 160 ml of methylene chloride and 2.7 g of Hunig base. Column chromatography (SiO2, hexane/ethyl acetate 3 1) gives pure title compound.

TLC Rf (D) of 0.15.

12V) N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-L-Val.

Analogously to example 7b) of 1.97 g of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-L-Val-benzyl complex ester in 50 ml of ethyl acetate hydronaut using 0.4 g of 10-aqueous Pd/C to the title compound. This material is used without further purification the n-3(S)- carbonyl-Val-Phe(C)Phe-(L)-Val(L)-Phe-morpholine-4-alamid.

Analogously to example 5 180 mg of N-Boc-1,2,3,4-tetrahydroisoquinoline-3(S)-carbonyl-L-Val in 4 ml of DMF enter into interaction with 232 mg THIEF, 71 mg Not, 011 ml of NMM and a solution of 250 mg of H-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 4) in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate) gives the title compound, which according to amino acid analysis (GC, Chirasil L-Val: the /e Bayer, Z. Naturforschung B. 1983, 38, 12881) as a by-product contains epimer, approximately 14 D-Val.

TCX Rf (B) 0,4; FAB-MS (M + H)+987; IR (KBR): 1697, 1643, 1523, 1496.

Example 13. Boc-Phe(C)-Phe-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1 375 mg of 5(S)-Boc-amino(4-(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-(p-F-Phe)-morpholine-4-ylamide in 7 ml of DMF desilicious with 275 mg TBAF with obtaining the title compound, which after crystallization from a mixture of diethyl ether and hexane is obtained pure.

TCX Rf (B) 0,50; FAB-MS (M + H)+747.

The source material was obtained as follows.

13a) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1l) 250 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (lamido (see getting example 9D), dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 2 1) gives the title compound.

TLC Rf (AND) 0,43; FAB-MS (M + H)+861.

Example 14. Boc-Phe(C)Phe-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1 238 mg of 5(S)-Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2-(R)- phenylmethanol-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide in 7 ml of DMF desilicious using 204,5 mg TBAT the title compound, which after infusion with a mixture of diethyl ether and hexane 1 1 and column chromatography (SiO2, ethyl acetate) is obtained pure.

TCX Rf (B) 0,37; FAB-MS (M + H)+759.

The source material was obtained as follows.

14a) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R))- phenylmethanol-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 1l) 250 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 5 ml of DMF enter into interaction with 230,6 mg THIEF, 70,4 mg NOBT, 130 μl of NMM and to 206.6 mg of H-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide (receipt see example 10), dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 2 1) gives the title with the S="ptx2">

Analogously to example 1 430 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-(Cha-morpholine-4-ylamide in 5 ml of DMF desilicious using 320 mg TBAT the title compound, which after column chromatography (SiO2the ethyl acetate) and soaking in hexane obtained pure.

TCX Rf (E) of 0.51; FAB-MS (M + H)+735.

The source material was obtained as follows.

15A) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 1l) 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 3 ml DMF enter into interaction with 277 mg THIEF, of which 84.5 mg Not and 0.22 ml of NMM and 231 mg of H-(L)-Val-(L)-(-Cha-morpholine-4-ylamide (receipt see example 11a), dissolved in 2 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 2 1) gives the title compound.

TCX Rf (A) 0,28; FAB-MS (M + H)+849.

Example 16. Boc-Phe(C)Phe-(L)-Ile)-(L)-Phe-morpholine-4-alamid.

Analogously to example 1, USD 329.8 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Ile-(L)-Phe-morpholine-4-ylamide in 5 ml of DMF desilicious using 242,7 mg TBAF obtaining titeln the 743.

The source material was obtained as follows.

16a) Z-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 1B) 294 mg of Z-(L)-Ile in 10 ml of dichloromethane with 229 mg DCC and 260 mg of N-(L)-Phe-morpholine-4-ylamide (example 1H) transferred to title compound, which after column chromatography (SiO2, ethyl acetate/hexane 1 1) is obtained in pure form.

TCX Rf (A) 0,43; FAB-MS (M + H)+482.

16B) H-(L)-ILe-(L)-Phe-morpholine-4-alamid.

Analogously to example 1H), 0,398 g of Z-(L)-ILe-(L)-Phe-morpholine-4-ylamide in 15 ml of methanol by hydrogenolysis with 0.12 g of 10-aqueous Pd/C was transferred to the title compound, which after column chromatography (SiO2, dichloromethane/methanol 9 1) is obtained in pure form.

TCX Rf (E) of 0.5; FAB-MS (M + H)+348.

16B) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R))- phenylmethanol-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 1l), to 240.5 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 5 ml of DMF enter into interaction with 242 mg THIEF, 73,8 mg NOBT, output reached 125.5 μl of NMM and 190 mg of N-(L)-Ile-(L)-Phe-morpholine-4-ylamide. Column chromatography (SiO2, ethyl acetate/hexane 1 1) gives the title compound.

TCX Rf (A) OF 0.21; FAB-MS (M + c-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-Gly-morpholine-4-ylamide in 5 ml of DMF desilicious using 282,7 mg TBAF with obtaining the title compound and, finally, insist in diethyl ether.

TLC Rf (B) 0,23; FAB-MS (M + H)+639.

The source material was obtained as follows.

17a) of Z-Gly-morpholine-4-alamid.

Analogously to example 1m), of 8.37 g of Z-Gly-HE in 500 ml of dichloromethane with the aid of 8.25 g DCC and 3,49 ml of the research was transferred to the title compound.

TLC Rf (B) of 0.28.

17B) H-Gly-morpholine-4-alamid.

Analogously to example 1H), 10.8 g of Z-Gly-morpholine-4-ylamide in 600 ml of methanol by hydrogenolysis with 3 g 10-aqueous PD/C was transferred to the title compound, which after filtering off the catalyst and evaporation of the filtrate is used directly in the nearest stage.

TCX Rf (B) is 0.2; IR (CH2Cl2): 1654, 1461, 1440.

17B) Z-(L)-VaI-Gly-morpholine-4-alamid.

Analogously to example 1H), 3.7 g of Z-(L)-valine in 75 ml of dichloromethane with the aid of 2.06 g DCC and 1.44 g of H-Gly-morpholine-4-ylamide transferred to the title compound.

TLC Rf (B) of 0.21.

17g) H-(L)-VaI-Gly-morpholine-4-alamid.

Analogously to example 1H), of 3.78 g of Z-(L)-VaI-Gly-morpholine-4-ylamide in 160 ml of methanol by hydrogenolysis with 0.6 g of 10-aqueous Pd/C was transferred to the title compound, which after filtering off the catalyst by column chromatography (SiO2, dichloromethane/methane is 67, 1439.

17) 5(S)-(Boc-amino)-4(S)of tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-VaI-Gly-morpholine-4-alamid.

Analogously to example 1l), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 5 ml of DMF enter into interaction with 302 mg THIEF, to 92.1 mg Nowt, 156,5 μl of NMM and 175,5 mg of H-(L)-VaI-Gly-morpholine-4-ylamide. Column chromatography (SiO2, ethyl acetate/hexane 1 9 --> ethyl acetate) gives the title compound.

TCX Rf (B) OF 0.44; FAB-MS (M + H)+753.

Example 18. Boc-he(C)Phe-(L)-Ile-Gly-morpholine-4-alamid.

Analogously to example 1, 362,4 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Ile-Gly-morpholine-4-ylamide in 5 ml of DMF desilicious using 292,7 mg TBAF to cover connecting and, finally, insist in diethyl ether.

TLC Rf (B) 0,30; FAB-MS (M + H)+653.

The source material was obtained as follows.

18a): Z-(L)-Ile-Gly-morpholine-4-alamid.

Analogously to example 1B), 2.65 g of Z-(L)-Ile in 75 ml of dichloromethane is injected into the interaction of 2.06 g DCC and 1.44 g of H-Gly-morpholine-4-ylamide (example 17B). After soaking in diethyl ether to obtain the title compound.

TCX Rf (E) of 0.7.

18b) H-(L)-Ile-Gly-MOLISA with 0.6 g of 10-aqueous Pd/C was transferred to the title compound, after filtering off the catalyst by column chromatography (SiO2, dichloromethane/methanol 9 1) is obtained in pure form.

TCX Rf (E) 0,3; FAB-MS (M + H)+258; IR (CH2Cl2): 1653, 1510, 1467, 1439.

18V): 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Ile-Gly-morpholine-4-alamid.

Analogously to example 1l), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenyl-2(R)-fenilmetilketenom acid (example 2G) in 5 ml of DMF enter into interaction with 301,8 g a THIEF, to 92.1 mg Nowt, 156,5 μl of NMM and 185 mg of H-(L)-Ile-Gly-morpholine-4-ylamide. Column chromatography (SiO2, ethyl acetate/hexane 9 1) gives the title compound.

TCX Rf (B) 0,40; FAB-MS (M + H)+767.

Example 19. Boc-Phe(C)Phe-(L)-VaI-(L)-(-VaI-morpholine-4-alamid.

Analogously to example 1, 416 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-VaI-(L)-VaI-morpholine-4-ylamide in 10 ml of DMF desilicious using 330 mg TBAF to cover connecting and, finally, insist in diethyl ether.

TCX Rf (B) 0,39; FAB-MS (M + H)+681.

The source material was obtained as follows.

19a) Z-(L)-VaI-(L)-VaI-morpholine-4-alamid.

Analogously to example 1m), 2.0 mg of Z-(L)-VaI-(L is ETANA, transferred to the titular connection.

TLC Rf (B) of 0.5.

19b) H-(L)-VaI-(L)-VaI-morpholine-4-alamid.

Analogously to example 1H), 2.3 g of Z-(L)-VaI-(L)-VaI-morpholine-4-ylamide in 220 ml of methanol by hydrogenolysis with 0.5 g 10-aqueous Pd/C was transferred to the title compound, which after filtering off the catalyst by column chromatography (SiO2, dichloromethane --> dichloromethane/methanol 19 1 --> 9:1) and trituration in a mixture of diethyl ether/hexane is obtained in pure form.

TCX Rf (E) 0,74; FAB-MS (M + H)+286; IR (CH2Cl2): 1642, 1507, 1461, 1440.

19c) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-VaI-(L)-VaI-morpholine-4-alamid.

Analogously to example 1l), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 5 ml of DMF enter into interaction with 277 mg THIEF, of which 84.5 mg Not, 156,5 μl of NMM and 194 mg of H-(L)-VaI-morpholine-4-ylamide. Column chromatography (SiO2, ethyl acetate/hexane 2 1) gives the title compound.

TCX Rf (AND) 0,27; FAB-MS (M + H)+795.

Example 20. Boc-Phe(C)Phe-(L)-VaI-(L)-(-Phe-thiomorpholine-4-alamid.

Analogously to example 1, 484 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-VaI-(L)-Phe-calm surroundings/hexane 2 1) and insisting in hexane gives the title compound.

TCX Rf (AND) 0,31; FAB-MS (M + H)+745.

The source material was obtained as follows.

Analogously to example 1K), 1,99 g of Z-(L)-VaI-(L)-Phe-OH (Bachem, Bubenforf, Switzerland) in 40 ml of dichloromethane is injected into the interaction of 1.03 g DCC and a solution of 0.52 g thiomorpholine in 40 ml of dichloromethane to obtain the title compound, which after extraction is obtained in the form of butter.

TCX Rf (E) 0.8; IR (CH2Cl2): 1725, 1675, 1642, 1499, 1465, 1454.

20B) H-(L)-VaI-(L)-Phe-thiomorpholine-4-alamid.

Under ice cooling, 2 g of Z-(L)-VaI-(L)-Phe-thiomorpholine-4-ylamide mixed with 45 ml NVG (acetic acid, 33-Naya (Fluca, Burchs, Switzerland) and stirred for 1.5 h at RT. Then the reaction mixture is evaporated, distribute the balance between the three portions of ethyl acetate, saturated sodium hydrogen carbonate solution, water and brine, dry the organic phase over Na2SO4and evaporated. Column chromatography (SiO2, methylene chloride/methanol 9 1) gives the first of the title compound.

TCX Rf (E) of 0.56; FAB-MS (M + H)+350; IR (CH2Cl2): 1641, 1502, 1463, 1454, 1448; amino acid analysis (GC, Chirasil-L-VaI-column) E. Bayer, Z. Naturforchung, B 1983, 38, 1281): TRet(L)-VaI-derived) at 8.36 min (> 99 ), TRet(L)-Phe-derived) 22,73 min (> 94%).

20V) 5(S)-(Boc-amine is nelogicno example 1l), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G), in 5 ml of DMF enter into interaction with 277 mg THIEF, of which 84.5 mg Not, 219 ml of NMM them 238,4 mg of H-(L)-VaI-Phe-thiomorpholine-4-ylamide dissolved in 3 ml of DMF. Column chromatography (SiO2, ethyl acetate/hexane 1 1) gives the title compound.

TCX Rf (A) 0,43; FAB-MS (M + H)+859.

Example 21.

In a similar manner as described in one of the previous examples, or below in detail by way receive the following connections:

A) 1) Boc-(p-F/Phe(C)(p-F(Phe-(L)-BaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 1, 83 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-(p-forfinal-2(R)- (p-performer)-hexanoyl-(L)-VaI-(L)-Phe-thiomorpholine-4-ylamide using 60 mg TBAF 0.95 ml of DMF was transferred to the title compound: FAB-MS (M + H)+765.

The source material was obtained as follows.

1)a) N-Boc-(p-forfinally).

0.4 l of a mixture of dioxane with water in the ratio 1: 1, 20 g (109 mmol) of p-pertanyaannya (Fluka, Buchs, Switzerland) was injected into the interaction with 35.5 g (163 mmol) of Boc-anhydride and 150 g (of 1.09 mol) of potassium carbonate. After 4 h, the reaction mixture is acidified with citric acid solution and extracted with three Partita sodium and evaporated. Dissolution of the residue in a small amount of methylene chloride and crystallization due to the additive hexane gives the title compound.

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

At a temperature of from -5oC to -10oC solution of 17.9 g (63 mol) of N-Boc-(p-pertanyaannya) 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 mol) of isobutyl ether of Harborview acid in 44 ml of abs. THF. After stirring 0.5 h at RT the precipitate is sucked off. The filtrate upon cooling was added dropwise to 4.77 g (126 mol) sodium borohydride in 28 ml of water. After stirring 4 h at RT acidified with 10 citric acid. THF partially evaporated on a rotary evaporator and the residue is distributed between the three portions of ethyl acetate, the two portions of 2 n sodium hydroxide solution water, saturated sodium bicarbonate 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 the title compound.

TLC Rf (A) 0,36;1H-NMR (200 MHz, CD3OD): 7,24 (DD, 8 and 5 Hz, 2H); 6,98 (t, 8 Hz, 2H); to 3.73 (m, 1H); 3,47 (D. 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).

1)) N-B is slingload in 44 ml of methylene chloride was added dropwise of 4.44 ml (of 62.4 mmol) DMSO, dissolved in 76 ml of methylene chloride. After stirring 15 h added 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 a mixture of methylene chloride with THF 1 1 --> deposition) and stirred an additional 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 was added dropwise 278 20 ml aqueous solution of potassium hydrosulfate, then 220 l of hexane. Leave to warm up to CT, the aqueous phase is separated and extracted 2 times with ether. The organic phase, after washing with saturated sodium bicarbonate solution, water and brine, drying over sodium sulfate and evaporation to give the title compound, which without further purification used in the nearest stage.

1H-NMR (200 MHz, Dl3): 9,63 (c. 1H); from 6.9 to 7.2 (2m, 4H); 5,04 (m, 1H): was 4.42 (m, 1H); 3,10 (m, 2H); 1,43 (C. N).

1) g) 5(S)-(1/S)-amino)-2-(p-forfinal)ethyl)-dihydrofuran-2-(3H)-he.

Analogously to example 21 (B) 1) b), 16.7 g of ethyl ester of 2-iodopropionic acid in 124 ml of toluene, 8,1 g Zn/Cu and 12.4 ml of dimethylacetamide get homoeopath zinc. It using the cannula transferred into a chilled before (-40) - (-25)oC trichloracetonitrile (obtained from 5,11 ml Tetra is 5 min -25oC and again cooled to -40oC. Then was added dropwise a solution of 9.28 are g N-Boc-(p-pertanyaannya) in 33 ml of methylene chloride and stirred for 15 h at about -20oC, and finally for one hour at 0oC additionally. The reaction mixture is poured into 0,43 kg of ice water and 0.55 l of tert. -butyl methyl ether and within 10 min intensively stirred. Separate the aqueous phase is extracted twice with ether, washed the organic phase with water, saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated. Get crystal ethyl ester and get 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-forfinal)-hexanoic acid as an intermediate product. This intermediate product in 244 ml of toluene and 7,34 ml of acetic acid is heated for 2 hours at 100oC. Cooled the reaction mixture is mixed with 0.5 l of water, separating the aqueous phase is extracted twice with ether, the organic phase is washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 2 1) gives pure title compound.

TLC Rf (G) 0,22; FAB-MS (M + H)+324. ()D= 20,7(c 1, ethanol).

1) e) 5(S)-(1/S) (1.0 g 5(S)-(Boc-amino)-2-(p-forfinal/ethyl)-dihydrofuran-2-(3H)-it, dissolved 7.9 ml GTP, deprotonated using 6,05 ml of bis(trimethylsilyl)amide lithium in the form of a 1 M solution in THF and alkylate using 0,673 g p-ftorangidridy at -75oC (1 h). Column chromatography (SiO2, methylene chloride/ether 49 1) gives pure title compound.

TCX Rf (H) 0,17:1H-NMR (200 MHz, CCl3): 7,19 7,05 and 7.04 6,88 (2m in 4H; 4,50 (D. 10 Hz, HN); 4,11 (m, 1H); a 3.87 (km, about 8 Hz, 1H); 3,1 2,7 (m, 5H); 2,33 2,14 and 2.02 of 1.85 (2 m in 1H); 1,35 (C. N).

1) (e) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-forfinal)-2(R)-p-performer)-hexanoic acid.

Analogously to example 1), 790 mg of 5(S)-(1/S)-(Boc-amino)-2-(p-forfinal/ethyl)-3(R)-(p-performer)- dihydrofuran-2-(3H)-she's in 29 ml of dimethoxyethane and 15 ml of water hydrolyzing with 7.3 ml of 1 M solution of lithium hydroxide to obtain the title compound, which is directly applied next.

1) g) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-p-performer)-hexanoic acid.

Analogously to example 1K), 956 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-(-6-(p-forfinal)-2(R)-p-performer)- hexanoic acid in 2.3 ml of DMF similarbut with 1.47 g of tert. butyldimethylchlorosilane and 1.19 imidazole. The hydrolysis of the silyl ester function of grinding with potassium carbonate in the e connection.

TCX Rf (G) 0,13; FAB-MS (M + H)+564.

1) C) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsiloxy)-6-(p-forfinal)-2(R)- performer-hexanoyl-(L)-Val-Phe-morpholine-4-alamid.

Analogously to example 9F), 110 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal-2(R)-(p-performer)-hexanoic acid and to 71.5 mg of H-(L)-Val-(L)-Phe)-morpholine-4-ylamide (example 1H), 1,83 mg TU. The pure title compound is obtained after column chromatography (SiO2, methylene chloride/ether 3 1).

TLC Rf (O) 0,14; FAB-MSD (M + H)+897.

2) Boc-(p-F/Phee(C)(p-F/Phe-(L)-VaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 1, 150 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-(p-forfinal-2(R)- (p-performer)-hexanoyl-(L)-VaI-(L)-(-p-F-Phe)-morpholine-4-ylamide using 105 mg TBAF in 2.5 ml DMF was transferred to the title compound.

FAB-MS (M + H)+783.

The source material was obtained as follows.

2) a) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-(p-forfinal)-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-(p-Phe)-morpholine-4-alamid.

Analogously to example 9 (e), 100 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsiloxy)-6-(p-forfinal)-2(R)- (p-performer)-hexanoic acid (example 21 B) 1) f) and 68.5 mg of H-(L)-Val-(L)-(p-F-Phe)-morpholine-4-lamioideae.

TCX Rf (O) 0,17; FAB-MS (M + H)+897.

3) Boc-(p-F(Phe(C)(p-F(Phe)-(L)-VaI-(L)-(p-CH3-Phe)- morpholine-4-alamid.

Analogously to example 1, 126 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-performer)- hexanoyl-(L)-VaI-(L)-(p-CH3O-Phe)-morpholine-4-ylamide with 87 mg TBAF in 2 ml of DMF was transferred to the title compound.

FAB-MS (M + H)+795.

The source material was obtained as follows.

3) a) 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-(p-forfinal)-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-(n-CH3O-Phe)- morpholine-4-alamid.

Analogously to example 9 (e), 80 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-performer)-hexanoic acid (example 21 B) 1 (e), and 56.7 mg of H-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide (example 10 LW) in 1.3 ml of NMM/CH3CN, 0.25 M, enter into interaction with 590,2 mg TU to obtain the title compound.

FAB-MS (M + H)+909.

4) Boc-(p-F(Phe)(C)(p-F(Phe)-(L)-VaI-(L)-(Cha)-morpholine-4-alamid.

Analogously to example 1, 230 mg of 5(S)-(Boc-amino)4-(S)-(tert.-butyldimethylsilyloxy)-6-(p-forfinal-2(R)- (p-performer)-hexanoyl-(L)-VaI-(L)-(Cha)-morpholine-4-ylamide with 164 mg TBAF 3.8 ml of DMF was transferred to the title compound.

Analogously to example 9 (e), 150 mg of 5(S)-Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-(p-forfinal-2(R)- (p-performer)-hexanoic acid (example 21 B) 1 (e), and 99.4 mg of H-(L)-Val-(L)-Cha-morpholine-4-ylamide (example 11 (a), 2.4 ml of NMM/CH3CN, 0.25 M, enter into interaction with 111 mg TU to obtain the title compound.

FAB-MS (M + H)+885.

5) Boc-(p-F(Phe)(p-F(Phe-(L)-Ile-(L)-Phe-morpholine-4-alamid.

B) 1) Boc-Phe(C))(p-F(Phe-(L)-VaI-(L)-)-Phe-morpholine-4-alamid.

Analogously to example 1, 0.31 g of 5(S)-(Boc-amino)-4(S) - tert.-butyldimethylsilyloxy)-6-phenyl)-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-ylamide subjected to removal of the protective group using TWAT in 3.0 ml of DMF to obtain the title compound, which after column chromatography (SiO2, ethyl acetate) is obtained pure.

TCX Rf (B) 0,55; FAB-MS (M + H)+747.

The source material was obtained as follows.

1) a) Ethyl ester of 2-iodopropionic acid.

A suspension of 170 ml of ethyl ether 2-bromopropionic acid (Fluka, Buchs, Switzerland) and 950 g of sodium iodide in 1.8 l of acetone is stirred for 20 h at 60oC. the Reaction mixture ottilia sodium thiosulfate and finally, brine, dried over sodium sulfate and evaporated. Distillation (83oC; 2 mbar) gives the pure title compound.

MS M+228;1H-NMR (200 MHz, l3): 4,17 (K. 7 Hz, 2H); 3,34 and 2,97 (d 7 Hz, 2 x 2H); 1.28 (in T. 7 Hz, 3H).

1) (b) 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-dihydrofuran-2-(3H)-he.

Similarly, A. E. Ce Vamp, A. T. waguchi, R. P. Volante and I, Shinkai Tetrahedron Lett. 32, 1967. 1991. In a nitrogen atmosphere to a solution of 17.4 g of ethyl ester of 2-iodopropionic acid in 130 ml of toluene added 8,03 g Zn (Cu): P. D. Smith, H. E. Simmons, W. E. Parham, M. D. Bhavsar, Org Synth. Coll. Vol. 5, 855, 1973 and 12,96 ml of dimethylacetamide and intensively stirred for 1 h at RT and 4 h at 80oWith advanced. Get the solution homoeopath zinc. In the second apparatus (nitrogen atmosphere), the solution to 5.58 ml (to 18.9 mmol) of tetraisopalmitate in 16.4 ml of toluene and 91.8 ml of methylene chloride under mild cooling is mixed with 5,90 ml (53.8 mmol) of titanium tetrachloride, stirred for 15 min at RT (forming a yellow solution) is cooled to -40oC, undergoes partial crystallization of trichloracetonitrile. Using the cannula decanted cooled to CT solution homoeopath zinc from metal solids and added dropwise to trichloracetonitrile, and the temperature support for 5 min -25oC and again cooled to -40oC. Then was added dropwise a solution of 9.0 g of N-Boc-phenylalanine (receiving: D. J. Kempf, J. Org. Che, 51, 3921. 1986) of 32.8 ml of methylene chloride and stirred for 15 h at about -20oC finally, a further 1 h at 0oC. the Reaction mixture was poured into 0.5 kg of ice water and 0.5 l of ether and intensively stirred for 10 minutes to Separate the aqueous phase is extracted twice with ether, the organic phase is washed twice with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. Obtained as an intermediate product of crystalline ethyl ester 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenylhexanoic acid. This intermediate product in 295 ml of toluene and 9 ml of acetic acid is heated for 2.5 h at 80oC. the Reaction mixture is mixed with 0.5 l of water, separating the aqueous phase is extracted with two portions of ether, washed the organic phase with saturated sodium bicarbonate solution, water and brine and dried over sodium sulfate. Partial evaporation of the organic phase and mixed with hexane gives the crystalline title compound, which according to the analytical research contains about 10 (4R)-epimer (TLC Rf (D) 0.08). Column chromatography (SiO2hexane/e is SS="ptx2">

1) b), 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-3(R)-(p-performer)- dihydrofuran-2-(3H)-he.

Similarly, A. K. Ghosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500. 1991. Under nitrogen atmosphere a solution of 300 mg (0,982 mmol) of 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-dihydrofuran-2-(3H)-she's in 6 ml of THF at -75oC mix 1.92 ml of bis-(trimethylsilyl)-lithium amide, 1 M in THF (Aldrich) and further stirred for 15 min at this temperature. Then added dropwise 132 μl (of 1.077 mmol) p-ftorangidridy (Fluka, Buchs, Switzerland) and stirred for 30 min at -50oC. After further cooling to -75oC, add 0.3 ml of propionic acid and then 0.3 ml of water. Heated to 0oC, diluted with ethyl acetate, washed with 10-aqueous citric acid solution, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate 4 1) gives pure title compound.

TCX Rf (G) 0,54; FAB-MS (M + H)+414.

1) g) 5(S)-(Boc-amino)-4(S)-hydroxy)-6-phenyl)-2(R)-(p-performer)-hexanoic acid.

Analogously to example 1i), 1,46 g 5(S)-(1/S)-(Boc-amino)-2-(phenylethyl)-3(R)-(p-performer) -dihydrofuran-2-(3H)-she's in 57 ml of dimethoxyethane and 29 ml of water hydrolyzing with a 14.1 ml of 1 M races is.

1) e) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)-p - performer)-hexanoic acid.

Analogously to example 1K), 0.9 g of 5(S)-(Boc-amino)-4(S)-hydroxy)-6-phenyl-2(R)-p-performer)-hexanoic acid in 4 ml of DMF similarbut using 1,49 g of tert.-butyldimethylchlorosilane 1.2 g of imidazole. The hydrolysis of the silyl ester function with the help of 1.9 g of potassium carbonate in 50 ml of methanol/THF/water 3 1 1 gives, after acidification with a solution of citric acid and extraction with ethyl acetate the title compound. TCX Rf (G) 0,2.

1) (e) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 9 (e), 200 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsiloxy)-6-phenyl-2(R)- (p-performer)-hexanoic acid and 134 mg of H-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 1H) 3.6 mg NMM/CH3, 0.25 M, enter into interaction with 153 mg of HBTU. After crystallization from hexane get the pure title compound.

TCX Rf (A) of 0.25.

2) Boc-Phe(C)(p-F(Phe-(L)-VaI-(L)-(Cha)-morpholine-4-alamid.

Analogously to example 1), 120 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-VaI-(L)-(Cha)-morpholine-4-ylamide with 87 mg TBAF 1.4 ml DMF">

The source material was obtained as follows.

2) a) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-Cha-morpholine-4-alamid.

Analogously to example 9 (e), 100 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoic acid (example 21 D) 1) e) and 68 mg of N-(L)-Val-(L)-(Cha-morpholine-4-ylamide (example 11 (a), 1.8 ml of NMM/CH3CN, 0.25 M, is injected into the interaction from 76.4 g U.

TCX Rf (D) of 0.50.

B) 1) Boc-Phe(C)(CN/Phe-(L)-VaI-(L)-(Phe)-morpholine-4-alamid.

Analogously to example 1, 60 mg of 5(S)-(Boc-amino)4(S) - tert.-butyldimethylsilyloxy)-6-phenyl)-2(R)- (p-cyanovinylene)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-ylamide using 64,3 mg TBAF in 1.0 ml DMF to remove the protective group to obtain the title compound. Column chromatography (SiO2the ethyl acetate gives the pure title compound.

TCX Rf (B) 0,26; FAB-MS (M + H)+754.

The source material was obtained as follows.

1) (a) 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-3(R)-(p-cyanovinylene)- dihydrofuran-2(3H)-he.

Analogously to example 21 D) 1) C), 1.5 g of 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-dihydrofuran-2-(3H)-it (example 21 B) 1) b), dissolved in 32 ml of THF, deprotonated with the help of 9.8 ml of 1 M solution of bis-(provided in 3 ml of THF. Column chromatography (SiO2hexane/ethyl acetate 1 1) gives the pure title compound.

TCX Rf (G) of 0.33.

1) (b) 5(S)-(Boc-amino)-4(S)-hydroxy)-6-phenyl)-2(R)-(p-cyanovinylene)-hexanoic acid.

Analogously to example 1i), 0.50 g of 5(S)-(1/S)-(Boc-amino)-2-(phenylethyl)-3(R)-(p-cyanovinylene)- dihydrofuran-2-(3H)-she's in 19 ml of dimethoxyethane and 10 ml of water hydrolyzing with 4.8 ml of 1 M solution of lithium hydroxide to obtain the title compound.

TCX Rf (E) of 0.3.

1) b), 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-cyanovinylene)-hexanoic acid.

Analogously to example 1K), and 0.62 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-cyanovinylene)-hexanoic acid 6.2 ml DMF similarbut using 0,98 tert.-butyldimethylchlorosilane and 0.79 g of imidazole. The hydrolysis of the silyl ester function with 1.2 g of potassium carbonate in 31 ml of methanol/THF/water 3 1 1 gives after acidification with citric acid solution and extract with ethyl acetate the title compound.

TCX Rf (G) of 0.29. FAB-MS (M + H)+553.

1) g) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-cyanovinylene)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 9F), 72 mg of 5(S)-(Boc-amino)-4(S)-(tert.-buildine is of 1.14 mg NMM/CH3CN, 0.25 M, enter into interaction with 50 mg TU to obtain the title compound.

TLC Rf (A) 0,19.

2) Boc-Phe(C)(p-CN/Phe-(L)-Ile-(L)-(Phe)-morpholine-4-alamid.

Analogously to example 1, 510 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-cyanovinylene)-hexanoyl-(L)-Ile-(L)-(Phe)-morpholine-4-ylamide distil using 362,3 mg TBAF in 10 ml of DMF. The reaction mixture was poured into ice water, extracted three times of methylene chloride, washed the organic phase with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated. Column chromatography (SiO2the ethyl acetate gives the pure title compound.

TLC Rf (B) OF 0.51; FAB-MS (M + H)+768.

The source material was obtained as follows.

2) a) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl)-2(R)- (p-cyanovinylene)-hexanoyl-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 9 (e), 360 mg of 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-cyanovinylene)-hexanoic acid (example 21 D) 1) g) and 253 mg of H-(L)-Ile-(L)-Phe-morpholine-4-ylamide (example 16 b) 6,36 ml of NMM/CH3CN, 0.25 M, enter into interaction with 276 mg TU. Distribution of residue after evaporation between the stands is, drying the organic phase over sodium sulfate and evaporation gives the title compound.

TLC Rf (D) of 0.07.

G) 1) Boc-Phe(C)(p-F(Phe-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 1, 350 mg (0,395 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-VaI-(-p-F-Phe)-morpholine-4-ylamide with 374 mg (1,19 mmol) TBAF in 3 ml of DMF was transferred to the title compound.

FAB-MS (M + H)+765.

The source material was obtained as follows.

1) (a) 5(S)-(Boc-amino)-4(S) - tert.-butyldimethylsilyloxy)-6-phenyl)-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholine-4-alamid.

Analogously to example 9F), 265 mg (0,485 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoic acid (example 21 D) 1) e) and 188 mg (0,53 mmol) N-(L)-Val-(L)-(p-F-Phe)-morpholine-4-ylamide (example 9D) in 4.6 ml of NMM/CH3CN, 0.25 M, enter into interaction with 202,6 mg (0,53 mmol) HBTU: TCX Rf (D) of 0.28.

2) Boc-Phe(C)(p-F(Phe-(L)-VaI-(L)-(p-CH3O-PHe)-morpholine-4-alamid

Analogously to example 1), 280 mg (0,312 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-VaI-(L)-(p-CH3O-Phe)-morpholine-4 - alamid with 295 mg (0,94 mmol) TBAF in 3 ml of DMF pastoe the title compound.

TCX Rf (B) 0,56; FAB-MS (M + H)+777.

The source material was obtained as follows.

2) a) 5(S)-(Boc-amino)-4(S)of tert. -butyldimethylsiloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-Val-(L)-(n-CH3O-Phe)-morpholine-4 - alamid.

Analogously to example 9F), 200 mg (0,366 mmol) of 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-n-phenyl-2(R)- (p-performer)-hexanoic acid (example 21 D) 1) e) and 146 mg (0,402 mmol) N-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide (example 10D) in 3.6 ml of NMM/CH3CN 0.25 M enter into interaction with 153 mg (0,402 mmol) U: TCX Rf (L) is 0.22.

3) Boc-Phe(C)(p-F(Phe-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 1), 220 mg (0,251 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-Ile-(L)-Phe-morpholine-4-alamid using 2490 mg (0.75 mmol) TBAF in 3 ml of DMF was transferred to the title compound. Column chromatography (SiO2, ethyl acetate/tetrahydrofuran 9 1) gives pure title compound.

TCX Rf (0) 0,3; FAB-MS (M + H)+761.

The source material was obtained as follows.

3) a) 5(S)-(Boc-amino)-4(S)-tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoyl-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 9F), 200 mg (0,366 mmol) 5(140 mg (0,403 mmol) N-(L)-Ile-(L)-Phe)-morpholine-4-ylamide (example 16 b) in 3.5 ml of NMM/CH30.25 M enter into interaction with 153 mg (0.40 mmol) of HBTU.

TLC Rf (D) of 0.16.

D) 1) Boc-Phe(C)(p-CH3O(Phe-(L)-Val-(L)-Phe)-morpholine-4-alamid.

Analogously to example 1) 417 mg (0.48 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoyl-(L)-VaI-(L)-Phe-morpholine-4-ylamide with 301 mg (0.95 mmol) TBAF in 5 ml of DMF was transferred to the title compound.

TCX Rf (F) 0,4; FAB-MS (M + H)+759.

The source material was obtained as follows.

1) a) p-methoxybenzylidene.

A solution of 1.7 ml (12.8 mmol) of 4-methoxy-benzylchloride (Fluka, Buchs/Switzerland) in 25 ml of acetone was stirred at room temperature with 9.4 g (and 62.6 mmol) of sodium iodide. Gas chromatography of the reaction mixture after 90 min shows full conversion, so the reaction mixture was poured into ether and washed her 10 th solution of sodium thiosulfate and brine. Drying the organic phase with Na2SO4and evaporation gives the title compound.

1H-NMR (200 MHz, CD3OD): of 3.78 (s, 3H), of 4.54 (s, 2H), 6,8 - 6,95 and 7.2 to 7.4 (2m, 2N).

1) (b) 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-3(R)-(p-methoxyphenethyl)- dihydrofuran-2-(3H)-he.

Analogously to example 21 d) 1)) 2,98 g (9,74 mmol) of 5(S)-(1/S)-(Boc-Amu of 19.5 ml of 1 M solution of bis-(trimethylsilyl)-amide lithium in THF and alkylate using 2.9 g (11.7 mmol) of a solution of p-methoxybenzylidene in tetrahydrofuran (45 min). Column chromatography (SiO2, hexane/ethyl acetate 2 1) and insisting in diisopropyl ether to give pure title compound.

TCX Rf (D) of 0.32.

1) b), 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl)-2(R)-(p-methoxyphenethyl)- hexanoic acid

Analogously to example 1, 1.7 g (3,99 mmol) of 5(S)-(1/S)-(Boc-amino)-2-phenylethyl)-3(R)-(p-methoxyphenethyl)- dihydrofuran-2-(3H)-she's in 43 ml of dimethoxyethane and 11 ml of water hydrolyzing with 16 ml of 1 M solution of lithium hydroxide. Stirring in ether gives the pure title compound.

TCX Rf (F) OF 0.53; FAB-MS (M + Na)+466.

1) g) 5(S)-(Boc-amino)-4(S)of tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoic acid.

Analogously to example 1K), 0,93 mg (2.10 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy)-6-phenyl-2(R)-(p-methoxyphenethyl)- hexanoic acid in 20 ml of DMF similarbut using 1.4 g (for 9.64 mmol) of tert.-butyldimethylchlorosilane and 1,17 g (17,2 mmol) of imidazole. The hydrolysis of the silyl ester function with 1.7 g of potassium carbonate in methanol (23 ml) / THF (7 ml) / water (7 ml) and stirring the crude product in hexane to give pure title compound.

FAB-MS (M + H)+558.

1) e) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexamethyldisilane)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoic acid and 197 mg (0.59 mmol) of N-(L)-Val-(L)-Phe)-morpholine-4-ylamide (example 10) in 5.2 ml of NMM/CH3CN 0.25 M enter into interaction with 224 mg (0.59 mmol) of HBTU.

FAB-MS (M + H)+873.

(E) (1) Boc-Phe(C)(p-CH3)-Phe-(L)-VaI-(L)-(p-CH3O-Phe)-morpholine-4 - alamid

Analogously to example 1) 200 mg (0.22 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoyl-(L)-VaI-(L)-(p-CH3O-Phe)- morpholine-4-ylamide using 210 mg (0.66 mmol) TBAF in 3 ml of DMF was transferred to the title compound.

Column chromatography (SiO2, methyl chloride/methanol 19 1) gives pure title compound.

TCX Rf (F) 0,66; FAB-MS (M + H)+789.

The source material was obtained as follows.

(1) (a) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoyl-(L)-VaI-(L)-(p-CH3O-Phe)- morpholine-4-alamid.

Analogously to example 9F), 200 mg (0,358 mmol) of 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenethyl)-hexanoic acid and 143 mg (0,39 mmol) N-(L)-VaI-(L)-(p-CH3O-Phe)-morpholine-4-ylamide (example 10 d) 3.6 mol PMM/CH3CN 0.25 M enter into interaction with 149 mg (0,39 mmol) BTU; the compound obtained is directly used in further reactions.

W) 1) Boc-Phe(C)(p-CF3)-Phe-(L)-Val-(L)-Phe)-morpholine-4-alamid.

Analogues of the Il-hexanoyl-(L)-VaI-(L)-Phe-morpholine-4 - ylamide with 124 mg (0,39 mmol) TBAF in 3 ml of DMF was transferred to the title compound. Precipitation with diisopropyl ether from a concentrated solution in DMF gives the pure title compound

FAB-MS (M + H)+797.

The source material was obtained as follows.

1) (a) 5(S)-(1(S)-(Boc-amino)-2-phenylethyl-3(R)-(p-trifluoromethyl-phenylmethyl)- dihydrofuran-2-(3H)-he.

Analogously to example 21 (B) (1)) 0 1.0 g (3,26 mmol) of 5(S)-(1(S)-Boc-amino)-2-phenylethyl)-dihydrofuran-2-(3H)-it (example 21 (B) (1)), dissolved in 20 ml of THF, deprotonated at -75oWith the help of 6.5 ml of 1 M solution of bis-(trimethylsilyl)-amide lithium in THF and alkylate using 0,93 g (3,91 mmol) of p-trifluoromethyl-benzylbromide (Fluka, Buchs, Switzerland) at the initial temperature at -75oC (heating for 45 min to -60oC). Column chromatography (SiO2, hexane/ethyl acetate 2 1) gives pure title compound.

TCX Rf (L) 0,4; FAB-MS (M + H-butene)+408.

1) (b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-trifluoromethyl-phenylmethyl)- hexanoic acid.

Analogously to example 1i), 4.3 g (9.3 mmol) of 5(S)-(1(S)-(Boc-amino)-2-(phenylethyl)-3(R)-(p-triftormetilfullerenov)- dihydrofuran-2-(3H)-it, 100 ml of dimethoxyethane and 25 ml of water hydrolyzing with 37 ml of 1 M solution of lithium hydroxide to obtain the title compound.

TCX Rf (H) of 0.68.

Analogously to example 1K), 3.2 g (of 6.65 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-p-trifluoromethyl-phenylmethyl)- hexanoic acid in 25 ml of DMF similarbut using 4,6 (30,6 mmol) tert.-butyldimethylchlorosilane and 3.7 g (of 54.5 mmol) of imidazole. The hydrolysis of the silyl ester function with 5.5 g of potassium carbonate in a mixture of methanol (75 ml), THF (22 ml) / water (12 ml) gives the title compound which is then directly used in the subsequent reactions.

1) g) 5(S)-(Boc-amino)-4(S)of tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-triftormetilfullerenov)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 9F), 200 mg (0,335 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-triftormetilfullerenov)-hexanoic acid and 123 mg (0,369 mmol) N-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 10), 3.2 ml of NMM/CH3CN 0.25 M enter into interaction with 140 mg (0,347 mmol) TU; the title compound is then directly used in the subsequent reactions.

3) 1) Boc-Phe(C)Phe-(L)-Val(L)-Tyr-morpholine-4-alamid.

Analogously to example 1), 360 mg (0,418 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-VaI-(L)-Tyr-morpholine-4-ylamide with 263 mg (0.84 mmol) TBAF in 3 ml of DMF was transferred to the title compound.

In ice, the suspension 14,04 g (40 mmol) of Z-(L)-Tyr-HE in 750 ml of methylene chloride add the remaining 9.08 g (44 mmol) DCC and stirred for 20 minutes Then add s,81 g (80 mmol) NOBT and the solution 5,23 g (60 mmol) of the research in 50 ml of methylene chloride. After stirring for 18 h at RT was filtered, the filtrate washed with saturated solution of NaHCO3, water and brine and the aqueous phase is extracted with two portions of methylene chloride. Column chromatography (SiO2, ethyl acetate), dried with Na2SO4and the evaporated organic phases give the title compound.

TCX Rf (B) of 0.39.

The source material was obtained as follows.

1) b) N-(L)-Tyr-morpholine-4-alamid.

A solution of 2.05 g (5.3 mmol) of Z-(L)-Tyr-morpholine-4-ylamide in 91 ml of methanol hydronaut in the presence of 0.5 g of 10-aqueous Pd/C for 1.5 h at RT. Filtering using zeolite (auxiliary filter substance kieselguhr, John-Mavnille Corp.) and evaporation of the filtrate to give the title compound.

TCX Rf (methanol) 0,34.

1)) Z-(L)-Val-(L)-Tyr-morpholine-4-alamid.

At 0oC in a solution of 6.3 g (25 mmol) of Z-(L)-Val-OH in 400 ml of methylene chloride add 5,18 g (25 mmol) DCC and of 3.73 g (27.5 mmol) NOBT and stirred for 20 minutes Then add CT follow the same procedure described in example 41 (a) (a).

TCX Rf (B) of 0.50.

1) g) H-(L)-Val-(L)-Tyr-morpholine-4-alamid.

Hydrogenation of a solution of 4.83 g (10 mmol) of Z-(L)-Val-(L)-Tyr-morpholine-4-ylamide in 182 ml of methanol in the presence of 1 g of 10-aqueous Pd/C for 1.5 h at RT gives at the end of the filter with zeolite, evaporation of the filtrate and column chromatography (SiO2, methylene chloride/methanol 9 1) of the title compound.

TCX Rf (F) OF 0.30, FAB-MS (M + H)+350.

1) e) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-Tyr-morpholine-4-alamid.

Analogously to example 1l), 300 mg (0,569 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (example 2G) in 5 ml of DMF activate with 277 mg (0,626 mmol) THIEF, of which 84.5 mg (of 0.625 mmol) NOBT and 157 ml (1,42 mmol) NMM and enter into interaction with 198,6 mg (0,568 mmol) N-(L)-Val-(L)-Tyr-morpholine-4-ylamide in 2 ml of DMF (2 h, CT). Column chromatography (SiO2, ethyl acetate/hexane 2 1) gives the title compound.

TCX Rf (I) 0,26; FAB-MS (M + H)+859.

1) (e) (p-Triftormetilfullerenov)-hexanoyl-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 9F), 200 mg (0,335 mmol) of 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- (p-trifloromethyl) in 3.2 ml of NMM/CH3CN 0.25 M with 140 mg (from 0.37 mmol) U. Specified in the title compound immediately used further.

Example 22.

A) Boc-Cha(C)-(p-F)Phe-(L)-Ile(L)-Phe-morpholine-4-alamid.

Analogously to example 1), 0.15 g of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoyl-(L)-Ile-(L)-Phe-morpholine-4-alamid using 117 mg TBAF in 1.7 ml of DMF was transferred to the title compound.

TCX Rf (AND) 0,18; FAB-MS (M + H)+767.

The source material was obtained as follows.

A) a) 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-cyclohexyl)-2(R)- (p-performer)-hexanoyl-(L)-Ile-(L)-Phe-morpholine-4-alamid.

Analogously to example 9F), 102 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-performer)-hexanoic acid (example 1), and 70.8 mg of H-(L)-Ile-(L)-Phe-(-morpholine-4-ylamide (example 16 b) is 1.77 ml of NMM/CH3CN, 0.25 M, is injected into the interaction from 77.4 mg TU.

TCX Rf (A) 0,17; FAB-MS (M + H)+881.

B) Boc-Cha-(C)(p-F(Phe-(L)-Val-(L)-Phe-thiomorpholine-4-alamid.

Analogously to example 1), 0.16 g of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-N-hexanoyl-(L)-Val-(L)-Phe-thiomorpholine-4-alamid with 114 mg TBAF in 1.8 ml DMF was transferred to the title compound.

Analogously to example 9F), 100 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- (p-performer)-hexanoic acid (example 1K), and 70 mg of N-(L)-Val-(L)-Phe-thiomorpholine-4-ylamide (example 20 b), 1.7 ml of NMM/CH3CN (0.25 M) enter into interaction with 76 mg U. After 18 h at RT part of the title compounds receive directly from the reaction mixture by filtration. The additional amount of the title compound is obtained by distribution of the residue after evaporation of the filtrate between the three portions of ethyl acetate, water, two portions of the 10-aqueous citric acid solution, water, two portions of saturated sodium bicarbonate solution, water and brine, drying the organic phases over sodium sulfate and evaporation.

TCX Rf (A) 0,55; FAB-MS (M + H)+883.

Example 23. A gelatin solution.

Sterile filtered aqueous solution of one of the biologically active substances of the formula I mentioned in the above or the below-mentioned examples 1

2 39 and 32, which further comprises 20 cyclodextrin, and a sterile, preserved with phenol gelatin solution at NCI active substance 3 mg

Gelatin 150,0 mg

Phenol 4,7 mg

Distilled water with 20 cyclodextrin 1.0 mg

Example 24. Sterile dry substance for injection.

5 mg of one of the above - or below examples 1 to 22 and 32 of the 39 compounds of the formula I as biologically active substances dissolved in 1 ml of an aqueous solution with 20 mg of mannitol and 20 cyclodextrins as agent for dissolution. The solution is sterile filtered and aseptically filled in a vial with a capacity of 2 ml, deeply cool and lyophilizers. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological sodium chloride solution. The solution is applied intravenously or intramuscularly. The composition can also be placed in a two-chamber ampoule for injection.

Example 25. Nasal aerosol (spray).

In a mixture of 3.5 ml of Myglyol 812and 0.08 g of benzyl alcohol are suspended 500 mg of finely ground (< 5.0 µm) powder of one of the above or the below-mentioned examples 1 to 22 and 32 of the 39 compounds of the formula I as biologically active substances. This suspension is placed in a container with a dispensing valve (valve). It fills 5.0 g of freon 12Runder pressure through the veins of the m contains approximately 100 single doses, you can enter individually.

Example 26. Lacquered tablets.

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

Biologically active substance 1000 g

Corn starch 680 g

Colloidal silicic acid 200 g

Magnesium stearate and 20 g

Stearic acid 50 g

Carboximetilkrahmal sodium 250 g

Water required number

A mixture of one of these in the above or the below-mentioned examples 1 to 22 and 32 of the 39 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 of demineralized water are processed in a wet mass. It rubbed through a sieve with openings 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 tableindex or following examples 1 to 22 and 32 of the 39 compounds of the formula I, for example, Boc-Phe(C)Phe-(L)-Val-(L)-Phe-morpholine-4-ylamide, as a biologically active substance and 625 mg POPG (1-Palmitoyl-2-oleoyl-phosphatidylcholine 1-hexadecanoyl-2-(9-CIS-octadecenoyl)-3-sn-phosphatidylcholine) was dissolved in 25 ml of ethanol. The solution was diluted ten-fold amount of water. To this ethanol solution at RT was added dropwise to the available amount of water at a rate of 10 ml per minute. The ethanol is removed from the mixture by tangential dialysis ("Cross. Flow Filtration") against 1750 ml of water (system: Minitan700 cm2the membrane of polyethersulfone with limit exceptions (Ausschlussgrense) 100 KD, firm Millipore (USA). The mixture in the application of the same system concentrated to 15 mg of biologically active substances by ultrafiltration. After adding 1.24 mg/ml citric acid and 1.24 mg/ml dinitrigenoxide. 2H2O to establish a pH of 4.2 and 1 mg/ml sorbic acid as an antimicrobial preservative, the variance is again concentrated to 15 mg/ml and applied to the cups, for example, with a capacity of 20 ml, the particles of the dispersion have a diameter of 0.1 to 2 μm. They are stable at 2 to 8oC at least six months and is suitable for oral administration.

Example 28. Orally consumed variance 2.

Cooking osushestvleniya ethanol solution.

Example 29. Orally consumed variance 3.

The preparation is carried out analogously to example 27, however, the use of 25 mg of biologically active substances and 125 mg POP for making ethanol solution.

Example 30. Orally consumed variance 4.

The preparation is carried out analogously to example 27, however, the application of 50 mg of biologically active substances and 50 mg POP for making ethanol solution.

Example 31. Orally consumed variance 5.

The preparation is carried out analogously to one of the examples 27 to 30, however, the use of biologically active substances and phosphatidylcholine from soy or phosphatidylcholine from egg yolk (70 100-Noah purity) instead POP for making ethanol solution. In the desirable case, add an antioxidant, ascorbic acid, at a concentration of 5 mg/ml

Example 32. Boc-(p-F(Phe)(C)(p-CF3-(L)-Val-(L)-Phe)-morpholine-4-alamid.

Analogously to example 1, 265 mg (0.48 mmol) of 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-triftormetilfullerenov)- hexanoyl-(L)-VaI-(L)-Phe-morpholine-4-ylamide using 180 mg TBAF 4.2 ml of DMF was transferred to the title compound.

TCX Rf (S) 0,3;2-(p-forfinal)-ethyl)-3(R)- (p-triftormetilfullerenov)-dihydrofuran-2-(3H)-he.

Analogously to example 21 D) 1)), 1.0 g of 5(S)-(1(S)-(Boc-amino)-2-(p-forfinal)-ethyl)-dihydrofuran-2-(3H)-she dissolved in 6.3 ml THF, deprotonated using 6,05 ml of bis-(trimethylsilyl)-amide lithium in the form of a 1 M solution in THF and alkylate using 0,739 g of a solution of p-triftormetilfosfinov (Fluka, Buchs, Switzerland) at -75oC (40 min). Column chromatography (SiO2, hexane/ethyl acetate 2 1) gives pure title compound.

TCX Rf (D) OF 0.48; FAB-MS (M + H)+482.

32) (b) 5(S)-(Boc-amino)-4(S)-hydroxy(-6-(p-forfinal)-2(R)- (p-triftormetilfullerenov)-hexanoic acid.

Analogously to example 1i), of 1.05 g (3,99 mmol) of 5(S)-(1(S)-(Boc-amino)-2-(p-forfinal)-ethyl)-3(R)- (p-triftormetilfullerenov)-dihydrofuran-2-(3H)-she of 35.5 ml dimethoxyethane and 17.9 ml of water hydrolyzing with the help of 8.7 ml of 1 M solution of lithium hydroxide to obtain the title compound, which was directly used further.

32)), 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-triftormetilfullerenov)-hexanoic acid.

Analogously to example 1K), 1.06 g of 5(S)-(Boc-amino)-4(S)-hydroxy(-6-(p-forfinal)-2(R)- (p-triftormetilfullerenov)-hexanoic acid 2.3 MDL DMF similarbut with 1.47 g of tert.-butyldimethylchlorosilane and 1.18 g of imidazole. The hydrolysis of ester C is (SiO2, hexane/ethyl acetate 2 1) of the title compound.

TLC Rf (D) of 0.15.

21H-NMR (200 MHz, CD3OD): to 7.59 and 7,39 (2 days 8 Hz, 2H). 7,19 and 6,98 (2 m N), 6,47 and 5,90 (D. about 9 Hz, together 1H); 3.9 to the 3.65 (m, 2H); 3,15 2,8 (m, 4H); 2,53 2,37 2,07 and 1,9 1,6 1,4 (3 m distance according 1H); 1,37 1,22 (m N). 0,94 (C. N); 0,2 0,1 (m 6N).

32) g) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-p-triftormetilfullerenov)-hexanoyl-(L)-Val-(L)-Phe - morpholine-4-alamid.

Analogously to example 9 (e), 300 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-pharmacypharmacy)-hexanoic acid and of 107.5 mg of H-(L)-Val-(L)-Phe-morpholine-4-ylamide (example 1H), 2.8 ml of NMM/CH3CN, 0.25 M, enter into interaction with 122 mg U.

FAB-MS (M + H)+929.

Example 33. Boc-(p-F(Phe(C)(p-CF3-(L)-Val-(L)-(p-Phe)-morpholine-4-alamid.

Analogously to example 1), 270 mg of 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-triftormetilfullerenov)-hexanoyl-(L)-VaI-(L)- (p-Phe)-morpholine-4-ylamide using 180 mg TBAF 4.2 ml of DMF was transferred to the title compound.

TCX Rf (S) 0,2 FAB-MS (M + H)+833.

The source material was obtained as follows.

33 (a) 5(S)-(BOC-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(t-performative.-butyldimethylsilyloxy)-6-(p-forfinal) -2(R)-(p-triftormetilfullerenov)-hexanoic acid (example 32) and of 113.2 mg of H-(L)-Val-(L)-(p-F-Phe)-morpholine-4-ylamide (example 9D), 2.8 ml of NMM/CH3CN, 0.25 M, enter into interaction with 202 mg U.

FAB-MS (M + H)+947.

Example 34. Boc-(p-F(Phe)C(p-CF3Phe-(L)-VaI-(L)-(p-CH3O-Phe)- morpholine-4-alamid.

Analogously to example 1, 193 mg of 5(S)-(Boc-amino))-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-triptoreline)-hexanoyl-(L)-VaI-(L)- (p-CH3O-Phe)-morpholine-4-alamid with 127 mg TBAF in 3 ml of DMF was transferred to the title compound.

TLC Rf (AND) 0,47; FAB-MS (M + H) 845.

The source material was obtained as follows.

34 (a) 5(S)-(Boc-amino)-4(S)-(tert.-butyldimethylsilyloxy)-6- (p-forfinal)-2(R)-(p-triftormetilfullerenov)-hexanoyl-(L)-Val-(L)- (n-CH3O-Phe)-morpholine-4-alamid.

Analogously to example 9F), 180 mg (0,366 mmol) of 5(S)-(Boc-amino)-4(S)-tert. -butyldimethylsilyloxy-6-(p-forfinal)-2(R)- (p-triftormetilfullerenov)-hexanoic acid (example 33) and 117,2 mg of H-(L)-Val-(L)-(p-CH3O-Phe)-morpholine-4-ylamide (example 10B), 2.8 ml of NMM/CH3CN 0.25 M enter into interaction with 123 mg U.

FAB-MS (M + H)+959.

Example 35. Morpholinomethyl-(L)-Val-Phe(C)Phe-(L)-VaI-(L)-Phe-morpholine-4-alamid.

Analogously to example 5, 102 mg of N-morpholinomethyl-(L)-VaI in 4 ml of DMF activate with 186 mg THIEF, 57 mg Not and 0.09 ml of NMM and enter in useraction mixture was poured into water, extracted with a large amount of ethyl acetate (poorly soluble) and washed with water, saturated sodium bicarbonate solution, water and brine. Rubbing the crude product in ether gives the pure title compound.

FAB-MS (M + H)+877.

The source material was obtained as follows.

35a) N-Chlorosulfonylphenyl.

The intense cooling to 23,5 ml of research about when 0oC add to 32.7 ml sulfurylchloride. Then, the suspension is gently heated to 60oC, and starts the allocation of Hcl. After 5 h at 60oC allocation Hcl ends. Chilled brown reaction mixture was poured on ice, produced in this oil is extracted with ether, washed with water, 5% sodium bicarbonate solution and water and dried over sodium sulfate. Distillation at elevated temperature and reduced pressure (90oC, 1 mbar) the evaporated organic phase gives the title compound.

1H-NMR (200 MHz, DMSO-d6) of 3.80 and 3,29 (2 so 5 Hz, 4H).

35B) N-Morpholinoethyl-(L)-Val.

To 6.3 g of n-Chlorosulfonylphenyl in 20 ml of THF was added dropwise to 2 g (L)-valine dissolved in 50 ml of 1 N. NaOH, and stirred for 17 h at RT. Yellow emulsion is mixed with 15 ml of 1 is tnou phase is dried over sodium sulfate and evaporated. Crystallization from ether gives, according to1H-NMR spectrum, a by-product. The pure title compound is obtained from the residue after evaporation of the filtrate by crystallization from hexane.

TCX Rf (E) of 0.25.

Example 36. Morpholinoethyl-Phe-(C)Phe-(L)-VaI-(L)-Phe-morpholine-4-alamid.

A solution of 200 mg of H-Phe-(C)-Phe-(L)-VaI-(L)-Phe-morpholine-4-alamid (example 4) in 5 ml of DMF is mixed with 0,132 ml of triethylamine and 71 mg of N-chlorotriphenylmethane (example 36) in 1 ml DMF. Because after 2 h at RT according to TLC there are a lot of H-Phe-(C)-Phe-(L)-Phe-morpholine-4-ylamide, then again add 71 mg of N-chlorosulfonylphenyl. After 18 h, poured into water, extracted three times with ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated. Column chromatography (SiO2, methylene chloride/methanol 9 1) gives pure title compound.

TCX Rf (E) 0,60; FAB-MS (M + H)+778.

Example 37. N-(N-(2-Pyridylmethyl)-N-methylaminomethyl)-(L)-Val- (Phe(C)-Phe-(L)-Val-(L)-Phe-morpholine-4-alamid.

Analogously to example 5), 152 mg of N-(N-(2-pyridylmethyl)-N-methylaminomethyl)-N-methylaminomethyl)- (L)-valine (receipt, see European patent 402646 A1, 1990) in 5 ml of DMF activate using 279 mg THIEF, 85 mg Not what about the connection. Column chromatography (SiO2, ethyl acetate/acetone 9 1 --> acetone) gives after soaking in the ether of pure title compound.

TCX Rf (E) 0,28; FAB-MS (M + H)+876.

Example 38. 5(S)-(BOC-amino)-4(S)-acetoxy)-6-phenyl)-2(R)- phenylmethanol-(L)-Val-(L)-(-Phe-morpholine-4-alamid.

To 400 mg of BOC-(C)-Phe-(L)-VaI-(L)-Phe-morpholine-4-ylamide (example 2) in 8 ml THF added 0,114 ml of triethylamine, 1 mg dimethylaminopyridine and 0.08 ml of acetanhydride. After 30 min at RT colorless solution was poured into water and extracted with 3 portions of ethyl acetate. The organic phase after washing with water, saturated sodium bicarbonate solution, water and brine, drying over sodium sulfate and evaporation to give the title compound, which after column chromatography (SiO2, hexane/ethyl acetate 1 2) is obtained pure.

TCX Rf (B) 0,59; FAB-MS (M + H)+771.

Example 39. Boc-Phe-(C)-Phe-(L)-VaI-(L)-Tyr-morpholine-4-alamid.

Analogously to example 1), 360 mg (0,418 mmol) of 5(S)-(BOC-amino)-4(S)-tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethyl-hexanoyl-(L)-Val-(L)-Tyr-morpholine-4-alamid subject interaction for the removal of the protective radicals of 263 mg (0,94 mmol) TBAF in 7 ml of DMF to obtain specified in the connection name.

TLC Rf (B) 0,28; F.

To the ice slurry in the amount of 14,04 g (40 mmol) of Z-(L)-Tyr-HE in 750 ml of methylene chloride add the remaining 9.08 g (44 mmol) DCC and prevent for 20 minutes Then add 10,81 g (80 mmol) Nout and the solution 5,23 g (60 mmol) of the research in 50 ml of methylene chloride. After 18 h stirring at RT the solution is filtered. The filtrate was washed with a saturated solution of NaHCO3, water and brine and the aqueous phase is extracted with two portions of methylene chloride. Column chromatography (SiO2, ethyl ester acetic acid) to receive evaporated and dried with Na2SO4the organic phase is specified in the connection name.

TCX (Rf (methanol) to 0.39.

b) H-(L)-Tyr-morpholine-4-alamid.

A solution of 2.05 g (5.3 mmol) of Z-(L)-Tyr-morpholine-4-ylamide in 91 ml of methanol hydronaut in the presence of 0.5 g of 10-aqueous Pd/C for 1.5 h at room temperature. After filtration through CtliteR(auxiliary filtering means kieselguhr, firm John-Manville Corp.) and evaporation of the filtrate get mentioned in the title compound. TLC Rf (methanol) 0,34.

in) Z-(L)-Val-(L)-Tyr-morpholine-4-alamid.

At 0oC to a solution of 6.3 g (25 mmol) of Z-(L)-Val-OH in 400 ml of methylene chloride add 5,18 g (25 mmol) DCC and of 3.73 g (27.5 mmol) Not boil in those whom remesiana for 18 h at room temperature emit analogously to example 39A) product specified in the header. DC TVX Rf (B) of 0.50.

g) H-(L)-Val-Tyr-morpholine-4-alamid.

Hydronaut a solution of 4.83 g (10 mmol) of 2-(L)-Tyr-morpholine-4-ylamide in 182 ml of methanol using 1 g of 10-aqueous Pd/C for 1 h at room temperature. After filtration through CeliteRobtained filtrate chromatiert (SiO2, methylene chloride methanol 9 1), TCX provides the above-mentioned connection.

Rf (F) FAB-MS (M + H)+350.

e) 5(S)-(Boc-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-(L)-Tyr-morpholine-4-alamid.

Analogously to example 1K) conducting the reaction of 300 mg (0,569 mmol) of 5(S)-(BOC-amino)-4(S)-(tert. -butyldimethylsilyloxy)-6-phenyl-2(R)- fenilmetilketenom acid (obtained in 2D) in 5 ml DMF with 277 mg (0,626 mmol) THIEF, of which 84.5 mg (of 0.625 mmol) Nowt and 157 ml (1,42 mmol) NMM as activator and 198,6 mg (0,568 mmol) N-(L)-Val-(L)-Tyr-morpholine-4-ylamide in 2 ml of DMF for 2 h at room temperature. After thin-layer chromatography (SiO2, ethyl ester acetic acid (hexane 2 1) receive the product specified in the header.

TCX Rf (U) OF 0.26, FAB-MS (M + H)+859.

The results of the tests on the biological activity and toxicity of the claimed compounds are given in table. 1 3 and applications IV V. table. 1 shows that trebuetsya the effectiveness of the compounds against HIV infected virus human cell line lymphocytes. There is also the obvious benefit of these compounds mainly in micromolar quantities and below. From table. 3 shows that when administered orally, tested the connection (which serves as the object for the other compounds) reaches in the blood of mice concentrations exceeding ED in the above table. 2 cell system. First experience in humans shows a similar positive pharmacodynamic picture. The fact that even in such cases (in healthy individuals) HAD exceeded, suggests that therapeutic effect may be in the final activity has been detected (see Annex IV), and, finally, in Appendix V summarizes Toxicological data. Taking into account the fact that the speech in this case is about a difficult to treat disease detected toxicity of low to moderate toxicity category appears to be well tolerated.

I. Data on the inhibition of HIV-1 protease.

The use of Icosapentate and the application of the method of determining the degree of inhibition of HIV protease set forth above in the description, you receive the following IC50values for each of these compounds:

Example IC50 12 0,0055

13 0,25

14 0,18

15 0,24

16 0,054

17 0,028

18 0,06

19 0,18

20 0,043

21B) 1) 0,037

21B) 2) 0,014

21B) 3) 0,005

21B) 4) 0,18

21 G) 1) 0.04

21 G) 1) 0.04

21 G) 2) TO 0.055

21G) 3) 0,033

21G) 4) 0,07

21G) 5) 0,01

D) 1) 0,0014

D) 5) 0,0017

21E) 1) 0,022

G) 1) 0,025

22B) 0,14

22I) 0,018

33 0,015

34 0,016

35 0,022

36 0.02

37 0,31

38 0,0045

II. The inhibitory activity of the compounds of formula I on the replication of HIV in MT-2 cells.

The application detailed in the description of tests involving the use of TM-2 cells receive the following AD-values for the inhibition of the activity of reverse transcriptase (measure viral presence) for each of the above examples of connections:

The compound from example AD M

1 0,1

2 0,1

3 0,1

5 1

6 1

7 1

8 10

9 0,5

10 0,5

11 1

12 1

13 0,1

14 0,1

15 0,5

16 1

17 0,5

18 0,5

20 0,1

21B) 2) 0,1

21B) 2) 0,1

21B) 4) 1

21 G) 1) 0,1

21G) 4) 0,1

D) 1) 0,1

D) 5) 0,1

21E) 1) 0,1

22B) 0,1

22I) 0,1

33 0,1

34 0,1

35 1

36 1

37 10

38 1

III. The pharmacokinetics of compounds of formula I in mice.

The concentration of the compound of example 2, thus, all of the above points, clearly exceeds AD-values obtained in the test for MT-2 cells (0.1 M, see table. 2).

IV. The pharmacokinetics of the compound from example 2 in humans.

In the first study we used the following doses: 150, 300, 600, 900 and 1200 mg (oral administration). The compound of example 2 is quickly absorbed. The obtained plasma concentrations clearly exceed ED-values in the test for MT-2 cells. With the introduction of 600 mg after meals get the concentration in the plasma, which is within 8 to 12 hours is kept at a level exceeding ED in the test for MT-2 cells.

V. Toxicology.

After introduction into the body of monkeys compound of example 2 at a dose of 300 mg/kg not find any sign of toxicity. In rats, signs of toxic effect on the liver are found only at doses exceeding 30 mg/kg Compound did not show mutagenic effects in the Ames test and in relation to the cells of the ovary of the Chinese hamster.

Thus, we can assume that Semino-4-oxohexanoate acid of the formula I

< / BR>
where R1denotes hydrogen, (lower alkoxy) carbonyl, benzofuranyl, pyridylcarbonyl, morpholinylcarbonyl, tetrahydroisoquinoline, morpholinomethyl or N-(pyridylmethyl)-N-methylaminoethanol;

B1means a connection or a divalent radical of the amino acids valine, N-end of which is connected with R1and C-end amino group on the carbon atom bearing R2CH2-;

R2and R3independently from each other represent cyclohexyl or phenyl, whereby phenyl may be substituted in p-position Deputy, selected from lower alkoxyl, halogen, trifloromethyl and cyano group;

A1and A2together represent the bivalent radical of a dipeptide, selected from the group of Val-Phe, Val-Cha, Val-(p-F)Phe, Val-(p-CH3O)Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe and Val-Tyr; N end of which is connected to the group-C and C-end with a group NR4R5;

R4and R5together with the associated nitrogen atom signify thiomorpholine or morpholino, or protected lower alkanoyl hydroxyl group of these compounds.

2. Connection on p. 1, in which R1means hydrogen, tert-butoxycarbonyl, pyridine-3-carbonyl, morpholinoethyl, 3-benzofuranyl or 1,2,3,4-tetrahydroisoquinoline-3-carb is what phenyl unsubstituted or may be substituted in p-position by a radical, selected from the group of methoxy, fluorine, trifluoromethyl and cyano; A1and A2together represent the bivalent radical of a dipeptide, selected from the group of Val-Phe, Val-Cha, Val-(p-F) Phe, Val-(p-CH3O) Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe, Val-Tyr, N-end of which is connected with a group of C O and C-end with a group NR4R5, R4and R5together with the associated nitrogen atom signify thiomorpholine or morpholino.

3. Connection on p. 1, where R1denotes tert-butoxycarbonyl; B1denotes a bond; R2and R3independently of one another denote phenyl; A1and A2together form a bivalent radical of a dipeptide (L)-Val-(L)-Phe, N-end is associated with a group of C-O and C-end with a group NR4R5and R4and R5together with the connecting nitrogen atom denote morpholino.

4. Connection on p. 1, where R1denotes tert-butoxycarbonyl; B1denotes a bond; R2denotes phenyl; R3denotes a p-methoxyphenyl; A1and A2together form a bivalent radical of a dipeptide (L)-Val-(L)-Phe, N-end is associated with a group of C-O and C-end with a group NR4R5and R4and R5together with the connecting nitrogen atom denote morpholino.

5. The method of obtaining p is XI)-carbonyl, benzofuranol, pirimicarb, morpholinylcarbonyl, tetrahydroisoquinoline, morpholinomethyl or N-(pyridylmethyl)-N-methylaminoethanol;

B1means a connection or a divalent radical of the amino acids valine, N-end of which is connected with R1and C-end amino group on the carbon atom bearing R2CH2-;

R2and R3, independently of one another denote phenyl or cyclohexyl, and phenyl may be substituted in p-position Deputy, selected from lower alkoxyl, halogen, trifloromethyl and cyano group;

A1and A2together represent the bivalent radical of a dipeptide, selected from the group of Val-Phe, Val-Cha, Val-(p-F) Phe, Val-(p-CH3O) Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe and Val-Tyr, N-end of which is connected to the group-C and C-end with a group NR4R5,

R4, R5together with the associated nitrogen atom signify thiomorpholine or morpholino, or derivatives of these compounds, substituted lower alkanoyl and actigraphy,

characterized in that the carboxylic acid of the formula II

< / BR>
or its reactive derivative,

where R1denotes hydrogen, (lower alkoxy)-carbonyl, benzofuranyl, pyridylcarbonyl, morpholinylcarbonyl, tetrahydroisoquinoline valenty radical amino acids valine, N-the end of which is connected with R1and C-end amino group on the carbon atom bearing R2CH2-;

R2and R3independently of one another denote phenyl or cyclohexyl, and phenyl may be substituted in p-position Deputy selected from lower alkoxide, halogen, trifloromethyl and ceanography,

condense with aminoguanidinium formula III

< / BR>
or its reactive derivative,

where A1and A2together form a bivalent radical of a dipeptide of the formula Val-Phe, Val-Cha, Val-(p-F) Phe, Val-(p-CH3O) Phe, Val-Gly, Ile-Gly, Val-Val, Ile-Phe, Val-Tyr, N-end is associated with a group of C-O and C-end with a group NR4R5,

R4and R5together with the connecting nitrogen atom denote thiomorpholine or morpholino, and free functional groups in the original materials of formulas II and III, except for participating in the reaction, if necessary, are in protected form, and, if desired otscheplaut existing protection group.

6. Derivatives p. 1 active in suppressing the Asp protease of HIV-1.

 

Same patents:

The invention relates to a new agent for sweetening derived from L-aspartic or L-glutamic acid, and method thereof

The invention relates to new biologically active peptide, inhibiting the hypersecretion of thyroid-stimulating hormone (TSH) and prolactin (PRL), caused by natural hypothalamic peptide with thyroliberin (tireotropin-releasing hormone, TRH)

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, pharmaceutics.

SUBSTANCE: it is suggested to apply Pro-Gly-Pro tripeptide known as anticoagulant to keep stable norglycemia and stable normoinsulinemia in circulation at no side effects because the above-mentioned tripepetide is being natural human and animal metabolite.

EFFECT: higher efficiency of application.

3 cl, 5 ex, 2 tbl

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

FIELD: medicine, experimental medicine.

SUBSTANCE: one should introduce tripeptide Pro-Gly-Pro for laboratory animals as injections at the quantity of 0.09-1.0 mg/kg body weight, and, also, gelatin as fodder additive. The method suggested enables to suppress appetite, decrease the quantity of fodder intake that leads to decreased body weight as a result.

EFFECT: higher efficiency.

2 cl, 5 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: biotechnology.

SUBSTANCE: invention relates to a method for preparing foodstuff containing hypotensive peptides and it using as an anti-hypertensive agent that can be used as a foodstuff. Method involves stages for fermentation of casein-containing fermenting material with lactobacillus microorganism, nanofiltration of the prepared peptide-containing fermentation product and isolation of the product. Prepared product is used as an anti-hypertensive agent and as a foodstuff also. Invention provides preparing a foodstuff with the high content of hypotensive peptides enriched by bivalent ions.

EFFECT: improved preparing method of foodstuff.

22 cl, 1 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agent used for correction of metabolic vascular syndrome and diseases accompanying with vascular wall penetrability disorder and capillaries fragility and can be used as agent enhancing resistance of capillaries. Invention proposes peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH corresponding to the sequence 1 [SEQ ID NO:1] possessing biological activity and eliciting enhancing effect on resistance of capillaries. Also, invention proposes pharmaceutical composition enhancing resistance of capillaries and containing effective amount of peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] as an active component and a pharmaceutically acceptable carrier. Pharmaceutical composition is prepared in form suitable for parenteral administration. Also, invention proposes a method for prophylaxis and/or treatment of microcirculation disorders in organs and tissues and involves administration in patient pharmaceutical composition containing effective amount of peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] as an active component in the dose 0.01-100 mcg/kg of body mass for at least once per a day for period necessary for providing the therapeutic effect. Administration is carried out by parenteral route. Proposed group of inventions provides preparing a novel peptide possessing biological activity eliciting in enhancing resistance of capillaries and using this peptide for preparing pharmaceutical composition enhancing resistance of capillaries.

EFFECT: enhanced and valuable medicinal properties of peptide and pharmaceutical composition.

7 cl, 3 tbl, 2 dwg, 6 ex

FIELD: peptides, medicine, hepatology, pharmacy.

SUBSTANCE: groups of inventions relates to medicinal agents used in treatment of liver diseases. Invention proposes a pharmaceutical composition stimulating regeneration of liver tissue and comprising the effective amount of peptide glutamyl-aspartyl-leucine as an active component of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO:1] and a pharmaceutically acceptable carrier. Invention proposes peptide glutamyl-aspartyl-leucine of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO;1] stimulating regeneration of liver tissue. Also, invention proposes a method for stimulating liver tissue involving administration in a patient a pharmaceutical composition containing peptide glutamyl-aspartyl-leucine of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO:1] as an active component used in the dose 0.01-100 mcg/kg of body mass for at least once per a day for period required for appearance of the therapeutic effect. Invention provides the development of peptide possessing the biological activity eliciting in stimulating regeneration of liver tissue, and pharmaceutical composition containing this peptide as an active component. Using this composition stimulates regeneration of liver tissue based on recovery of synthesis of tissue-specific proteins and normalization of functions of liver cells.

EFFECT: valuable properties of peptide and pharmaceutical composition.

7 cl, 5 tbl, 1 dwg, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to drugs used in prophylaxis and treatment of the locomotor system, in particular, degenerative-dystrophic joint and backbone diseases. Invention proposes a pharmaceutical composition normalizing metabolism in osseous and cartilage tissues and comprising the effective amount of peptide alanyl-glutamyl-aspartic acid of the general formula: H-Ala-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] as an active component, and pharmaceutically acceptable carrier. Invention proposes peptide alanyl-glutamyl-aspartic acid of the general formula: H-Ala-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] possessing the biological activity manifesting as normalization of metabolism in osseous and cartilage tissues. Invention proposes a method for prophylaxis and treatment of locomotor system by normalization of metabolism in osseous and cartilage tissues involving administration in a patient of a pharmaceutical composition containing as an active component peptide alanyl-glutamyl-aspartic acid of the general formula: H-Ala-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] in the dose 0.01-100 mcg/kg of the body mass for at least once per a day for time necessary for achievement of the therapeutic effect. Invention can be used as agent normalizing metabolism in osseous and cartilage tissues.

EFFECT: valuable medicinal properties and high effectiveness of peptide and pharmaceutical composition.

6 cl, 2 tbl, 1 dwg, 1 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to dipeptide mimetic selected from glutaminyl thiazolidine or glutaminyl pyrrolodine and salts thereof as well as to using of such compounds in treatment of abnormal glucose tolerance, glucoseuria, diabetes mellitus and other disordered as well as complications associated with diabetes mellitus in mammalians.

EFFECT: new effectors of dipeptidyl peptidase IV.

18 cl, 3 tbl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to application of dipeptide with the general formula Nα-(γ-L-glutamyl)-L-lysine, for stimulation of function of the reproductive system by modulating the neuroendocrine status in aging and in hypogonadal condition. The pharmaceutical composition is invented, which contains Nα-(γ-L-glutamyl)-L-lysine, and the method of stimulation of function of reproductive system.

EFFECT: described compound efficiently stimulates function of reproductive system.

5 cl, 9 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to inhibitors of enzymes cleaving protein after proline, such as depeptidyl peptidase IV inhibitors, as well as to their pharmaceutical compositions, and methods of application of such inhibitors. Particularly, inhibitors under this invention are improved in comparison with those currently in use in the present art by selecting special classes of side chains in P1 and/or P2 positions of inhibitor which contains carboxylic acid grouping.

EFFECT: compounds of specified formulas I, II and III can have the improved therapeutic index, partially owing to reduced toxicity and improved specificity in relation to target protease.

15 cl, 2 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds, which possess agonistic or antagonistic activity of NGF and BDNF neutrophins and represent monomer or dimmer substituted dipeptides, which are analogues of exposed outside parts of loops 1 and 4 of said neutrophins, close to beta-bends of said loops or coinciding with them. Effects in vivo are demonstrated by claimed compounds within dose interval 0.01-10 mg/kg in intraperitoneal introduction.

EFFECT: claimed compounds possess neuroprotective and differentiating activity on cell models, increase concentration of phosphorylated form of tyrosine kinase A and proteins of heat shock Hsp32 and Hsp70 in concentrations10-5-10-9 M, they also possess neuroprotective, antiparkinsonian, anti-stroke, antiischemic, antidepressant, antiamnestic activity on animal models and demonstrate activity on experimental models of Alzheimer's disease.

20 cl, 33 dwg, 23 tbl, 18 ex

FIELD: pharmacology.

SUBSTANCE: group of inventions refers to application of low molecular peptide mimetics of the nerve growth factor: hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine) - GC-2 compound; hexamethylenediamide bis-(N-acetyl-lysyl-glutamic acid) - GC-4 compound; amide N-aminocaproyl-glycyl-lysine - GC-5 compound; hexamethylenediamide bis-(N-aminocaproyl-glycyl-lysine) - GC-6 compound as compounds with angiogenic activity.

EFFECT: creation of new highly effective means to stimulate neoangiogenesis at different ischemic processes.

4 cl, 3 dwg, 2 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to compounds of formula I , as well as their enantiomers, diastereomers and salts, which can be used in the solid-phase synthesis of peptides. In formula I, R1 is C1-4-alkyl, R2 is hydrogen or C2-4-alkenyl, R3 is 9H-fluoren-9-ylmethoxycarbonyl (Fmoc) and R4 is C12-20-alkyl. The invention also relates to application of formula I compounds in the solid-phase synthesis of peptides that contain a block of glutamic acid (Glu)-fatty alkyl in the side chain attached to the lysine residue (Lys) of the peptide chain.

EFFECT: effective treatment.

9 cl, 5 ex

FIELD: synthesis of biologically active compounds.

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

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

36 cl, 121 ex

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