Antiviral esters isosteres substrate aspartates or their salts, a method of production thereof, pharmaceutical preparation and composition

 

(57) Abstract:

Describes new compounds of General formula (I), where R1- acyl radical selected from lower alkoxy-lower alkanoyl (including lower alkoxycarbonyl), in which the moiety of the lower alkoxy is not substituted or substituted by one or more radicals selected independently of one another from halogen, lower alkoxy or pyrrolidinyl, which is not substituted or substituted by one or more radicals selected independently of one another from oxo or hydroxyl; lower alkanoyl, which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1-benzopyranyl, piperidinyloxy, tetrahydropyranyloxy or tetrahydrofurane, which in each case is not substituted or substituted by one or more substituents selected independently of one another from oxo, hydroxyl, amino, lower alkyl and lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; arylcarbamoyl, which is replaced by heterocyclyl or morpholine-lower alkyl; phenyl-lower alkanoyl, which is substituted by hydroxyl, lower alkyl; and arylsulfonyl; the remainder, which is connected through SUB> - cyclohexyl or phenyl which is not substituted or substituted by one or more radicals selected independently of one another from hydroxyl, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, where pyridyl is linked via a carbon atom in the ring, and lower alkoxy-lower alkoxy; R3- cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, which is not substituted or substituted by one or more radicals selected independently of one another from phenyl, cyanophenyl, phenyl-lower alkyl, halogen, cyano, hydroxyl, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, where the pyridine is linked via a carbon atom in the ring, a lower alkoxy-lower alkoxy, alkylenedioxy and phenyl-lower alkanesulfonyl, which is not substituted or substituted in the phenyl radical by one or more radicals selected independently of one another from halogen; R4- lower alkyl, cyclohexyl or phenyl; R5- lower alkyl, n = 1 or 2, or its salt, provided that there is at least salt-forming group. The new compounds of formula (I) possess antiviral activity. They are characterized by good pharmacokinetics, bioavailability and/or good tolerance. Op is s, 5 table.

The invention relates to a simple esters isosteres substrates aspartate protease and their salts, a process for the production of these compounds and their salts, to pharmaceutical preparations which comprise these compounds or their salts, and to the use of these compounds or their salts (either individually, or in combination with other active compounds which are effective against retroviruses) for therapeutic or diagnostic treatment of the human or animal body or for pharmaceuticals.

According to the world health organization, currently more than 15 million people are infected with HIV-1 or HIV-2.

Up to the present time for the treatment of retroviral diseases such as AIDS, used mainly inhibitors of reverse transcriptase, the enzyme that converts retroviral RNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), and trinatriumfosfaat, ammonium 21-tungsten-9-antimonate, 1-- D-ribofuranosyl-1,2,4-triazole-3-carboxamide and dideoxycytidine, and adriamycin. Also attempted to introductionat receptor cells T4, which is present in chelovecheskoye and their introduction in these cells, and therefore, responsible for their ability to infection in the body, such as a recombinant molecule or molecular fragment. This would have the effect of reverse titration of binding sites for the virus, so the virus would no longer be able to contact the cells. Also used compounds that act on other way, inhibiting viral penetration through the cell membrane, such as, for example, polymannose.

In addition, it was reported the first clinical experiment in which hydroxyethanoic ISOStAR, N-tert-buildimage-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-hinolincarbonova-L - asparaginyl] amino]butyl] -(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro 31-8959), is used as an inhibitor of HIV protease. This compound had an inhibitory effect on the HIV protease in vitro and suppressed viral replication in experiments with cells, and suitable levels in the blood have been achieved in rodents even when orally administered compounds [see Roberts N. A. et al., Biochemical Soc. Transactions 20, 513-516 (1992)]; suitable levels in the blood were also achieved in humans [see, for example, G. J. Muirhead et al., Brit. J. Clin. Pharmacol. 34, 170P-171P (1992)]. The so-called "surrogate marker" (taiwania AIDS) was first demonstrated positive effects in patients with AIDS (see, "Roche statement on HIV Protease Inhibitor Ro 31-8959) European Trial Results", which was distributed among the participants of the 9th International Congress on AIDS, held in Berlin, 7-11 June 1993).

In the AIDS virus, HIV-1 and HIV-2 or other retroviruses, for example, the respective viruses in cats (FIV) and monkeys (SIV), proteolytic maturation, e.g., capsid proteins of the virus affected aspartate protease, such as HIV-protease. Without this proteolytic maturation impossible the production of any infectious viral particles. Based on the Central role of these aspartate proteases, such as HIV-1 protease or HIV-2 protease, in viral maturation, or on the basis of the results of experiments, for example, obtained from infected cell cultures suggest that effective obstruction in vivo ripening stages, called by the protease, will prevent the accumulation of Mature virions. Therefore, the corresponding inhibitors can be used in a therapeutic way.

The aim of the present invention to provide a new class of compounds which have, in particular, favorable pharmacological properties, such as x is ü achieved by the development of new esters of isosteres substrates aspartate protease, represents a compound of formula I

< / BR>
where R1denotes the acyl radical selected from lower alkoxy-lower alkanoyl (including lower alkoxycarbonyl), in which the moiety of the lower alkoxy is not substituted or substituted by one or more radicals selected independently of one another from halogen, lower alkoxy or pyrrolidinyl, which is not substituted or substituted by one or more radicals selected independently of one another from oxo or hydroxyl; lower alkanoyl, which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1-benzopyranyl, piperidinyloxy, tetrahydropyranyloxy or tetrahydrofurane, which in each case is not substituted or substituted by one or more substituents selected independently of one another from oxo, hydroxyl, amino, lower alkyl and lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl, arylcarbamoyl, which is replaced by heterocyclyl or morpholinyl-lower alkyl; phenyl-lower alkanoyl, which is substituted by hydroxyl, lower alkyl; and arylsulfonyl; the remainder, which is linked via a carbonyl group of the amino acids valine and which'neill, which is not substituted or substituted by one or more radicals selected independently of one another from hydroxyl, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, where pyridyl is linked via a carbon atom in the ring, and lower alkoxy-lower alkoxy;

R3denotes cyclohexyl, cyclohexenyl, phenyl naphthyl or tetrahydronaphthyl, which is not substituted or substituted by one or more radicals selected independently of one another from phenyl, cyanophenyl, phenyl-lower alkyl, halogen, cyano, hydroxyl, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, where the pyridine is linked via a carbon atom in the ring, a lower alkoxy-lower alkoxy, lower alkylenedioxy and phenyl-lower alkanesulfonyl, which is not substituted or substituted in the phenyl radical by one or more radicals selected independently of one another from halogen,< / BR>
R4denotes lower alkyl, cyclohexyl or phenyl,

R5denotes lower alkyl, and

n = 1 or 2

or its salt, provided that there is at least one salt-forming group.

Preferred compounds according to the invention are the compounds of formula I in which R1

In the compounds of the formula I R2and R3there are preferably in the following combinations: R2= phenyl and R3= cyanophenyl; R2= phenyl and R3
= 4-(phenyl-lower alkoxy)phenyl; R2= cyclohexyl and R3= 4-lower alkoxyphenyl; R2= phenyl and R3= phenyl; R3= phenyl and R3= 4-[(pyridine-2-yl or pyridin-3-yl)-lower alkoxy]phenyl; R2= phenyl and R3= 3,4-lowest alkylenedioxy; R2= cyclohexyl and R3= 4-(lower alkoxy-lower alkoxy)phenyl; or R2= phenyl and R3= 2,3,4-tri-lower alkoxyphenyl;

or its salt, provided that there is at least one salt-forming group.

While the preferred compounds of formula I in which R1choose from ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2 - cryptgetkeyparam, 2-(methoxy)ethoxycarbonyl, 2-methoxy-1-(R, S) - methylethanolamine, 1,1-dimethyl-2-methoxyethoxymethyl, 5(S) -2-oxopropylidene, 1-ethoxycarbonylpyrimidine-4 - yl-carbonyl, TRANS-(L)-4-hydroxyproline, N-(benzyloxycarbonyl)-TRANS-(L)-4-hydroxyproline, (L)-thiazolidin-4 - ylcarbonyl, indole-2-ylcarbonyl, 4H-1-benzopyran-2-ylcarbonyl, N-metilprednisolone, tetrahydropyran-2(R,S)-ylcarbonyl, (tetrahydropyran-4-yl)-(L)-lactol (= 2(S)-(tetrahydropyran-4-yloxy) propionyl), 3(S)-tetrahydropyranyloxy, 2-aminothiazol-4-lacetera, 6-(4-Mei is n-4-ylcarbonyl]-(L)-poured, 3-hydroxy-2-methylbenzoyl, 4-nitrobenzenesulfonyl, 4-aminobenzenesulphonyl, 2-methyl-4-nitrobenzenesulfonyl and 4-amino-2-methylbenzenesulfonyl; R2and R3selected from cyclohexyl, cyclohexen-1-yl, phenyl, 4-biphenylyl, 2'-cyanobiphenyl-4-yl, 4-(benzyloxy)phenyl, 2,4-dipthera, 4-cyanophenyl, 2-, 3 - or 4-methoxyphenyl, 4-isobutylacetophenone, trimethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 3,4 - methylenedioxyphenyl, 4-(pyridine-2 - or pyridine-3-ylethoxy)phenyl, 4-methoxy-2-ftoheia, 4-fluoro-2-methoxyphenyl, 4-methoxy-2 - hydroxyphenyl, 4-methoxy-2,3-dimetilfenil, 4-(2-phenylethyl)phenyl, 2-ftoheia, 4-hydroxyphenyl, acid, 5,6,7,8-tetrahydro-1-naphthyl, 4-ptomaphila, 4-cyanonaphthalene, 4 - lower alkoxymethyl and 4-(2,6-dichlorobenzenesulfonyl)phenyl; R4denotes isopropyl, cyclohexyl or phenyl; R5denotes ethyl or methyl; and n is 2 or 1; or its salt, provided that there is at least one salt-forming group.

New esters of isosteres substrates for aspartate protease include the following group of compounds described by the above formula I, in which R1denotes the acyl radical selected from lower alkoxy-lower alkanoyl (including lower alkoxycarbonyl from one another from halogen, phenyl and lower alkoxy, or a radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidine, thiazoline, indolyl or 4H-1-benzopyranyl, which is not substituted or substituted by one or more radicals selected independently of one another from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; lower alkanoyl, which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1 - benzopyranyl, piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, thiazolidinone, thiazolidone, intolerance or 4H-1-benzopyranyl, which in each case is not substituted or substituted by one or more substituents selected independently of one another, from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; arylcarbamoyl or geterotsiklicheskikh, which is replaced by heterocyclyl or heterocyclyl-lower alkyl; phenyl-lower alkanoyl, which is substituted by hydroxyl and lower alkyl; and arylsulfonyl;

the remainder, which is connected through carbonylcontaining acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminocaproic acid, 4 - aminocaproic acid, 5-aminocaproic acid, valine, Norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4 - aminophenylalanine, 4-chlorophenylalanine, 4-carboxyaniline, - phenylseleno, phenylglycine, - naphtylamine, cyclohexylamine, cyclohexylglycine, tryptophan, aspartic acid, phenyl-lower alkylacrylate, asparagine, aminomalonate acid, monoamide aminomalonate acid, glutamic acid, phenyl-lower Alkylglucoside, glutamine, histidine, arginine, lysine, hydroxylysine, ornithine, ,- diaminoalkanes acid and diaminopropionic acid;

or residue, which is linked via a carbonyl group, one of the above amino acids, while the remainder N-allerban on the nitrogen atom of one amino group of the above-mentioned acyl radicals,

R2and R3independently of one another represent cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, which is not substituted or substituted by one or more radicals selected independently of od is on, hydroxyl, lower alkoxy, phenyl-lower alkoxyl, pyridyl - lower alkoxy, where pyridyl is linked via a carbon atom in the ring, a lower alkoxy-lower alkoxy, lower alkoxycarbonyl - lower alkoxy, carboxy-lower alkoxy, hydroxyl-lower alkoxy having at least two carbon atoms, where the hydroxyl is not attached in position 1, carbarnoyl-lower alkoxy, cyano-lower alkoxy, lower alkylenedioxy and phenyl-lower alkanesulfonyl, which is not substituted or substituted in the phenyl radical by one or more radicals, selected independently of one another from halogen,

R4- lower alkyl, cyclohexyl or phenyl,

R5- lower alkyl, and

n = 1 or 2

or their salts, provided that there is at least one salt-forming group.

Within the scope of the present invention of the General terms used above and below, preferably have the following meanings, unless something else:

The prefix "lower" or "lower", for example, in terms of lower alkyl, lower alkanoyl or phenyl-lower alkyl, denotes a radical having not more than 7, in particular not more than 4, carbon atoms, whereby these radicals may be unbranched iLike indicate the connection salt and so on.

The asymmetric carbon atoms that may be present in the atoms of the substituents R1- R5may be in the configuration (R), (S) or (R, S), preferably in the configuration (R) or configuration (S). These compounds can, therefore, exist as isomer mixtures or pure isomers, in particular, diastereomeric mixtures, enantiomeric mixture or, preferably, pure enantiomers.

An additional indication of "alternative or additional means either that the respective specified values Deputy in conjunction with the relevant groups of values substituent that is not specified in this supplemental Directive, together form a group of substituents, or that these values as appropriate substituent form a group by themselves, or that the values that are not specified in this supplemental Directive, also themselves form a group of values Deputy.

Preferred compounds of formula I have the formula I'

< / BR>
where the radicals have the meanings defined in respect of compounds of formula I.

Lower alkoxy-lower alkanoyl R1denotes the moiety of the lower alkoxy, the, while the lowest alkanoyl is preferably formyl (corresponding radical then is a radical of the lower alkoxycarbonyl, in particular, methoxycarbonyl, etoxycarbonyl or tert-butoxycarbonyl), acetyl or propionyl.

Piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolyl, indolyl or 4H-1-benzopyranyl are unsubstituted or substituted by one or more radicals selected independently of one another from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl, in particular, unsubstituted or substituted by one or two mentioned radicals selected independently of one another.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

Piperidinyl represents, in particular, piperidine-4-yl, which is not substituted or preferably substituted on the nitrogen atom by lower alkyl, such as methyl, or lower alkoxycarbonyl, such as etoxycarbonyl.

Pyrrolidinyl represents, in particular, pyrrolidin-2-yl or-5-yl, which is not substituted or preferably substituted by oxo or hydroxyl at carbon atom and substituted phenyl-Nissi the IU (R,S) or, in particular, in the form (S) on the connecting carbon atom, and, in particular, is a 2-oxopyrrolidin-5(S)-yl, (L)-TRANS-4-hydroxypropyl or (L)-N-benzyloxycarbonyl-TRANS-4-hydroxyprolin.

Tetrahydropyranyl represents, in particular, tetrahydropyran-2-yl or-4-yl, which is preferably not substituted or preferably attached in the form (R), form (S) or, in particular, in the form (R,S), provided that it is attached on the 2nd carbon atom.

Tetrahydrofuranyl represents, in particular, tetrahydrofuran-3-yl, which is preferably not substituted and preferably attached in the form (R), the form (R,S) or, in particular, in the form (S).

Diazolidinyl represents, in detail, thiazolidin-4-yl, which is preferably not substituted, and is preferably in the form (S), form (R, S) or, in particular, in the form of (R) (= form (L)) on the connecting carbon atom.

Thiazolyl represents, in particular thiazol-4-yl, which is preferably substituted amino, such as 2-amino-4-thiazolyl.

Indolyl represents, in particular indol-2-yl, which is preferably not substituted.

4H-1-Benzopyranyl represents, in particular, 4H-1-benzopyran-2-yl, which is not sinosatellite of piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidine, thiazoline, indolyl or 4H-1-benzopyranyl that may be present in compounds, preferably connected with carbon, while the deputies of the lower alkoxy, the lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl preferably associated with nitrogen or carbon.

The moiety of the lower alkoxy, R1lower alkoxy-lower alkanoyl is unsubstituted or substituted by one or more, in particular from 1 to 3 inclusive, from among these radicals, particularly preferably from 1 to 3 times with halogen, in particular fluorine; or (preferably 1 time) one of the other mentioned radicals, particularly preferably 1-fold) lower alkoxy, especially methoxy, or (preferably 1 time) pyrrolidinium, especially pyrrolidin-2-yl or-5-yl, which is not substituted or, in particular, substituted by oxo; or, alternatively, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl.

In the lower alkanoyl R1which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1-benzopyranyl, piperidinyloxy, the si or 4H-1-benzopyranyl, which in each case is not substituted or substituted by one or more (preferably one) substituents selected, independently of one another, from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; lower alkanoyl represents, in particular, formyl (in each case with one of the aforementioned radicals is obtained appropriately substituted carbonyl radical), acetyl or 2 - or 3-propionyl, but it is preferably of the form (R), form (R,S) or, in particular, form (S) when the Deputy is linked in position 2, while the remaining radicals have the above values. Particularly preferred N-lower alkoxycarbonylmethyl lowest alkanoyl, for example - carbonyl, such as N-ethoxycarbonylpyrimidine-4-ylcarbonyl, pyrrolidinyl lowest alkanoyl, such as carbonyl, which is substituted by hydroxyl on a carbon atom and/or phenyl-lower alkoxycarbonyl on the nitrogen atom and which is preferably in the form (R), the form (R, S) or, in particular, the form (S) on binding carbon atom, such as (L-TRANS-4-hydroxypropyl or (L)-N-benzyloxycarbonyl-TRANS-4 - hydroxyprolin, aminothiazoline lowest alkanoyl, for example, acetyl, such as the lowest alkanoyl, for example-carbonyl, such as indole-2 - ylcarbonyl, 4H-1-benzopyranyl lowest alkanoyl, for example - carbonyl, which is substituted by oxo, such as 4-oxo-4H-1-benzopyran - 2-ylcarbonyl, N-lower alkylpiperidines lowest alkanoyl, for example-carbonyl, such as N-methylpiperidin-4-jocstarbunny, tetrahydropyranyloxy lowest alkanoyl, for example, propionyl or - carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)propionyl or tetrahydropyran-2(R,S)-jocstarbunny, or tetrahydropyranyloxy lowest alkanoyl, for example-carbonyl, such as tetrahydrofuran-3 (S)-jocstarbunny.

The heterocycle is preferably unsubstituted or substituted heterocyclic ring, having from 5 to 7, preferably 5 or 6 atoms in the ring, of which 1 or 2 carbon atoms in the ring is replaced by a heteroatom selected from O, N and S, is an unsaturated or fully or partially saturated and may be a simple ring or benzododecinium, cyclopentanecarbonyl or cyclohexanecarbonyl, where the substituents are preferably chosen, independently of one another, from one or more (preferably one or two) substituents selected from oxo, hydroxyl, amino, lower alkyl, lower alkoxide the Razin-1-yl, pyridinyl, for example, pyridine-3-yl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidine, thiazoline, indolyl and 4H-1-benzopyranyl, which in each case is not substituted or substituted by one or more radicals selected, independently of one another, from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl, preferably unsubstituted or substituted by one or, alternatively, the two mentioned radicals; and is mainly morpholinium, such as morpholine-4-yl, lowest alkylpiperazine, in particular, N-lower alkylpiperazine, for example, 4-lower alkylpiperazine-1-yl, such as 4-methylpiperazin-1-yl, or pyridinyl, such as pyridine-3-yl.

Aryl preferably represents C6-C14-aryl, for example phenyl, naphthyl, such as 1 - or 2-naphthyl, or, alternatively, fluorenyl, such as fluoren-9-yl, and is unsubstituted or substituted by one or more (preferably 1 to 3) radicals, which are selected, independently of one another from lower alkyl, phenyl-lower alkyl, halogen, cyano, hydroxyl, lower alkoxy, phenyl-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylenedioxy and phenyl-lower alkanesulfonyl, which is not substituted or substituted in the phenyl radical by one or more radicals selected independently of one another, from halogen, such as chlorine; and (alternative or additional) of nitro; and, in particular, refers to phenyl.

In arylcarbamoyl, which is replaced by heterocyclyl or heterocyclyl-lower alkyl, such as, in particular, methyl, or heterocalixarenes, which is replaced by (similarly, one or more of these radicals), the aryl and heterocyclyl have the aforementioned values, preferably have the meanings mentioned as preferred; preferably, if there is only one Deputy heterocyclyl or heterocyclyl-lower alkyl.

Of these radicals is preferred arylcarbamoyl, which is substituted once heterocyclyl-lower alkyl, and heterocalixarenes, which is substituted once by heterocyclyl.

Arylcarbamoyl, which is replaced by heterocyclyl-lower alkyl, represents in particular, morpholinyl lowest alkylbenzoic, such as 4-(morpholine-4-ylmethyl)benzoyl.

Heterocalixarenes, which is replaced by heterocyclyl, represents, in particular, lower alkylpiperidines, naprimer 2 - or 3-(4-lower alkyl [such as methyl]-piperazine-1-yl)-pyridine-2-ylcarbonyl or 3-ylcarbonyl.

Phenyl-lower alkanoyl (in the context of the term "phenyl-lower alkanoyl also includes benzoyl = phenylcarbinol), which is substituted by hydroxyl and lower alkyl, preferably has, in each case, Deputy hydroxyl and lower alkyl, in particular, hydroxyl and methyl or ethyl, phenyl ring and, in particular, is an appropriately substituted benzoyl, such as 3-hydroxy-2-methylbenzoyl.

Arylsulfonyl (= aryl-SO2-) preferably contains as an aryl radical, as defined above, in particular, phenyl, substituted amino, nitro, amino and lower alkyl or nitro and lower alkyl, and is mainly 4-nitrobenzenesulfonyl, 4 - aminobenzenesulphonyl, 2-lower alkyl(in particular 2-methyl)-4 - nitro-benzosulfimide or 4-amino-2-lower alkyl(in particular 2-methyl)-benzosulfimide.

The corresponding radicals, which fall under the definition of "phenyl-lower alkanoyl, which is substituted by hydroxyl and lower alkyl" and "arylsulfonyl" R1can, and above and below, at all levels of determination R1also to stand alone or to be omitted.

The balance of amino acids, which is linked via a carbonyl group (carb can be obtained by removal of the group HE is in the carboxyl group (-COOH), selected from glycine (H-Gly-OH), alanine (H-Ala-OH), 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5 - aminopentanoic acid, 3-aminocaproic acid, 4 - aminocaproic acid or 5-aminocaproic acid, valine (H-Val-OH), Norvaline (aminovaleric acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine ( - aminocaproic acid, H-Nle-OH), serine (H-Ser-OH), homoserine ( - amino -- hydromassage acid), threonine (H-Thr-OH), methionine (D-Met-OH), cysteine (H-Cys-OH), phenylalanine (H-Phe - OH), tyrosine (N-Tight-HE), 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyaniline, - phenylseleno (hydroxyphenylglycine), phenylglycine, - naphthylamine (H-Nal-OH), cyclohexylamine (H-Cha-OH), cyclohexyl-glycine, tryptophan (L-Trp), aspartic acid (H-Asp-OH), - phenyl-lower alkyl-aspartate, such as - bansilalpet, asparagine (L-Asn-OH), aminomalonate acid, monoamide aminomalonate acid, glutamic acid (H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), - hydroxylysine, ornithine, diaminopurine acid), 3-aminopropanoic acid ,- diaminoalkanes acid and diaminopropanol acid; and preferably wybir the Nina, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyaniline, - phenylseleno, phenylglycine, - naphtylamine, cyclohexylamine, cyclohexylglycine, tryptophan, aspartic acid, phenyl-lower alkylacrylate, such as - bansilalpet, asparagine, monoamide aminomalonate acid, glutamic acid, phenyl-lower Alkylglucoside, such as benzylphthalate, glutamine, histidine, arginine, lysine, hydroxylysine and ornithine; especially preferred are - bansilalpet, aspartic acid, asparagine or, particularly valine; moreover, the corresponding amino group (group) and other functional groups are free or (if possible) are present in salt form; and these amino acid radicals having asymmetric carbon atoms are in the form of (D), form (L) or (D,L), preferably in the form (L).

In the remainder of one of the mentioned amino acids, which is linked via a carbonyl group and which N-allerban on the amino group by using one of the above-mentioned acyl radicals, acyl radicals selected from lower alkoxy-lower alkanol, in which the moiety of the lower alkoxy is not replaced and is, the Roma, phenyl, or a radical selected from piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolidine, thiazoline, indolyl or 4H-1-benzopyranyl, which is not substituted or substituted by one or more radicals selected, independently of one another, from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; lower alkanoyl, which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1-benzopyranyl, piperidinyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, tetrahydropyranyloxy, thiazolidinone, thiazolidone, intolerance or 4H-1 - benzopyranyl, which in each case is not substituted or substituted by one or more substituents selected, independently of one another, from oxo, hydroxyl, amino, lower alkyl, lower alkoxycarbonyl and phenyl-lower alkoxycarbonyl; arylcarbamoyl or geterotsiklicheskikh, which is replaced by heterocyclyl or heterocyclyl-lower alkyl; (alternative or additional) phenyl-lower alkanoyl, which is substituted by hydroxyl and lower alkyl; and (alternative or additional) harilal necessaty residue selected from residues mentioned above in relation to residues of amino acids linked through a carbonyl group, in particular, of the residues mentioned above as preferred. Particularly preferred lower alkoxy-lower alkanolamine, such as lower alkoxycarbonylmethyl, for example, methoxycarbonylmethyl, or diazolidinylurea, in particular, thiazolidin-4-Jalil, which is preferably in the form (S), form (R,S), or, especially in the form of R (= form (L)) on the atom at the 4-carbon ring of thiazolidine, in each case, the residue is poured is preferably in the form (L); or, alternatively, aspartyl, N-phenyl-lower alkoxycarbonyl-(L) -- (O-phenyl-lower alkyl)aspartyl, such as N-benzyloxycarbonyl-(L) -- (O-benzyl)aspartic, asparaginyl or N-phenyl-lower alkoxycarbonylmethyl, such as N-benzyloxycarbonylation.

R1choose mainly from tert-butoxycarbonyl, 2,2,2-cryptgetkeyparam, 2-(methoxy)ethoxycarbonyl, 5(S)-2-oxopropylidene, 1-etoxycarbonyl - piperidine-4-ylcarbonyl, TRANS-(L)-4-hydroxyproline, (L)-thiazolidin-4 - ylcarbonyl, indole-2-ylcarbonyl, 4H-1-benzopyran-2-ylcarbonyl, N-metilprednisolone, tetrahydropyran-2(R, S)-icarb is arbonia, 2-aminothiazol-4-lacetera, 6-(4-methylpiperazin-1-yl)pyridine-3-ylcarbonyl, 4-(morpholine-4 - ylmethyl)benzoyl, N-methoxycarbonyl-(L)-felling and N-[(L)- thiazolidin-4-ylcarbonyl] -(L)-poured, and in addition, from (L)-asparagine, N-benzyloxycarbonyl-(L)-asparaginyl, (L)-aspartyl and N-benzyloxycarbonyl-(L) -- (O-benzyl)aspartyl, or (alternatively or additionally) choose from methoxycarbonyl, 2-methoxy - 1(R,S)-methylethanolamine, 1,1-dimethyl-2-methoxyethoxymethyl and 3-hydroxy-2-methylbenzene.

R2and R3- cyclohexyl, cyclohexenyl, phenyl, naphthyl (such as 1 - or 2 - naphthyl) or tetrahydronaphthyl are, independently of one another, unsubstituted or substituted as indicated, the substituents phenyl or cyanophenyl are alternative or complementary to the other group mentioned substituents; and lower alkylenedioxy linked to 2, preferably adjacent carbon atoms of the respective rings. Preferably, cyclohexenyl and tetrahydronaphtyl not replaced, then as cyclohexyl and, in particular, phenyl and naphthyl are not substituted or substituted by one, two or three radicals which are selected, independently of one another from lower alkyl, in particular methyl; phenyl (alternative is Lila, in particular, 2-phenylethyl, halogen, in particular fluorine; cyano; hydroxyl; lower alkoxy, in particular methoxy, or in addition, isobutoxy, lower alkoxy-lower alkoxy, in particular 2 - methoxyethoxy, lower alkylenedioxy, in particular, ethylene-1,2 - dioxy, or, in particular, methylendioxy, which is linked to 2 adjacent carbon atoms of the corresponding ring, phenyl-lower alkoxyl, in particular, benzyloxy, pyridyl-lower alkoxy, where pyridyl is linked via a carbon atom in the ring, such as pyridine-2-pyridine-3 - or, alternatively, pyridine-4-yl-methoxy, and phenyl-lower alkanesulfonyl (=phenyl-lower alkyl-S(= O)2-), which is not substituted or substituted, in particular phenyl radical, one or more, in particular, 2 radicals selected from halogen, in particular chlorine, especially dichlorophenyl lowest alkanesulfonyl, such as 2,6-dichlorobenzenesulfonyl (= 2,6 - dichlorobenzenesulfonyl), and, in addition, a halo-lower alkyl, preferably having not more than 3 halogen atoms, in particular fluorine atoms, for example, trifloromethyl, lower alkoxycarbonyl - lower alkoxy, such as ethoxycarbonylmethoxy, carboxy - lower alkoxy, such as carbomethoxy, hydroxy-lower alkoxy have bamol-lower alkoxy, such as carbamoylphenoxy (H2N - C(=O)-CH2-O-), and cyano-lower alkoxy, such as cyanoethoxy.

Preferably, R2and R3selected from cyclohexyl, cyclohexenyl such as cyclohexen-1-yl, phenyl, phenyl-lower-alkoxyphenyl, in particular 4-phenyl-lower-alkoxyphenyl, such as 4-(benzyloxy)phenyl, dipthera, in particular, 2,4 - dipthera, cyanophenyl, in particular, 4-cyanophenyl, lower alkoxyphenyl, such as 2,3 - or 4-lower alkoxyphenyl, for example 4-isobutylphenyl and, in particular, 2-, 3 - and, in particular, 4-methoxyphenyl, tri-lower alkoxyphenyl, in particular, trimethoxyphenyl, for example, with the Vice-lower alkoxy in positions 3, 4, 5, as in 3,4,5-trimethoxyphenyl, 2,4,5, as in 2,4,5-trimethoxyphenyl, in positions 2, 4, 6, as in 2,4,6-trimethoxyphenyl, where the three radicals-lower alkoxy or methoxy radicals preferably attached asymmetrically to the phenyl ring, mainly in positions 2, 3, 4, such as 2,3,4-trimethoxyphenyl, lower alkoxy-lower alkoxyphenyl, such as 4-(lower alkoxy-lower alkoxy)phenyl, especially 4-(2-methoxyethoxy)phenyl, lower alkylenedioxy, in which the radical lower alkylenedioxy associated posledstviya, such as 3,4-methylenedioxyphenyl, pyridyl-lower-alkoxyphenyl, such as 4-(pyridine-2 - or pyridine-3-yl-lower alkoxy) phenyl, in particular, pyridine-3-yl - lower alkoxyphenyl, for example pyridine-3-yl-methoxyphenyl; and in addition, a 4-lower alkoxy-2-ftoheia, such as 4-methoxy-2 - forfinal, 4-fluoro-2-lower-alkoxyphenyl, such as 4-fluoro-2 - methoxyphenyl, 4-lower alkoxy-2-hydroxyphenyl, such as 4 - methoxy-2-hydroxyphenyl, phenyl, which is substituted up to three times lower alkyl, such as methyl, lower alkoxy such as methoxy, for example 4-lower alkoxy-2,3-di-lower alkylphenyl, such as 4-methoxy-2,3-dimetilfenil, phenyl-lower alkylphenyl, such as 4-phenyl-lower alkylphenyl, for example, 4-(2-phenylethyl)phenyl, ftoheia, such as 2-forfinal, hydroxyphenyl, such as 4 - hydroxyphenyl, di-lower-alkoxyphenyl, in particular the acid, for example, 2,4-di-lower alkoxyphenyl, such as 2,4-acid, 3,4-di-lower alkoxyphenyl, such as 3,4 - acid, 2,5-di-lower alkoxyphenyl, such as 2,5 - acid, or 2,6-di-lower alkoxyphenyl, such as 2,6 - acid, tetrahydronaphthyl, in particular, 5,6,7,8 - tetrahydro-1-naphthyl, aloneftis, such as fornetti, in particular, 4-fernetti, CEC 4-methoxy-1-naphthyl, and dihalogen-lower alkanesulfonyl, in particular, dichlorophenyl-lower alkanesulfonyl, such as 4-(2,6-dichlorobenzenesulfonyl) phenyl; or alternatively, or in addition to the aforementioned radicals, selected from biphenylene, such as 4-biphenylyl, and (cyanophenyl)phenyl such as 2'-cyanobiphenyl-4-yl.

Especially preferred compounds of formula 1 in which R3indicates 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl, while the remaining radicals R1-R5and n have the above - or below.

Preferred compounds of formula I, which contain the combination of R5and R3in table 1 at the end of the description.

The combination of R2and R3particularly preferred are those mentioned above under the numbers 2), 4), 6), 8), 16), 24), 26), 27), 30) and 44), especially 6) and, in particular, 30).

R4preferably represents lower alkyl, especially methyl or isopropyl and sec-butyl (= 1-methylpropyl).

R5as the lower alkyl preferably denotes methyl or ethyl.

Variable n is preferably equal to 1.

Salts of compounds of formula I, what role with the bases (when in compounds of formula I are acidic group), or mixed salts or internal salts, when there are several salt-forming groups.

Salts are mainly used pharmaceutically, non-toxic salts of compounds of formula I.

Such salts are formed, for example, from compounds of the formula I having an acid group such as carboxyl group, alphagroup or phosphoryl group, which is substituted by one or two hydroxyl groups, and represents, for example, their salts with suitable bases, such as salts of non-toxic metals derived from metals of groups Ia, Ib, IIa, IIb of the Periodic table of elements, mainly suitable alkali metal salts, for example, salts of lithium, sodium or potassium, or salts of alkaline earth metals, for example, salts of magnesium or calcium, and also zinc salts or ammonium, and also salts formed with organic amines, such as mono-, di - or trialkylamine, in particular, mono-, di - or tri-lower alkylamines followed, which is not substituted or substituted by hydroxyl, or with Quaternary ammonium compounds, for example, N-methyl-N-ethyl-amine, diethylamine, triethylamine, mono-, bis - Il is Lamin or Tris(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy-lower alkyl)amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, N-methyl-D-glucamine or Quaternary ammonium salts such as tetrabutylammonium salt. The compounds of formula I which have a basic group such as amino group, can form acid additive salts, for example, with inorganic acids, for example, kaleidotrope acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfate(-O-SO3H) acids or phosphoric acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleimide acid, methylmaleimide acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucurono acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, almond acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, monowai acid, nicotinic acid or isonicotinic acid, and also with Amin is Isletas, and methansulfonate, econsultation, 2-hydroxyethanesulfonic, ethane-1,2 - disulfonate, benzosulfimide, 4-methylbenzenesulfonate, naphthalene-2-acid, 2 - or 3-phosphoglycerate, glucose-6-phosphate or N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid.

The compounds of formula I which possess acidic and basic groups can also form internal salts.

Pharmaceutically unsuitable salts, for example, perchlorate or picrate, can also be used for isolation or purification. Only the pharmaceutically acceptable salts, which are non-toxic when applied correctly, are suitable for therapeutic use and are therefore preferred.

The compounds of formula I have valuable pharmacological properties. They have antiviral activity, particularly against viruses HIV-1 and HIV-2, which are considered to be the causative agents of AIDS, and suddenly have synergistic effects when used in combination with other compounds with activity against retroviral aspartate-FR is partat-protease HIV-1 or HIV-2, and therefore suitable for the treatment of retroviral diseases such as AIDS or its preliminary stages (e.g., ARDS (respiratory distress syndrome in adults)). The compounds of formula I also have impacts against the relevant animal retroviruses, such as SIV (the monkey) or FIV (cats).

In this context, the compounds of formula I possess a particularly favorable pharmacodynamic properties, for example, a good pharmacodynamics, such as high biological availability and/or high levels in the blood (especially when administered orally) and/or good tolerance.

The inhibitory activity of the compounds of formula I on the proteolytic activity of the protease of HIV-1 can be demonstrated, for example, using a method similar to that described by A. S. Richards et al., J. Biol. Chem. 265(14), 7733-7736 (1990). In this case, the inhibition of HIV protease-1 (obtained in accordance with the work of S. Billich et al., J. Biol. Chem. 263(34), 17905-17908 (1990)) measured in the presence of acetamiprid RRSNQVSQNYPIVQNIQRR (artificial substrate of the protease of HIV-1 derived peptide synthesis using known methods (see J. Schneider et al. Cell 54, 363-368 (1988)), which as a substrate analogue sod is at and the products of fission analyze liquid chromatography high resolution (IHVR).

The investigated active compound dissolved in dimethyl sulfoxide. Enzyme test is carried out by adding the appropriate dilutions of the inhibitor in 20 mm buffer - morpholinepropanesulfonic (MES), pH of 6.0, the mixture for testing. The latter contains the above acetamiprid (122 mm) in 20 mm MES buffer, pH of 6.0. 100 μl is used for each mixture for testing. The reaction starts by adding 10 μl of a solution of the protease of HIV-1 and end after 1 h incubation at 37oC adding 10 ál of 0.3 M HClO4. After centrifugation of the samples at 10,000 x g for 5 min and 20 μl of the obtained supernatant is loaded into the column size 125 x 4.6 mm GHURNucleosil C18 - 5 ál (oversensitive substance of the company Macherey &Nagel, düren, Germany, on the basis of silica gel, which contains a circuit C18-alkyl). Unsplit acetamiprid and products of fission elute from the column using the following gradient: 100% eluent 1 - > 50% eluent 1 + 50% eluent 2 (eluent 1: 10% acetonitrile, 90% H2Oh, 0,1% triperoxonane acid (TFA); eluent 2: 75% acetonitrile, 25% H2Oh, and 0.08% TFA) over 15 min with a speed of movement of the solvent front 1 ml/min Fragments lirovannomu peptide determined quantitatively by esmaeili at a concentration in the range of 10-5up to 10-9M. In this context, preferably gain values IC50(IC50= the concentration that reduces the activity of the protease of HIV-1 by 50% compared to the activity of the control connection without inhibitor comprising from about 5 to 10-5up to 10-9M

In another test can be seen that the compounds of formula I or protect cells, which are usually infected with HIV from such intrusion, or at least delay such infection. This test uses cell line MT-2 leukemia cells T man (Science 229, 563 (1985)), which is extremely sensitive to the cytopathic effect of HIV, because it continuously produces - HTLV-1 (the virus that causes leukemia). Cells MT-2 grown in RPMI medium 1640 (Gibco, Scotland; RPMI contains amino acid mixture without glutamine), which contribute 10% fetal calf serum, heat inactivated, glutamine and standard antibiotics. Cells are always free of Mycoplasma. Virus HIV-1 (strain LAV) were cultured in A cell 3.01 (NIH, Bethesda, USA), that is, cell line, which is used for culturing HIV-1 and which is obtained from the cell line CEM. The measurement of reverse transcriptase (see below) shows that the viral titer of preparement of the test compound and 50 μl of each of the test substrate in the culture medium and 100 μl BEACH-1 in culture medium (800 TCID 50/ml, TCID 50 = infectious dose tissue culture = dose that infects 50% of cells (MT-2) is added to 10 104exponentially growing cells MT-2, which are initially introduced into 50 µl of culture medium in 96-well microtiter plates. After 4 days of incubation, a sample consisting of 10 μl of the supernatant are then removed from each well for measuring the activity of reverse transcriptase. The titer of the enzyme reverse transcriptase, which is specific to retroviruses, used as a measure of viral titer. To determine the titer of the extracted sample is first added to another 96-well microtiter plate and maintained at a temperature of -20oC until measurement.

When making measurements of 30 μl of the reverse transcriptase inhibitor cocktail was added to each well. The reverse transcriptase inhibitor cocktail containing 50 mm Tris ,,- Tris(hydroxymethyl)methylamine, Ultra pur, Merck, Germany), pH 7.8; 75 mm KCl, 2 mm dithiothreitol, 5 mm MgCl20.1% of Nonidet P-40 (detergent; Sigma, Switzerland), 0.8 mm etc, 10 μg/ml poly-A (Pharmacia, Uppsala, Sweden) and 0.16 μg/ml oligo(T) (= pdT(12 - 18), Pharmacia, Uppsala, Sweden) as a matrix primer. The mixture is filtered through a filter of 0.45 μm Acrodisc (Gelman Sciences, Inc. , Ann Arbor, USA) and maintained at tempering radioactivity, equal to 10 µci/ml

After mixing the tablet incubated at 37oC for 2 hours followed by 5 μl of the reaction mixture is transferred onto DE81 paper (Whatman, one filter per well). The dried filters are washed three times for 5 min with 300 mm NaCl/25 mm trinacria citrate and then once with ethanol, and then air-dried again. Radioactivity on the filters was measured in a 96-well counter Packard Matrix (Packard, Zurich, Switzerland). Then ED90 calculated and defined as the concentration of test compounds that reduce the activity by 90% compared with the control connection without the use of the test compounds.

In this test the compounds of formula I preferably inhibit viral replication at concentrations from 5 to 10-5up to 10-8M

Thus, the compounds of formula I are suitable for the active delay HIV-1 replication in cell culture.

You can also measure the levels in the blood of the compounds of formula I.

For this purpose, the compounds of the formula I are dissolved, for example, in methylsulfoxide (DMSO) at a concentration of 240 mg/ml of the resulting solution is diluted with 20% (wt./about.) hydroxypropyl- - cyclodextrin (HP-CD) to generate and artificial feeding through a stomach tube, at a dose of 120 mg/kg Animals killed after 30, 60, 90 and 120 min after drug administration, after which take away the blood. In each moment of time exploring 3-4 animals. Blood heparinized and processed for analysis as follows: internal standard added to heparinized blood with obtaining a final concentration of 4 μm. The blood is centrifuged. 0.25 ml of plasma is selected and deproteinized equal volume of acetonitrile. After centrifugation the supernatant is dried under vacuum and the residue suspended in 20 ál of 3 M NaCl and 100 μl of 0.05 M phthalate buffer, having a pH of 3.0. The suspension is extracted first, 1 ml, then 0.2 ml of diisopropyl ether. A solution of diisopropyl ether evaporated to dryness and the residue is dissolved in 50% (vol. /about.) aqueous acetonitrile. This solution explore obremenitve GHUR.

Analysis obremenitve GHUR is carried out using a column NucleosilC18 size h,6 mm (oversensitive substance of the company Macherey &Nagel, düren, Germany, silica-based, which derivatisation C18hydrocarbon residue), which balance the mobile phase of 50% acetonitrile in water /0.1% of triperoxonane acid. The speed of movement of the solvent front to costum blood and used to construct standard curves, which are then used to determine the concentrations in vivo.

These and related experiments, and experiments, including parenteral administration, show that when using compounds of formula I can be obtained levels in the blood, which is higher than the ED90in the above analysis of cells. For this reason, the compounds of this nature are also suitable to prevent the growth of viruses in vivo.

The combination of inhibition of in vitro aspartate protease, inhibition of viral replication in cell culture and measuring levels in the blood in rodents such as rat or mouse, is used to determine the clinical potential inhibitors of aspartate protease (see, for example, Roberts, N. A., et al., Biochemical Soc. Transactions 20, 513-516 (1992)).

Blood levels that are higher than the values of the ED90in the above-mentioned cell analysis, also can be seen in the introduction (e.g., oral) compounds of the formula I to the dogs. Therefore, the combination of data from cell experiment, levels in the blood of rodents and levels in the blood of dogs also makes possible the use of the compounds for the treatment of retroviral diseases, particularly those diseases in which disgust, control and treatment of infections caused by retroviruses, in particular HIV, such as HIV-1 or HIV-2 in cell cultures, in particular, the cell cultures cell lines lymphocytes from the mammal, which is especially beneficial in case the application is very valuable cell cultures, which, for example, produce specific antibodies, vaccines or substance-mediators, such as interleukins, and so on, and so have a greater commercial value.

Finally, the compounds of formula I can be used as standards in experiments, for example, as standards GHUR or as standards for comparison of animal models in relation to different inhibitors of aspartate protease, for example, in relation to the levels in the blood, which can be achieved.

The compounds of formula I can be administered separately or in combination (in the form of a continuous combination of suitable drugs or combinations of the individual active compounds or specific drugs, enter in a chronologically staggered sequence) with other substances that are active against retroviruses, in particular HIV, such as HIV-1 or HIV-2, or their salts, provided that there is manilasydney analogues, in particular, 3'-azido-3'-deoxythymidine (= AZT =RETROVIR, Burroughs-Wellcome), 2',3'-dideoxycytidine (= zalcitabine =HIVID, Hoffmann-LaRoche), 2',3'-dideoxyinosine (= DDI =VIDEX, Bristol-Myers-Squibb) or (2R,CIS)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)- pyrimidine-2-one (= lamivudin, Glaxo), or non-nucleoside analogues, such as 11-cyclopropyl-5,11-dihydro-4-methyl-(6N)-dipyrido [3,2-b; 2',3'-e]-[1,4]diazepin-6-he; and, first, with one or more (in particular, one or two) from a number of other inhibitors of retroviral aspartate proteases, especially aspartate proteases from HIV, such as HIV-1 and HIV-2, in particular one or more (preferably one or two), in particular: (a) one of the inhibitors listed in the application EP 0346847 (published December 20, 1989) and the application for EP 0432695 (published June 10, 1991; corresponds to US patent 5196438, published March 23, 1993)especially with the connection denoted by Ro 31-8959 (= saquinavir; Hoffmann-LaRoche) formula

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b) one of the inhibitors mentioned in the application EP 0541168 (published may 12, 1993; corresponds to US patent 5413999), in particular with the connection indicated by L-735,524 (= indinavir =CRIXIVAN; Merck & Co., Inc.) formula

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in one of the ing connection marked ABT-538 (Abbott) formula

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g) of the compound denoted by KVX-478 (or VX-478 or 141W94; Glaxo Wellcome, Vertex and Kissei Pharmaceuticals) formula

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d) the compound denoted by AG-1343 (Agouron) formula

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e) connection, denoted INSTITUTE-272 (Nippon Mining) formula

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W) of the compound denoted by U-96988 (decision Upjohn) formula

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and/or C) of the compound denoted by BILA-2011 BS (= palinavir; Boehringer-Ingelheim) formula

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or in each case its salt, provided that there are soleobrazutaya group.

Particularly, when the compound of formula I together with one or more of the indicated inhibitors of retroviral aspartate proteases, in fact, one can observe synergistic effects, that is unexpected, because the inhibitors act on the same enzyme. The particular advantage of such compositions is lowering the required dosage and stronger antiviral activity, which can be achieved at the same time, the active compounds are used in combination, compared with what can be achieved with the use of the individual active compounds. This gives advantages in terms of possible side effects of the individual compounds and leads to reduced Chi is the likely development of resistance.

The activity of the compositions and, in particular, synergistic effects can be checked, for example, by means of experiments using cell lines and mononuclear peripheral blood cells (lymphocytes and monocytes).

Cells CEM-SS (see Nara, P. L., et al., AIDS Res. Human Retroviruses 3, 283 - 302 (1987), or Nara, P. L., et al., Nature 332, 469-470 (1988)) and permanently infected cell line H9/HTLV-IIIB NIH 1983 (cell H9/HIV-1/IIIB) Gallo (see Popovic, M., et al., Science 224, 497 - 500 (1984); Popovic, M., et al., Lancet (1984) ii, 1472-1473; or Rather, L., et al., Nature 313, 277-284 (1985)), for example, used for experiments using cell lines.

For experiments using peripheral mononuclear blood cells, cells isolated from the blood of healthy HIV-seronegative people using a combination of leukapheresis and counterflow elutriation centrifugation in accordance with known methods (see Alteri, E., et al., Antimicrob. Agent Chemother. 37(10), 2087-2092 (1993)).

Lymphocytotropic isolate HIV-I/LAV (LAV. 04/A. 301), for example, is used as a virus (see Science 220, 868-871 (1983)).

Compound, for example, the compound of formula I, and one of the other inhibitors of retroviral aspartate proteases mentioned above,

for example, saquinavir or indinavir, dissolve the tissue culture (see below). The final concentration of free DMSO is less than 0.5%.

Experiments to study the antiviral activity is as follows.

Cell line remain in full culture medium of the following composition: RPMI 1640 (GIBCO, Paisley, Scotland), supplemented with 10% fetal calf serum (SEROMED, Berlin, Germany), 10 mm 4-(2-hydroxyethyl)piperazine-1-econsultancy (= HEPES) and 2 mm L-glutamine (AMIMED, Muttenz, Switzerland). Antiviral activity of the compounds examined in coculturing system using cells CEM-SS and permanently infected cells H9/HIV-1/IIIB. The compounds tested as individual substances or as the composition of two active substances in certain respects concentrations. Cells H9/HIV-1/IIIB mixed, after twice washing and suspension in fresh medium, cells CEM-SS in the ratio of 1:50. 100 μl of the cell mixture is loaded into each well of 96-well plate to tissue cultures, and the wells contain in each case 400 cells H9/HIV-1/IIIB and 2 104cells CEM-SS. Immediately after loading the cells twofold serial dilutions of the tested compounds was added (100 μl per well) in each case in groups of six. Instead act as control (CC). Final volume of 200 µl per well. After 24 h incubation at 37oC in 5% CO2remove 150 ál of each supernatant, without removing any of the cells, and replaced with 150 μl of fresh medium, which contains (or, in the case of VC, does not contain) a fresh test substance or fresh subjects substances. 10 μl samples of culture supernatants harvested on day 4 and added to another 96-well microtiter tablet, which, if necessary, stored at -20oC. Production of viruses is determined in the form of virus-associated activity of the reverse transcriptase (RT) in accordance with the following method, which is already described above (see Alteri, E., et al., Antimicrob. Agent Chemother. 37(10), 2087-2092 (1993)).

When making measurements of 30 μl of the reverse transcriptase inhibitor cocktail was added to each well. The reverse transcriptase inhibitor cocktail containing 50 mm Tris (( ,,-Tris(hydroxymethyl)methylamine, Ultra pur, Merck, Germany), pH 7.8; 75 mm KCl, 2 mm dithiothreitol, 5 mm MgCl2;0.1% of Nonidet P-40 (detergent; Sigma, Switzerland), 0.8 mm etc, 10 μg/ml poly-A (Pharmacia, Uppsala, Sweden) and 0.16 μg/ml oligo(T) (= pdt(12-18), Pharmacia, Uppsala, Sweden) as a matrix primer. The mixture is filtered through a filter of 0.45 μm Acrodisc (Gelman Sciences Inc., Ann Arbor, USA) and stored at -20oC. Before the 10 µci/ml

After mixing the tablet incubated at 37oC for 1.5 hours followed by 5 μl of the reaction mixture is transferred onto DE81 paper (Whatman, one filter per well). The dried filters are washed three times for 5 min with 300 mm NaCl/25 mm triacrylate and then once with ethanol, and then air-dried again. Radioactivity on the filters was measured in a 96-well counter Packard Matrix (Packard, Zurich, Switzerland). Antiviral effect is given in the form of a percentage reduction in RT activity compared with the values of VC.

When using the mononuclear cells of peripheral blood, a mixture of mononuclear cells (lymphocytes and monocytes), which is obtained as described above were cultured in the presence of 0.25 μg/ml of phytohemagglutinin (Wellcome Diagnostics, Temple Hill, Dartford, England) for 2 days in RPMI 1640 (GIBCO, Paisley, Scotland), 50 int. units/ml penicillin, 50 µg/ml streptomycin (AMIMED, Muttenz, Switzerland), 2 mm L-glutamine (AMIMED, Muttenz, Switzerland) and 10 mm HEPES buffer (GIBCO, Paisley, Scotland). Successful activation register by measuring the increase in size of cells (analysis of scatterplots excited fluorescence sorted cells). Cells resuspended in complete medium containing 10% human serum AB (Sigma, St. Louise, USA)Rui Supplement 100 units per 1 ml of human recombinant IL-2 interleukin-2 (Genzyme, Cambridge, USA). 9 104cells were seeded on each well (0.3 ml) in 96-well tablets, with the bottom of the hole with a U-configuration. Antiviral compounds added either separately or in combination with five cell cultures in each case (pentality) directly after infection. 2/3 of culture medium with or without antiviral compounds (compounds) replace every three days. Research completed on the 13th day after infection. The progress of viral infection is measured by determining the activity of RT, as described above with respect to the cell lines.

In preferred groups of compounds of formula I, referred to below, the definitions of the substituents of the above General definitions can be used in a meaningful way, for example, to replace more General definitions with more specific definitions or, in particular, those definitions characterized as being preferred; in each case the definition is preferred, which is characterized as being preferred or as being examples.

Preferred is a compound of the formula I (in particular, formula (I') in which R1means Allin is particularly tert-butoxycarbonyl, etoxycarbonyl or methoxycarbonyl; lower alkoxy-lower alkanoyl (in particular, appropriately substituted lower alkoxycarbonyl), which is replaced by the moiety of the lower alkoxy, one or more times by halogen, in particular fluorine, lower alkoxy or pyrrolidinyl, which is not substituted or is substituted by oxo, such as 2,2,2-cryptgetuserkey, 2-methoxyethoxymethyl, 2-methoxy-1(R,S)-methylethanolamine, 1,1-dimethyl-2-methoxyethoxymethyl or 2-oxopyrrolidin-5(S)-ylmethoxycarbonyl; N-lower alkoxycarbonylmethyl-lower alkanoyl, for example-carbonyl, such as N-ethoxycarbonylpyrimidine-4-ylcarbonyl; pyrrolidinyl-lower alkanoyl, such as carbonyl, which is substituted by hydroxyl on a carbon atom and/or phenyl-lower alkoxycarbonyl on the nitrogen atom and which is preferably in the form (R), the form (R,S) or, in particular, the form (S) on binding carbon atom, such as (L)- TRANS-4-hydroxypropyl or (L)-N-benzyloxycarbonyl-TRANS-4 - hydroxypropyl; aminothiazoline-lower alkanoyl, for example, acetyl, such as 2-amino-4-thiazoleacetic; thiazolyl-lower alkanoyl, for example-carbonyl, such as thiazol-2-ylcarbonyl; indolyl-lower alkanoyl, for example-carbonyl, tamgho as 4-oxo-4H-1 - benzopyran-2-ylcarbonyl; N-lower alkylpiperidines-lower alkanoyl, for example-carbonyl, such as N-methylpiperidin-4 - jocstarbunny; tetrahydropyran-yloxy-lower alkanoyl, for example, -propionyl or-carbonyl, such as 2(S)- (tetrahydropyran-4-yloxy)-propionyl or tetrahydropyran-2(R,S)- jocstarbunny; tetrahydropyranyloxy-lower alkanoyl, for example-carbonyl, such as tetrahydrofuran-3(S)-jocstarbunny; morpholinyl-lower alkylbenzene, such as 4-(morpholinyl-4 - ylmethyl)benzoyl; lower alkylpiperazine-pyridylcarbonyl, such as N-lower alkyl-piperazinylcarbonyl, in particular 4 - lower alkylpiperazine-1-empiricallybased, for example, 2-or 3-(4 - lower alkyl [such as methyl] piperazine-1-yl)-pyridine-2 - ylcarbonyl or-3-ylcarbonyl; phenyl-lower alkanoyl, which is substituted by hydroxyl or lower alkyl, in particular, stands, preferably having, in each case, Deputy hydroxyl and lower alkyl, in particular, hydroxyl and methyl, phenyl ring and, in particular, is an appropriately substituted benzoyl, such as 3-hydroxy-2-methylbenzoyl; and phenylsulfonyl, substituted amino, nitro, amino and lower alkyl, such as methyl, or nitro, and lower al is ethyl)-4-nitrobenzenesulfonyl or 4 - amino-2-lower alkyl (in particular, 2-methyl)-benzazolyl; the remainder, which is connected via the carboxyl group of the amino acids selected from valine, Norvaline, leucine, isoleucine and norleucine, and in addition, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4 - chlorophenylalanine, 4-carboxyaniline, - phenylseleno, phenylglycine, -naphtylamine, cyclohexylamine, cyclohexylglycine, tryptophan, asparagine, monoamide aminomalonate acid, glutamic acid, glutamine, histidine, arginine, lysine, hydroxylysine and ornithine; preferred is valine; moreover, the corresponding amino group (group) and other functional groups are free or (if possible) are in salt form; and these amino acid radicals having asymmetric carbon atoms are in the form of (D), form (L) or (D,L), preferably in the form (L);

or residue, which is linked via a carbonyl group, one of the above amino acids and which is N-allerban the amino group of one of the above-mentioned acyl radicals, in particular, a valine residue, which is linked via a carbonyl group and which N-allerban one of the above-mentioned acyl glad oxycarbonyl, or diazolidinylurea, in particular, thiazolidin-4-Jalil, which is preferably in the form (S), form (R,S) or, in particular, the form (R) (= form (L) on the atom at the 4-carbon ring of thiazolidine; however, in each case, the residue is poured is preferably in the form (L);

R2and R3chosen, independently of one another, cyclohexyl, cyclohexenyl, such as cyclohexen-1-yl, phenyl, biphenylyl, such as 4-biphenylyl, (cyanophenyl)phenyl such as 2'-cyanobiphenyl-4-yl, phenyl-lower-alkoxyphenyl, in particular 4-phenyl-lower-alkoxyphenyl, such as 4-(benzyloxy)phenyl, dipthera, in particular, 2,4-dipthera, cyanophenyl, in particular, 4-cyanophenyl, lower alkoxyphenyl, such as 2-, 3 - or 4-lower alkoxyphenyl, for example 4-isobutylacetophenone and, in particular, 2-, 3 - and, in particular, 4-methoxyphenyl, tri-lower alkoxyphenyl, in particular, trimethoxyphenyl, for example, with the Vice-lower alkoxy in positions 3, 4, 5, as in 3,4,5-trimethoxyphenyl, in positions 2, 4, 5, as in 2,4,5 - trimethoxyphenyl, in positions 2, 4, 6, as in 2,4,6 - trimethoxyphenyl, where the radicals tri-lower alkoxy or methoxy radicals preferably attached asymmetrically to the phenyl ring, mainly in the alkoxy-lower alkoxyphenyl, especially 4-(2 - methoxyethoxy)phenyl, lower alkylenedioxy, in which the radical lower alkylenedioxy connected by two oxygen atoms from two adjacent carbon atoms of the phenyl ring, for example, methylendioxyphenyl, such as 3,4-methylenedioxyphenyl, pyridyl-lower alkoxyphenyl, pyridyl which is linked via a ring carbon atom, such as 4-(pyridine-2 - or pyridine-3-yl-lower alkoxy)phenyl, in particular, pyridine-3-yl - lower alkoxyphenyl, for example, pyridine-3-limitatively; and besides of 4-lower alkoxy-2-ftoheia, such as 4-methoxy-2 - forfinal, 4-fluoro-2-lower-alkoxyphenyl, such as 4-fluoro-2 - methoxyphenyl, 4-lower alkoxy-2-hydroxyphenyl, such as 4 - methoxy-2-hydroxyphenyl, phenyl, which is substituted up to three times lower alkyl, such as methyl, lower alkoxy such as methoxy, such as 4-lower alkoxy-2,3-di-lower alkylphenyl, for example, 4-methoxy-2,3-dimetilfenil, phenyl-lower alkylphenyl, such as 4-phenyl-lower alkylphenyl, for example, 4-(2-phenylethyl) phenyl, ftoheia, such as 2-forfinal, hydroxyphenyl, such as 4-hydroxyphenyl, di-lower-alkoxyphenyl, in particular, of the acid, for example, 2,4-di-lower alkoxyphenyl, such as 2,4-dimethoxyphenyl, or 2,6-di-lower alkoxyphenyl, such as 2,6 - acid, tetrahydronaphthyl, in particular, 5,6,7,8 - tetrahydro-1-naphthyl, aloneftis, such as fornetti, in particular, 4-fernetti, cyanomitra, such as 4-canonity, lower alkoxymethyl, in particular 4-lower alkoxymethyl, such as 4-methoxy-1-naphthyl, and dihalogen-lower alkanesulfonyl, in particular, dichlorophenyl-lower alkanesulfonyl, such as 4-(2,6-dichlorobenzenesulfonyl)phenyl; and the corresponding radicals, preferably present in one of the combinations listed above are preferred, in particular, in one of the combinations listed above under numbers 2), 4), 6), 8), 16), 24), 26), 27), 30) and 44), that is, R2= phenyl and R3= cyanophenyl (in particular, 4-cyanophenyl); R2= phenyl and R3= 2,4-differenl; R2= phenyl and R3= 4-lower alkoxyphenyl, in particular 4-methoxyphenyl; R2= 4-(lower alkoxy-lower alkoxy)phenyl, in particular 4-(2-methoxyethoxy)phenyl and R3= 4-(phenyl-lower alkoxy)phenyl, in particular 4(benzyloxy)phenyl; R7= cyclohexyl and R3= 4-lower alkoxyphenyl, in particular 4-methoxyphenyl; R2= phenyl and R3= phenyl; R2= phenyl and R3= 4-((pyridin-2-yl or, in cenditions, in particular, 3,4-methylenedioxyphenyl; R2= cyclohexyl and R3= 4-(lower alkoxy-lower alkoxy)phenyl, in particular 4-(2-methoxyethoxy)phenyl; or, particularly preferably, R2= phenyl and R3= 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl;

R4denotes lower alkyl, preferably isopropyl, or, alternatively, cyclohexyl or phenyl;

R5denotes lower alkyl, especially methyl, or, in addition, n-propyl; and

n = 2, or, preferably, 1;

or its salt, provided that there is at least one salt-forming group.

More preferred is a compound of formula I, in which:

R1denotes the acyl radical selected from lower alkoxy-lower alkanoyl, such as, in particular, lower alkoxycarbonyl, especially tert-butoxycarbonyl, etoxycarbonyl or methoxycarbonyl; lower alkoxy-lower alkanoyl (in particular, appropriately substituted lower alkoxycarbonyl), which is replaced by the moiety of the lower alkoxy, one or more times by halogen, in particular fluorine, lower alkoxy or pyrrolidinyl, which is not substituted or is substituted by oxo, such as 2,2,2-cryptgetuserkey, 2-myoxinol, for example-carbonyl, such as N-ethoxycarbonylpyrimidine-4-ylcarbonyl; pyrrolidinyl-lower alkanoyl, such as carbonyl, which is substituted by hydroxyl on a carbon atom and/or phenyl-lower alkoxycarbonyl on the nitrogen atom and which is preferably in the form (R), the form (R,S) or, in particular, the form (S) on binding carbon atom, such as (L)-TRANS-4-hydroxypropyl or (L)-N-benzyloxycarbonyl-TRANS-4-hydroxypropyl; aminothiazoline-lower alkanoyl, for example, acetyl, such as 2-amino-4 - thiazoleacetic; thiazolyl-lower alkanoyl, for example-carbonyl, such as thiazol-2-ylcarbonyl; indolyl-lower alkanoyl, for example-carbonyl, such as indole-2-ylcarbonyl; 4H-1 - benzopyranyl-lower alkanoyl, for example-carbonyl, which is substituted by oxo, such as 4-oxo-4H-1-benzopyran-2-ylcarbonyl; N-lower alkyl-piperidinyloxy-lower alkanoyl, for example-carbonyl, such as N-methylpiperidin-4-jocstarbunny; tetrahydropyranyloxy-lower alkanoyl, for example, - propionyl or-carbonyl, such as 2(S)-(tetrahydropyran-4-yloxy)-propionyl or tetrahydropyran-2(R, S)-jocstarbunny; tetrahydropyranyloxy - lower alkanoyl, for example-carbonyl, such as tetrahydrofuran-3(S)-jocstarbunny; is carbonyl, such as N-lower alkylpiperidines, in particular 4-lower alkylpiperazine-1-empiricallybased, for example, 2-or 3-(4-lower alkyl [such as methyl] piperazine-1-yl)-pyridine-2-ylcarbonyl or - 3-ylcarbonyl;

the remainder, which is connected via the carboxyl group of the amino acids selected from valine, Norvaline, leucine, isoleucine and norleucine, and in addition, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyaniline, -phenylseleno, phenylglycine, -naphtylamine, cyclohexylamine, cyclohexylglycine, tryptophan, asparagine, monoamide aminomalonate acid, glutamic acid, glutamine, histidine, arginine, lysine, hydroxylysine and ornithine; preferred is valine; and the corresponding amino group (group) and other functional groups are free or (if possible) are in salt form; and these amino acid radicals having asymmetric carbon atoms are in the form of (D), form (L) or (D,L), preferably in the form (L);

or residue, which is linked via a carbonyl group, one of the above amino acids and which is N-allerban am on the ohms of the carbonyl group and that N-allerban one of the above-mentioned acyl radicals, in particular, lower alkoxy-lower alkanolamine, such as lower alkoxycarbonylmethyl, for example, methoxycarbonylmethyl, or diazolidinylurea, in particular, thiazolidin-4-Jalil, which is preferably in the form (S), form (R,S) or, in particular, the form (R) (= form (L) atom at the 4-carbon ring of thiazolidine; however, in each case, the residue is poured is preferably in the form (L);

R2and R3chosen, independently of one another, cyclohexyl, cyclohexenyl, such as cyclohexen-1-yl, phenyl, phenyl-lower-alkoxyphenyl, in particular 4-phenyl-lower-alkoxyphenyl, such as 4-(benzyloxy)phenyl, dipthera, in particular, 2,4-dipthera, cyanophenyl, in particular, 4-cyanophenyl, lower alkoxyphenyl, such as 2-, 3 - or 4-lower alkoxyphenyl, for example 4-isobutylphenyl and, in particular, 2-, 3 - and, in particular, 4-methoxyphenyl, tri-lower alkoxyphenyl, in particular, trimethoxyphenyl, for example, with the Vice-lower alkoxy in positions 3, 4, 5, as in 3,4,5-trimeton-sitemile, in positions 2, 4, 5, as in 2,4,5-trimethoxyphenyl, in positions 2, 4, 6, as in 2,4,6-trimethoxyphenyl, where the three radicals-lower alkoxy or methoxy radicals preferably attached asymmetrically to phenoxyphenyl, such as 4-lower alkoxy-lower alkoxyphenyl, especially 4-(2 - methoxyethoxy)phenyl, lower alkylenedioxy, in which the radical lower alkylenedioxy connected by two oxygen atoms from two adjacent carbon atoms of the phenyl ring, for example, methylendioxyphenyl, such as 3,4-methylenedioxyphenyl, pyridyl-lower alkoxyphenyl, pyridyl which is linked via a ring carbon atom, such as 4-(pyridine-2 - or pyridine-3-yl-lower alkoxy) phenyl, in particular, pyridine-3-yl-lower alkoxyphenyl, for example, pyridine-3-limitatively; and, in addition, a 4-lower alkoxy-2-ftoheia, such as 4-methoxy-2-forfinal, 4-fluoro-2-lower-alkoxyphenyl, such as 4-fluoro-2-methoxyphenyl, 4-lower alkoxy-2-hydroxyphenyl, such as 4 - methoxy-2-hydroxyphenyl, phenyl, which is substituted up to three times lower alkyl, such as methyl, lower alkoxy such as methoxy, for example, 4-lower alkoxy-2,3-di-lower alkylphenyl, such as 4-methoxy-2,3-dimetilfenil, phenyl-lower alkylphenyl, such as 4-phenyl-lower alkylphenyl, for example, 4-(2-phenylethyl) phenyl, ftoheia, such as 2-forfinal, hydroxyphenyl, such as 4-hydroxyphenyl, di-lower-alkoxyphenyl, in particular, acid, n is Setenil, 2,5-di-lower alkoxyphenyl, such as 2,5 - acid, or 2,6-di-lower alkoxyphenyl, such as 2,6 - acid, tetrahydronaphthyl, in particular, 5,6,7,8 - tetrahydro-1-naphthyl, aloneftis, such as fornetti, in particular, 4-fernetti, cyanomitra, such as 4-canonity, lower alkoxymethyl, in particular 4-lower alkoxymethyl, such as 4-methoxy-1-naphthyl, and dihalogen-lower alkanesulfonyl, in particular, dichlorophenyl-lower alkanesulfonyl, such as 4-(2,6-dichlorobenzenesulfonyl)phenyl; and the corresponding radicals, preferably present in one of the combinations listed above are preferred, in particular, in one of the combinations listed above under numbers 2), 4), 6), 8), 16), 24), 26), 27), 30) and 44), that is, R2= phenyl and R3= cyanophenyl (in particular, 4-cyanophenyl); R2= phenyl and R3= 2,4-differenl; R2= phenyl and R3= 4-lower alkoxyphenyl, in particular 4-methoxyphenyl; R2= 4-(lower alkoxy-lower alkoxy)phenyl, in particular 4-(2-methoxyethoxy)phenyl and R3= 4-(phenyl-lower alkoxy)phenyl, in particular 4(benzyloxy)phenyl; R2= cyclohexyl and R3= 4-lower alkoxyphenyl, in particular 4-methoxyphenyl; R2= phenyl and R3= methoxyphenyl; R2= phenyl and R3= 3,4-lowest alkylenediamines, in particular, 3,4-methylenedioxyphenyl; R2= cyclohexyl and R3= 4- (lower alkoxy-lower alkoxy)phenyl, in particular 4-(2 - methoxyethoxy)phenyl; or, particularly preferably, R2= phenyl and R3= 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl;

R4denotes lower alkyl, preferably isopropyl, or, alternatively, cyclohexyl or phenyl;

R5denotes lower alkyl, especially methyl; and

n = 2, or, preferably, 1;

or its salt, provided that there is at least one salt-forming group.

More preferably the compound of formula I (in particular, I') in which:

R1choose from ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-cryptgetkeyparam, 2-(methoxy)ethoxycarbonyl, 2-methoxy-1-(R, S)-methylethanolamine, 1,1-dimethyl-2-methoxyethoxymethyl, 5(S)-2-oxopropylidene, 1-ethoxycarbonylpyrimidine-4 - ylcarbonyl, TRANS-(L)-4-hydroxyproline, N-(benzyloxycarbonyl)-TRANS-(L)-4 - hydroxyproline, (L)-thiazolidin-4-ylcarbonyl, indole-2-ylcarbonyl, 4H-1 - benzopyran-2-ylcarbonyl, N-metilprednisolone, tetrahydropyran-2(R, S)-ylcarbonyl, 2-aminothiazol-4-lacetera, 6-(4-methylpiperazin-1-yl)-pyridine-3-ylcarbonyl, 4-(morpholine-4-ylmethyl)benzoyl, N-methoxycarbonyl-(L)-poured, M-[(L)- thiazolidin-4-ylcarbonyl]-(L)-valil, 3-hydroxy-2-methylbenzoyl, 4-nitrobenzenesulfonyl, 4-aminobenzenesulphonyl, 2-methyl-4 - nitrobenzenesulfonyl and 4-amino-2-methylbenzenesulfonyl; it is particularly preferred tert-butoxycarbonyl;

R2and R3selected from cyclohexyl, cyclohexen-1-yl, phenyl, 4-biphenylyl, 2'-cyanobiphenyl-4-yl, 4- (benzyloxy)phenyl, 2,4-dipthera, 4-cyanophenyl, 2-, 3 - or 4 - methoxyphenyl, 4-isobutylacetophenone, trimethoxyphenyl, for example, having the substituents in positions 3, 4, 5, as in 3,4,5 - trimethoxyphenyl, in positions 2, 4, 5, as in 2,4,5 - trimethoxyphenyl, or in positions 2, 4, 6, as in 2,4,6-trim - toxiferine, and methoxy radicals preferably attached asymmetrically to the phenyl ring, mainly in positions 2, 3, 4, for example, 2,3,4-trimethoxyphenyl, 4-(2-methoxyethoxy) phenyl, 3,4-methylenedioxyphenyl and 4-(pyridine-2 - or pyridine-3 - ylethoxy)phenyl, and, in addition, from 4-methoxy-2-ftoheia, 4 - fluoro-2-methoxyphenyl, 4-methoxy-2-hydroxyphenyl, 4-methoxy-2,3 - dimetilfenil, 4-(2-phenylethyl)phenyl, 2-ftoheia, 4-hydroxyphenyl, dimethoxyethan is a, 4-ptomaphila, 4-cyanonaphthalene, 4 - lower alkoxymethyl and 4-(2,6-dichlorobenzenesulfonyl)phenyl; R2and R3preferably present in the following combinations: R2= 4-benzyloxyphenyl and R3= 4-benzyloxyphenyl; R2= phenyl and R3= 4-cyanophenyl; R2= phenyl and R3= 2-forfinal; R2= phenyl and R3= 2,4-differenl; R2= phenyl and R3= 4-(2-phenylethyl) phenyl; R2= phenyl and R3= 4-(2,6-dichlorobenzenesulfonyl)phenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-benzyloxyphenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-hydroxyphenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-methoxyphenyl; R2= 4-(2 - methoxyethoxy)phenyl and R3= 4-(2-methoxyethoxy)phenyl; R2= 4-benzyloxyphenyl and R3= 4-methoxyphenyl; R2= 4-hydroxyphenyl and R3= 4-methoxyphenyl; R2= 4-methoxyphenyl and R3= 4-methoxyphenyl; R2= 4-isobutylphenyl and R3= 4-methoxyphenyl; R2= 4-methoxyphenyl and R3= phenyl; R2= cyclohexyl and R3= 4-methoxyphenyl; R2= phenyl and R3= 4-methoxy-2-forfinal; R2= phenyl and R3= 4-fluoro-2 - methoxyphenyl; R2= phenyl and R3= 4-methoxy-2-hydroxyphenyl; R2= 4-methoxyphenyl and R4 is benzyloxyphenyl; R2= cyclohexyl and R3= 4-hydroxyphenyl; R2= cyclohexyl and R3= 4-methoxyphenyl; R2= cyclohexyl and R3= 4-(2-methoxyethoxy)phenyl; R2= phenyl and R3= phenyl; R2= phenyl and R3= 4-benzyloxyphenyl; R2= phenyl and R3= 4-hydroxyphenyl; R2= phenyl and R3= 4-isobutoxide; R2= phenyl and R3= 4-(pyridine-2-ylethoxy) phenyl; R2= phenyl and R3= 4-(pyridine-3-ylethoxy)phenyl; R2= phenyl and R3= 4-methoxyphenyl; R2= phenyl and R3= 3,4-methylenedioxyphenyl; R2= phenyl and R3= 3,4-acid; R2= phenyl and R3= 3-methoxyphenyl; R2= phenyl and R3= 2,3,4-trimethoxyphenyl; R2= phenyl and R3= 3,4,5-trimethoxyphenyl; R2= phenyl and R3= 2,4-acid; R2= phenyl and R3= 2-methoxyphenyl; R2= phenyl and R3= 2,3-dimethyl-4 - methoxyphenyl; R2= phenyl and R3= 2,4,5-trimethoxyphenyl; R2= phenyl and R3= 2,4,6-trimethoxyphenyl; R2= phenyl and R3= 5,6,7,8-tetrahydro-1-naphthyl; R2= phenyl and R3= 2,5-acid; R2= phenyl and R3= 2,6-dimethoxyaniline; R2= phenyl and R3= 4 - methoxy-1-naphthyl; R2= phenyl and R3= 4-cyano-1-naphthyl; R2= ( R2= 3,4-methylenedioxyphenyl; R2= cyclohexyl and R3= 3,4-acid; R2= cyclohexyl and R3= 3-methoxyphenyl; R2= cyclohexyl and R3= 3,4,5-trimethoxyphenyl; R2= cyclohexyl and R3= 2,4-acid; R2= cyclohexyl and R3= 2-methoxyphenyl; R2= cyclohexyl and R3= 4-methoxy-2,3 - dimetilfenil; R2= cyclohexyl and R3= 2,4,5-trimethoxyphenyl; R2= cyclohexyl and R3= 2,4,6-trimethoxyphenyl; R2= cyclohexyl and R3= 5,6,7,8-tetrahydro-1-naphthyl; R2= cyclohexyl and R3= 2,5-acid; R2= cyclohexyl and R3= 2,6-acid; R2= -cyclohexyl and R3= 4-methoxy-1-naphthyl; R2= cyclohexyl and R3= 4-cyano-1-naphthyl; R2= cyclohexyl and R3= 4-fluoro-1-naphthyl; or (alternative or additional) R2= phenyl and R3= 4-biphenylyl; R2= 4-benzyloxyphenyl and R3= 4-biphenylyl; R2= 4-hydroxyphenyl and R3= 4-biphenylyl; R2= 4-methoxyphenyl and R3= 4-biphenylyl; R2= phenyl and R3= 2'-cyanobiphenyl-4-yl; R2= 4-benzyloxyphenyl and R3= 2'-cyanobiphenyl-4-yl; R2= 4-hydroxyphenyl and R3= 2'-cyanobiphenyl - 4-yl; R2= 4-methoxyphenyl and R3= 2'-cyan is the following combinations: R2= phenyl and R3= 2,3,4-trimethoxyphenyl; R2= cyclohexyl and R3= 2,3,4-trimethoxyphenyl; and in addition, R2= phenyl and R3= 4-methoxyphenyl; or R2= cyclohexyl and R3= 4-methoxyphenyl;

R4denotes isopropyl, or, alternatively, cyclohexyl or phenyl;

R5denotes methyl or also ethyl or n-propyl; and

n = 2, or, particularly, 1;

or its salt, provided that there is at least one salt-forming group.

More preferably the compound of formula I, in which

R1choose from tert-butoxycarbonyl, 2,2,2 - cryptgetkeyparam, 2-(methoxy)ethoxycarbonyl, 5(S)-2 - oxopropylidene, 1-ethoxycarbonylpyrimidine-4 - ylcarbonyl, TRANS-(L)-4-hydroxyproline, N-(benzyloxycarbonyl)-TRANS-(L)- 4-hydroxyproline, (L)-thiazolidin-4-ylcarbonyl, indole-2-ylcarbonyl, 4H-1-benzopyran-2-ylcarbonyl, N - metilprednisolone, tetrahydropyran-2(R,S) - ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lactol (= 2(S)- (tetrahydropyran-4-yloxy)propionyl), 3(S)-tetrahydropyranyloxy, 2-aminothiazol-4-lacetera, 6-(4-methylpiperazin-1-yl)-pyridine-3-ylcarbonyl, 4-(morpholine-4-ylmethyl)benzoyl, N-methoxycarbonyl-(L)-poured, N-[(L)-t is selected from cyclohexyl, cyclohexen-1-yl, phenyl, 4-(benzyloxy)phenyl, 2,4-dipthera, 4-cyanophenyl, 2-, 3 - or 4-methoxyphenyl, 4-isobutylacetophenone, trimethoxyphenyl, for example, with methoxyaniline in positions 3, 4, 5, as in 3,4,5-trimethoxyphenyl, in positions 2, 4, 5, as in 2,4,5-trimethoxyphenyl, or in positions 2, 4, 6, as in 2,4,6-trimethoxyphenyl, and methoxy radicals preferably attached asymmetrically to the phenyl ring, mainly in positions 2, 3, 4, for example, 2,3,4-trimethoxyphenyl, 4-(2 - methoxyethoxy)phenyl, 3,4-methylenedioxyphenyl and 4-(pyridine-2 - or, in particular, pyridine-3-ylethoxy)phenyl, and, in addition, from 4-methoxy-2-ftoheia, 4-fluoro-2-methoxyphenyl, 4-methoxy-2 - hydroxyphenyl, 4-methoxy-2,3-dimetilfenil, 4-(2 - phenylethyl)phenyl, 2-ftoheia, 4-hydroxyphenyl, acid, such as 2,4-acid, 3,4-acid, 2,5-acid or 2,6-acid, 5,6,7,8-tetrahydro-1-naphthyl, 4-ptomaphila, 4-cyanonaphthalene, 4-lower alkoxymethyl and 4-(2,6 - dichlorobenzenesulfonyl)phenyl; R2and R3preferably present in the following combinations: R2= 4-benzyloxyphenyl and R3= 4-benzyloxyphenyl; R2= phenyl and R3= 4-cyanophenyl; R2= phenyl which the sludge; R2= phenyl and R3= 4-(2,6-dichlorobenzenesulfonyl)phenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-benzyloxyphenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-hydroxyphenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-methoxyphenyl; R2= 4-(2-methoxyethoxy)phenyl and R3= 4-(2-methoxyethoxy)phenyl; R2= 4-benzyloxyphenyl and R3= 4-methoxyphenyl; R2= 4-hydroxyphenyl and R3= 4-methoxyphenyl; R2= 4-methoxyphenyl and R3= 4-methoxyphenyl; R2= 4-isobutylphenyl and R3= 4-methoxyphenyl; R2= 4-methoxyphenyl and R3= phenyl; R2= cyclohexyl and R3= 4-methoxyphenyl; R2= phenyl and R3= 4-methoxy-2-forfinal; R2= phenyl and R3= 4-fluoro-2 - methoxyphenyl; R2= phenyl and R3= 4-methoxy-2-hydroxyphenyl; R2= 4-methoxyphenyl and R3= cyclohexyl; R2= 4-methoxyphenyl and R3= cyclohexen-1-yl; R2= cyclohexyl and R3= 4-benzyloxyphenyl; R2= cyclohexyl and R3= 4-hydroxyphenyl; R2= cyclohexyl and R3= 4-methoxyphenyl; R2= cyclohexyl and R3= 4-(2-methoxyethoxy)phenyl; R2= phenyl and R3= phenyl; R2= phenyl and R3= 4-benzyloxyphenyl; R2= phenyl and R3= 4-hydroxy what UB>2= phenyl and R3= 4-(pyridine-3-ylethoxy)phenyl; R2= phenyl and R3= 4-methoxyphenyl; R2= phenyl and R3= 3,4-methylenedioxyphenyl; R2= phenyl and R3= 3,4-acid; R2= phenyl and R3= 3-methoxyphenyl; R2= phenyl and R3= 2,3,4-trimethoxyphenyl; R2= phenyl and R3= 3,4,5-trimethoxyphenyl; R2= phenyl and R32,4-acid; R2= phenyl and R3= 2-methoxyphenyl; R2= phenyl and R3= 2,3-dimethyl-4-methoxyphenyl; R2= phenyl and R3= 2,4,5 - trimethoxyphenyl; R2= phenyl and R3= 2,4,6-trimethoxyphenyl; R2= phenyl and R3= 5,6,7,8-tetrahydro-1-naphthyl; R2= phenyl and R3= 2,5 - acid; R2= phenyl and R3= 2,6-dimethoxyaniline; R2= phenyl and R3= 4-methoxy-1-naphthyl; R2= phenyl and R3= 4-cyano-1-naphthyl; R2= phenyl and R3= 4-fluoro-1-naphthyl; R2= cyclohexyl and R3= 3,4-methylenedioxyphenyl; R2= cyclohexyl and R3= 3,4-acid; R2= cyclohexyl and R3= 3-methoxyphenyl; R2= cyclohexyl and R3= 3,4,5-trimethoxyphenyl; R2= cyclohexyl and R3= 2,4-acid; R2= cyclohexyl and R3= 2-methoxyphenyl; R2= cyclohexyl and R3= 2,3,4-three is trihydro-1-naphthyl; R2= cyclohexyl and R3= 2,5-acid; R2= cyclohexyl and R3= 2,6-acid; R2= cyclohexyl and R3= 4-methoxy-1-naphthyl; R2= cyclohexyl and R3= 4-cyano-1 - naphthyl; or R2= cyclohexyl and R3= 4-fluoro-1-naphthyl; with the most preferred are the following combinations: R2= phenyl and R3= 2,3,4-trimethoxyphenyl; R2= cyclohexyl and R3= 2,3,4-trimethoxyphenyl; R2= phenyl and R3= 4-methoxyphenyl; or R2= cyclohexyl and R3= 4-methoxyphenyl; and most preferred are the following combinations: R2= phenyl and R3= 2,3,4-trimethoxyphenyl; R2= cyclohexyl and R3= 2,3,4-trimethoxyphenyl;

R4denotes isopropyl, or, alternatively, cyclohexyl or phenyl;

R5denotes ethyl or in particular methyl; and

n = 2, or, particularly, 1;

or its salt, provided that there is at least one salt-forming group.

Most preferably the compound of formula I (in particular, I') in which:

R1indicates the lowest alkoxycarbonyl or lower alkoxycarbonyl, which is substituted up to three times by halogen, in particular fluorine, and which means, in particular, tert-butox>2= phenyl and R3= cyanophenyl, in particular, 4-cyanophenyl; R2= phenyl and R3= differenl, in particular, 2,4-differenl; R2= phenyl and R3= 4-lower alkoxyphenyl, in particular 4-methoxyphenyl; R2= 4-(lower alkoxy-lower alkoxy)phenyl, in particular 4-(2-methoxyethoxy)phenyl and R3= 4-(phenyl-lower alkoxy)phenyl, in particular 4-benzyloxyphenyl; R2= cyclohexyl and R3= 4-lower alkoxyphenyl, in particular 4 - methoxyphenyl; R2= phenyl and R3= phenyl; R2= phenyl and R3= 4-phenyl-lower alkoxyphenyl, in particular 4-benzyloxyphenyl; R2= phenyl and R3= 4- (pyridin-3-yl-lower alkoxy)phenyl, in particular 4-(pyridine-3-ylethoxy)phenyl; R2= phenyl and R3= 3,4-lowest alkylenediamines, in particular, 3,4-methylenedioxyphenyl; R2= phenyl and R3= 2,3,4-tri-lower alkoxyphenyl (especially preferred), in particular 2,3,4-trimethoxyphenyl (most preferred), or, alternatively, R2= cyclohexyl and R3= 4-(lower alkoxy-lower alkoxy)phenyl, in particular. 4-(2-methoxyethoxy)phenyl;

R4means isopropyl;

R5denotes methyl; and

n = 1.

Most preferably the compound of formula I', in which

R1about ipanel, in particular, 4-methoxyphenyl, or, preferably, 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl; R4means isopropyl; R5denotes methyl; and n = 1.

The compounds of formula I named in the examples, or their pharmaceutically acceptable salts, provided that there is at least one salt-forming group are most preferable.

In the scope of the present invention preferred are the following compounds:

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)- [(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-cyanophenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o-forfinal)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[p-(2-phenylethyl)phenyl] methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-{ [n-(2,6 - dichlorobenzenesulfonyl)phenyl]methyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[(p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-isobutoxide)-2(R)-[(p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl- (L)-Val-N-(2-methoxyethyl)amide;

5(S)-{ [(1-ethoxycarbonylpyrimidine-4-yl)carbonyl] amino} -4(S)-hydroxy - 6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl) amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)- (cyclohexylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(4-methoxyphenyl)-2(R)- [cyclohexen-1-ylmethyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl - 2(R)-[(4-benzyloxy-phenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(4-hydroxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S) -hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl- (L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)- (phenylmethyl)hexanoyl-(L)-[(phenyl)Gly]-N-(2-methoxyethyl)amide

5(S)-[(1-methyl-4-piperidinylcarbonyl)amino]-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]g is(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(2(R, S)-tetrahydroprotoberberine)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxy-ethyl) - amide;

5(S)-(5(S)-oxopentanenitrile)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide;

5(S)-(2-methoxyethoxymethyl)-4(S)-hydroxy-6-cyclohexyl-2(R) -[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-((L)-thiazolidin-4-ylcarbonyl)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(4-oxo-4H-1-benzopyran-2-ylcarbonyl)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide;

5(S)-(indolyl-2-ylcarbonyl)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(methoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6-cyclohexyl - 2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-([N-((L)-thiazolidin-4-ylcarbonyl)-(L)-Val] -amino)-4(S) -hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide;

5(S)-(benzyloxycarbonyl-(L)-4-[TRANS-hydroxypropyl] amino)-4(S)-hydroxy - 6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl) is (L)-Val-N-(2-methoxyethyl)amide;

5(S)-(2-amino-4-thiazoleacetate)-4(S)-hydroxy-6-cyclohexyl-2(R) -[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(6-(4-methyl-1-piperazinil)-3-pyridylcarbonyl)- 4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(4-(4-morpholinylmethyl)benzoylamine)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(O-[4-tetrahydropyranyl] -(L)-lactosamine)-4(S)-hydroxy-6-cyclo - hexyl-2(R)-1(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-(2-methoxyethyl)amide;

(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-isobutoxide)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(2-pyridyloxy)phenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5 (S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5 (S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4,5-triphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5 (S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4,5-trimethoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4,6-trimethoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(5,6,7,8-tetrahydro-1-naphthyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,5-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,6-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-methoxy-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-cyano-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-fluorescent-1-naphthyl) methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Ala-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] -2(R)- [(p-CH] -2(R)- [(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide; and

5(S)-(BOC-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] -2(R)- {[p-(2-methoxyethoxy)phenyl] methyl} hexanoyl-(L)-Val-N-(2-methoxyethyl)amide, or its salt, provided that there is at least one salt-forming group.

Thus preferably the compound of formula I, which are selected from the following compounds:

5(S)-(2-methoxy-1(R, S)-methylethanolamine)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl)amide,

5(S)-(etoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6-cyclohexyl-2(R) -[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(1,1-dimethyl-2-methoxyethylamine)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-biphenylyl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(4-biphenylyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[(4-biphenylyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2-2(R)-[({ 2'- cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[({ 2'- cyanobiphenyl)-4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-[({ 2'-cyanobiphenyl) -4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide and

5(S)-(3-hydroxy-2-methylphenylsiloxane)-4(S)-hydroxy-6-(p - methoxyphenyl)-2(R)-[({ 2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide,

or its salt, provided that there is at least one salt-forming group.

Another object of the present invention is a method of obtaining the compounds of formula I or its salts, namely, that

a) condense acid formula

R1-OH (II)

or its reactive derivative, where R1has the same values that R1in the compounds of formula I, with aminoguanidinium formula

,

or its reactive derivative, where n and the radicals have the meanings given for compounds of formula I, with free functional groups, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of the formulae II and III, and helps eliminate present protective groups.

In particular, as aminos the particular, formula

)

where1is the bivalent residue of the amino acids defined above for formula I, which is attached to the carbonyl group to the connecting nitrogen atom shown in formula Ia', and amino group, R'1and R'1denotes one of the radicals specified for R1in formula I, except reallymoving or N - acylated amino acid residue, as defined in the formula I, so that B1and R'1together are linked via its carbonyl group to the remainder of the N-acylated amino acids defined for R1in formula I, while n and the remaining radicals have the meanings given for compounds of formula I can be obtained by the method, according to which:

b) carboxylic acid

R'1-OH (IV)

or its reactive derivative, where R1may be a radical defined for R1in the compounds of the formula I, in addition to the remainder palleroni or N-acylated amino acids, which is connected via its carbonyl group, is subjected to condensation with aminoguanidinium formula

< / BR>
(in particular, formulas

)

or its reactive derivative, where1matter which free functional groups, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of the formula IIIa (or IIIa') and IV, and helps eliminate present protective groups.

The compounds of formula I or their salts can be obtained in the following ways:

C) condensation of the carboxylic acid of the formula

< / BR>
(in particular, formulas

)

or its reactive derivative, where the radicals have the meanings given for compounds of formula I, with aminoguanidinium formula

< / BR>
(in particular, formulas

)

or its reactive derivative, where n and the radicals have the meanings given for compounds of formula I, with free functional groups, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of formula V (or V') and VI (or VI'), and the elimination of the present protective groups, or

g) the condensation of the carboxylic acid of the formula

< / BR>
(in particular, formulas

)

or its reactive derivative, where the radicals have the meanings given for compounds of formula I, with aminoguanidinium formula

< / BR>
or its reactive about the performance communications group, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of the formula VII or VII' and VIII, and, if desirable, the elimination of the present protective groups, or

d) or

(i) esterification of hydroxycodone formula

< / BR>
(in particular, formulas

< / BR>
or its alcoholate, where n and the radicals have the meanings given for compounds of formula I, the compound of the formula

W1- R6, (X)

where R6has the values defined for compounds of formula I, a W1denotes a leaving group, or

(ii) esterification reactive derivative hydroxycodone formula IX (or IX') of the compound of the formula

HO-R6, (Xa)

or its alcoholate, where R6has the above specified value, with free functional groups, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of the formula IX (or IX'), X and XA, and the elimination of the present protective groups, or

(e) the elimination of the protective groups present in the compounds of the formula I (in particular, I'), where the substituents have the above values, provided that seadisposal a) - e) can, if not stated specifically, the starting materials for use in the form of salts, provided that there are soleobrazutaya group, and/or, if desired, the compound of formula I (or I'), which receive one of the above methods (a) to (e) and which has at least one salt-forming group is converted into its salt, and/or transform the obtained salt into the free compound or into another salt, and/or share isomeric mixture of compounds of formula I (or I'), which can be obtained, and/or make a new compound of formula I (or I') to another new compound of formula I (or I').

The above methods are described in more detail below.

In the description of the relevant variants of the method of obtaining compounds of the radicals R1, R2, R3, R4and R5and n are as above, so below, the values specified for compounds of the formula I, unless something else.

In each case, obtaining the compounds of the formula

,

where n and the radicals have the meanings specified for compounds of formula I, preferably in obtaining compounds of formula I.

In their respective ways of connection formulas marked by an apostrophe, i.e., I', Ia', III', IIIa', V', VI', what disiniame without specified stereospecificity formula I, Ia, III, IIIa, V, VI, VII and IX; a mixture of the corresponding compounds in which the carbon atoms (in the sequence C(5), C(2) and C(4)), bearing the radical R2-CH2-, the radical R3-CH2and IT is located between them, are in the configuration of (2R, 4S, 5S) and configuration (2S,4R,5R) and in each case, less favorable, than the connection marked by an apostrophe, but it is more preferable than the corresponding compounds without any specified stereospecificity.

Further a mixture of the corresponding compounds having the configuration of (2R, 4S,5S) and configuration (2S,4R,5R), or, in particular, the compounds of formulas, which in each case correspond to and are marked by an apostrophe, can preferably each be used instead of the compounds of formulas I, Ia, III, IIIa, V, VI, VII and IX, provided that it has a chemical sense. This also applies to the following section on additional measures methods and source materials.

Method (a) (obtaining amide bond)

In the original substances of the formulae II and III functional groups, with the exception of the groups participating in the reaction or not interacting in the reaction conditions, independently of one another are protected by protective groups.

Protective carboxylic, amino, hydroxyl and mercaptopropyl include, in particular, those protective groups (traditional protective group), which are commonly used in the synthesis of peptide compounds or cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars. These protective groups may already be present in the precursors and should protect the functional group from undesired side reactions, such as acylation, etherification with the formation of simple or complex esters, oxidation, solvolysis, etc., In certain cases, a protective group, in addition, may have the effect aimed at obtaining selective reactions, for example, stereoselective reactions. Typical protective groups is that they are easily disconnected, that is, without undesirable side reactions, for example, by solvolysis, recovery, photolytic or even enzymatic method, for example, under physiological conditions, and that they are not present in the final products. The compounds of formula I containing protected functional groups, in which the protective groups are detached under physiological conditions, can have a higher degree of metabolic stability or pharmacodynamic properties, taki.

Protection of functional groups such protective groups are themselves protective group and the reaction to their elimination are described, for example, in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, Th.W. Greene, "Protective

Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Volume 3 (E. Gross and J. Meienhofer, editors), Academic Press, London and New York 1981, in "Methods der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th Edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" (Amino Acids, Peptides and Proteins), Verlag Chemie, Weinheim, Deerfield Beach and Basel, 1982, Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate: (Chemistry of the Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974.

Carboxyl group protected, for example, such a group as the group of ester, which can selectively cleave under mild conditions. Carboxyl group which is protected in esterified form, atrificial mainly by the group of lower alkyl, which is preferably branched in position 1 of the group of lower alkyl or protected by suitable substituents in position 1 or 2 groups lower alkyl.

Protected carboxyl group, which atrificial group of lower alkyl represents, for example, methoxycarbonyl or etoxycarbonyl.

Secure the th alkyl, represents, for example, tert-lower alkoxycarbonyl, for example, tert-butoxycarbonyl.

Protected carboxyl group, which atrificial group of lower alkyl, substituted in position 1 or 2 group of the lower alkyl suitable substituents, represents, for example, 1-aryl - lower alkoxycarbonyl, such as arylethoxysilanes having one or two aryl radical, where the aryl is a phenyl, unsubstituted or substituted once, twice or three times, for example, by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxyl, halogen, for example chlorine, and/or nitro, for example, benzyloxycarbonyl, benzyloxycarbonyl, substituted mentioned substituents, for example, 4-nitrobenzenesulfonyl or 4-methoxybenzeneboronic, diphenylmethylene or diphenylmethylene, substituted mentioned substituents, for example, di(4-methoxyphenyl)methoxycarbonyl, and, in addition, carboxyl, which is esterified by a group of lower alkyl, where the lower alkyl group substituted in position 1 or 2 is suitable substituents, for example 1-lower alkoxy-lower alkoxycarbonyl, such as methoxyethoxymethyl, 1-metaxakis or 1-ethyldiethanolamine, roulettecasino, where a group of Arola represents benzoyl, not substituted or substituted, e.g. by halogen, such as bromine, for example, ventilatsioonil, 2-halo-lower alkoxycarbonyl, for example, 2,2,2-trichlorocyanuric, 2 - pomatoceros or 2-iodocholesterol, and 2- (tizamidine silyl)lower alkoxycarbonyl, where the substituents, independently of one another represent in each case, aliphatic, analiticheskii, cycloaliphatic or aromatic hydrocarbon moiety, is not substituted or substituted, for example, lower alkyl, lower alkoxy, aryl, halogen and/or nitro, for example, lower alkyl, which is not substituted or substituted, as described above, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilane lowest alkoxycarbonyl, such as 2-tri-lower alkyltrimethylammonium, for example, 2-trimethylsilylethynyl or 2-(di-n-butylmethylether)etoxycarbonyl or 2-trainsimulator, such as trivinylcyclohexane.

The carboxyl group can also be protected organic group siliconecable group. Organic similarcaterpillar group represents, for example, three-NISSEI group may also be substituted by two groups of lower alkyl, for example, methyl, amino or carboxyl group of the second molecule of formula I. Compounds containing such protective groups can be obtained, for example, using the appropriate three-lower alkylchlorosilanes, such as tert-butyldimethylchlorosilane, as cilleruelo agent.

The carboxyl group is protected in the internal form of ester hydroxyl group which is present in the molecule at a suitable distance, for example, in position relative to the carboxyl groups, i.e., in the form of a lactone, preferably-lactone.

Protected carboxyl group is preferably tert-lower alkoxycarbonyl, for example, tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 9-fluorenylmethoxycarbonyl or diphenylmethylene or protected carboxyl group in the form of a lactone, in particular-lactone.

Protected amino group protected aminosidine group, for example, in the form of group acylamino, arylmethylidene etherified mercapto-amino, 2-acyl-lower ALK-1-enylamine or silylamine or sidegroup.

The group acylamino acyl denotes, for example, acyl radicals of organic carbon is substituted or substituted, for example, by halogen or aryl, or benzoic acid, which is not substituted or substituted, e.g. by halogen, lower alkoxy or nitro, or, preferably, Palmyra carbonic acid. Such acyl groups are preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example, 2-haloacetic, such as 2-chloro-, 2-bromo-, 2-iodine-, 2,2,2-Cryptor - or 2,2,2-trichloroacetyl, benzoyl, which is not substituted or substituted, e.g. by halogen, lower alkoxy or nitro, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, lower alkoxycarbonyl, preferably branched in position 1 moiety of the lower alkyl or suitably substituted in position 1 or 2, for example, tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, 1-aryl-lower alkoxycarbonyl, such as arylethoxysilanes with one, two or three aryl radical, which denote phenyl not substituted or substituted one or more times, for example, lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy such as methoxy, hydroxyl, halogen, such as chlorine, and/or nitro, for example, benzyloxy is)methoxycarbonyl, roulettecasino, in which a group of Arola represents benzoyl, not substituted or preferably substituted, for example halogen, such as bromine, for example, ventilatsioonil, 2-halo - lower alkoxycarbonyl, for example, 2,2,2-trichlorocyanuric, 2 - pomatoceros or 2-iodoxybenzoic, 2(tizamidine silyl)lower alkoxycarbonyl, for example 2-tri-lower alkylsilane lowest alkoxycarbonyl, such as 2-trimethylsilylacetamide or 2-(di-n-butylmethylether)etoxycarbonyl or triallelic lowest alkoxycarbonyl, such as 2-trivinylcyclohexane.

The group arylmethylidene, for example, the group of mono-, di - or, in particular, triarylmethane, aryl radicals represent, in particular, phenyl radicals are not substituted or substituted. Examples of such groups are benzyl, diphenylmethyl - or, in particular, trailmen.

In the group esterified, mercaptamine mercaptopropyl is present mainly in the form substituted aaltio or aryl-lower alkylthio, where aryl refers to, for example, phenyl which is not substituted or substituted, for example, lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen, such as x is used as aminosidine group, acyl refers to, for example, the corresponding radical of the lower alkenylboronic acid, benzoic acid, which is not substituted or substituted, for example, lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen, such as chlorine, and/or nitro, or, preferably, Palmyra of carbonic acid, such as lower alkyl-polyether carbonic acid. Appropriate protective groups are mainly 1-lowest alkanoyl-lower ALK-1-EN-2-yl, for example 1-lower alkanoyl-prop-1-EN-2-yl, such as 1-actipro-1-EN-2-yl, or lower alkoxycarbonyl-lower ALK-1-EN-2-yl, for example, the lowest alkoxycarbonyl-1-EN-2-yl, such as 1-taxicab-nilprp-1-EN-2-yl.

Silylamine means, for example, a group of three or lower alkylsilane, for example, trimethylsilane or tert-butyldimethylsilyl. Silicon atom group silylamine can also be replaced by only two groups of lower alkyl, for example methyl groups, and the amino group or carboxyl group of the second molecule of formula I. Compounds having such a protective group can be obtained, for example, using appropriate CHLOROSILANES, such as tert-butyldimethylchlorosilane, as Siora; suitable corresponding anions are, mainly, the anion of a strong inorganic acids, such as sulfuric acid, phosphoric acid and kaleidotrope acid, for example, the anion of chlorine or bromine, or organic sulphonic acids, such as p-toluensulfonate.

Preferred aminosidine groups are lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, fluorenyl lowest alkoxycarbonyl, 2-lower alkanoyl-lower ALK-1-EN-2-yl or lower alkoxycarbonyl-lower ALK-1-EN-2-yl, especially tert-butoxycarbonyl or benzyloxycarbonyl.

A hydroxyl group can be, for example, protected acyl group, for example, the lower alkanoyl, which is not substituted or substituted with halogen, such as chlorine, for example, acetyl or 2,2-dichloroacetyl, or, in particular, the acyl radical, which is specified for a protected amino group, Palmyra carbonic acid. A hydroxyl group can also be protected by tri-lower alkylsilanes, for example, trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, easily detachable tarifitsiruemih group, for example, alkyl group, such as tert-lower alkyl, for example tert-butyl, an oxa - or thia-aliphatic or-cyclea the example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa-or 2-thiacyclohexane having 5-7 atoms in the nucleus, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia-analogue, and also 1-phenyl-lower alkyl, such as benzyl, diphenylmethyl or trityl, while the phenyl radicals can be substituted, for example, halogen, for example chlorine, lower alkoxy, for example methoxy, and/or nitro. Preferred hydroxyamino group is, for example, 2,2,2-trichlorocyanuric, 4-nitrobenzenesulfonyl, diphenylcarbinol, benzyl or trityl.

Two hydroxyl groups, in particular, adjacent hydroxyl groups present in the molecule or an adjacent hydroxyl group and amino group may, for example, be protected divalent protective groups such as a methylene group which is preferably substituted, for example, by one or two radicals are lower alkyl or oxo, for example, unsubstituted or substituted by alkylidene, for example, the lower alkylidene, such as isopropylidene, cycloalkylation, such as cyclohexylidene, carrot protected due to the formation of complex internal ester (lactone), in particular, -lactone.

Preferably, a protected hydroxyl group protected by tri-lower alkylsilanes or in the form of a lactone, in particular, tert-butyldimethylsilyl or-lactone.

Mercaptopropyl, for example, the cysteine may be protected, in particular, the S-alkylation using an unsubstituted or substituted alkyl radicals, similarobama, through education teasedale, S-acylation or by formation of asymmetric disulfide groups. Preferred mercaptoamines groups are, for example, benzyl, which is not substituted or substituted in the phenyl radical, for example, by using, methoxy or nitro, such as 4 - methoxybenzyl, diphenylmethyl, which is not substituted or substituted in the phenyl radical, for example, with methoxy, such as di(4-methoxyphenyl) methyl, triphenylmethyl, pyridylmethyl, trimethylsilyl, benzyldimethyl, tetrahydropyranyl, acylaminoacyl, such as atsetamidometil, isobutyrylacetate or 2-chloracetamide, benzoyl, benzyloxycarbonyl or alkyl, in particular lower alkylaminocarbonyl, such as ethylaminomethyl, and lower alkylthio, such as S-ethylthio or S-tert-butylthio or S-sulfo.

Within value is detachable manner with the protected functional group, for example, a carboxyl group, it should also be understood as the protective group, for example, carboxyl-protective group. Suitable polymer carrier of this type is, in particular, polystyrene resin, which is labourintensive copolymerization with divinylbenzene and which is of suitable bridge members for reversible binding.

Acids of formula II are carboxylic acids or sulfonic acids and either have a free carboxyl group or a free alphagroup or present as their reactive derivatives, such as activated complex ester, which is obtained from the free carboxy or sulfasalizine, as a reactive anhydride or, alternatively, as a reactive cyclic amide. Reactive derivatives can also be formed in situ.

Activated esters of compounds of formula II having a carboxyl group are, in particular, esters, which are not saturated at the linking carbon atom tarifitsiruemih radical, such as vinyl ester, such as a complex vinyl ether (obtained, for example, t is esters), complex carbamoylation esters (obtained, for example, by treating the appropriate acid with the reagent isoxazole; method 1,2-oxazole or method Woodward) or 1-lower alkoxyphenyl ester (obtained, for example, by treating the appropriate acid lowest alkoxyethanol; ethoxyacetylene method), or esters of the type amidino, such as N,N'-disubstituted amicinemici (obtained, for example, by treating the corresponding acid with a suitable N, N'- disubstituted by a carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amicinemici (obtained, for example, by treating the corresponding acid with a suitable N,N-disubstituted by cyanamide; cyanamide method), the corresponding complex akrilovye esters, in particular, phenyl esters which are substituted by substituents that attracts electrons (obtained, for example, by treatment with appropriate acids 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 agent such as N,N'-dicyclohexylcarbodiimide; method of activated aryl esters), cyanomethylene esters (on the d cyanomethylene esters), the thioethers, in particular, phenylthiourea, which is not substituted or substituted, for example nitro (obtained, for example, by treating the corresponding acid with thiophenolate, which is not substituted or substituted, for example, using nitro, among other things, using anhydrous method or carbimide method; method of activated thiol esters), or, in particular, complex amino esters or amidoamine (obtained, for example, by treating the corresponding acid with N-hydroxyaminoindan or N - hydroxyamide connection, for example, N-hydroxysuccinimide, N - hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3 - dicarboximide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3 - benzotriazin-4-one, for example, in accordance with anhydrite method or carbodiimide method; method of activated complex N-hydroxyamino). Can also be used in the internal esters, for example, -lactones.

Anhydrides of acids may be symmetric or preferably mixed anhydrides of these acids, for example anhydrides with inorganic acids, such as galodamadruga, in particular, the acid chlorides (obtained, for example, by treating the appropriate acid t is, the C of a corresponding acid ester via the corresponding hydrazide and treatment of nitrous acid; azide method), anhydrides of profirov carbonic acid, for example, lower alkyl-polufinale carbonic acid (obtained, for example, by treating the appropriate acid lowest alkylchlorosilanes, for example, isobutylparaben, or 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline; method of mixed anhydrides Of-alkylphenol acid), or trichlorocarbanilide (obtained, for example, by treating the appropriate acid bis (trichloromethyl) carbonate in a simple ether/pyridine); anhydrides with dialogitem, especially dichlorohydrin phosphoric acid (obtained, for example, by treating the corresponding acid with phosphorus oxychloride; acid chloride method phosphoric acid), anhydrides with other derivatives of phosphoric acid (for example those that can be obtained with phenyl N-phenyltetramagnesium or by reaction of amides alkylphosphoric acid in the presence of anhydrides of sulfonic acids and/or additives that reduce racemization, such as N-hydroxybenzotriazole, or in the presence of diethylthiophosphate) or a derivative of phosphoric acid,aimie, for example, by treating the corresponding acid with a lower alkane - or phenyl-lower alcantarillados, which is not substituted or substituted, as for example, phenylacetyl-chloride, revalorisation or triftoratsetilatsetonom; method of mixed anhydrides of carboxylic acids or organic sulfonic acids (obtained, for example, by treating a salt, such as alkali metal salt, of the corresponding acid with a suitable organic sulphonylchloride, such as lower alkane - or aryl-, for example methane - or p-toluensulfonyl chloride; 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 of aromatic character, such as amides with imidazoles, for example imidazole (obtained, for example, by treating the corresponding acid with N,N'-carbonyl diimidazol; method of imidazoles) or pyrazole, for example, 3,5-dimethylpyrazole (obtained, for example, through the acid hydrazide by treatment with acetylacetone; method pyrazolidinone is, can also be obtained in situ. Thus, N,N'-disubstituted amicinemici can be obtained in situ by interaction of a mixture of original substances of the formula III and the acid of formula II, used as Alliluyeva agent, in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, for example, in the presence of a suitable base, such as N-hydroxybenzotriazole. In addition, amino esters or amidoamine acids used as alleluya agents, can be obtained in the presence of the parent substance of the formula III, which is subject to acylation by reacting a mixture of the appropriate acid and the source of amino compounds in the presence of N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, and N-hydroxyamine or N-hydroxyamide, for example, N-hydroxysuccinimide, in the presence or absence of a suitable base, such as 4-dimethylaminopyridine. In addition, the activation can be achieved in situ by reacting N,N,N',N'-tetraalkylammonium compounds such as O - benzotriazol-1-yl-N,N,N', N'-tetramethylurea hexafluorophosphate (preferably in the presence of tertiary nitrogen bases, in particular, N-methylmorpholine). Phosphoric Academy of Sciences of the CSOs as hexamethylphosphoramide, in the presence of an anhydride of sulfonic acids, such as 4 - toluensulfonate, with salt, such as tetrafluoroborate, for example, tetrafluoroborate sodium, or other derivative hexamethylphosphoramide, such as benzotriazol-1 - yloxytris(dimethylamino)phosphonium hexafluoride, preferably in the presence of additives that reduce racemization, such as N - hydroxybenzotriazole, or in the presence or absence of a tertiary nitrogen base, such as N-methylmorpholine. It is also possible to carry out the reaction with di-lower alkyl cyanophosphonate, such as diethylthiophosphate, in the presence of a tertiary nitrogen base, such as triethylamine. Finally, derivatives harpalinae acid carboxylic acids of formula II can be obtained directly in situ by reacting the corresponding alcohol with phosgene or its equivalent, such as triphosgene (= bis(trichloromethyl)carbonate), in the presence or absence of a tertiary nitrogen base, such as triethylamine, followed by interaction with the compound of the formula III.

The amino compounds of formula III, which takes part in the reaction, preferably bears at least one reactive hydrogen atom, in particular when interact is optimized, for example, by interacting with postitem, such as diethylcarbamoyl, 1,2 - phenylthiomethyl, ethyldichloroarsine, ativanklonopin or tetraethylpyrophosphate. Derivatives of such compounds with amino group is, for example, carbamoylated, and participating in the reaction of the amino group substituted by halocarbonyl, for example, chlorocarbonyl.

Condensation to obtain the amide bond can be carried out in a known per se manner, for example as described in standard works such as Houben-Weyl, Methods der organischen Chemie", (Methods of Organic Chemistry), 4th Edition, Volume 15/II (1974), Volume IX (1955) Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (E. Gross and J. Meienhofer, editors), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, M. Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the appropriate amine may preferably be carried out in the presence of a conventional condensing agent. Examples of customary condensing agents are carbodiimides, for example, diethyl-, dipropyl-, N-ethyl-N'-(3 - dimethylaminopropyl)carbodiimide, or, in particular, dichlorochlordene, and also the corresponding carbonyl compounds, for example, carbonyldiimidazole, the compounds 1,2-oxazole, for example, 2-ethyl-5-phenyl-1,2-oxazole-3'- sushi-1 - etoxycarbonyl-1,2-dihydroquinoline, N,N,N',N'-tetramethyluronium compounds such as O-benzotriazol-1-yl-N,N,N',N' -tetramethylpropylenediamine, and in addition, activated derivatives of phosphoric acid, for example, diphenylphosphoryl, diethylphosphoramidite (= diethylthiophosphate), phenyl-N-phenylphosphonothioic, bis-(2-oxo-3-oxazolidinyl)fosinopril or 1-benzothiazolylthio(dimethylamino)phosphonium hexaflurophosphate.

If necessary or desirable, then add an organic base, preferably a base trisemester nitrogen, for example, the three lowest alkylamine, for example, with a volume radicals, for example, ethyldiethanolamine or unbranched radical, for example, triethylamine, and/or a heterocyclic base, such as pyridine, 4-dimethylaminopyridine or, preferably, N - methylmorpholin. The base also may be associated with a polymer carrier, such as polystyrene, for example, in the form of a polymer base (= diisopropylaminomethyl).

Reagents, reducing racemization, such as N-hydroxybenzotriazole may be added, possibly in combination with organic bases, above.

Condensation of activated esters, reactionactos in the presence of an organic base, for example, a simple three lower bonds alkylamines, such as triethylamine or tributylamine, polymer base or one from among the above-mentioned organic bases. If desired, you can optionally use a condensing agent, described in relation to carboxylic acids.

The condensation of acid anhydrides with amines can, for example, be carried out in the presence of inorganic carbonates, for example, carbonates, ammonium or alkali metal or hydrogen carbonates, such as sodium carbonate or sodium bicarbonate or potassium (usually together with a sulfate).

Carbonylchloride or 4-nitrophenylarsonic and derivative harpalinae acid derived from the acid of formula II, preferably condense with the corresponding amines in the presence of an organic amine, for example, the above-mentioned tri-lower alkylamines followed, or heterocyclic bases, in the presence or absence of acid sulfate salt.

The condensation is preferably carried out in inert aprotic, preferably anhydrous solvents or mixtures of solvents, for example, in carboxamide, for example, formamide or dimethylformamide, alojamiento hydrocarbon, such as methylene chloride, chetyre, complex ester, e.g. ethyl acetate, or a nitrile, for example, acetonitrile, or mixtures thereof; if desired, at reduced or elevated temperature, for example at a temperature of from about -40oC to +100oC, preferably at a temperature of from about -20oC to +50oC, and without inert gas (= protective gas or in the atmosphere of inert gas, for example nitrogen or argon.

You can also use water, for example, alcoholic solvents or mixture of solvents such as ethanol or aromatic solvents such as benzene or toluene. Lowest alkane, such as acetone, can also optionally be added in the presence of hydroxides of alkali metals as grounds.

Condensation can also be carried out in accordance with techniques known as solid-phase synthesis, which returns us to the works of R. Merrifield and described, for example, in Angew. Chem. 97, 801-812 (1985), Sciences) 71, 252-258 (1984), or in the work of R. A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131-5135 (1985).

Many types of reactions given above in respect of carboxylic acids of formula II and similar reactive derivative of sulfonic acids, also in the case of compounds of formula II having attachment solforosi I'.

So, can be used activated esters of sulfonic acids, for example, the corresponding complex akrilovye esters which are substituted, in particular, a nitro group, such as a complex 4-nitrophenolate esters, it is possible to use the amine component of the formula III as an alkali metal amide, for example, arylamide alkali metal, such as aniline sodium, or alkali metal salt of nitrogen-containing heterocycles, for example, pyrrole potassium.

You can also use reactive anhydrides, such as, for example, corresponding to the symmetric (which can be obtained, for example, by reacting alkanesulphonic silver salts with alkanolammonium) or, preferably, an asymmetric anhydrides of the acids, for example anhydrides with inorganic acids, such as sulphonylchloride, in particular, sulphonylchloride (obtained, for example, by treatment of the corresponding sulfonic acids of the formula II with inorganic acid chlorides, for example, thionyl chloride or pentachloride phosphorus), organic carboxylic acids (obtained, for example, by processing sulphonylchloride salt of carboxylic acid such as a salt of an alkali metal,disrupting, for example, from the corresponding sulphonylchloride and of sodium azide or from the corresponding hydrazide his handling of nitrous acid by analogy with the above azide method).

The release of functional groups that are protected by a protective group to obtain the compounds of formula I, having protected function carried out using one or more of the methods specified as method e).

Method b) (receipt of amide linkages)

In the original substances of the formulae IIIa and IV functional groups, with the exception of participating in the reaction or not interacting in the reaction conditions, independently of one another are protected by protective groups.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactionsare derivatives, and methods used for condensing, fully analogous to those described above as method a) to obtain the amide bond, based on the compounds of formulas II and III, if the carboxylic acid of the formula IV are used instead of those which have the formula II, and the amino compounds of formula IIIa are used instead of those which have the formula III.

Exemption functional is Westlaw using one or more of the methods, specified as method e).

The way in) (obtaining amide bond)

In the original substances of formulas V and VI functional groups, with the exception of participating in the reaction or not interacting in the reaction conditions, independently of one another are protected by protective groups.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactionsare derivatives, and methods used for condensing, fully analogous to those described above as method a) to obtain the amide bond, based on the compounds of formulas II and III, if the carboxylic acid of formula V are used instead of those which have the formula II, and the amino compounds of the formula VI are used instead of those which have the formula III.

In addition to reactive derived by analogy with the method (a), a reactive carboxylic acid derivative of formula V may also be relevant - lactone of the formula settle down under

< / BR>
(in particular, formulas settle down under')

,

where the radicals R1, R2and R3have the meanings given for compounds of formula I. the Reaction is then continued directly with the final product in the presence of the o) unsubstituted lower alanovoy acid, such as triglossia acid, for example, trichloroacetic acid, or, in particular, acetic acid or other organic acids similar acidity, for example, 2-hydroxypyridine, at preferred temperatures of from 10 to 100oC, in particular from 60 to 100oC, in the presence or preferably in the absence of solvents, preferably with simultaneous exclusion of the atmosphere, for example, in a sealed glass tube. Preferably, the compound of formula VI, in particular, VI', to use a slight excess, for example, from 1.01-fold to 4-fold molar excess, relative to the compounds of formula settle down under, in particular, settle down under', and, on the other hand, a weak organic acid, if present, is used in slight excess, in equimolar amounts or in a slight deficit relative to the compounds of formula VI, in particular, VI', for example, at 0.3-fold to 2-fold molar ratio.

The release of functional groups that are protected by a protective group to obtain the compounds of formula I, having protected function carried out using one or more of the methods specified as method e).

Method g) (obtaining amide relations interact in the reaction conditions, independently of one another are protected by protective groups.

The protective group, the free carboxylic acids and their reactive derivatives, available amines and their reactionsare derivatives, and methods used for condensing, fully analogous to those described above as method a) to obtain the amide bond, based on the compounds of formulas II and III, if the carboxylic acid of formula VII are used instead of those which have the formula II, and the amino compounds of formula VIII are used instead of those which have the formula III.

The release of functional groups that are protected by a protective group to obtain the compounds of formula I, having protected function carried out using one or more of the methods specified as method e).

Method d) (receiving a live link - nucleophilic substitution)

In the original substances of formulas IX, X and Xa functional groups, with the exception of participating in the reaction or not interacting in the reaction conditions, independently of one another are protected by protective groups.

Protective groups and methods for their introduction correspond to those shown in method a).

In nucleophilic substitution, Soedinenii formula, X denotes a leaving group, or, in the case of (ii), the compound of formula IX is in the form of a reactive derivative and interacts with a hydroxyl group, subject to esterification. In this context, a hydroxyl group, interact, the corresponding hydroxyl compounds turn into salt its alcoholate in situ, or in the preceding independent reactions. In salt of the anion hydroxyl group (-OH) present in anionic form (as-O-), and oppositely charged ion is mainly a metal cation, such as a cation of an alkali metal, such as+Cs+or, in particular, Na+.

Leaving group W1represents, in particular, nucleophilic leaving group selected from hydroxyl which is esterified with a strong inorganic or organic acid, such as hydroxyl, esterified mineral acid, for example, kaleidotrope acid, such as hydrochloric acid, Hydrobromic acid or itestosterone acid, or strong organic acid, such as lower alkanesulfonyl, which is not substituted or substituted, e.g. by halogen, such as fluorine, or an aromatic shall ethyl, halogen, such as bromine, and/or nitro, for example, methanesulfonate, p-bromatological or p-toluensulfonate, or hydroxyl which is esterified with attestations acid. Also you can get a connection in situ by substitution of the corresponding radical W1such as Cl, another radical W1for example 1 (preferably using alkali metal iodide, such as NaI), followed by conducting the reaction in the reaction mixture.

In the reactive derivative of the compound of formula IX leaving group such as described above with respect to W1present instead of the hydroxyl group.

The etherification is preferably occurs in the presence of a relatively weak base such as a carbonate of an alkali metal, e.g. sodium carbonate or potassium, or a strong base, for example, hydroxyacetamido base such as the hydroxide of the metal, for example, alkali metal hydroxide, such as sodium hydroxide or potassium, or, in particular, by using a metal alcoholate corresponding hydroxycodone or obtaining in situ in the presence of a strong base, for example, alkali metal hydride,under suitable solvents or mixtures of solvents, in particular, aprotic solvents such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMPU, simple ester, such as a simple diethyl ether, dioxane or tetrahydrofuran, carboxamide, such as dimethylformamide, or a mixture of two or more such solvents, at temperatures from 0oC to temperature phlegmy, in particular, from the 20oC to temperature phlegmy, and, if necessary, in an atmosphere of protective gas, such as nitrogen or argon.

Depending on the reaction conditions, the substitution can occur in the form of a nucleophilic substitution of the first or second order.

Since in the reaction according to method d) possible number of adverse reactions (e.g., racemization due to the formation of carbanions and so on), this method sometimes can be done only under very carefully controlled reaction conditions (for example, careful measurement used a base or corresponding alcoholate, and so on). Possible interfering reactions and suitable reaction conditions immediately become clear to the average person skilled in the art. In a preferred variant of the method in accordance with the present invention for producing compounds of formula I method d) were excluded for this is the compounds of formula I, having protected function carried out using one or more of the methods specified as method e).

Method (e) (removal of protective groups)

Cleavage of the protective groups that are not components of the target final product of formula I, for example, carboxy-, amino-, hydroxy - and/or mercaptoamines groups, carry out a known per se manner, for example, using solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by restoring, in particular, hydrogenolysis or by other reducing agents, as well as photolysis, optionally stepwise or simultaneously, you can also use fermentive methods. Cleavage of the protective groups are described, for example in the standard works mentioned above in the section "protective group".

So, protected carboxyl, for example, the lowest alkoxycarbonyl (which is preferably branched in position 1), such as tert-lower alkoxycarbonyl, lower alkoxycarbonyl, which is substituted in position 2 tizamidine silyl group or in position 1 lower alkoxy or lower alkylthio or diphenylmethylene, which is not substituted or substituted, can be converted into a free carb is th acid or triperoxonane acid, optionally with the simultaneous addition of nucleophilic compounds, such as phenol or anisole. Benzyloxycarbonyl, which is not substituted or substituted, may be, for example, converted into the free compound by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as palladium-based catalyst. In addition, substituted benzyloxycarbonyl, such as 4-nitrobenzenesulfonyl, can be turned into free carboxyl recovery, for example, by treatment with dithionite alkali metal, such as dithionite sodium, or regenerating metal, for example zinc, or a salt of the reducing metal, such as chromium salt(II), for example, chloride, chromium(II), usually in the presence of the agent, releasing hydrogen, which together with the metal to produce hydrogen at the time of allocation, such as acid, mainly suitable carboxylic acid, such as lower alcantarea acid, which is not substituted or substituted, e.g. by hydroxyl, for example, acetic acid, formic acid, glycolic acid, diphenylpyraline acid, lactic acid, mandelic acid, 4-charmingalina acid or tartaric acid,the missing metal or metal salt, as described above, 2-halo-lower alkoxycarbonyl (optionally after conversion of 2-bromo-lower alkoxycarbonyl to the appropriate group, 2-iodine-lower alkoxycarbonyl) or roulettecasino you can also turn into a free carboxyl. Roulettecasino can be split by treatment with a nucleophilic, preferably salt-forming reagent, such as thiophenoxide sodium or sodium iodide. The carboxyl group can also be obtained in the free form of the 1-aryl-lower alkoxycarbonyl, for example, arylethoxysilanes such as benzyloxycarbonyl, by hydrolysis in the presence of a base such as alkali metal hydroxide, e.g. sodium hydroxide or potassium. 2-(Tri-substituted silyl)lower alkoxycarbonyl, such as 2-tri-lower alkylsilane lowest alkoxycarbonyl, you can also turn into a free carboxyl by treating the salt of hydrofluoric acid, which produces the fluoride anion, such as fluoride of an alkali metal, e.g. sodium fluoride or potassium, in the absence or in the presence of a macrocyclic polyether ("crown ether"), or a fluoride of an organic Quaternary base, such as fluoride, Tetra-lower alkylamine or three fluoride-outstay aprotic polar solvent, such as dimethylsulfoxide, N,N-dimethylformamide or N,N-dimethylacetamide. Carboxyl, which is protected in the form of organic cellarstone, such as tri-lower alkylalkoxysilane, for example, trimethylsilylacetamide can be released by solvolysis in the traditional way, for example, by treatment with water, alcohol or acid or fluoride, as described above. Esterificated carboxy can be converted into the free compound enzyme, for example, using esterase or peptidase, for example, esterified arginine or lysine, such as methyl ester of lysine, using trypsin. Carboxyl, which is protected in the form of an internal ester, such as a lactone, can be liberated by hydrolysis in the presence of hydroxyacetamido base, such as hydroxide, alkaline earth metal or, in particular, alkali metal hydroxide, for example NaOH, KOH or LiOH, in particular, LiOH, corresponding protected hydroxyl group is converted into a free form at the same time.

The protected amino group is transformed into the free compound known per se in a way that varies depending on the nature of the protective groups, preferably using salessales in the presence of acids, for example, mineral acids such as galoidvodorodnykh acid, for example hydrochloric acid or Hydrobromic acid, in particular, Hydrobromic acid or sulfuric acid or phosphoric acid, preferably in the presence of hydrochloric acid, or a relatively strong organic acids, such as formic acid, trichloroacetic acid or triperoxonane acid in polar solvents such as water or carboxylic acid, such as acetic acid or formic acid, halogen substituted hydrocarbons, such as chlorinated lower alkanes, for example, dichloromethane or chloroform, or ethers, preferably cyclic ethers, such as dioxane, or organic carboxylic acids which are liquid at the reaction temperature, without solvent, for example, formic acid. 2-Halo-lower alkoxycarbonyl (if desired, after the conversion of 2-bromo-lower alkoxycarbonyl group 2-iodine-lower alkoxycarbonyl), kolmetsooniline or 4 nitrobenzisoxazole can, for example, split by treatment with a suitable reducing agent, such as zinc, in the presence of appropriate by treatment with a nucleophilic, preferably salt-forming reagent, such as thiophenoxide sodium, and 4 nitrobenzisoxazole - through processing dithionite alkali metal, for example, dithionite sodium. Substituted or unsubstituted, diphenylethylenediamine, tert-lower alkoxycarbonyl or 2-(tizamidine silyl) lower alkoxycarbonyl, such as 2-tri-lower alkylsilane - lower alkoxycarbonyl, can be split by treatment with a suitable acid, for example formic or triperoxonane acid, for example in Alojamientos hydrocarbon, such as methylene chloride or chloroform (in particular, if the hydroxyl, which is protected by a benzyl, not subject to becoming loose coupling), 1-aryl-ISSI alkoxycarbonyl, such as substituted or unsubstituted, benzyloxycarbonylamino can be, for example, be split by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst, for example, associated with a carrier such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanol-amides, for example dimethylformamide, ethers, such as cyclic is irty, such as methanol, ethanol or propanol, and particularly preferred methanol, and preferably at room temperature, substituted or unsubstituted, triarylmethane or formylamino can be split, for example, by treatment with acid such as mineral acid, e.g. hydrochloric acid, or organic acid, e.g. formic acid, acetic acid or triperoxonane acid, optionally in the presence of water, and triphenylamine can be split, in particular, by hydrogenolysis using precious metal or oxide of the precious metal as a catalyst, such as platinum, palladium or, in particular, palladium hydroxide, moreover, the catalyst preferably is associated with a carrier such as carbon, silica gel or aluminum oxide, in an inert solvent such as an ester, or preferably lower alkyl-lower alkanoate, such as ethyl acetate, at 20 - 80oC, in particular 50 - 70oC, if desired, at elevated pressure, for example between 1 and 10 bar, whereas the amino group protected in the form of silylamine, can be converted into the free compound, for example, by means of hydrolysis or alcoholysis. The amino group protected by 2-haloaluminate, such as tilt alkali metal in the presence of a base and subsequent solvolysis, such as alcoholysis or hydrolysis, the obtained substituted product. The amino group protected by 2-(tizamidine silyl) lower alkoxycarbonyl, such as 2-tri-lower alkylsilane lowest alkoxycarbonyl, also can be converted into the free amino group by treatment with a salt of hydrofluoric acid, producing a fluoride anion, as described above in connection with the release of the appropriately protected carboxyl group. Silyl, such as trimethylsilyl or tert-butyldimethylsilyl associated directly with a heteroatom, such as nitrogen, can similarly be split fluoride ions, preferably with a fluoride of an organic Quaternary nitrogen bases, such as fluoride, Tetra-lower alkylamine or fluoride three lowest alkylaryl-lower alkylamine, for example, fluoride of tetraethylammonium or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or N,N-dimethylacetamide, or, in particular, a simple ether, such as tetrahydrofuran, at 0 - 50oC, in particular at room temperature.

The amino group, which semiticisms hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or skeletal Nickel catalyst for hydrogenation, by restoring the merkaptosoedineny, such as dithiothreitol or mercaptoethanol, or by treatment with zinc in the presence of acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as galijasevic hydrocarbon, for example methylene chloride, or in water or in a mixture of water and an organic solvent, such as alcohol or dioxane, at a temperature of from about 20 to 25oC and during cooling or heating.

Hydroxyl group, or mercaptopropyl, which protected the corresponding acyl group, tri-lower alkylsilane group or a substituted or unsubstituted 1-aryl (such as 1-phenyl) lower alkyl group, converted into the free compound similar to the method used in respect of suitably protected amino group. Hydroxyl group, or mercaptopropyl protected 2,2-dichloroacetyl, converted into the free compound, for example, the main hydrolysis, whereas hydroxyl group, or mercaptopropyl that is protected by tert-lower alkyl or 2-oxa - or 2-what Alison, for example, by treatment with a mineral acid or a strong carboxylic acid, for example, triperoxonane acid. Hydroxyl group which is protected, benzyloxy, turn in free form, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst such as a palladium catalyst, for example, associated with a carrier, such as charcoal, preferably in polar solvents, such as di-lower alkyl-lower alkanolamide, for example, dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkalinity, for example, ethyl acetate, chlorinated hydrocarbons such as dichloromethane, or alcohols, such as methanol, ethanol or propanol, and particularly preferred methanol, or mixtures of two or more of these solvents, preferably, for example, at room temperature. Mercaptopropyl, which is protected by pyridylmethylamine can be, for example, to turn into a free form salts of mercury(II) at pH 2-6, or a mixture of zinc/acetic acid or electrolytic recovery; atsetamidometil or isobutyronitrile or 2-chloracetamide, narbutaite and S-sulfo, for example, using tialize with thiophenols, thioglycolic acid, thiophenoxide sodium or 1,4-dithiothreitol. Two hydroxyl groups or adjacent to the amino group and hydroxyl group, which are secured together by means of bivalent protective group, preferably a methylene group substituted once or twice by lower alkyl, such as lower alkylidene, for example, isopropylidene, cycloalkylation, for example, cyclohexylidene, or benzylidene, can be converted into a free form by acid solvolysis, especially in the presence of mineral acids or strong organic acids. Group three is the lowest alkylsilane similarly otscheplaut using acidolysis, for example, mineral acid, preferably hydrofluoric acid or a strong carboxylic acid. The hydroxyl can also be converted into a free form of the three lower alkylsilane by treating the salt of hydrofluoric acid, which produces the fluoride anion, such as fluoride of an alkali metal, e.g. sodium fluoride or potassium, in the absence or in the presence of a macrocyclic polyether ("crown ether"), or a fluoride of an organic Quaternary base, such as fluoride, Tetra-lower alkylamine or f is one, in the presence of an aprotic polar solvent such as dimethylsulfoxide or N,N - dimethylacetamide. 2-Halo-lower alkoxycarbonyl split using the above restorations, for example, the recovery of metal, such as zinc, or salts, a reducing metal, such as chromium salt(II), or sulfur, for example, dithionite or sodium, preferably sodium sulfide and sulfur in carbon. Esterified hydroxyl group, for example, lower alkanoyloxy, such as atomic charges, can also be converted into the free compound enzyme, using esterases, whereas acylated amino can be converted into a free form by using the appropriate peptidase.

Temperature for release of protected functional groups are preferably between -80oC and the boiling temperature of the reaction mixture, in particular from -80 to 110oC, particularly preferably from -20 to 50oC, for example, from 10 to 35oC, for example, at room temperature or 80oC to the boiling temperature of the reaction mixture, for example, about 100oC.

When there are several protected functional groups, protective groups in SELENITES, for example, by processing triperoxonane acid or hydrogen in the presence of a hydrogenation catalyst such as palladium on coal. On the other hand, groups can be selected so that they can be split, rather than simultaneously, on the contrary, in the desired sequence with the corresponding intermediate compounds.

Additional measures to methods

If necessary, implement additional measures to methods, according to which the functional group of the parent compounds, not participating in the reaction, can be exempt from protection or translate in protected form, for example, protected by one or more of the protective groups mentioned in method a). Protective groups can be derived fully or in part, using one of the methods specified in method e).

Salts of compounds of formula I having at least one salt-forming group can be obtained by methods known per se. Thus, salts of compounds of formula I having acidic groups can be formed, for example, by treatment with compounds of metals, such as alkali metal salts of the corresponding organic carboxylic acids, for example, sodium salt of 2-ethylcaproic eastwoodiae hydroxides, carbonates or bicarbonates, such as the hydroxide, carbonate or bicarbonate of sodium or potassium, the corresponding calcium compounds or ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid additive salts of compounds of the formula I get in the traditional way, for example, by treatment with an acid or a corresponding anion exchange reagent. Internal salts of compounds of formula I containing acidic and basic soleobrazutaya group, for example, a free carboxyl group and a free amino group can be formed, for example, by neutralising salts, such as acid additive salts, to the isoelectric point, for example, with the use of weak bases, or by treatment with ion exchangers.

Salts can be converted into the free compounds in a traditional way; metal salts and ammonium salts can be converted, for example, by treatment with suitable acids or acidic ion exchangers, acid additive salts can be converted, for example, by processing the respective main reagent, in particular, inorganic compounds is hydrogen carbonates, such as the hydroxide, carbonate or bicarbonate of sodium and potassium, the corresponding calcium compounds or ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent, in suitable solvents, for example, galijasevic hydrocarbons, such as dichloromethane, in the presence or absence of water; or by handling basic ion exchangers.

Stereoisomeric mixtures of compounds of the formula I, i.e. a mixture of diastereoisomers and/or enantiomers, for example, racemic mixtures can be separated into the respective isomers are known per se manner using appropriate methods of separation. So, diastereoisomer mixture, for example, can be divided into separate diastereoisomers by fractional crystallization, chromatography, separation into fractions using solvents or other suitable methods. The racemates can be separated from each other after the conversion of the optical antipodes in diastereoisomer, for example, by interacting with optically active compounds, for example, optically active acids or bases, by chromatography on colaninno reaction of only one of the two enantiomers. This separation can be done either at the level of one of the original products, either at the level of the compounds of formula I.

In the compound of the formula I where the radicals R1, R2or R3or more such radicals substituted 1-phenyl-lower alkoxy, such as benzyloxy, radical 1-phenyl-lower alkoxy can be derived, as described in method e). Receive a corresponding compound of formula I, where the hydroxyl is present instead of 1-phenyl-lower alkoxy.

In the resulting compound of formula I of the carboxyl group is present in free form or in reactive form may be etherification, or esterified carboxyl group can be converted into a free carboxyl group.

In order to atrificial carboxyl group of the compounds of formula I, can be used, if desired, the free acid or the free acid can be converted into one of the reactive derivatives of the above in method (a), and subject to the interaction with the corresponding alcohol, or, for the esterification of free acid or reactive salt, for example, cesium salt, can be subjected to interaction with a reactive derivative of the first broadcast of organic sulfonic acids, the corresponding alcohol (with halogen or the radical of an organic sulphonic acids, such as toluensulfonate, instead of the hydroxyl group). The esterification of the carboxyl group can also be implemented using other conventional alkylating agents, for example, using diazomethane, low-alkylhalogenide, esters of sulfonic acids, Meerwein salts or 1-substituted 3-alltrista.

With the aim of turning esterified carboxyl group in the free carboxyl group, you can use one of the methods described above in connection with the removal of a carboxyl protective group, or, if desired, the alkaline hydrolysis under normal conditions, such as those shown in method (e), preferably in the presence of alkali metal hydroxide, such as LiOH, in a suitable solvent, such as alcohols, e.g. methanol or ethanol, water, or their mixtures. Group low alkoxycarbonyl-lower alkoxy, which is present as a substituent, for example, R2and/or R3phenyl or naphthyl, can be turned by a recovery in the group hydroxy-lower alkoxy (in which the moiety of the lower alkoxy has at least 2 carbon atoms), for example, restoring podnah reaction conditions, for example, with the use of LiBH4in 1,2-dimethoxyethane at temperatures from 0oC to temperature phlegmy, preferably about 15-30oC.

In the compound of formula I present a free amino or imino group can be allievate, for example, to attach a radical of the lower alkoxycarbonyl to nitrogen piperidinylcarbonyl R1. The acylation is performed in analogy with the method mentioned above in method a) or by analogy with one of the methods specified security groups.

In the resulting compound of formula I in which the substituents have the abovementioned meanings and there is at least one free hydroxyl group and an additional functional groups optionally present in protected form of free hydroxyl group, such as hydroxyl group at the phenyl or naphthyl R2and/or phenyl or naphthyl R3you can atrificial, this hydroxyl group can be etherification radical lowest alkanoyl, phenyl-lower alkanoyl, lower alkoxycarbonyl-lower alkanoyl, carbarnoyl-lower alkanoyl, pyridyl-lower alkanoyl, cyano-lower alkanoyl or lower alkoxy-lower alkanoyl, and these alcohols school groups, for example, as defined for W1in compounds of formula X.

The etherification can be carried out by analogy with the method in accordance with method d), and preferably carried out using diazomethane or lower alkyl-, phenyl-lower alkyl-, lower alkoxy-lower alkyl-, carbarnoyl-lower alkyl-, pyridyl-lower alkyl-, cyano -, lower alkyl - or lower alkoxy-lower alkylhalogenide or esters of sulfonic acids. The reaction is preferably carried out using the appropriate lower alkyl, phenyl-lower alkyl-, lower alkoxy-lower alkyl-, carbarnoyl-lower alkyl-, pyridyl-lower alkyl-, cyano -, lower alkyl - or lower alkoxy-lower alkylhalogenide, such as iodides, bromides or chlorides, in the presence of bases, preferably hydroxyl reason, in particular, the hydroxide base metal, such as sodium hydroxide or potassium or, especially, metal carbonate or bicarbonate

metal, such as sodium, potassium or, mainly, cesium, in suitable solvents or mixtures of solvents such as N, N-di-lower alkyl-lower alkanolamide, such as dimethylformamide or dimethylacetamide, ketones, such as lower alkenone, for example, acetone, who predpochtitelno 0 - 60oC, for example, 0 - 50oC.

In the compound of formula I, the groups present and appropriate protective groups, or, alternatively, the corresponding radicals R1except for hydrogen, may be derived using one of the methods specified in method (e), in particular, by hydrolysis, for example, in the presence of bases, such as hydroxides of alkali metals or hydroxides of alkaline earth metals such as sodium hydroxide, or acids, such as organic acids and mineral acids, for example, galoidvodorodnykh acid, such as hydrochloric acid. The hydrolysis is carried out under normal conditions, for example in aqueous solution or in an anhydrous solvent, in particular, ethers, such as dioxane, at temperatures from -50oC to temperature phlegmy corresponding reaction mixture, for example, at 0 - 50oC, preferably in the presence of a protective gas, such as argon or nitrogen, or by hydrogenolysis (for example, in the case benzyloxycarbonyl radicals), preferably in polar solvents, such as alcohols, e.g. methanol or ethanol, esters, such as lower alkyl-lower alkanoates, for example, ethyl acetate, above which preferably is connected with the carrier, such as charcoal.

In the compound of formula I in which at least one of the radicals R2or R3denotes a phenyl group and/or present one or more additional phenyl ring, and the phenyl radicals in each case can be substituted, as described above, the corresponding phenyl radical (radicals) can be gidrirovanii selectively with the formation of appropriate tsiklogeksilnogo radicals. The hydrogenation is preferably carried out in the presence of a catalyst, allowing the selective hydrogenation of double bonds in the presence of amide bonds, in particular, the catalyst containing the oxides of heavy metals such as catalyst oxide Rh(III)/Pt(VI) in accordance with the work of Nishimura (S. Nishimura, Bull. Chem. Soc. Japan 33, 566 (1960), in suitable solvents, particularly in water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanol, at 0 - 150oC, preferably 10 - 50oC, for example, at room temperature, under hydrogen pressures of 0.01 - 50,0 bar, for example, at standard pressure or low pressure.

In the compound of the formula I, in which at me you can gidrirovanii selectively with the formation of the corresponding tsiklogeksilnogo radical. The hydrogenation is preferably carried out in suitable solvents or mixtures of solvents, preferably in an alcohol, such as methanol or ethanol, ether complex, for example, lower alkyl-lower alkanoate, such as ethyl acetate, or mixtures of these solvents, in the presence of catalysts, in particular palladium, which preferably is associated with a carrier, such as charcoal, preferably activated carbon, 10 - 50oC, preferably at room temperature and at slightly elevated or reduced pressure or preferably under standard pressure.

In the compound of the formula I, in which the nitro group linked to the aromatic radicals (aryl), in particular, if R1means arylsulfonyl with one or more nitrosomethylurea, such as 4-nitrobenzenesulfonyl, nitro can be restored in amino using, in particular, hydrogenation in appropriate solvents or mixtures of solvents, preferably in an alcohol, such as methanol or ethanol, ether complex, for example, lower alkyl-lower alkanoate, such as ethyl acetate, or mixtures of these solvents, in the presence of a catalyst, for example, skeletal catalyst, such as SC is ri room temperature, at slightly elevated or reduced pressure or preferably under standard pressure.

Pharmaceutical preparations and methods

The present invention also relates to pharmaceutical preparations which contain compounds of the formula I, especially of formulae I'.

Pharmacologically used compounds of the present invention can be used, for example, to obtain pharmaceutical preparations containing an effective amount of the active compound together, or mixed, with a significant amount of inorganic or organic, solid or liquid, pharmaceutically applicable carrier.

The pharmaceutical preparations according to the invention are those which are intended for enteral, such as nasal, transbukkalno, rectal or oral, or parenteral, such as intramuscular or intravenous, the introduction of mammals (humans and animals) and which contain an effective amount of the pharmacologically active compound or its pharmaceutically salt used or together with a significant amount of pharmaceutically used media.

The dose of the active soedinennyh pharmacokinetic circumstances, subject to treatment of disease and mode of administration of the drug.

The present invention also relates to pharmaceutical preparations and method of treating diseases caused by retroviruses, such as AIDS or its preliminary stages, in particular, when HIV-1 or, especially, HIV-2 causes the disease, or, alternatively, to treat similar diseases or their preliminary stages in mammals besides humans that are caused, for example, SIV in monkeys or FIV in cats. In this case, preferably, when the amount therapeutically effective against retroviral diseases such as AIDS or its preliminary stages, or similar diseases of mammals, except man, the new compounds of formula I or, particularly, formula I' include pharmaceutical preparation suitable for administration to a mammal, especially humans, for the treatment of retroviral diseases, such as, preferably, AIDS, or, alternatively, a similar disease in a mammal, except man, or when a therapeutically effective amount of the new compounds of formula I or, particularly, formula I is administered in accordance with the method of treatment of a mammal, for example, to people, to the relevant diseases in mammals, except the person requires treatment of this nature, with the specified amount of the drug therapeutically effective against retroviral diseases such as AIDS or its preliminary stages, and associated diseases in a mammal, except man. Dosage, introduced mammals, such as humans weighing approximately 70 kg is from about 3 mg to 10 g, preferably from 20 mg to 4 g, for example, from about 100 mg to 2.5 g per patient per day, and they are distributed, preferably, from 1 to 3 separate doses prescribed to adult patients. "Therapeutically effective" means, in particular, that the beginning of a particular disease may be delayed compared with the condition of the patient receiving the drug that at least one symptom may be delayed or weakened, at least one type of cells (e.g., CD4 person may be fully or partially protected from the disease or that the disease can be completely cured.

The pharmaceutical preparations contain from about 1%-95%, preferably 20%-90%, active compound. The pharmaceutical preparations according to the invention can, the opening, tablets or capsules.

The pharmaceutical preparations of the present invention receive a known per se manner, for example, using traditional techniques of solubilization, freeze-drying, mixing, granulating or coating.

It is preferable to use solutions of the active compounds, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, and in the case of lyophilised preparations which contain the active substance alone or together with a carrier, for example mannitol, they can be prepared before use. The pharmaceutical preparations can be sterilized and/or to enter additional substances, such as preservatives, stabilizers, cross-linking agents and/or emulsifiers, soljubilizatory, salts for adjusting osmotic pressure and/or buffered solutions, and get them known per se by, for example, using traditional techniques of solubilization or lyophilization. These solutions or suspensions may contain substances which increase the viscosity, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone and the ical or semi-synthetic oils, which are traditional for the purposes of injection. Oils of this type, which should be mentioned are, in particular, liquid esters of acids of the fatty series, which as the acid component contains long-chain fatty acid having 8-22, in particular, 12-22, carbon atoms, for example lauric acid, tridecane acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, arachidonoyl acid, beenbuy acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassicicola acid or linoleic acid, with or without added antioxidants, for example, vitamin E, - carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these complex fatty acid ester has at most 6 carbon atoms and represents a one - or polyhydric alcohol, for example, monatomic, diatomic or triatomic alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol, or their isomers, especially glycol and glycerin. Therefore, you should mention such esters of the fatty acid series, such as etiloleat, isopropylmyristate, isogrid saturated fatty acids range in chain length C8-C12that comes from Huls AG, Germany), with particularly preferred vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and especially peanut butter.

Preparation of drugs for injection carried out in the traditional way, under sterile conditions, as for example, to fill their vials or test tubes and sealing of containers.

Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid carriers, if desired with subsequent granulation of the mixture and, if desired or necessary, with the addition of suitable excipients, followed by processing in tablets, tablets coated core or capsule, or get dispersion, preferably phospholipids, which are filled glass tubes. In addition, the active compounds may be introduced into synthetic media, which releases the first dose, or even allow them to diffuse.

Suitable carriers include, in particular, fillers such as sugars, for example, lacto is tricky acidic calcium phosphate, and also binders, such as starch pastes using, for example, corn starch, wheat starch, rice starch or potato starch, gelatin, tragant, methylcellulose, hypromellose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the abovementioned starches, and, in addition, karboksimetilirovaniya starch, cross-linking polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate. Adjuvants are mainly viscosity regulators and lubricants, for example silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate and/or polyethylene glycol. Tablets coated core are appropriate wrappers that are, or are not resistant to gastric juice, using, inter alia, concentrated sugar solutions, which contain or do not contain the Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or to obtain membranes that are resistant to gastric juice, use solutions according to the CLASS="ptx2">

Capsules are hard gelatin capsules as well as soft, sealed capsules made of gelatine and a softener, such as glycerol or sorbitol. Hard capsules can contain the active compound in the form of a granulate, for example, contain excipients, such as lactose, binders, such as starches, and/or glidant, such as magnesium stearate, and, optionally, containing stabilizers. Capsules, the active compound is preferably suspended or dissolved in a suitable oily auxiliary substances, such as traditional vegetable, synthetic or semi-synthetic oils. Oils of this type, which should be mentioned are, in particular, liquid esters of acids of the fatty series, which as the acid component contains long-chain fatty acid, for example, having 8-22, in particular, 12-22, carbon atoms, for example lauric acid, tridecane acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, arachidonoyl acid, beenbuy acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, br is in E, - carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these complex fatty acid ester has at most 6 carbon atoms and represents a one - or polyhydric alcohol, for example, monatomic, diatomic or triatomic alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol, or their isomers, especially glycol and glycerin. Therefore, you should mention such esters of the fatty acid series, such as etiloleat, isopropylmyristate, isopropyl, "Labrafil M 2375" (polyoxyethyleneglycol supplied from Gattefoss, Paris), "Miglyol 812" (triglyceride of saturated fatty acids range in chain length C8-C12that comes from Huls AG, Germany), with particularly preferred vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and especially peanut butter. Vaseline oil is also acceptable. You can add stabilizers such as emulsifiers, wetting agents or surfactants, binders, such as starch pastes using, for example, corn starch, wheat starch, rice starch or potato starch, gelatine, tragant, min(s) and/or polyvinylpyrrolidone, and/or antibacterial agents. Suitable emulsifiers are, in particular, oleic acid, non-ionic surfactants of the type of ester of polyhydroxystearic and fatty acid series, for example, arbitrageurs, -oleate, -stearate, -palmitate, -tristearate or trioleate, the addition products to polyoxyethylene ethers of polyhydroxystearic and fatty acid series, such as polyoxyethylenesorbitan, -oleate, -stearate, -palmitate, - tristearate or trioleate, polietilenglikolya esters of fatty acids, such as polyoxyethylene, polyoxyethyleneglycol(300 or 400) stearate, polyethylene glycol-2000-stearate, in particular ethylenoxide - propyleneoxide block copolymers of typePluronic (Wyandotte Chem. Corp.; trademark of BASF, Germany) or Synperonic (ICI). If the active substance is not soluble in these oils, it is preferably present in the form of a suspension, the particle size of the active substance is from about 1 to 100 microns.

Dyes or pigments can be added to the tablets or coated tablets, as well as in capsule shell, for example, for identification or tagging of different dosages of active compound is enemy, that are effective against retroviral diseases, and used in accordance with the above description.

The present invention also relates, accordingly, to method or the method of treating diseases caused by retroviruses, such as AIDS or its preliminary stages, in particular, when HIV-1 or, especially, HIV-2 causes the disease, or, alternatively, to treat similar diseases or their preliminary stages in mammals besides humans that are caused, for example, SIV in monkeys or FIV in cats, the method or treatment method is the introduction of combination, a therapeutically effective against retroviral diseases such as AIDS or its preliminary stages, or similar diseases of mammals, except man, and the new compounds of formula I or, particularly, formula I' (or even several such compounds), and b) other compounds, or two or more such compounds, are effective against retroviruses, in particular, or several, preferably one from among the inhibitors mentioned above as being preferred, reverse transcriptase or, in particular, retroviral aspartate proteases (included, for example, stood, ordosemys in such treatment, for the treatment of retroviral diseases, such as, preferably, AIDS, or, in addition, similar diseases in mammals, except humans), with the specified amount of the drug therapeutically effective against retroviral diseases such as AIDS or its preliminary stages, and associated diseases in a mammal, except man. The combined dosage of the individual active compounds, introduced mammals, such as humans weighing approximately 70 kg is from about 3 mg to 10 g, preferably from 20 mg to 4 g, for example, from about 50 mg to 2.5 g per patient per day, and they are distributed, preferably, from 1 to 3 single doses which may, for example, be of the same size. Usually children appoint half the dose, you get adult patients. "Therapeutically effective" means, in particular, that the beginning of a particular disease may be delayed compared to a patient not receiving treatment, and that at least one symptom may be delayed or weakened, and that at least one type of cells (e.g., CD4-human) can be completely finding also relates to compositions, containing a) at least and preferably one compound of formula I or its salt, provided that there is a salt-forming group, and b) one or two (preferably) or more other active compounds which are effective against retroviruses, in particular HIV, such as HIV-1 or HIV-2, selected in particular from the above-mentioned reverse transcriptase inhibitors, in particular, the above-mentioned other inhibitors of retroviral aspartate proteases (in particular, the inhibitors described above in each case as being preferred), in the presence or absence of one or more pharmaceutically acceptable carriers, as combination products for simultaneous or chronologically particular use during the period of time which is small enough for the active compounds both of component a) and component b) were present simultaneously in the body of the patient (such as blood), for the treatment of retroviral diseases, which responds to the active compounds of this type. The basic principle is that the observed synergism.

The present invention also relates to pharmaceutical preparations containing (predpochtite formula I and b) one or more of these active compounds, that are effective against retroviruses, with or without one or more pharmaceutically acceptable carriers, with the preferred active compounds described above in each case as being preferred.

In addition, the present invention relates to the use of a combination of (a) compounds of formula I and b) one or more of the above-mentioned active compounds which are effective against retroviruses (including HIV, such as HIV-1 or HIV-2) to obtain pharmaceutical preparations used as compositions against retroviral infections, especially due to HIV, such as HIV-1 or HIV-2; however, the preferred compounds mentioned in each case as being preferred.

The present invention also relates to the production of the above-mentioned product or mixture of compounds for use in therapeutic treatment of the human or animal body. In this context, the composition and obtaining pharmaceutical drugs for the individual components of the product with a view to its gradual or simultaneous administration or for mixtures of compounds similar to those that meet the above FA the part is a combination of (a) compounds of formula I, marked as 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2(R)-[2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)- Val-N-(2-methoxyethyl)amide, and (b) one or both of the active compounds saquinavir and indinavir.

The active compounds of formula I and/or other active compounds that are effective against retroviruses, may be, in each case substituted their pharmaceutically salts used.

Educt

New source materials and/or intermediate compounds and methods for their production are also subject of the present invention. Preferably, if the original substance used and the reaction conditions are chosen so as to obtain the compounds listed above as preferred.

All of the original substance can be obtained by analogy with the methods specified in the examples, or, for example, in the description of the applications EP 0532466 (published March 17, 1993) or EP 0618222 (published 5 October 1994), and data applications introduced in the present description as a reference.

Upon receipt of all of the original substances available functional groups that are not eligible for participation in the respective reactions can be released from the protection or, if necessary, between the m data groups can be introduced at appropriate stages by analogy with the methods mentioned here. Protective group or a protected group can result in free form in a suitable time by analogy with the methods specified in method e). Source materials and intermediate compounds having soleobrazutaya group in each case can be used as free compounds or their salts, and salts, at each stage, can be obtained, or converted again into the free compounds.

By analogy with the stages of the method described above with respect to additional measures to methods, radicals hydroxylamino phenyl R2and/or phenyl, R3in the intermediate compounds can be atrificial, at appropriate stages of the method, the radical lower alkanoyl, phenyl-lower alkanoyl, lower alkoxy - carbonyl-lower alkanoyl, carbarnoyl-lower alkanoyl, pyridyl - lower alkanoyl, cyano-lower alkanoyl or lower alkoxy - lower alkanoyl. The etherification can preferably be carried out using diazomethane or lower alkyl-, phenyl-lower alkyl-, lower alkoxy-lower alkyl-, carbarnoyl-lower alkyl-, pyridyl-lower alkyl-, cyano -, lower alkyl - or lower alkoxy - lower alkyl-halides or esters of sulfonic acids. The reaction is preferably done by email-lower alkyl-, pyridyl-lower alkyl-, cyano -, lower alkyl - or lower alkoxy-lower alkyl-halides such as iodides, bromides or chlorides, in the presence of bases, preferably hydroxyl reason, in particular, the hydroxide base metal, such as sodium hydroxide or potassium or, especially, metal carbonate or metal bicarbonate, such as sodium carbonate, potassium or, mainly, cesium, in suitable solvents or mixtures of solvents such as N,N-di-lower alkyl-lower alkanolamide, such as dimethylformamide or dimethylacetamide, ketones, such as lower alkenone, for example, acetone, or ethers, such as dioxane, or their mixtures, at temperatures from - 10oC to temperature phlegmy, preferably 0 to 60oC, for example 0 to 50oC.

In the intermediate compounds, in which at least one of the radicals R2or R3denotes a phenyl group and/or present one or more phenyl rings and the phenyl radicals in each case can be substituted, as described above, the corresponding phenyl radical can, at appropriate stages of the reaction by analogy with the stages of the method described above with respect to additional measures to STRs is calow. The hydrogenation is preferably carried out in the presence of a catalyst, allowing the selective hydrogenation of double bonds in the presence of peptide bonds, in particular, the catalyst containing the oxides of heavy metals such as catalyst oxide Rh(III)/Pt (VI) in accordance with the work of Nishimura (S. Nishimura, Bull. Chem. Soc. Japan 33, 566 (1960), in suitable solvents, particularly in water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example, in methanol, at 0 - 150oC, preferably 10 - 50oC, for example, at room temperature, under hydrogen pressures from 0.01 to 50 bar, for example, at standard pressure or low pressure.

In the intermediate compounds, in which at least one of the radicals R2or R3means cyclohexenyl corresponding cyclohexadienyl radical can, at appropriate stages of the method according to analogy with the stages of the method described above with respect to additional measures to methods, gidrirovanii selectively with the formation of the corresponding tsiklogeksilnogo radical, for example, in suitable solvents or mixtures of solvents, preferably in an alcohol, such as MTA solvents, in the presence of catalysts, in particular palladium, which preferably is associated with a carrier, such as charcoal, preferably activated carbon, 10 - 50oC, preferably at room temperature and at slightly elevated or reduced pressure or, in particular, under standard pressure

Provided that the stereochemistry of the asymmetric carbon atoms is not defined directly by choosing the symbols of the respective links, the configuration of asymmetric carbon atoms, which in each case is preferred, denoted in formulas using symbols selected from (S), (R) and (S, R), which in each case is given in parentheses. In addition, other isomers or isomeric mixtures can also be specified instead.

Carboxylic acids of formula II and IV or of their reactive derivatives, which are known, commercially available or can be obtained by known per se methods.

The compounds of formula III and III' are known or can be obtained by known per se methods. For example, they can be obtained from compounds of the formula

< / BR>
where R2has the values defined for compounds of formula I, and Pa denotes am oxycarbonyl, such as benzyloxycarbonyl (or its analogues, in which the hydrogen replaces Pa, and these analogs can then be protected accordingly), which in the first stage transform by restoring into the corresponding compounds of formula

< / BR>
(or their analogues with hydrogen instead of Pa), where the radicals have the above values.

Recovery of amino acid derivatives of the formula XI with the corresponding aldehyde XII is carried out, for example, by restoring them to the appropriate alcohols with further oxidation of the latter to form an aldehyde of formula XII.

The restoration of alcohols is carried out, in particular by hydrogenation of the corresponding golodnikov or other activated carboxylic acid derivatives XI, specified in method a) or by the interaction of activated derivatives of the compounds of the formula XI, in particular anhydrides with organic carboxylic acids, preferably those derived from esters kalamurina acid, for example, isobutylphthalate (which preferably is produced by the interaction of the compounds of formula XI in the presence of basic amines, for example tri-lower alkylamine, at temperatures from -50 to 80oC, preferably 0 to 50oC), with complex hydrides, such as borohydride metals, for example, borohydride sodium in aqueous solution, in the presence or in the absence of organic solvents at temperatures of -50 - 80oC, preferably 0 to 50oC. Subsequent oxidation of the resulting alcohols is preferably carried out using oxidizing agents which selectively convert the hydroxyl group to the aldehyde group, for example, chromic acid or its derivatives, such as pyridinium or tert-buildroot, aromathera acid, sulfuric anhydride, in the presence of heterocyclic bases, such as pyridine/SO3(preferably dissolved in di-lower alkylsulfonate, such as dimethyl sulfoxide, aromatic solvents such as toluene, or mixtures of these solvents), and nitric acid, manganese dioxide or selenium dioxide, in water, aqueous or organic solvents, such as golozhabernyi solvents such as methylene chloride, carboxamido, such as dimethyl-formamide, and/or cyclic ethers, such as tetrahydrofuran, in the presence or in the absence of basic amines, for example, three-Nissi is whether -10 to 50oC, for example, as described in the application EP-A-O 236734, or by interaction with decarbonylation, such as oxacillin, and di-lower alkyl-sulfoxidov, such as dimethyl sulfoxide, in Alojamientos hydrocarbon, such as dihlormetilen, in the presence of a tertiary nitrogen base, such as triethylamine, at preferred temperatures from -70 to 0oC, for example, at a temperature of about -60oC.

Also, you can directly restore the compounds of formula XI in the aldehydes, for example, by hydrogenation in the presence of partially poisoned palladium catalyst, or restoration of the appropriate esters of amino acids, for example, a complex lower alilovic esters, such as complex ethyl esters, complex hydrides, for example, borohydride, such as borohydride sodium, or, preferably, alumosilicate, for example, lithium aluminum hydride, three (tert-butoxy) by lithium aluminum hydride or, in particular, diisobutylaluminium, in nonpolar solvents, for example hydrocarbons or aromatic solvents such as toluene, at temperatures from -100 to 0oC, preferably from -70 to 30oC. When, first make products suitable the Mach aqueous solvents, such as alcohol/water, for example, ethanol/water, at temperatures from -20 to 60oC, preferably 10 - 30oC. Then the obtained semicarbazone subjected to interaction with reactive aldehyde, for example formaldehyde, in an inert solvent, for example, polar organic solvent, such as carboxamide, for example, dimethylformamide, at temperatures from -30 to 60oC, preferably from 0 to 30oC, followed by interaction with an acid, for example, a strong mineral acid, such as galoidvodorodnykh acid, in aqueous solution, in the absence or in the presence of the above-described solvent, at temperatures from -40 to 50oC, preferably from -10 to 30oC., the Corresponding esters are obtained by the interaction of amino acids with the corresponding alcohols, for example ethanol, in similar conditions used in the condensation in method b), for example, by reacting with inorganic halogenide, such as thionyl chloride in mixtures of organic solvents, such as mixtures of aromatic and alcoholic solvents such as toluene and ethanol, at temperatures from -50 to 50oC, preferably -10 to 20oC.

In order niepozorny tetraallylsilane, preferably halomethyl three lowest alkylsilanes, such as chloromethylmethylether, in an inert solvent, for example ether, such as diethyl ether, cyclic ether, such as dioxane, or a complex ester, such as ethyl acetate, at temperatures from -100 to 50oC, preferably from -65 to 40oC, to obtain the compounds of formula

,

where R6, R7and R8denote lower alkyl, for example methyl, and the remaining radicals have the above values. The compounds obtained in the presence of a Lewis acid such as telefonat of boron TRIFLUORIDE in an inert solvent, in particular, alojamiento hydrocarbon, such as methylene chloride or chloroform, followed by treatment of the aqueous base, e.g. sodium hydroxide solution, at temperatures from -30 to 80oC, preferably from 0 to 50oC, with elimination and removal of protective groups, in turn olefinic compounds of the formula

,

where R2has the values defined for compounds of formula I. Aminosidine group Pa, for example, tert-butoxycarbonyl again injected into the corresponding olefin, as described in method (a) in relation to the introduction of aminosidine groups, in particular, with isoltrap from -50 to 80oC, preferably from 0 to 35oC receive secure aminomethane formula

,

where the radicals have the above values. The double bond then turn in oxirane (ethylene oxide), preferably stereoselective using peroxides, in particular, peroxycarbonates acid, for example, galatarasay acid, such as m-chloroperbenzoic acid, in an inert organic solvent, preferably Alojamientos hydrocarbon, such as methylene chloride or chloroform, at temperatures from -50 to 60oC, preferably from -10 to 25oC, and, if desired, by separation of diastereoisomers, while receiving the epoxides of the formula

< / BR>
where the radicals have the above values. The dibasic ester of malonic acid, for example, diethylmalonate or diethylmalonate, add to the resulting epoxides, for example, activating methylene group of the dibasic ester of malonic acid using an alkali metal, e.g. sodium, in a polar anhydrous solvent such as an alcohol, e.g. methanol or ethanol, at temperatures from -50 to 80oC, preferably from 0 to 35oC, followed by treatment of the acid solution, for example, carboxylic acid, such as lim is ethoxy or ethoxy, and the remaining radicals have the abovementioned meaning, and if desirable, R2restore the cyclohexyl those compounds in which the radical denotes phenyl not substituted or substituted as described for compounds of formula I, in particular, by hydrogenation, preferably in the presence of catalysts, such as oxides of precious metals, for example, a mixture of oxides of Rh(III)/Pt(VI) (in accordance with the previously mentioned work Nishimura), preferably in polar solvents, such as alcohols, e.g. methanol, at normal pressure or pressures up to 5 bar, preferably at normal pressure, at temperatures from -20 to 50oC, preferably from 10 to 35oC, with subsequent interaction obtained directly or after hydrogenation of compounds of formula XVII with a reagent that introduces the radical R3-CH2is, for example, formulas

R3- CH2- W (XIII),

where R3has the values specified for compounds of formula I, W denotes a nucleophilic leaving group, preferably selected from hydroxyl which is esterified with a strong inorganic or organic acid, such as hydroxyl, esterified mineral acid, for example, gasoduto the slot, or a strong organic acid, such as lower alkanesulfonyl, which is not substituted or substituted, e.g. by halogen, such as fluorine, or an aromatic acid, for example, benzosulfimide, which is not substituted or is substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or nitro, for example, methanesulfonate, trimethylsulfonium or p-toluensulfonate, and hydroxyl which is esterified with attestations acid, in particular, bromide, anhydrous polar solvent, for example, alcohol such as ethanol, in the presence of an alkali metal, for example, sodium, at temperatures from -50 to 80oC, preferably from 0 to 35oC, to form compounds of the formula

,

where the radicals have the above values. The compounds of formula XIX hydrolyzing and decarboxylases. The hydrolysis is carried out, for example, a base such as an alkali metal hydroxide, e.g. lithium hydroxide, or NaOH, at a temperature from -50 to 80oC, preferably from 0 - 35oC, in an organic solvent, for example ether, such as 1,2-dimethoxyethane, or alcohol, such as ethanol. Subsequent decarboxylation lead by heating in an inert rest is UP>C, preferably from 70 Yes 120oC, thus obtaining the compound of the formula

< / BR>
where the radicals have the above values. The obtained isomers (R, S, S) and (S,S,S) shared by column chromatography and the isomer (R,S,S) is used again. With the aim of breaking lactoovo cycle the compound obtained is subjected to interaction with a base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium hydroxide, in an inert solvent, such as a simple ether, for example, dimethoxyethane, or alcohol, such as ethanol, to form compounds of formula

< / BR>
where the radicals have the above values. Hydroxyl protective group Py, for example, one of the hydroxyl protective groups specified in the method (a), in particular, a group of three or lower alkylsilane injected under the conditions specified there, in the compound obtained using the appropriate halo-tri-lower alkylsilane, for example, tert-butyldimethylchlorosilane, in a polar solvent such as di-lower alkyl-lower alkanolamide, such as dimethylformamide, in the presence of spatially constrained amino compounds, such as cyclic amine, for example, imidazole, at temperatures from -50 to 80oC, preferably is of again by interacting with the basic salt of the metal, in particular, the alkali metal hydroxide or carbonate of an alkali metal, or, preferably, the carbonate of an alkali metal such as potassium carbonate, preferably in an alcohol, such as methanol or ethanol, cyclic ether, such as tetrahydrofuran, in the water or, in particular, in a mixture of 2 or 3 of these solvents, preferred 0 to 50oC, in particular 10 to 35oC, to obtain the compounds of formula

< / BR>
where the radicals have the above values. The compounds of formula III or III', with radicals described in method a) receive, for example, from one of a number of compounds of the formula XXII by condensation with the compound of the formula VI, where the radicals have the meanings given in the way in), in conditions that are similar to those described in method a), in particular, by reacting in situ in the presence of a condensing agent such as N,N - dicyclohexylcarbodiimide, ethylcyanoacrylate, benzotriazol-1 - yloxytris(dimethylamino)phosphonium hexaflurophosphate or O - benzotriazol-1-yl-N,N,N', N'-tetramethylurea hexaflurophosphate, spatial difficult amine, such as triethylamine, or N-methylmorpholine, and, if desired, compounds that prevent racemization, such as 1-hydroxybenzotriazole, such as dimethylformamide, cyclic ether, such as tetrahydrofuran, or a nitrile, such as acetonitrile, at preferred temperatures from -50 to 80oC, in particular from 0 to 35oC, optionally in an atmosphere of protective gas, such as argon or nitrogen, and subsequent removal of the protective group of the RA under conditions similar to those described in method e) (provided that RA is not a radical, which corresponds to the radical R1having the values defined above for compounds of formula I that could lead directly to the formation of compounds of formula (I), and finally, if desirable, with the removal of Py and/or additional protective groups in conditions similar to those described in method e). Order to obtain compounds of the formula III or III', are also successful in condensing the compounds of formula XXII with compounds which introduce the radical - HN-(CHR4)-CO- (starting material: the corresponding amino acids of H2N-(CHR4)-COOH and-NH-CH2-(CH2)n-O-R5(source material: the corresponding aminosidine H2N-(CH2)n-O-R5) the compounds of formula III or III' in the same terms as specified in the method (a), preferably by reacting compounds than the unity of formula (i) VI or VI' (corresponds to the compound of formula XXII, where Pa = hydrogen), (ii) VIII, or (iii) X, where the remaining radicals in each case have the above values, and the original substances may also be present as reactive derivatives, the conditions specified under the designation of (i) the way in), (ii) in method g), or (iii) in method e), you can also split the protective group Py from compounds of the formula III or III' using one of the methods described in method e).

The following path can also be taken to obtain the compounds of formula XX of the above-mentioned compounds of formula XVII:

Hydrolysis of racemic compounds of formula XVII (which can be obtained from the racemate of compounds of formula XV of the corresponding racemate of compounds of formula (XVI) and decarboxylation under conditions similar to those used for the hydrolysis and decarboxylation of compounds of formula XIX, produce compounds similar to the compound of formula XIX, in which, however, the radicals R3-CH2and R9-(C=O) is omitted (in both cases, instead, is a hydrogen atom), and which is present as a racemate (or of a mixture of diastereoisomers, provided that R3and/or R9there is an additional center of asymmetry); this poznachaen one of the above-mentioned nucleophilic leaving group, in particular, halogen, for example iodine, or preferably bromine or chlorine, at first by its deprotonation in the presence of a strong base, such as bis(tri-lower alkylsilane)amide of alkaline metal, for example, bis(trimethylsilyl)amide, lithium, and then alkylation of his compound of the formula R3-CH2-W (preferably receiving the compound [1'(S),3(R)-(R3- CH2-),5(S)] - [1'(R),3(S)-(R3-CH2-),5(R)] of the formula XX, that is, the racemate in respect of these asymmetric carbon atoms).

The above compounds of formula XIV may also be present in the configuration (R,S) instead of the specified configuration (S) at the carbon atom carrying the radical-NH2while the compounds of formulas XI, XII and XIII, and, in particular, the compounds of formulas XV, XVI, XVII, XIX, XX, XXI and/or XXII can also be present in the configuration (R,S) instead of the configuration (S) at the carbon atom carrying the radical Pa-NH-. The above compounds of formulas XV, XVI and XVII may also be present in the form of racemates. There might also be other mixture of optical antipodes of these formulas. The corresponding compounds of formula V, for example, can be obtained from these racemates or mixtures (e.g., racemates or mixtures of the antipodes, if R1does not contain any center 2- is configuration (S), the carbon atom bearing BUT is in configuration (S), and the carbon atom bearing3-CH2- is in the configuration (R) (2R,4S,5S); or these carbon atoms have opposite configuration (2S, 4R,5R); or even present a mixture of compounds of the formula V or I, who have both of these configurations. The corresponding racemic mixture or a mixture of diastereoisomers can be divided into appropriate stages (preferably) in a separate isomers.

The compounds of formula XX, in which the radicals have the abovementioned meanings, are obtained from compounds of formula XII, in which the radicals have the abovementioned meanings, by reacting aldehydes of the formula XII with esters of 2-GeoProMining acid, in particular, lower alkyl-2-iodopropionic, such as ethyl 2-iodopropionic, to obtain compounds of the formula

,

where the radicals have the stated values and the carbon atom carrying the radical Pa-NH-, may also be present such as in the configuration (R,S).

The reaction is carried out first with the formation of homoeopath complex lower alkyl ester (e.g. ethyl) 2-GeoProMining acid in the presence of a mixture of Zn/Cu in di-lower alkyl-lower alkanolamide, such as the STI 20 - 80oC, optionally in an atmosphere of protective gas, such as nitrogen or argon. Then the reaction mixture is treated with the corresponding Tetra (lower alkyl)orthotitanate, such as Tetra(isopropyl)orthotitanate, preferably in a protective gas atmosphere, such as nitrogen or argon, in an aromatic solvent such as toluene or xylene, in the presence of helodermatid, such as methylene chloride, using tetrachloride titanium such as titanium tetrachloride, at temperatures from -50 to 50oC, in particular from 40 to 25oC, and the mixture is stirred with formation of the corresponding di-lower alkylate of dihalomethane or, preferably, lower alkylate of trihalomethane, in particular, diisopropylate of trichlorethane. A solution of Zn-homoeopath added dropwise to the latter mixture at temperatures from -50 to 0oC, in particular, from -40 to -25oC, and the aldehyde of formula XII in helodermatidae, for example, methylene chloride, is then added dropwise at preferred temperatures from -50 to 30oC, in particular from 40 to 5oC, with the formation of the precursor in the form of a complex lower alkyl (in particular ethyl-)ether, particularly for complex ethyl ester compounds of the formula XXIII. This ester sancheska solvent, such as an aromatic compound, for example, toluene or xylene, in the presence of acid, such as carboxylic acid, e.g. acetic acid, at temperatures from 20oC to the boiling temperature of the reaction mixture, in particular 70 - 100oC. If necessary, diastereoisomer share, for example, by chromatography, for example on silica gel, using a mixture of organic solvents such as a mixture of alkane and ether complex, for example, lower alkane and ether complex lower alkyl-lower alkanoyl, such as a mixture of hexane or ethyl acetate.

The corresponding compound of formula XX is then obtained from the compounds of formula XXIII by deprotonation with a strong base, with the formation of a carbanion at the carbon adjacent to oxopropoxy lactate and subsequent nucleophilic substitution of the radical W the compounds of formula XVIII, where R3and W have the above values in connection with obtaining compounds of formula XIX (W marked, in particular, bromine), the reaction preferably leads stereoselective to the configuration (R) at the carbon atom in the compound of formula XX, which carries a radical R3-CH2-. Reaction with strong base, in particular with silicone amido the l)lithium amide, or di-lower alkylamino alkali metal, such as diisopropylamide lithium, preferably carried out in an inert organic solvent, in particular, in a simple ether, e.g. a cyclic ether such as tetrahydrofuran or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), or in mixtures of these solvents, at temperatures from -100 to 0oC, in particular, from -78 to -50oC, whereas nucleophilic substitution is carried out in situ by adding the compounds of formula R3-CH2-W in the same solvent and at temperatures in the range from -100 to 0oC, in particular, from -60 to -40oC.

The compound of the formula XIV, in which the radicals have the stated values and in which the carbon atom carrying the group-NH2preferably is in the configuration of (R, S) can also be obtained by conversion of ester of formic acid, for example, lower alkylphosphate, such as ethyl formate, in arylamide formic acid by reacting it with aluminum at 20 - 70oC, in particular 50 - 60oC. This amide is then dehydration in a protective gas atmosphere, such as nitrogen or argon, preferably using galoyanized, such as the acid chloride phosphoric acid, phosgene or, arid, in the presence of a base, for example, tri-lower alkylamine, such as triethylamine, or, in particular, mono - or dziklicska amine, such as pyridine or quinoline, at 50 - 100oC, in particular 80 - 100oC. This leads to the formation of arylisocyanate, which is transformed into the corresponding lithium salt by interaction with organolithium salt, for example, the lower alkyllithium, such as n-utility, and the reaction is preferably carried out in an inert organic solvent, in particular, in a simple ether, such as dioxane or diethyl ether, or alkene, for example, hexane or mixtures of these solvents, at temperatures from -120 to -50oC, in particular, from -100 to -70oC. the Resulting lithium salt is then subjected to interact in situ with the compound of the formula R2-CH2-W, where R2has the values specified for compounds of formula I, and W have the values specified above for compounds of formula XVIII, in particular, denotes bromine, preferably by adding R2-CH2-W dropwise in an organic solvent, for example ether, such as tetrahydrofuran, at 0 - 50oC, in particular 20 to 30oC. This leads to the formation of isocyanide formula

< / BR>
nom solution, to which is added the acid, for example, in water kaleidotrope acid, such as hydrochloric acid, in particular, concentrated hydrochloric acid, at temperatures from -20 to 30oC, in particular 0 to 10oC, to obtain the compounds of formula XIV, in which the radicals have the above values and in which the carbon atom carrying the group-NH2preferably is in the configuration of (R,S).

The amino compounds of the formula III or III' or their reactive derivatives are known or can be obtained by known per se methods, for example, by condensation of the amino acids of the formula H-B1-OH, where1has the values specified for compounds of formula III or III' or their reactive derivatives with amino compounds of the formula III or III' or their reactive derivatives, with reactive derivatives and condensation conditions similar to described in method a).

The compounds of formula V or V' receive, for example, provided that the protective group Pa in the formula XXI or XXII does not correspond directly to the radical R1from amino compounds of the formula XXI or XXII, for example by introducing a carboxyl protective group, as described in sposo1-OH or its reactive derivative, where the radicals have the meanings specified for compounds of the formula I, under conditions that are similar to the conditions of the condensation described in method a).

The compounds of formula settle down under or settle down under' receive, for example, provided that the protective group Pa in formula XX does not correspond directly to the radical R1of the lactone of formula XX, preferably from isomer (R,S,S), for example, by removal of the protective group Pa, as described in method e), by condensation with a carboxylic acid of formula R1-OH or its reactive derivative, where the radicals have the meanings specified for compounds of the formula I, under conditions that are similar to the conditions of the condensation described in method a).

The compounds of formula VI (or VI') are obtained, for example, from the corresponding amino acids of the formula

< / BR>
(in particular, formulas

< / BR>
where the radicals have the stated meanings, or their reactive derivatives, and amino compounds of formula VIII, where the radicals in each case defined above, or its reactive derivative, by condensation, by analogy with the method described in method a), and, if desired, using the same reactive or V') by the condensation of an amino acid of formula XXV (or XXV'), defined above, which introduces the radical NH-CH(R4)-COOH. The reaction is carried out in conditions similar to those described in method a), using the corresponding free compounds or their reactive derivatives, or they can be obtained from compounds of formula settle down under (or settle down under') by condensation with the amino acid of formula XXV (or XXV') defined above, which introduces the radical NH-CH(R4)-COOH. The reaction is carried out in conditions similar to those described in method b), using the corresponding lactones of the formula settle down under, especially formulas settle down under'.

Aminosidine formula VIII are known or may be obtained by known per se methods.

The compounds of formula IX (or IX') are known or can be obtained by known per se methods, for example, by condensation of the compounds of formula VII

(or (VII'), where the radicals have the stated meanings, and (if necessary hydroxylamino) amine of the formula

H2N-CH2-(CH2)n-OH (XXVI),

or its reactive derivative, where n has the meanings given for compounds of formula I, reaction conditions similar to those described in method a).

The compounds of formula X or Xa are known, commercially available or mahouts known or can be obtained by known per se methods, or they may be available commercially. As an example, we can mention obtaining the compounds of formula XVIII or formula R2-CH2-W, where W denotes Br or I, by reacting a corresponding precursor in which W denotes Cl, iodide or bromide of an alkali metal, such as NaI, for example, ketones, such as lower alkane, for example, acetone, at temperatures from 0 to 50oC, in particular at room temperature, or with three or pentaiodide or-bromide of phosphorus, such as PBr3for example, hydrocarbons, for example, aromatic hydrocarbons such as toluene, at preferred temperatures from 0 to 40oC, for example, at room temperature.

Predecessor (W= Cl) commercially available, known or can be obtained by known per se methods.

For example, the precursor, in which a hydroxyl group is present instead of Cl(= W), can be converted into the corresponding chlorinated compound by interacting with PCl3, PCl5or, especially SOCl2in the presence of tertiary nitrogen bases, for example, the base polymer or pyridine, in an appropriate solvent, for example ether, such as diethyl ether, and>C, in particular from 0 to 25oC. Predecessors, in which a hydroxyl group is present instead of W, is known, can be obtained by known per se methods, either available commercially.

The other starting compound known to be made by methods which are known per se, and/or are commercially available.

The following intermediate compounds mentioned under (i) - (iv) are new compounds.

(i) a Compound of formula XIXA

< / BR>
(in particular, of formula XIXA'

< / BR>
where Q denotes hydrogen; aminosidine group, preferably aminosidine the RA group as defined for compounds of formula XI (in particular, one of aminosidine groups specified in the method (a)); or the radical R1defined for compounds of formula I, except those radicals, which fall under the definition of the protective group Pa; R2has one of the values specified in connection with the definition of the compounds of the formula I; R3denotes phenyl, tizamidine radicals selected from lower alkyl, lower alkoxy and halogen, or denotes a lower alkylenediamines, in particular 2,3,4-tri-lower alkoxyphenyl, especially 2,3,4-trimethoxyphenyl; and R9denotes lower alkoxy, for example, labels the equipment compound of formula XIXA, in particular, the formula XIXA', in which Q denotes hydrogen or, in particular, 1-phenyl-lower alkoxycarbonyl, in particular, benzyloxycarbonyl, 1-phenyl-lower alkyl, in particular benzyl, or mainly, lower alkoxycarbonyl, such as tert - butoxycarbonyl; R2represents cyclohexyl or, in particular, phenyl; R3indicates 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl; R9denotes lower alkoxy, for example methoxy or ethoxy; or its salt, provided that there are soleobrazutaya group.

The compounds of formula XIXA or XIXA' or correspond to the compounds of formula XIX where Q denotes aminosidine group RA, or can be obtained from these compounds by removal of the protective groups by analogy with the conditions described in method (e) (obtaining compounds of formula XIXA or XIXA', where Q=H), and, if desired, by introducing the radical R1by treatment with an acid of formula II, as described above in method (a), by analogy with the conditions specified in method a).

(ii) a Compound of the formula settle down under

< / BR>
(in particular, formulas settle down under'

< / BR>
especially formulas settle down under"

,

where Q denotes hydrogen; aminosidine group, preferably aminosidine gr)); or the radical R1defined for compounds of formula I, except those radicals, which fall under the definition of the protective group Pa; R2has one of the values specified in connection with the definition of the compounds of the formula I; R3denotes phenyl, tizamidine radicals selected from lower alkyl, lower alkoxy and halogen, or denotes a lower alkylenediamines, in particular 2,3,4-tri-lower alkoxyphenyl, especially 2,3,4-trimethoxyphenyl; or its salt, provided that there are soleobrazutaya group.

Particularly preferably the compound of formula settle down under, in particular, formulas settle down under', in particular formulas settle down under"', in which Q denotes hydrogen or, in particular, 1-phenyl-lower alkoxycarbonyl, in particular, benzyloxycarbonyl, 1-phenyl-lower alkyl, in particular benzyl, or mainly, lower alkoxycarbonyl, such as tert-butoxycarbonyl; R2represents cyclohexyl or, in particular, phenyl; R3indicates 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl; or its salt, provided that there are soleobrazutaya group.

Preferably the compound of formula settle down under", which is denoted by 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl] -3(R)- (2,3,4-trimethoxyaniline 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)- (2,3,4-trimethoxyphenyl)dihydrofuran-2-(3H)-he.

The compounds of formula settle down under, or formulas settle down under', or formulas settle down under" can be obtained from corresponding compounds of formula XIX or XIXA by analogy with the methods described above for the conversion of compounds of formula XIX in the compounds of formula XX; either they directly correspond to the compounds of formula XX where Q denotes aminosidine group Pa, or can be obtained directly from these compounds by removal of protective groups in conditions similar to those described in method e) (obtaining compounds of formula XIXA or XIXA', where Q=H), and, optionally, the introduction of the radical R1interaction with the acid of formula II, as described above in method (a), in the same terms as defined in method 1).

(iii) a Compound of formula VA

< / BR>
(in particular, of formula VA'

,

where Q denotes hydrogen; aminosidine group, preferably aminosidine the RA group as defined for compounds of formula XI (in particular, one of aminosidine groups specified in the method (a)), or the radical R1defined for compounds of formula I, except those radicals, which fall under the definition of the protective group Pa; R2has one of the values specified in connection with the definition of the compounds of the formula I; R3about the mean lowest alkylenedioxy, in particular, 2,3,4-tri-lower alkoxyphenyl, especially 2,3,4-trimethoxyphenyl; Py*denotes hydrogen or hydroxyamino group, preferably one of the protective groups mentioned in method (a), particularly the three lowest alkylsilane, such as tert-butyldimethylsilyl; and E denotes hydroxyamino or carboxyamide group, preferably defined in the method and, in particular, lower alkoxy, such as methoxy, ethoxy or tert-butoxy, or tri-lower alkylsilane, in particular, tert - butyldimethylsilyloxy, or a radical -(C=O)-E denotes a reactive derivative of the carboxyl group, in particular, denotes a carboxyl group in the form of a complex of activated ester or reactive anhydride or a reactive cyclic amide, preferably by analogy with those described for the reactive derivatives of the formula II in method a); or its salt, provided that there are soleobrazutaya group.

Particularly preferably the compound of formula settle down under, in particular, formulas settle down under', especially formulas settle down under", where Q denotes hydrogen or, in particular, 1-phenyl-lower alkoxycarbonyl, in particular, benzyloxycarbonyl, 1-phenyl-lower alkyl, in particular benzyl, illi, in particular, phenyl; and R3indicates 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl; Py*denotes hydrogen or hydroxyamino group, preferably one of the protective groups mentioned in method (a), particularly the three lowest alkylsilane, such as tert-butyldimethylsilyl; and E denotes hydroxyamino or carboxyamide group, preferably defined in the method and, in particular, lower alkoxy, such as methoxy, ethoxy or tert-butoxy, or tri-lower alkylsilane, in particular, tert-butyldimethylsilyloxy, or a radical -(C=O)-E denotes a reactive derivative of the carboxyl group, in particular, denotes a carboxyl group in the form of a complex of activated ester or reactive anhydride or a reactive cyclic amide, preferably by analogy with those described for the reactive derivatives of the formula II in method a); in particular, hydroxyl and lower alkoxy; or its salt, provided that there are soleobrazutaya group.

Preferably the compound of formula VA', which is denoted by 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [2,3,4-trimethoxyphenyl)methyl]hexanoic acid, or its salt.

Particularly preferably the compound of formula VA', which is denoted by 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoic acid, or its salts, particularly the alkali metal salt, e.g. sodium salt, which can crystallize very effectively).

Also especially preferably, the compound of formula VA', which is denoted by 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl]hexanoic acid, or its salt.

The compounds of formula VA and formula VA' correspond to the compounds of formulas V and V', respectively, which are already described above.

The compounds of formula VA and formula VA' correspond directly to the compounds of formulas V and V', respectively, when Q denotes aminosidine group RA Py*denotes hydrogen and E denotes hydroxyl. Other appropriate compounds of formula VA and formula VA', in which at least one of the radicals Py*or E has the meanings given for compounds of formula VA and formula VA', which differ from those mentioned above, can be obtained from these latter compounds by introducing protective groups, for example, as opisanie a), or due to the receipt of a reactive derivative of carboxylic acid, as described in method a). The corresponding compounds in which Q has a value other than RA, can be obtained from these compounds of formula VA and formula VA', or compounds of formulas V and V' by removal of protective groups by analogy with the conditions described in method (e) (obtaining compounds of formula VA and VA', where Q=H), and, if desired, the introduction of the radical R1interaction with the acid of formula II, as described above in method (a), by analogy with the conditions specified in method a).

(iv) a Compound of formula VIIA

< / BR>
(in particular, the formula VIIA'

< / BR>
where R1has the values specified for compounds of the formula I; R2has one of the values specified in connection with the definition of the compounds of the formula I; R3denotes phenyl, tizamidine radicals selected from lower alkyl, lower alkoxy and halogen, or denotes a lower alkylenediamines, in particular 2,3,4-tri-lower alkoxyphenyl, especially 2,3,4-trimethoxyphenyl; Py*denotes hydrogen or hydroxyamino group, preferably one of the protective groups mentioned in method (a), particularly the three lowest alkylsilane, such as tert-butylidene a), in particular, lower alkoxy, such as methoxy, ethoxy or tert-butoxy, or tri-lower alkylsilane, in particular, tert - butyldimethylsilyloxy, or a radical -(C= O)-E denotes a reactive derivative of the carboxyl group, in particular, denotes a carboxyl group in the form of a complex of activated ester or reactive anhydride or a reactive cyclic amide, preferably by analogy with those described for the reactive derivatives of the formula II in method a); or its salt, provided that there are soleobrazutaya group.

Particularly preferably the compound of the formula VIIA, in particular, of the formula VIIA', where R1denotes a phenyl-lower alkoxycarbonyl, in particular, lower alkoxycarbonyl, such as tert-butoxycarbonyl; R2represents cyclohexyl or, in particular, phenyl; R3indicates 2,3,4-tri-lower alkoxyphenyl, in particular 2,3,4-trimethoxyphenyl; Py*denotes hydrogen or hydroxyamino group, preferably one of the protective groups mentioned in method (a), particularly the three lowest alkylsilane, such as tert-butyldimethylsilyl; and E denotes hydroxyamino or carboxyamide group, preferably priscillians, in particular, tert-butyldimethylsilyloxy, or a radical -(C=O)-E denotes a reactive derivative of the carboxyl group, in particular, denotes a carboxyl group in the form of a complex of activated ester or reactive anhydride or a reactive cyclic amide, preferably by analogy with those described for the reactive derivatives of the formula II in method a); in particular, denotes hydroxyl and lower alkoxy; or its salt, provided that there are soleobrazutaya group.

Particularly preferably the compound of formula VIIA', which is denoted by 5(S)-(Boc-amino)-4(S)-(tert (-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoic acid, or its salt.

The compounds of formula VIIA and formulas VIIA' or correspond to compounds of the formula VII and VII', respectively, and can be obtained as described above (when Py*= H and E= HE), or can be obtained (when Py*has one of these values, other than hydrogen, and/or E has one of these values, other than hydroxyl) from compounds of formula VII and VII', respectively, by introducing protective groups, for example, as described in connection with the introduction of Py in connection formosana derivatives of carboxylic acids in accordance with the description in method a).

The following applies mainly to all the ways mentioned above and below:

As a consequence of the close relationship between the compounds of formula I and their salts and the original substances (parent compounds and intermediate compounds in free form and in the form of their salts, the free compounds and/or their salts should be understood as meaning, similar or appropriate, where acceptable, the corresponding salts and/or loose connections.

All the above stages of the methods can be carried out under reaction conditions known per se, preferably under such conditions that specifically, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents and dissolve the latter, in the absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the form of H+in each case depending on the nature of the reaction and/or reagent, at reduced, normal or elevated temperature, for example at temperatures from about -100oC to 190oC, preferably from -80oC to 150oC, e.g. at atmospheric pressure or in a closed reactor, if desired, under reduced or elevated pressure, in an inert atmosphere, for example, in a protective gas atmosphere, such as nitrogen or argon, and/or in the absence of light.

If desired isomeric mixtures formed at any stage of the reaction, can be separated into the individual isomers, for example, diastereoisomers or enantiomers, or arbitrary mixtures of isomers, e.g. mixtures of racemates or diastereoisomers, for example, by analogy with the methods described in the section "additional measures to methods".

In certain cases, for example, in the case of hydrogenation, it is possible to achieve stereoselective reactions, which, for example, facilitated the selection of individual isomers.

Solvents which may be selected suitable for each reaction include, for example, water, esters, such as lower alkyl-lower alkanoates, for example, ethyl acetate; ethers, such as aliphatic ethers, for example diethyl ether or 1,2 - dimethoxyethane, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene, toluene, o-, m-, or p-xylene, liquid acyclic hydrocarbons, such as hexane or heptane, alcohols, such as methanol, ethanol Em, amides of acids, such as dimethylformamide or dimethylacetamide, ketones, such as lower alkenone, for example, acetone, heterocyclic solvents, for example, bases, such as heterocyclic nitrogen base, such as pyridine, or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)- pyrimidone (DMPU), carboxylic acids such as acetic acid or formic acid, the anhydrides of carboxylic acids, such as anhydrides of the lower alanovoy acid, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of these solvents, e.g. aqueous solutions, if the description of the methods do not specify anything else. The mixture of solvents of this nature can also be used when processing, for example, by chromatography or separation.

The compounds, including their salts, can also be obtained in the form of hydrates, or their crystals can include the solvent used for crystallization.

Processing after carrying out the reaction is carried out in accordance with methods which are known per se, preferably by analogy with the methods described in the examples.

The present invention also otnositsea stage of the method, is used as the starting material, followed by missed stage of the method, either using the original compound formed in the reaction conditions, or its reactive derivative, for example, in protected form or as a salt or compound, which may be obtained in accordance with the new method will have in terms of method and subjected to further processing in situ. In the method of the present invention is used preferably those of the original compounds that lead to obtaining the compounds described above as particularly valuable. Preferred mainly the reaction conditions, such as the one outlined in the examples of the present description.

While there is a need or a desire, protected starting compound can be used at all stages of the method, and the protective group can be split at appropriate stages of the reaction.

Protective groups, their introduction and their release is described in the methods (a) and (e).

Examples

The following examples serve the purpose of illustrating the present invention, however, in no case do not limit its scope. Temperatures are given in degrees Celsius (oC). If the tempo is UB> that indicate the ratio of the distance traveled by a specific substance to the distance travelled by the eluent front, determined by thin-layer chromatography (TLC) thin-layer plates of silica gel (Merck, Darmstadt, Germany) using the following solvent system:

System eluents TLC:

And the ethyl Acetate

B methylene chloride/methanol 9:1

In Hexane/ethyl acetate - 1:1

G Hexane/ethyl acetate to 2:1

L Hexane/ethyl acetate to 3:1

E methylene chloride/methanol 12:1

W Hexane/ethyl acetate to 6:1

3 methylene chloride/tetrahydrofuran - 2:1

And methylene chloride/simple ether 25:1

To Hexane/ethyl acetate to 1:2

L Chloroform/methanol/water/acetic acid 85:13:1,5:0,5

M methylene chloride/methanol 10:1

N methylene chloride/methanol 15:1

Of ethyl Acetate/methanol 9:1

P methylene chloride/ethanol 10:1

R methylene chloride/ethyl acetate/ethanol - 30:20:1

With Toluene/ethyl acetate to 9:1

T methylene chloride/tetrahydrofuran - 4:1

The abbreviation "Rf(A)" means, for example, that the value of Rfit was determined in the solvent system A. the ratio of the amounts of solvents to one another is always given in parts by volume (v/v). Quantitative relations are also given in parts by volume when Opredelenie code for eluents TLC is also used for example, to specify eluents in column chromatography.

Chromatography medium pressure:

Phase: LiChroprepSi 60 (Merck, Dieticon/Switzerland); pressure of 10-15 bar.

Gradients GHUR:

I 20% - 100% a) in b) over 35 min

II 20% - 100% a) in b) over 20 min

III 5% - 40% a) in b) over 15 min

Eluent: acetonitrile + 0.05% of triperoxonane acid; eluent b: water + 0.05% of triperoxonane acid. Column (250 x 4.6 mm) filled obremenitve substance WITH18- Nucleosil(silica gel, average particle size 5 μm, which is covalently derivatization octadecylsilane, Macherey&Nagel, düren, Germany). Detection by ultraviolet absorption at a wavelength of 215 nm. Retention time (tRet) are given in minutes. The speed of movement of the solvent front is 1 ml/min.

Mass spectroscopic measurements, as a rule, carried out by the method of the bombardment of accelerated atoms. Unless specified otherwise, the mass values are for protonated ion of the molecule (M+N)+.

Values for infrared spectra are given in cm-1while the corresponding solvent is indicated in parentheses.

Abbreviations which tradicionnyi, what it is known, the configuration of the atom of carbon is indicated by prefixes (D - or (D). Glycyl associated with the rest of the molecule through aminatta, and carboxyl carbon indicated with [(cyclohexyl)Gly] - when replaced by the atom - carbon tsiklogeksilnogo radical, and using -[(phenyl)Gly] - when replaced by the atom - carbon of the phenyl radical.

Abbreviations:

abs. - absolute (indicates that the solvent is anhydrous);

anal. the calc. - the calculated value for elemental analysis (theoretical value);

anal. neid. - found value for elemental analysis (actual);

ATM - atmosphere (1 ATM corresponds 1,013 bar);

Bocc - tert-butoxycarbonyl;

BOP - benzotriazol-1-yloxytris(dimethylamino)phosphonium hexaflurophosphate;

TCL - thin layer chromatography;

DCC - dicyclohexylcarbodiimide-dimethoxyethan - 1,2-dimethoxyethan;

DIPE - diisopropyl ether;

DMF is dimethylformamide;

DMPU - 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone;

EDC hydrochloride, N-ethyl-N'-(3-dimethylaminopropyl)- carbodiimide;

a simple ether - simple diethyl ether;

us. - saturated;

h - hour(clock);

HBTU - O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea g mass spectroscopy

the sodium sulfate means centricular (Na2SO4);

NMM is N-methylmorpholine;

RT - room temperature;

RE rotary evaporator;

saline solution is a saturated solution of sodium chloride;

THF - tetrahydrofuran;

TBAF - trihydrate tetrabutylammonium fluoride;

Z - benzyloxycarbonyl.

Example 1: 5(S)-(BOC-Amino)-4(S)-hydroxy-6-(p - benzyloxyphenyl)-2(R)-[p-benzyloxyphenyl)methyl] hexanoyl-(L)- Val-N-(2-methoxyethyl)amide

93 mg (0,301 mmol) TBAF add in an atmosphere of N2to a solution of 135 mg (0,151 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6- (p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 1.3 ml of DMF, and the mixture was stirred at RT for 16 h, the Reaction mixture was poured into water and this mixture is extracted with 4 portions of ethyl acetate. The organic phase is washed us. a solution of NaHCO3, water and saline, dried with Na2SO4and evaporated. Boiling twice with DIPE results specified in the title compound in pure form: tRet(II) = 18,5 min; FAB-MS(M+H)+= 782.

Starting material was obtained as follows/

1A) Z-(L)-Val-N-(2-methoxyethyl)amide

19,8 g (of 78.8 mmol) of Z-(L)-valine in 720 ml of 0.25 M NMM/CH3CN obrabecim what U add in a thick white suspension, and this mixture is thoroughly stirred at RT for 24 h, the Reaction mixture was evaporated under high vacuum and the residue is dissolved in ethyl acetate; the solution is extracted with water, 2 times with 10% citric acid solution, water, 2 times us. a solution of NaHCO3and a salt solution. The aqueous phase is extracted twice with ethyl acetate, and the organic phase is dried Na2SO4and evaporated. Crystallization from ethyl acetate/hexane, 1:1, results indicated in the title compound: TLCf(G) = 0,6; tRet(II) = 11,5 minutes

1B) H-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenation of 22.8 g (74 mmol) of Z-(L)-Val-(2-methoxyethyl)amide in 496 ml of methanol at RT, and reduced pressure in the presence of 2.3 g of 10% Pd/C results, after filtering off the catalyst, evaporation of the filtrate and column chromatography (SiO2methylene chloride using a 2.5 ---> 5 ---> 7.5 ---> 10% methanol) cleaned the connection specified in the header, in the form of an oil: TLC Rf(B) = 0,3; FAB-MS(M+H)+= 175; 1H-NMR 360 MHz, CD3OD): of 0.90 and 0.95 (2D, J=7 Hz,(H3C)2C), and 1.9 (m, HC-Me2), was 3.05 (d, J=6 Hz, HC), 3,32 (s, H3C-O), 3,37 (m, H2C-O), 3,44 (m, H2C).

1B) 5(S)-(Boc-Amino) 4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxy is sildenafilcitrate) -6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl)] Caproic acid [see in example 1K] and 26 mg (0,148 mmol) H-(L)-Val-N-(2-methoxyethyl)amide are dissolved in 1.2 ml of 0.25 M NMM/CH3CN, and the solution process 56,3 mg (0,148 mmol) of HBTU. After 18 h of incubation at RT, the reaction mixture was evaporated and the residue is dissolved in ethyl acetate; the solution is thoroughly washed with water, 2 portions of 10% citric acid, water, 2 portions of a saturated solution of NaHCO3and finally brine. The inorganic phase is extracted twice more with ethyl acetate, and the organic phase is dried Na2SO4and evaporated to obtain specified in the connection header: tRet(II) = 24,4 min; FAB-MS(M+H)+= 896.

1G) p-Benzyloxybenzoate

A solution of 1.0 g (4.3 mmol) of 4-benzyloxybenzaldehyde (Fluka; Buchs/Switzerland) in 8 ml of acetone was stirred at RT with 3.13 g (of 20.9 mmol) of sodium iodide. After 90 min the gas chromatogram of the reaction mixture indicates that the reaction is complete; the reaction mixture is poured into ether and the mixture washed with 10% sodium thiosulfate solution and brine. Drying the organic phase with Na2SO4and evaporation yield specified in the connection header: 1H-NMR(200 MHz, CDCl3): 4,48 (s,2H), is 5.06 (s,2H), 6,85-to 6.95 (m,2H), 7,25-of 7.48 (m,7H).

1D) (S)-N-Boc-(p-benzyloxyaniline)

of 37.1 g (100 mm theoC 15,33 ml (110 mmol) of triethylamine, and the solution 14,36 ml (110 mmol) of isobutyl chloroformate in 70 ml of THF is added to this mixture. After stirring at RT for 0.5 h, the formed precipitate is filtered off with suction. Filtered the reaction mixture is added dropwise to EUR 7.57 g (200 mmol) of sodium borohydride and 44 ml of H2About (at a temperature of approximately 10-15oC), and the mixture was thoroughly stirred at RT for 3.5 hours the pH of the reaction mixture was adjusted to 2.0 by addition of 10% aqueous citric acid solution and the mixture is partially evaporated on RE. The residue is extracted with 3 portions of ethyl acetate and the organic phase washed with 2 x 2N NaOH solution, brine, us. a solution of NaHCO3and brine, dried with Na2SO4and evaporated; the crude product is boiled in hexane to obtain specified in the title compound: TLC Rf(C) = 0,50; FAB-MS(M+H)+= 358.

1e) (S)-N-Boc-(p-benzyloxyphenyl)

value of 4.76 g (37.5 mmol) of oxalicacid in 33.6 ml of methylene chloride is treated dropwise, at a temperature of -60oC and in an atmosphere of N2, solution of 3.5 ml (49 mmol) in DMSO (60 ml of methylene chloride. After stirring the mixture for 15 min add to 8.94 g (25 mmol) of (S)-N-Boc-(p-benzyloxyaniline) in 150 ml of methylene chloride and the mixture ZAT is eshivot within 30 minutes Add 222 ml of 20% aqueous solution of KHSO4and 187 ml of hexane and the mixture is heated to 0oC. the Aqueous phase is separated and extracted 2 times with ethyl acetate. The organic phase is washed us. a solution of NaHCO3and brine, dried with Na2SO4and evaporated to obtain specified in the title compound: TLC Rf(C) = 0,71;1H-NMR(200 MHz, CDCl3): the 1.44 (s,9H), 3,06 (d, J= 6 Hz, 2H), 4,39 (m, 1H), 5,03 (+Shir.with. H2-Oh+HN), 6,86-6,98 and 7,03-7,15 (2m, each 2H), 7,30-of 7.48 (m, 5H), 9,62 (s, 1H).

1G) 5 (S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] dihydrofuran-2-(3H)-he (see A. E. DeCamp et al., Tetrahedron Lett. 32, 1867 (1991))

6.0 g (91,8 mmol) Zn/Cu (receipt: see R. D. Smith, H. E. Simmons, W. E. Parham, M. D. Bravsar, Org.Synth., Coil. Vol. 5, 855 (1973)) and RS 9.69 ml of dimethylacetamide add, in an atmosphere of N2to a solution of 7.7 ml (to 57.1 mmol) ethyl 2-iodopropionic (example 1 l) in 100 ml of toluene and the mixture was thoroughly stirred at RT for 1 h and at 80oC for 4 h, the receiving solution homoeopath zinc. In the second apparatus a solution of 4.17 ml (14,2 mmol) tetraisopropyldisiloxane in 12 ml of toluene and 69 ml of methylene chloride is treated in an atmosphere of N2and with a slight cooling to 4.41 ml (40,2 mmol) of TiCl4; this mixture was stirred at RT for 15 min (get yellow solution) and cooled to -40oC obtaining ISAT using a cannula in isopropoxide of trichlorethane, which is cooled to -40oC, with the temperature support (-40oC to -30oC (the solution is dark red). The solution is heated to -25oC for 5 min and then cooled again to -40oC. and Then added dropwise a solution of 9.7 g (27 mmol) of (S)-N-Boc-(p-benzyloxyphenyl)alanine 24.5 ml of methylene chloride and the mixture is stirred at a temperature of approximately -20oC for 15 h and, finally, when 0oC for 1 h, the Reaction mixture was poured into 0.4 kg of ice water and 0.5 l of ether, after which the mixture is thoroughly stirred for 10 minutes the Aqueous phase is separated and extracted with 2 portions of ether; the organic phase is washed with water, us. a solution of acid sodium carbonate, water and brine, dried with sodium sulfate and evaporated, obtaining crystalline ethyl 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)hexanoate.

Intermediate connection, mentioned only that, is heated in 220 ml of toluene and was 6.73 ml of acetic acid at 100oC for 2.5 h the Cooled reaction mixture is treated with 0.5 l of water and the aqueous phase is separated and extracted with 2 portions of ether; the organic phase is washed us. a solution of acid sodium carbonate, water and brine, dried with sodium sulfate and upar: TLC Rf(E) = 0,28; tRet(l)=23,5 min;1H-NMR(200 MHz, CDCl3): of 1.40 (s, 9H), 2,03-2.2 and 2,44-2,64 and 2,73-2,98 (3 m, each 2H), 3.95 to and 4,48 (2 m, each 1H), to 4.62 (d,J=9 Hz,1H), 6.87 in-6,97 and 7,09-7,21 (2 m, each 2H), 7,27-of 7.48 (m, 5H).

1Z) 5(S)-[I(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] -3 (R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-he

2,74 g (6.0 mmol) of 5(S)-[1(8)-(Boc-amino)-2-(p - benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-she dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)- pyrimidinone, is treated at -70oC in an atmosphere of protective gas 11,73 ml of 1 M solution of bis(trimethylsilyl)amide lithium in THF and the mixture is stirred for 15 minutes with subsequent alkylation 1,946 g (6.0 mmol) of p-benzyloxy-benzylidene (example 1 g) in 3 ml THF (60 min). For hydrolysis of 2.23 ml of propionic acid and of 2.23 ml of water is added to the mixture which was then heated to oC. the Reaction mixture was poured into 30 ml of 10% citric acid solution and the mixture is extracted twice with ethyl acetate; the organic phase is washed twice with a saturated solution of acid sodium carbonate and once with brine. Drying with sodium sulfate and evaporation and subsequent column chromatography of the residue (SiO2, hexane/ethyl acetate, 4:1) and subsequent crystallization from ethyl acetate/hexane allow the floor is x2">

1i) 5(S)-(Boc-amino)-4(S)-hydroxy-6- (p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl] hexanoic acid

2.7 g (4,43 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-3(R)-[(p - benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-she's in 59 ml of dimethoxyethane and 31.8 ml of water is treated, excluding the air, of 14.8 ml of 1 M solution of lithium hydroxide. The mixture is then stirred at RT for 3 h and partially evaporated. The residue was poured into a mixture of ice, 181 ml us. solution of NH4Cl, 16,2 ml of 10% citric acid solution and 400 ml of ethyl acetate and THF added to dissolve precipitated solids. The aqueous phase is separated and extracted with 2 portions of ethyl acetate, and the organic phase washed with brine, dried with Na2SO4, evaporated and boiled in hexane: TLC Rf(C) = 0,07.

1K) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl] hexanoic acid

2,44 g (3.90 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-benzyloxyphenyl)-2R-[(p - benzyloxyphenyl)methyl] Caproic acid in 14 ml of DMF is stirred in an atmosphere of N2together with 2.70 g (17.6 mmol) of tert-butultimately-CHLOROSILANES and 2.18 g (32 mmol) of imidazole at RT for 18 h, the Reaction mixture was poured into ice water and the mixture extracted with 3 portions of ethyl is outstay Na2SO4and evaporated. The oil obtained is dissolved in 30 ml of methanol/THF/H2Oh, 3:1:1, and the solution is treated with 3.2 g2CO3and stirred at RT for 1 h, the Reaction mixture was partially evaporated and the aqueous residue was poured into 10% citric acid solution and ice, after which the mixture is extracted with 3 portions of ethyl acetate; the organic phase is washed twice with water and once with saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2:1-->1:1) of the crude product allows you to get the connection specified in the header: TLC Rf(C) = 0,53; FAB-MS(M+H)+= 740.

1l) Ethyl 2-iodopropionic

A suspension of 170 ml of ethyl 2-bromopropionate (Fluka; Buchs/Switzerland) and 950 g of sodium iodide in 1.8 l of acetone was stirred at 60oC for 20 h, the Reaction mixture was filtered and the filtrate is partially evaporated, and the residue was poured approximately 2.5 l of simple ether and the mixture was washed with 1.0 l of 1% sodium thiosulfate solution and brine, dried with Na2SO4and evaporated. Distillation (83oC and 20 Mbar) results specified in the title compound: MS(M)+= 228;1H-NMR (200 MHz, CDCl3): 4,17 (kV, 7 Hz, 2H), 3,34 and 2,97 (2 t 7 G is l-N-(2-methoxyethyl)amide

By analogy with example 1) 2,73 g (of 3.85 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(phenyl)-2(R)-[(p - cyanophenyl)methyl]- hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 90,4 ml DMF desilicious with the help of 3.65 g (11.6 mmol) and TBAF process. Crystallization from a mixture of methylene chloride and hexane allows to obtain specified in the header connection: tRet(II) = 14,0 min; FAB-MS (M+N)+= 595.

Starting material was obtained as follows.

2A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(p-cyanophenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

2,173 g (3.93 mmol) of 5 (S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-cyanophenyl)methyl] Caproic acid (receipt, see example 2D), 839 mg (4.07 mmol) of DCC and 596 mg (to 4.41 mmol) NOT type, excluding the air, by solution 753,2 mg (4,32 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) in 47 ml of THF. After 24 h stirring at RT the reaction mixture is filtered and the filtrate evaporated. The residue is partitioned between 3 portions of ethyl acetate, 10% citric acid, us. solution of NaHCO3and saline. Drying of the organic phase Na2SO4, evaporation and mixing of the residue in DIPE allow to obtain specified in the header connection: tRet(II) = 20,8 minutes

2B) 5 CLASS="ptx2">

8,03 g Zn/Cu (receipt: see R. D. Smith, H. E. Simmons, W. E. Parham, M. D. Bravsar, Org. Synth. Coll., vol.5, 855 (1973)) and 12,96 ml of dimethylacetamide is added in an atmosphere of N2to a solution of 17.4 g of ethyl-2-iodopropionic (example 1 l) in 130 ml of toluene and the mixture was thoroughly stirred at RT for 1 h and at 80oC for 4 h to obtain a solution homoeopath zinc. In the second system (atmosphere N2) the solution to 5.58 ml (18,9 mmol) tetraisopropyldisiloxane in 16.4 ml of toluene and 91.8 ml of methylene chloride is treated with a slight cooling 5,90 ml (53.8 mmol) of TiCl4; this mixture was stirred at RT for 15 min (get yellow solution) and cooled to -40oC, which leads to partial crystallization of isopropoxide of trichlorethane. Using a cannula, a solution of Zn-homoeopath, cooled to RT, decanted from the solid metal residue and added dropwise to isopropoxide of trichlorethane, with the temperature support (-40oC to -30oC (the solution is dark red). The mixture is heated to -25oC for 5 min and then cooled again to -40oC. and Then added dropwise a solution of 9.0 g (27 mmol) of (S)-N-)Boc - phenylalanine (receipt: see D. J. Kempf, J. Org. Chem. 51, 3921 (1986)) of 32.8 ml of methylene chloride and the mixture is stirred at a temperature of approximately -20oC for 2.5 h in 295 ml of toluene and 9 ml of acetic acid. The reaction mixture is treated with 0.5 l of water and the aqueous phase is separated and extracted with 2 portions of ether; the organic phases are washed with a saturated solution of acid sodium carbonate, water and brine, dried with sodium sulfate. Partial evaporation of the organic phases and processing hexane allow to obtain a crystalline compound that is specified in the header, approximately 10% of which is in accordance with results of the analysis, 5(R) epimer (TLC Rff(E) = 0,08). Column chromatography (SiO2, hexane/ethyl acetate, 2: 1) allows to obtain the purified compound indicated in the title: TLC Rf(E) = 0,14; []D= 17,7o(C=1; ethanol).

2B) 5(S)- [1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(p-cyanophenyl)methyl]-dihydrofuran-2-(3H)-on deprotonized of 9.8 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF and 1 alkylate 1.0 g of 4-bromomethylbiphenyl (Fluka; Buchs/Switzerland), dissolved in 3 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) allows to obtain the purified compound indicated in the title: TLC Rf(D) = 0,33.

2G) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-cyanophenyl) methyl] hexanoic acid

By analogy with example 1i) and 0.50 g of 5(S)-[1(S)-(Boc-amino)- 2-phenylethyl] -3(R)-[(p-cyanophenyl)methyl] dihydrofuran-2-(3H)-she's in 19 ml of dimethoxyethane and 10 ml of water hydrolyzing 4.8 ml of 1M solution of lithium hydroxide, obtaining specified in the title compound: TLC Rf(B) = 0,3.

2D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(p-cyanophenyl)methyl] hexanoic acid

By analogy with example 1K) and 0.62 g of 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2(R)-[(p-cyanophenyl)methyl] Caproic acid, 6.2 ml DMF similarbut 0,98 g of tert-butyldimethylchlorosilane and 0.79 g of imidazole. The hydrolysis of complex functions salelologa ether using 1.2 g of potassium carbonate in 31 ml of methanol/THF/H2O, 3: 1:1, allows to obtain, after acidification with a solution of citric acid and extraction with ethyl acetate, the connection specified in the header: TLC Rf(D) = 0,29; FAB-MS (M+N)+= 553.

Example 3: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o - forfinal)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)am who yl)methyl]-hexanoyl-(L)-Val-N- (2-methoxyethyl)amide in 5 ml of DMF desilicious using 249,3 mg (0,79 mmol) and TBAF process. Mixing with DIPE allows to obtain specified in the header connection: tRet(II) = 14,8 min; FAB-MS (M+N)+= 588.

Starting material was obtained as follows.

3A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(o-forfinal)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

168,9 mg (0,309 mmol) of 5(S)-(Boc-amino)- 4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(o - forfinal)methyl] Caproic acid (receipt, see example 3D), 77,1 mg (0,374 mmol) DCC and 45.5 mg (of 0.337 mmol), HOBT add in a protective gas atmosphere to a solution of 59.3 g (0.34 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) in 3.5 ml of THF. After 24 h stirring at RT the reaction mixture is filtered and the filtrate evaporated. The residue is partitioned between 3 portions of ethyl acetate, 10% citric acid, us. solution of NaHCO3and saline. Drying of the organic phase Na2SO4and allow evaporation to obtain specified in the header connection: tRet(II) = 22,3 minutes

3b) 5(S)-[1(S)-(Boc-amino)-2-(phenylethyl] -3(R)- [(o-forfinal)-methyl]-dihydrofuran-2-(3H)-he

By analogy with example 1H) 5.0 g (to 16.37 mmol) of 5(S)-[1 (S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2(3H)-it (example 2B), dissolved in 75 ml of THF, deprotonated at the 75oC to 32.7 ml of 1M solution of bis(trimethylsilyl)SUP>C (heating to a maximum temperature of -60oC for 60 min). Column chromatography (SiO2, hexane/ethyl acetate, 3:1) to receive the connection specified in the header: TLC Rf(D) = 0,61.

3b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R) - [(o-forfinal) methyl] hexanoic acid

By analogy with example 1i) 4.5 g (10,8 mmol) of 5(S)-[1(8)-(Boc-amino)-2-phenylethyl] -3(R)-[(o - forfinal)methyl] dihydrofuran-2-(3H)-she's in 170 ml of dimethoxyethane hydrolyzing of 43.5 ml of 1M solution of lithium hydroxide. One stripped off the remainder of the reaction mixture was poured into a mixture of ice, 120 ml of saturated ammonium chloride solution and 240 ml of 10% citric acid solution, and the mixture is then extracted with 3 portions of methylene chloride. The organic phase is washed with water and saline, dried in the presence of Na2SO4and evaporated: tRet(II) = 14,5 minutes

3G) 5(S)-(Boc-amino)-4(S)-(tert)-butyldimethylsilyloxy) - 6-phenyl-2(R)-[(o-forfinal)methyl]hexanoic acid

By analogy with example 1K) 1.5 g (3,47 mmol) of 5(S)-(Boc - amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o-forfinal)methyl] Caproic acid in 15.0 ml DMF similarbut 2.4 g (16 mmol) of tert - butyldimethylchlorosilane and 1.95 g (28.5 mmol) of imidazole. The hydrolysis of complex functions salelologa ether using 2.8 g of potassium carbonate in 50 ml of antibody, 2:1), the connection specified in the header: TLC Rf(D) = 0,33; tRet(II) = 20,7 minutes

Example 4: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(2,4-differenl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 1) 197,0 mg (0,274 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2,4-differenl)methyl] -hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5 ml of DMF desilicious using 173, 0mm mg (0,548 mmol) and TBAF process. Precipitation with DIPE from a concentrated solution in methylene chloride allows you to get listed in the title compound: TLC Rf(A) = 0,71; tRet(II) = 14,9 min; FAB-MS (M+N)+= 606.

Starting material was obtained as follows.

4A) 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy-6-phenyl-2(R)-[(2,4-differenl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

to 68.0 mg (0,39 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (example 1B), 80,5 mg (0,39 mmol) DCC and 57.5 mg (0,426 mmol), HOBT add, in an atmosphere of N2to 200 mg (0,354 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,4 - differenl)methyl] Caproic acid (receipt, see example 4D), 4.6 ml of THF. After 19 h of exposure at RT, the reaction mixture is treated by analogy with example 3A) to produce specified in the title compound: TLC Rf
By analogy with example 1H) 5.0 g (to 16.37 mmol) of 5(S)-[1 (S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-it (example 2B), dissolved in 100 ml of THF, deprotonated at a temperature of -75oC to 32.7 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate of 2.51 ml (at 19.6 mmol) of 2,4-diferenciada (Aldrich; Milwaukee, USA) initially at a temperature of -75oC (heating to a maximum temperature of -60oC for 120 min). Column chromatography (SiO2, hexane/ethyl acetate, 2:1) to receive the connection specified in the header: TLC Rf(D) = 0,5; tRet(II) = 17,2 minutes

4B) 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl-2(R)-[(2,4-differenl)methyl] hexanoic acid

By analogy with example 1i) 3.1 g (7,18 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)- [(2,4-differenl)methyl]-dihydrofuran-2-(3H)-she's in 77 ml of dimethoxyethane and 19 ml of water hydrolyzing 28,7 ml of 1M solution of lithium hydroxide (19 h at RT) to produce specified in the connection header: tRet(II) = 14,7 minutes

4G) 5(S)-(Boc-amino)-4(S)-(tert(-butyldimethylsilyloxy) - 6-phenyl-2(R)-[(2,4-differenl)methyl]hexanoic acid

By analogy with example 1K) 3.2 g (7,12 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl)-2R-[(2,4-differenl)methyl] Caproic acid in 67,0 ml DMF similarbut is 4.93 g (to 32.7 mmol) of tert-butyldimethylsilyl is in 77 ml of methanol, 20 ml THF and 20 ml of H2About can get, after column chromatography (SiO2, hexane/ethyl acetate, 2:1), the connection specified in the header: TLC Rf(D) = 0,22; tRet(II) = 20,8 minutes

Example 5: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{ [p-(2 - phenylethyl)phenyl]methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)AMI

By analogy with example 1) 115 mg (0,146 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R) -{ [p-(2-phenylethyl)phenyl] methyl} hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 2.1 ml of DMF desilicious with 92 mg (0,292 mmol) and TBAF extracted: TLC Rf(A) = 0,58; tRet= 18,1 minutes

The initial substance was obtained as follows.

5A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy-6-phenyl) 2(R)-{ [p-(2-phenylethyl)phenyl]methyl} hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

In an atmosphere of N2100 mg (0,158 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-{ [p-(2-phenylethyl)phenyl] methyl} Caproic acid (receipt, see example 5e) and 30 mg (0,174 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) are dissolved 1.52 ml of 0.25 M NMM/CH3CN, and the solution is treated to 66.0 mg (0,174 mmol) of HBTU. After 18 h of incubation at RT, the reaction mixture was poured into water and extracted with 3 portions of ethyl acetate. The organic phase washed with 5 concrete>
and evaporated to obtain specified in the connection header: tRet(II) = 24,4 minutes

5B) n-(2-phenylethyl)benzyl alcohol

Hydrogenation of 10.0 g (48 mmol) of 4-silbermedaille (Aldrich; Milwaukee, USA) in 100 ml THF, in the presence of 0.5 g of 5% Pd/C at RT and reduced pressure, filtration throughCelite (filter additive based on diatomaceous earth; Johns-Manville Corp., obtained from the company Fluka; Buchs/Switzerland) and evaporation of the filtrate allow you to get listed in the title compound, approximately 15% of which, in accordance with the spectrum of1H-5 NMR, consists of p-(2-phenylethyl)toluene: TLC Rf(A) = 0,62;1H-NMR (200 MHz, CDCl3): of 2.92 (s, 4H), and 4.68 (s, 2H), 7,15-7,35 (m, 9H).

5B) n-(2-phenylethyl)benzylbromide

3,14 ml (33.4 mmol) trichromate phosphorus in 11 ml of toluene is added dropwise, while cooling in an atmosphere of N2to at 8.36 g (85%, 33.4 mmol) n-(2-)phenylethyl)benzyl alcohol in 100 ml of toluene. After 2 h stirring at RT the reaction mixture was poured into ice water and the organic phase was separated, washed us. a solution of NaHCO3, water and finally brine. The aqueous phase is extracted twice with simple ether and the combined organic phases are dried with Na2SO4and evaporated to obtain specified in sagola the Nala approximately 20% of p-(2-phenylethyl)toluene.

5g) 5(S)-[1(S)-(Boc-amino)-2-(phenylethyl]-3(R) - {[n-(2-(phenylethyl) (phenyl] methyl} dihydrofuran-2-(3H)-he

A solution of 4.4 g (14,53 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-it (getting see example 26) 21.4 ml of abs. THF and 2.4 ml of DMPU process at -75oC and in an atmosphere of nitrogen, 28 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich; Steinheim, Germany), and the mixture is then stirred at this temperature for 15 minutes Then added dropwise a solution of 6.0 g (approximately 80%, 17.5 mmol) n-(2 - phenylethyl)benzylbromide 5.4 ml of abs. THF and the mixture was thoroughly stirred at -70oC for 30 minutes Then add to 5.4 ml of propionic acid at -75oC, then add to 5.4 ml of water. The mixture is heated to 0oC and diluted with 150 ml of ethyl acetate; the mixture is then washed with 80 ml of 10% citric acid solution, saturated sodium bicarbonate solution and saline. The aqueous phase re-extracted 2 times with ethyl acetate, and the organic phase is dried in the presence of sodium sulphate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 3: 1) allows to obtain the purified compound indicated in the title: TLC Rf(E) = 0,27; tRet(II) = 20,8 min; FAB-MS (M-Butene+N)+= 444.

5D) 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-{[p-is l)phenyl] methyl)dihydrofuran-2-(3H)-she's in 166 ml of dimethoxyethane and 85 ml of water hydrolyzing in a protective gas atmosphere 41 ml of a 1M solution of lithium hydroxide. After 3 h dimethoxyethan evaporated on RE and the residue is treated chilled on ice mixture 506 ml us. solution of NH4Cl, 42 ml of 10% citric acid solution and 207 ml of methylene chloride. Methanol is added to dissolve the product. The aqueous phase is separated and extracted twice with a mixture of methylene chloride/methanol, 10:1. The organic phase is washed with saline, dried in the presence of Na2SO4and evaporated: tRet(ll) = 17,8 minutes

5e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-{ [p-(2-phenylethyl)phenyl]methyl} hexanoic acid

to 5.08 g (9,81 mmol) of 5(S)-(Boc-amino)-4(8)-hydroxy-6-phenyl-2(R)- {[p-(2-phenylethyl)phenyl] methyl} Caproic acid in 22,0 ml DMF similarbut in a protective gas atmosphere to 6.80 g (45,1 mmol) tert - butyldimethylchlorosilane and of 5.48 g (80,4 mmol) of imidazole at RT for 20 h, the Reaction mixture was poured into 500 ml ice water and the mixture extracted with 3 portions of ethyl acetate; the organic phase washed with 10%th citric acid solution, 2 times with water and saline, dried in the presence of Na2SO4and evaporated. The residue is dissolved in 119 ml of methanol and 46 ml of THF, and this solution is treated 8,1 g K2CO3and 46 ml of water, then stirred at RT for 17 h

The reaction mixture is ethyl acetate; the organic phase is washed twice with water and once with saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2: 1 ---> 1:1 ---> ethyl acetate) allows to obtain the purified compound indicated in the title: TLC Rf(D) = 0,22; tRet(II) = 23,3 minutes

Example 6: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{ [n- (2,6-dichlorobenzenesulfonyl)phenyl]methyl}hexanoyl-(L)-Val-N-(2 - methoxyethyl) amide

By analogy with example 1,241 mg (0.27 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R) -{ [n-(2,6-dichlorobenzenesulfonyl)phenyl] methyl)hexanoyl-(L)- Val-N-(2-methoxyethyl)amide exempt from protection by using 170 mg (0.54 mmol) of TBAF in 3.6 ml of DMF for 17 hours Stirring in a small amount of ethyl acetate, the addition of DIPE and filtering produce purified compounds specified in the header: TLC Rf(B) = 0,67; tRef(II) = 16,1 min; FAB-MS (M+N)+= 792.

Starting material was obtained as follows.

6A) 5(S)- [1(S)-(Boc-amino)-2-(phenylethyl]-3(R)-{[n-(2,6 - dichlorobenzenesulfonyl)phenyl]methyl}dihydrofuran-2-(3H)-he

By analogy with example 5g), 5.0 g (16,34 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-she dissolved in 24 ml of abs. THF and 2.7 ml of DMPU deprotonized 9,67 g (25,4 mmol) n-(2,6-dichlorobenzenesulfonyl)bromide (Maybridge, Tintage/UK) in 50 ml of abs. THF. Protonation at a temperature of -75oC from 6.1 ml (81,7 mmol) of propionic acid and 6.1 ml of water, extraction and column chromatography (SiO2, hexane/ ethyl acetate, 2:1) allow to obtain the crude product, and crystallization from DIPE yields a connection that is specified in the header: TLC Rf(D) = 0,30; tRet(II) = 17,3 min

6b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{ [n- (2,6-dichlorobenzenesulfonyl)phenyl]methyl) hexanoic acid

By analogy with example 5D) 6.7 g (10,83 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-{[n-(2,6-dichlorobenzenesulfonyl)phenyl]methyl} dihydrofuran-2-(3H)-she's in 170 ml of dimethoxyethane hydrolyzing of 43.3 ml of a 1M solution of lithium hydroxide (17 hours at RT). The distribution between the three portions of methylene chloride, a solution of NH4Cl/citric acid and salt solution, followed by stirring the crude product in a simple ether yield specified in the connection header: tRet(II) = 15,5 minutes

6b) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R) - {[n-(2,6-dichlorobenzenesulfonyl)phenyl]methyl} hexanoic acid

By analogy with example 5e) 5.0 g (7.85 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[n-(2,6 - dichlorobenzenesulfonyl)phenyl]methyl}chapralis features of complex salelologa ether using 6.5 g of potassium carbonate in 85 ml of methanol, 22 ml of THF and 22 ml of water allows you to get listed in the title compound after column chromatography (SiO2, hexane/ethyl acetate, 1:1) and stirring with DIPE: TLC Rf) = 0,5; tRet(II) = 21,0 minutes

6g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- { [n-(2,6-dichlorobenzenesulfonyl)phenyl] methyl} hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

200 mg (0.27 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-{ [n-(2,6-dichlorobenzenesulfonyl)phenyl]methyl}Caproic acid and 51.7 mg (0,297 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) are dissolved in 2.6 ml of 0.25 M solution of NMM in CH3CN, process 112,6 mg (0,297 mmol) HBTU for 18 h at

RT under nitrogen atmosphere, followed by processing by analogy with example 5A), getting mentioned in the title compound: TLC Rf(D) = 0,21; tRet(II) = of 21.9 minutes

Example 7: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl) -2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

1,11 g (1.35 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide in 15 ml of DMF desilicious in nitrogen atmosphere of 0.85 g (2,70 mmol) TBAF. After 18 h at RT, the reaction mixture was poured into water and the mixture extracted with methylenechloride. Mixing in DIPE results specified in the title compound: TLC Rf(B) = 0,6; tRet(II) = 16,6 min; FAB-MS (M+H)+= 706.

7a) 5(S)-[1(S)-(Boc-amino)-2- (p-benzyloxyphenyl)ethyl]-3(R)-[(p-methoxyphenyl)methyl] dihydrofuran-2-(3H)-he

By analogy with example 5g), 2.9 g (? 7.04 baby mortality mmol) of 5(S)-[1(S)-(Boc-amino)- 2-(p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-it (getting see example 1G), dissolved in 10.3 ml of THF and 1.2 ml of DMPU, deprotonated at -70oC using a 14.1 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (at temperatures from -75oC to -50oC) 2.6 g (10,57 mmol) p - methoxybenzylidene (receipt see example 7D) in 10 ml of THF. Protonation at -75oC with the help of 2.6 ml (35,2 mmol) of propionic acid and 2.6 ml of water, extraction and column chromatography (SiO2, hexane/ethyl acetate, 2:1) allow to obtain the connection specified in the header: TLC Rf(D) = 0,48; tRet(II) = 18,8 minutes

7b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)- [(p-methoxyphenyl)methyl]hexanoic acid

2.6 g (4,89 mmol) of 5(S)-[1(S)-(Boc-amino)-2- (p-benzyloxyphenyl)ethyl]-3(R)-[(p-methoxyphenyl)methyl] dihydrofuran-2-(3H)- she's in 50 ml of dimethoxyethane hydrolyzing in a protective gas atmosphere N2with the use of 19.6 ml of a 1M solution of Ki is a mixture of 150 ml us. solution of NH4Cl, 25 ml of 10% citric acid solution and methylene chloride. The aqueous phase is separated and extracted twice with methylene chloride. The organic phase is washed with saline, dried in the presence of Na2SO4and evaporated to obtain specified in the title compound: TLC Rf(B) = 0,28; tRet(II) = 16,4 minutes

7b) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl] hexanoic acid

2.5 g (of 4.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p - benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]Caproic acid in 42,0 ml DMF similarbut in a protective gas atmosphere of 3.15 g (of 20.9 mmol) of tert-butyldimethylchlorosilane and 2,53 g (of 37.3 mmol) of imidazole at RT for 20 h, the Reaction mixture was diluted with ethyl acetate and the mixture washed us. a solution of NaHCO3, water and brine. The aqueous phase is extracted twice with ethyl acetate and the organic phases are dried in the presence of Na2SO4and evaporated. The residue is dissolved in 50 ml of methanol and 13 ml of THF, and this solution is treated with 3.8 g2CO3and 13 ml of water, then stirred at RT for 1 h, the Reaction mixture was then partially evaporated and the residue diluted with 10% chilled on ice with a solution of citric acid; then see who shat in the presence of Na2SO4and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 2: 1) allows to obtain the purified compound indicated in the title: TLC Rf(C) = 0,13; tRet(II) = 21,7 minutes

7G) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide

960 mg (1.44 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[(p-methoxyphenyl)methyl] Caproic acid and 290 mg (from 1.66 mmol) N-(L)-Val-N-(2-methoxyethyl)amide (example 1B) in 14.5 ml of 0.25 M NMM/CH3CN is subjected to interaction at RT for 20 h in nitrogen atmosphere with 630 mg (from 1.66 mmol) of HBTU. The mixture is evaporated and the residue is dissolved in ethyl acetate; the solution is washed with water, 2 times with 10% citric acid solution, once with water, twice us. a solution of NaHCO3, water and finally brine. The aqueous phase is extracted twice with ethyl acetate, and the organic phase is dried with Na2SO4and evaporated. Boiling the crude product in hexane allows you to get the connection specified in the header: TLC Rf(B) = 0,70; tRet(II) = 22,5 minutes

7D) p-methoxybenzamide

A solution of 1.7 ml (12.8 mmol) of 4-methoxybenzylamine (Fluka; Buchs/Switzerland) in 25 ml of acetone, peremeshivayte completed; this reaction mixture is poured into ether and the mixture washed with 10% sodium thiosulfate solution and brine. Drying the organic phase with Na2SO4and evaporation lead to the connection specified in the header: 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 (2 m, each 2H).

Example 8: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p - hydroxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

Hydrogenation of 500 mg (0,708 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(p - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 7) under reduced pressure in 33 ml of methanol in the presence of 0.11 g of 10% Pd/C leads to obtain, after filtration of the catalyst, evaporation of the filtrate and digestion with DIPE, specified in the title compound: TLC Rf(B) = 0,53; tRet(II) = 12,2 min; FAB-MS (M+H)+= 616.

Example 9: 5(S)-(Boc-amino)-4(S)-hydroxy-6- (p-methoxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

100 mg (rate £ 0.162 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[(p - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 8) in 3 ml of DMF/dioxane, 1:1, is treated at 0oC in nitrogen atmosphere 105 mg (0,324 mmol) Cs2CO3and the camping was poured into water and extracted with 3 portions of methylene chloride. The organic phase is washed with water and saline, dried in the presence of Na2SO4and evaporated. Mixing in DIPE in the bath with sonication results specified in the title compound: TLC Rf(B) = 0,62; tRet(II) = 14,2 min; FAB-MS (M+H)+= 630.

Example 10: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-isobutoxy)- phenyl)-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl) amide

100 mg (rate £ 0.162 mmol) of 5(S)-(Boc - amino)-4(8)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[(p - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 8) in 3 ml of DMF/dioxane, 1:1, is treated at 0oC in an atmosphere of protective gas 105 mg (0,324 mmol) Cs2CO3and 18.7 μl (rate £ 0.162 mmol) isobutylidene, after which the mixture was stirred at 50oC for 16 hours So as GHUR shows that starting material still present in the mixture, 5 equivalents of isobutylidene and 10 equivalents Cs2CO3add portions. After addition of each portion of the mixture stirred at 50oC for one day before until GHUR will show that all the number 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)- [(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide reacted. Processing by analogy with example 9 provides

Example 11: 5(S)-(Boc-amino)-4(S)-hydroxy-6- (p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

2,07 g (2,90 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6- (p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in 50 ml of DMF desilicious in nitrogen atmosphere to 1.83 g (5,80 mmol) TBAF. After 18 h the reaction mixture was poured into water and this mixture is extracted with 4 portions of ethyl acetate. The organic phase is washed us. a solution of NaHCO3, water and saline, dried with Na2SO4and evaporated. The stirring twice in DIPE results specified in the connection header: tRet(II) = 14,2 min; FAB-MS (M+N)+= 600.

Starting material was obtained as follows.

11a) 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl] dihydrofuran-2-(3H)-he

A suspension of 4.00 g (to 12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p - hydroxyphenyl)ethyl] dihydrofuran-2-(3H)-it (example 11e) in 240 ml of DMF/dioxane, 1:1, is treated in the nitrogen atmosphere of 8.1 g (are 24.88 mmol) Cs2CO3and 0.77 ml (to 12.44 mmol) under the conditions. After 18 h, the reaction mixture was poured into 190 ml of ice water and extracted with 3 portions of methylene chloride.

The organic phase is washed with water and saline, dried in the presence of Na2SO4and evaporated. Perenia: TLC Rf(C) = 0,43; tRet(II) = 13,5 min; FAB-MS (M+H)+= 336.

11b) 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl] -3(R)-(phenylmethyl)dihydrofuran-2-(3H)-he

By analogy with example 5g), of 4.17 g (to 12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl] dihydrofuran-2- (3H)-she dissolved in 22.4 ml of THF and 2.5 ml of DMPU, deprotonated at -70oC with the use of 24.0 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (-75oC, 1 h) 1.5 ml (to 12.44 mmol) benzylbromide. Protonation at a temperature of -75oC to 4.6 ml of propionic acid and 4.6 ml of water, extraction and column chromatography (SiO2, methylene chloride/simple ether, 25: 1) allow to obtain specified in the title compound: TLC Rf(C) = 0,74; tRet(II) = 16,6 min; FAB-MS (M+H)+= 426.

11b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)- (phenylmethyl) hexanoic acid

3.00 g (7.05 mmol) of 5(S)-[1(S)-(Boc-amino)-2- (p-methoxyphenyl)ethyl]-3(R)-(phenylmethyl)dihydrofuran-2-(3H)-she's in 112 ml of dimethoxyethane and 57 ml of water hydrolyzing in a protective gas atmosphere 28 ml of a 1M solution of lithium hydroxide. After 20 h exposure at RT, the reaction mixture was poured into chilled on ice, the mixture of 340 ml us. solution of NH4Cl, 28 ml of 10% solution of citric acid and 140 ml of methylene chloride. Methanol is added to the full rustoleum solution dried in the presence of Na2SO4and evaporated to obtain specified in the connection header: tRet= 14,0 min; FAB-MS (M+N)+= 444.

11g) 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R) - (phenylmethyl) hexanoic acid

2.9 g (6,54 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl), Caproic acid, 7.0 ml of DMF similarbut in a protective gas atmosphere 4.5 g (30 mmol) of tert-butyldimethylchlorosilane and the 3.65 g (53.6 mmol) of imidazole at RT for 20 h, the Reaction mixture was poured into 500 ml ice water and the mixture extracted with 3 portions of ethyl acetate; the organic phase washed with 10% citric acid solution, 2 times with water and saline, dried in the presence of Na2SO4and evaporated. Hydrolysis of the residue in 80 ml of methanol and 30 ml of THF using a 5.4 g of potassium carbonate and 30 ml of water, treatment after 3 h by analogy with example 7b) and column chromatography (SiO2, hexane/ethyl acetate, 2: 1) allow to obtain the purified compound indicated in the title: TLC Rf(D) = 0,13; tRet(II) = 20,3 minutes

11) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy - 6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

1.56 g (2.8 mmol) of 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyl is) in 27 ml of 0.25 M solution of NMM in CH3CN process of 1.17 g (3,09 mmol) HBTU for 20 h at RT under nitrogen atmosphere, followed by processing by analogy with example 5A), receiving specified in the header connection: tRet(II) = 21,1 min; FAB-MS (M+N)+= 714.

11e) 5(S)-[1(S)-(Boc-amino)-2- (p-hydroxyphenyl)ethyl] dihydrofuran-2-(3H)-he

Hydrogenation of 3.0 g (7,29 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] dihydrofuran-2-(3H)-she (receive, see example 1G) in 100 ml of methanol using 0.6 g of 10% Pd/C results, after filtering off the catalyst and evaporation of the filtrate indicated in the connection header: tRet(II) = 10,6 minutes

Example 12: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In an argon atmosphere 115,6 g (160,5 mmol) of 5(S)- (Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexane-2(R)- [(p-methoxyphenyl)methyl] -hexanoyl-(L)-Val-N-(2-methoxyethyl)amide are dissolved in 650 ml of DMF, and the solution process of 101.3 g (321 mmol) TBAF. After 20 h exposure at RT, the reaction mixture was poured into 1 kg of ice and 500 ml of ethyl acetate, the aqueous phase is separated and extracted with 2 portions of 500 ml of ethyl acetate in each case. The organic phase is washed with twice 500 ml of water, 500 ml us. solution of NaHCO3, 500 ml of water and 500 ml of salawag the Finance result stated in the title compound: TLC Rf(A) = 0,35; tRet(ll) = 17,1 min; FAB-MS (M+H)+= 606. IR (KBr): inter alia, 3328c, 2922c, 1685c, 1650c, 1622c, 1531c, 1512c, altitude: 1448m, 1390m, 1365m, 1246c, 1174c.

Starting material was obtained as follows.

12A) 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl] dihydrofuran-2-(3H)-he

The solution 122,2 g (400 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-she (receive, see example 2B) in 1500 ml of methanol hydronaut at RT and reduced pressure in the presence of 4.0 g of Nishimura catalyst [monohydrate Rh(III) and Pt(IV)-oxide, Degussa]. The filtering off the catalyst and evaporation of the filtrate yield specified in the title compound: TLC Rf(D) = 0,54; FAB-MS (M+N)+= 312.

12B) 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl] -3(R)-[(p - methoxyphenyl)methyl]dihydrofuran-2-(3H)-he

880 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF is added dropwise at -70oC in argon atmosphere and within 20 min to 130 g (400 mmol) of 5(S)-[1(S)-(Boc-amino)-2 - cyclohexylethyl]dihydrofuran - 2-(3H)-she dissolved in 1000 ml of abs. THF and 108 ml of DMPU. After 20 min, add dropwise a solution of 110 g (443 mmol) p - methoxybenzylidene (see getting in example 7D) in 60 ml of abs. THF and the mixture was thoroughly stirred at -75oC for 2 hours the mixture is Then protonium at -70oC with 152 ml of propionic acid and 2 l of a 15% aqueous solution of NaHCO3. The aqueous phase is separated and extracted with 1 l of ethyl acetate. The organic phase is washed twice with us. a solution of NaHCO3, water and saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 9:1) and crystallization from hexane allow you to get purified the connection specified in the header: TLC Rf(E) = 0,45; tRet(II) = 18,6 min; FAB-MS (M+H)+= 432.

12V) 5(S)-(Boc-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p - methoxyphenyl)methyl]hexanoic acid

To a solution of 103 g (239 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl] -3(R)- [(p-methoxyphenyl)methyl] dihydrofuran-2-(3H)-she's in 800 ml of 1,2-dimethoxyethane add 1000 ml of 1M aqueous LiOH solution in a protective gas atmosphere. After 3 hours of stirring at RT the reaction solution was poured into a chilled on ice, a mixture of 1.5 liters of us. solution of NH4Cl, 1 l of a solution of 10% citric acid and 2 l of simple ether. The aqueous phase is separated and extracted twice 1 l simple ether in each case. The organic phase is washed 4 times with ice water and 1 time with saline, dried with Na2SO4, evaporated and get listed in the title compound from the organic phase: tRet(II) = 16,0 min; FAB-MS (M+N)+= 450.

12g) 5(S)-(BOC,95 mol) of imidazole and 164 g (of 1.09 mol) of tert - butyldimethylchlorosilane add in an argon atmosphere to a cooled on ice to a solution of 124 g (238 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(n-methoxyphenyl)methyl] Caproic acid in 800 ml of DMF. After 17 h of exposure at RT the reaction mixture was poured in 1.9 l of ice water and the mixture extracted with 3 portions 0.8 l of ethyl acetate in each case; the organic phase is washed with water, us. a solution of NaHCO3, water, 10% citric acid solution, water and saline, dried in the presence of Na2SO4and evaporated. The residue is dissolved in 700 ml of methanol and 175 ml of THF and to this solution was added 175 g2CO3in 820 ml of water and stirred at RT for 1 h, the resulting emulsion is partially evaporated on RE and the residue diluted with ice water, after which the resulting mixture is acidified to pH 4 with 10% citric acid solution under vigorous stirring. The mixture is extracted with 3 portions of ethyl acetate; the organic phase is washed with water and saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2, hexane--->hexane/ethyl acetate, 95: 5--->9:1--->2:1--->1:1) results in the connection specified in the header: TLC Rf(E) = 0,15; tRet(II) = 22,7 minutes

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L) - Val-N-(2-methoxyethyl)amide

the 33.2 g (190 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) in 100 ml of DMF to the l)methyl]Caproic acid in 600 ml of DMF and the mixture is cooled to 10oC. Then add 31,1 ml (93% purity, 190 mmol) diethylthiophosphate (Aldrich; Milwaukee, USA) and 60,4 ml (432 mmol) of triethylamine. After 1 h exposure at RT, the reaction mixture was poured into 1.5 l of ice water and the mixture extracted with 3 portions of 0.5 l of ethyl acetate in each case; an ethyl acetate phase is washed 2 times with water, us. a solution of NaHCO3, water, 10% citric acid solution, water and saline, dried in the presence of Na2SO4and evaporated. Stirring in 2 l of hexane at 50oC, cooling to 5oC and filtration yield the purified compounds specified in the header: TLC Rf(A) = 0,7; TLC Rf(J) = 0,2; tRet(II) = 23,8 min; FAB-MS (M+H)+= 720.

Example 13: 5(S)-{ [1-ethoxycarbonylpyrimidine-4-yl)carbonyl] amino} -4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Chilled on ice, a solution of 250 mg (0,461 mmol) of 5(S)-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(n - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (hydrochloric salt) in 3.5 ml of THF in a nitrogen atmosphere is treated with 212 μl (1.15 mmol) of triethylamine and a solution of 101 mg (0,461 mmol) (1-ethoxycarbonylpyrimidine-4-yl)carbonylchloride (see example 136), this mixture is heated to RT. After 2 h reacciona is the target NaHCO3and brine, dried with Na2SO4and evaporated; the residue is boiled in DIPE, obtaining specified in the title compound: TLC Rf(B) = 0,39; tRet(II) = 14,4 min; FAB-MS (M+H)+= 689.

Starting material was obtained as follows.

13A) 5(S)-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (hydrochloric salt)

43,8 g (72,3 mmol) of 5(S)-(Boc-amino)- 4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 12) process, eliminating moisture and cooling with ice, using 250 ml of 3.8 M HCL/dioxane, and this mixture is stirred for 2 hours Then the reaction mixture is evaporated on RE and the residue is dissolved in 600 ml of dioxane, and the solution lyophilizer. Mixing freeze-dried 1 l simple ether, filtering and re-mixing in 0.7 l of ethyl acetate, followed by filtering results specified in the connection header: tRet(II) = a 10.1 min; FAB-MS (M+N)+= 506; anal. the calc.: With 60,94%, H 8,96%, N To 7.61%, Cl 6.42 per cent, H2O 1,76%; anal. calc.: With 60,7%, H 9,0%, N 7,7%, Cl 6,8%, H2O 1,76%. The second filtrate (ethyl acetate) evaporated and the residue is dissolved in ethyl acetate; this solution is washed us. a solution of NaHCO3, water and ska allows you to get 5(S)-[1(S)-amino-2-cyclohexylethyl]-3(R)-[(p-methoxyphenyl) methyl] dihydrofuran-2- (3H)-it: tRet(II) = 11,3 min; FAB-MS (M+N)+= 332; IR (CH2Cl2): inter alia 3390 cm., S, m, s, m, s, s, s, m.

13B) 4-chlorocarbonyl-1-ethoxycarbonylpyrimidine

The solution 578,2 g of 4-carboxy-1-ethoxycarbonylpyrimidine in 1200 ml of toluene is treated first, using 1.0 g of N,N-dimethylformamide, and then at 68 - 70oC for 2 h 369,0 g of thionyl chloride. The mixture is then stirred at 70oC for 30 min, after which the toluene is distilled off in vacuum and the residue obzharivayut in HV (high vacuum) at RT for approximately 30 min in HV. This results specified in the connection header in the form of a light yellow oil [IR (film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1. The product distills without decomposition at the melting temperature of 96-98oC (pressure of 0.08-0.09 mm RT.cent.).

13B) 4-carboxy-1-ethoxycarbonylpyrimidine

4-Carboxy-1-ethoxycarbonylpyrimidine derived from piperidine-4 - carboxylic acid (Aldrich, Steinheim, Germany), for example, by reacting piperidine-4-carboxylic acid with etelcharge.com in an aqueous solution of sodium hydroxide for 2 h at 0-5oC. Specified in the title compound is extracted from the aqueous phase by shaking with toluene. Toluene phase, sideradougou further use.

Example 14

The following connections receive by analogy with one of the examples presented above or below.

I) 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2(R)-[(o-fluoro-p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

II) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-fluoro-o - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

III) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o-hydroxy-p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

IV) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl) -2(R)-(cyclohexylmethyl)hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

80 mg (0,132 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-methoxyphenyl)-2(R)-[(cyclohexen-1-yl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 14V) in 4 ml of ethanol/ethyl acetate, 3:1, hydronaut in the presence of 40 mg of 5% Pd/C and at normal pressure. The filtering off the catalyst, washing the residue with methylene chloride/methanol and evaporation of the filtrate allow you to receive a relatively large amount of crystalline product in crude form, which is dissolved in methylene chloride/methanol, treated with silica gel and dried. Loading powder into a column with silica gel and elution with a mixture of methylene chloride/eteltetet/ethanol, 30:20:1, yield specified in the header is methoxyphenyl) -2(R)-(cyclohexen-1-ylmethyl)hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

In a protective gas atmosphere 344 mg (0,479 mmol) of 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6- (p-methoxyphenyl)-2(R)-[(cyclohexen-1-yl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide is dissolved in 9.9 ml of DMF, and this solution process 302 mg (0,958 mmol) TBAF. After 15 h of exposure at RT, the reaction mixture was poured into 160 ml of water and the mixture extracted with 3 portions of ethyl acetate. The organic phase is washed twice with us. a solution of NaHCO3and brine, dried with Na2SO4and evaporated. Boiling with DIPE results specified in the title compound: TLC Rf(O) = 0,56; TLC Rf(P) = 0,28; tRet(II) = 15,4 min; FAB-MS (M+N)+= 604.

Starting material was obtained as follows.

14 Va) Cyclohexenyl-1-ylmethanol

In a protective gas atmosphere a solution of 8.0 g (55.3 mmol) of 1-cyclohexanecarbonitrile (Pfaltz &Bauer, Waterbury, USA) in 168 ml of a simple ether cooled to -20oC and treated with 2.35 g (62 mmol) of lithium aluminum hydride. After stirring the mixture at -16oC for 1 h 256 ml of ethyl acetate is added dropwise (exothermic reaction) followed by the addition of 76 ml of 2 n NaOH solution. The mixture was stirred at RT for 30 min, add 160 g Na2SO4and the mixture is filtered. Na2SO4we use the one to receive the specified header connection:1H-NMR (200 MHz, CDCl3): 1,60 (m, 5H), from 2.00 (m, 2H2Callyl), of 3.97 (s, H2C-OH), to 5.66 (s, HColefin).

14 V) Cyclohexen-1-iletileri

A solution of 6.2 g (55.3 mmol) cyclohexen-1-ylmethanol in 800 ml of methylene chloride is treated at 0oC 27.5 g (83 mmol) of tetrabromomethane and 21.7 g (83 mmol) of triphenylphosphine. After 35 min the mixture was evaporated to RE in mild conditions. The residue was washed with 5 portions of pentane 40 ml each time. The combined pentane phase yield specified in the title compound after evaporation and distillation with ball refrigerator (140-160oC, 20 mbar):1H-NMR (200 MHz, CDCl3): 1,6 (m, 2 H2C) to 2.1 (m, 2H2allyl), 3,93 (s, H2C-Br), 5,88 (m, HColefin);13C-NMR (CDCl3): 22,3, 22,9, 25,9, 26,8 (4 CH2), 40,4 (CH2-Br), of 128.6, 135,1 (2 Colefin).

14 V) 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]-3(R)- [(cyclohexen-1-yl)methyl]dihydrofuran-2(3H)-he

The solution 6,36 g (of 18.9 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]dihydrofuran-2-(3H)-it (getting see example 11a) in 34 ml of abs. THF and 3.8 ml of DMPU process at -75oC and under nitrogen atmosphere, to 36.5 ml of 1M solution of bis(trimethylsilyl) amide lithium in THF (Aldrich). After 15 min added dropwise a solution of 3.3 g (of 18.9 mmol) cyclohexen-1 ileti the 7 ml of propionic acid and 7 ml of water are successively added at -75oC. the Reaction mixture is heated to 0oC and poured into 190 ml of ethyl acetate and 100 ml of 10% citric acid solution, whereupon the mixture is stirred for 5 minutes, the organic phase is separated and washed with saturated sodium bicarbonate solution and saline. The aqueous phase re-extracted 2 times with ethyl acetate and the organic phases are dried in the presence of sodium sulphate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 4:1 ---> 3:1) allows to obtain the purified compound indicated in the title: TLC Rf(D) = 0,54; tRet(II) = 18,7 min; FAB-MS (M-Butene+H)+= 430.

14 VG) 5(S)-[1(S)-(Boc-amino)-4(S) -hydroxy-6-(p-methoxyphenyl)-2(R)-[(cyclohexen-1-yl)methyl] hexanoic acid

1,25 g (only 2.91 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-methoxyphenyl)ethyl]-3(R)- [(cyclohexen-1-yl)methyl] dihydrofuran-2-(3H)-she at 43.4 ml dimethoxyethane and 22.1 ml of water hydrolyzing in a protective gas atmosphere in 10.8 ml of a 1M solution of lithium hydroxide. After 15 h the reaction mixture was poured into a chilled on ice, a mixture of 140 ml us. solution of NH4Cl, 12 ml of 10% citric acid solution and 58 ml of methylene chloride. The aqueous phase is separated and twice extracted with 2 portions of methylene chloride. The organic phase is washed with saline, dried in prisutstvie-butyldimethylsilyloxy)-6- (p-methoxyphenyl)-2(R)-[(cyclohexen-1-yl)methyl]hexanoic acid

1.19 g (2,66 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p - methoxyphenyl)-2(R)-[(cyclohexen-1-yl)methyl] Caproic acid dissolved in 2.9 ml of DMF in a protective gas atmosphere, and the solution is treated with 1.84 g (12.2 mmol) of tert-butyldimethylchlorosilane and 1.48 g (to 21.8 mmol)of imidazole at RT for 16 h, the Reaction mixture was poured into 200 ml ice water and the mixture extracted with 3 portions of ethyl acetate; the organic phase was washed with 10% citric acid solution, 2 times with water and saline, dried in the presence of Na2SO4and evaporated. The residue is dissolved in 32 ml of methanol and 12 ml of THF, and this solution is treated with 2.2 g2CO3and 12 ml of water, then stirred at RT for 3 h, the Reaction mixture was then partially evaporated on RE and the residue poured into a chilled on ice for 10% citric acid solution, after which the mixture is extracted with 3 portions of ethyl acetate; the organic phase is washed twice with water and once with saline, dried in the presence of Na2SO4and evaporated to obtain the connection specified in the header: TLC Rf(D) = 0,37; tRet(II) = 22,8 minutes

14 Ve) 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-(p-methoxyphenyl)-2(R)-[(cyclohexen - 1-yl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In the atmosphere Sapronova acid and 117 mg (0,674 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) are dissolved in 6.0 ml of 0.25 M NMM/CH3CN and add 255,5 mg (0,674 mmol) of HBTU. After 17 h of exposure at RT, the reaction mixture was evaporated in HV and the residue is dissolved in ethyl acetate; the solution is washed with water, twice with a solution of 10% citric acid, twice us. a solution of NaHCO3and finally brine. The aqueous phase is extracted with two portions of ethyl acetate and the combined organic phases are dried with Na2SO4obtaining specified in the connection header: tRet(II) = 23,3 minutes

Example 15: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl - 2(R)-[(4-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 1, 0.35 g (0.44 mmol) of 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] hexanoyl-(L)- Val-N-(2-methoxyethyl)amide in 3.0 ml of DMF are subjected to interaction with 0,278 g (0.88 mmol) of three-hydrate TBAF obtaining specified in the connection header. Processing, mixing with simple diethyl ether and filtration yield the purified compounds specified in the header: TLC Rf(B) = 0,52; tRet(II) = 18,06 min; FAB-MS (M+H)+= 682.

15a) 3 (R)-[(4-benzyloxyphenyl)methyl]-5(S)-[1(S)-(Boc-amino) -2-cyclohexylethyl]dihydrofuran-2-he

By analogy with example 5 g of 5.2 g (of 16.7 mmol) of 5(S)-[1(S)-(Boc-amino-2-cyclo is ml 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate at -75oC for 1 h to 5.2 g (16,07 mmol) of 4-benzyloxybenzaldehyde (receipt see example 1 g) in 15 ml THF. Processing at -75oC using a 6.2 ml (83,02 mmol) of propionic acid and water and subsequent processing allow to obtain, after column chromatography (SiO2, hexane/ethyl acetate, 4:1) cleaned the connection specified in the header: TLC Rf(hexane/ethyl acetate: 4:1) = 0,27; tRet(II) = 20,41 minutes

15B) 5(S)-(Boc-amino)-4(S) -hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] hexanoic acid

2.4 g (4,278 mmol) of 3(R)-[(4-benzyloxyphenyl)methyl]-5(S)-[1(S)-(Boc-amino)-2 - cyclohexylethyl] dihydrofuran-2-it in 10 ml of dimethoxyethane hydrolyzing in a protective gas atmosphere to 9.45 ml of 1M solution of lithium hydroxide. After 17 h of exposure at RT, the reaction mixture is treated with chilled on ice with a mixture of 324 ml us. solution of NH4Cl, 27 ml of a 10% aqueous citric acid solution and 134 ml of methylene chloride. Methanol is added to dissolve the product. The aqueous phase is separated and twice extracted with 2 portions of methylene chloride. The organic phase is washed with saline, dried in the presence of Na2SO4and evaporated. The crude product is purified column chromatography (SiO2, eluent C) obtaining specified in the header is connected is siloxy) -6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] hexanoic acid

By analogy with example 5e) 28.8 g (of 54.8 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2R- [(4-benzyloxyphenyl)methyl] Caproic acid in 288 ml of DMF in turn specified in the header connection using a 35.8 g (237,6 mmol) of tert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. Connection purified column chromatography (SiO2, hexane/ethyl acetate, 4:1-1:1); TLC Rf(E) = 0,34; tRet(gradient from 75 to 100% (a) and (b) within a period of 20 min) = 25,06 min; FAB-MS (M+N)+= 526.

15g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoyl-(L)- Val-N-(2-methoxyethyl)amide

By analogy with example d a solution of 3 g (to 18.7 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide and 10 g (15.6 mmol) of 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl) methyl]Caproic acid in 50 ml of DMF is cooled to a temperature of 5oC in an ice bath and treated with 2.9 ml (17,2 mmol) diethylthiophosphate, and then 5.5 ml of triethylamine. After stirring at RT the reaction mixture was poured into water and the mixture extracted with 3 portions of ethyl acetate; the combined organic phases are washed with water, 2 times us. a solution of NaHCO3and saline, dried in the presence of Na2SO4and concentrate under the title: TLC Rf(A) = 0.56, tRet(B) = 24,82 min; FAB-MS(M+H)+= 796.

Example 16: 5(S)-(Boc-amino)-4(S) -hydroxy-6-cyclohexyl-2(R)-[(4-hydroxyphenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide

By analogy with example 1, 0,547 g (0,775 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-cyclohexyl-2(R)-[(4-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5.0 ml DMF is subjected to interaction with 0,488 g (1,549 mmol) of three-hydrate TBAF obtaining specified in the connection header. Processing, mixing with simple diethyl ether and filtration yield the purified compounds specified in the header: TLC Rf(B) = 0,37; tRet(II) = 14,44 min; FAB-MS (M+H)+= 592.

The original connection was obtained as follows.

16A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-cyclohexyl-2(R)-[(4-hydroxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

0.64 g (0,804 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butultimately-silyloxy)-6-cyclohexyl-2(R)-[4- (benzyloxy)phenylmethyl] hexanoyl-(L)-Val-N-(2-methoxyethyl) amide in 20 ml of methanol hydronaut in the presence of 0.32 g of 10% Pd/C. a Named connection, which is obtained after filtering off the catalyst and evaporation of the filtrate, without additional purification is subjected to subsequent prevremeni logiciel-2(R) - [(4-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 1, 0.6 g (0,833 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(4 - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 5.0 ml DMF is subjected to interaction with 0,526 g (1,67 mmol) of three-hydrate TBAF obtaining specified in the connection header. Processing, mixing with simple diethyl ether and filtration yield the purified compounds specified in the header: TLC Rf(A) = 0,45; tRet(II) = 16,14 min; FAB-MS (M+H)+= 606.

The original connection was obtained as follows.

17A) 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R) - [(4-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

A solution of 0.75 g (1.06 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R) - [(4-hydroxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in 25 ml of dioxane is treated at 1,384 g (of 4.25 mmol) Cs2CO3and after 1 h 2,07 ml (21,24 mmol) under the conditions, after which the mixture was stirred at RT for 16 h, the precipitate is filtered and washed with ethyl acetate. The filtrate is washed successively with water, saturated sodium bicarbonate solution and saline. After drying in prisutstsovat, getting listed in the title compound: TLC Rf(J) or = 0.6; tRet(II) = 23,65 min; FAB-MS (M+N)+= 720.

Example 18: 5(S)-(2,2,2-cryptgetkeyparam)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(4-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

400 mg (0,791 mmol) of 5(S)-amino-4(S)-(hydroxy)-6-cyclohexyl - 2(R)-[(4-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in 5.0 ml DMF is treated at 0oC 0,276 ml (1.97 mmol) of triethylamine and rate of 0.193 g (1,186 mmol) triftoratsetata (US 3852464). After stirring for 10 min the reaction mixture was poured into water and extracted 3 times with ethyl acetate. The combined extracts are washed with aqueous saturated sodium bicarbonate solution and saline, dried in the presence of sodium sulfate and concentrate under reduced pressure. The residue is crystallized from a mixture of ethyl acetate/simple diethyl ether to obtain specified in the title compound: TLC Rf(B) = 0,78; tRet(II) = 15,36 min; FAB-MS (M+H)+= 632.

The original connection was obtained as follows.

18a) 5(S)-amino-4(S)-(hydroxy) -6-cyclohexyl-2(R)-[(4-methoxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

of 2.27 g (3,747 mmol) of 5(S)-(Boc-amino)-4 (S)-(hydroxy)-6-cyclohexyl-2(R)-[(4-methoxyphenyl)methyl] hexaoC. After stirring at RT for 2 h, the reaction mixture was evaporated and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase is washed again with saturated aqueous sodium bicarbonate solution and brine and evaporated to dryness. The residue is boiled with simple ether and then chromatographic (SiO2, methylene chloride/methanol: 9:1-1:1), obtaining mentioned in the title compound: TLC Rf(B) = 0,43; tRet(II) = 10,23 min; FAB-MS (M+H)+= 506.

Example 19: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- (phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 1 of 0.82 g (1,19 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- phenylmethanol-(L)-Val-N-(2-methoxyethyl)amide in 12.0 ml of DMF is subjected to interaction with 0,756 g (of 2.38 mmol) of three-hydrate TBAF obtaining specified in the connection header. Processing, mixing with simple diethyl ether and filtration yield the purified compounds specified in the header: TLC Rf(A) = 0,37; tRet(II) = 14,58 min; FAB-MS (M+N)+= 570.

The original connection was obtained as follows.

19a) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2- (3H)-he

(see example 2B) (see also A. E. g. Synth., Coll. Vol.5, 855 (1973)) and 280 ml of dimethylacetamide is added in nitrogen atmosphere to a solution of 375 g (of 1.65 mol) of ethyl-2-iodopropionic (example 1l) in 1700 ml of toluene and the mixture was thoroughly stirred at RT for 1 h at 80oC for 4 h to obtain a solution homoeopath zinc. In the second apparatus (nitrogen atmosphere) solution of 122 ml (0.40 mol) of tetraisopropyldisiloxane in 350 ml of toluene and 1900 ml of methylene chloride is treated with a slight cooling and when the internal temperature of 15-25oC 127 ml (1,14 mol) TiCl4; this mixture was stirred at RT for 15 min (get yellow solution) and cooled to -40oC (receiving partial crystallization of isopropoxide of trichlorethane). A solution of Zn-homoeopath, cooled to RT, filtered in an atmosphere of argon through a glass Frit G3 and added dropwise to isopropoxide of trichlorethane, while the temperature of the support -30oC -25oC (the solution is dark red). The mixture is heated to -25oC for 5 min and then cooled again to -40oC. and Then added dropwise a solution of 233 g (0.85 mol) of (S)-N-Boc-phenylalanine (receipt, see D. J. Kempf, J. Org. Chem. 51, 3921, 1986), then crystallized from hexane (oC for approximately 18 h), washed with cold hexane and dried in 1500 ml methylenchlorid mesh extracted with 10 l of ice water and 12 l of tert-butyl methyl ether, then the mixture was thoroughly stirred for 7-10 minutes. The aqueous phase is separated and extracted with 2 portions of 10 l of ether; the organic phases are washed with 8 liters of water, 8 l of us. solution of acid sodium carbonate, 8 l of water and 5 l of salt solution, dried with sodium sulfate and evaporated. As an intermediate connection get crystalline ethyl 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenylhexanoic. This intermediate compound is heated at 100oC for 2.5 h at 6500 ml of toluene and 230 ml of acetic acid. After cooling, the reaction mixture is poured with stirring into 6 liters of ice water and the aqueous phase is separated and extracted with 2 portions and 2000 ml of toluene; the organic phase is washed with 5 l of a saturated solution of acid sodium carbonate, 5 l of a 40% aqueous solution of acidic semitecolo sodium, 4 l of water, 4 l of saline solution and dried with sodium sulfate. Evaporation of the organic phase to balance weight of approximately 300 g and processing of the last 800 ml of hexane (with careful stirring for several hours) enables you to obtain crystalline lactone, IHVR which shows a content of approximately 10% (5R) epimer (TLCf(E) = 0,08; tRet(II) = 18,8 min). This substance is used at the next stage. Column chromatographie) = 0,14; tRet(II) = 19,2 min; []D= 17,7o(C=1; ethanol).

19b) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-fenilmetilketenom-2-(3H)-he

(see also A. K. Ghosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500 (1991))

Under nitrogen atmosphere a solution of 1934 (6,32 mol) of 5(S)-[1(S)-(Boc-amino)-2-feneley] dihydrofuran-2-(3H)-she 12.0 l of THF and 1.9 l of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone cooled to -75oC and treated when the internal temperature (the temperature of the reaction mixture below -70oC 14000 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich) and the mixture is then stirred at -75oC for 20 min for 1 h added dropwise 835 ml (7,00 mol) of benzylbromide, while the temperature of the reaction mixture does not support above -70oC. the mixture is Then thoroughly stirred at -75oC for 30 minutes Then 2320 ml propionic acid (90 min) and 232 ml of water (1 h) are sequentially added to a clear solution, while the temperature was raised to -10oC. the Reaction mixture was poured into 30 l of ethyl acetate and 35 l of 10% aqueous citric acid solution, after which the aqueous phase is separated and re-extracted 2 times with 10 l of ethyl acetate. The organic phase is washed three times 12 l of a saturated solution of sodium bicarbonate, 20 l of salt solution and twice with 20 l of water, after Celina 5 l Filtering one stripped off of the residue through a column of 4 kg of silica gel Merck (0,063 - 0,200 mm), washing the toluene and crystallization of the crude product from hexane (4 l of hexane to 1 kg of the crude product) allow to obtain the purified compound indicated in the title: TLC Rf(D) = 0,54; FAB-MS (M+N)+= 414.

19c) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylsulphonyl acid

A solution of 17.6 g of 5(S)- [1(S)-(Boc-amino) -2-phenylethyl]-3(R)-fenilmetilketenom-2-(3H)-she 710 ml dimethylethylenediamine ether and 352 ml of water is treated dropwise at 20oC for 10 min to 176 ml of a 1M solution of lithium hydroxide. After 1.5 h stirring the reaction mixture at RT the solvent is evaporated. The residue is poured into 1 l of cold 10% citric acid solution and the acid solution is extracted 3 times with 800 ml of ethyl acetate in each case. The combined extracts washed first with 800 ml water, and then 800 ml of saline solution. Then the organic solution is dried in the presence of Na2SO4and the solvent is distilled off. The crude compound indicated in the title, use at a later stage without additional purification. FAB-MS (M+N)+= 414.

19g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-phenylmethylsulphonyl key is under stirring 10 g of tert-butyldimethylchlorosilane and 8 g of imidazole. After stirring at RT for 18 h yellow clear solution was poured into ice water and the mixture extracted with 3 portions of 250 ml of ethyl acetate; the combined extracts are washed successively 3 times with 10% citric acid solution, 1 times with water, 3 times with aqueous saturated sodium bicarbonate solution, 1 times with water and finally brine, is dried in the presence of Na2SO4and the solvent evaporated. Then the obtained 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, then stirred at RT for 3 h, the Reaction mixture was then poured into water and the mixture extracted three times with simple ether. The collected ether extracts are washed twice with water and once with saline and dried in the presence of Na2SO4. After concentration the crude product is purified column chromatography (SiO2, hexane/ethyl acetate, 3,5: 1,5) to obtain the compound indicated in the title: TLC Rf(D) = 0,37; FAB-MS (M+N)+= 528.

19D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy - 6-phenyl-2 (R)-phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 1.25 g (2 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)capanaparoriver at RT for 30 min 0,208 ml (2,42 mmol) of (L)- Val-N-(2-methoxyethyl)amide. After stirring at RT for 5.5 h the mixture was poured into 300 ml of water and extracted with 3 portions of ethyl acetate; the combined organic phases are washed with water, 2 times us. a solution of NaHCO3and saline, dried in the presence of Na2SO4and concentrate under reduced pressure. After column chromatography (SiO2from D to A) get cleaned the connection specified in the header: TLC Rf(C) = 0,23.

Example 20: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- (phenylmethyl)hexanoyl-(L)-[(cyclohexyl) GIv-N-(2-methoxyethyl)amide

By analogy with example 1, 0.96 g (of 1.33 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- (phenylmethyl)hexanoyl-(L)-(cyclohexyl) Gly-N-(2 - methoxyethyl)amide in 33 ml of DMF is subjected to interaction with 0,836 g (2,66 mmol) of three-hydrate TBAF obtaining specified in the connection header. Treatment and column chromatography (SiO2from D to A) results in the connection specified in the header: TLC Rf(A) = 0,5; tRet(II) = 15,92 min; FAB-MS (M+H)+= 610.

The original connection was obtained as follows.

20A) N-Boc-(L)-(cyclohexyl)glycine

of 2.51 g (10 mmol) of Boc-(L)-phenylglycine (Fluka, Buchs, Switzerland) hydronaut at RT for 1 h under standard pressure in 50 ml of methanol is Privat and the resulting product, specified in the header, used in the subsequent stage without further purification: TLC Rf(A) = 0,41.

20B) of Boc-(L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl)amide

The solution 0,515 g (2 mmol) N-Boc-(L)-(cyclohexyl)glycine in 10 ml of methylene chloride is treated consistently, after cooling to 0oC, 0,413 g (2 mmol) of DCC and 0,297 g (2.2 mmol) NOWT. After 20 min the mixture was treated for 15 min with a solution 0,172 ml (2 mmol) of 2-methoxyethylamine (Aldrich, Buchs, Switzerland) in 8 ml of methylene chloride. After thorough mixing the mixture at RT for 19,5 h the precipitate is filtered off. The filtrate is washed successively with water and brine, and dried in the presence of sodium sulfate. After concentration under reduced pressure the crude product is purified column chromatography (SiO2, eluent J) to obtain the compound indicated in the title: TLC Rf(A) = 0,56.

20B) H-(L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl)amide

0.52 g (of 1.65 mmol)Boc-(L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl) amide stirred for 2 h in 8.7 ml of formic acid. After that, the mixture is evaporated on a rotary evaporator, and the remaining formic acid is removed under vacuum. The residue is mixed with aqueous saturated sodium bicarbonate solution and the mixture extravasation, dried in the presence of sodium sulfate and concentrate. The crude product is purified column chromatography (SiO2, eluent) to obtain the connection specified in the header: RLC Rf(A) = 0,6.

20g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-[(cyclohexyl)Gly]-N-(2 - methoxyethyl)amide

The solution 0,817 g (1.55 mmol) of 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)Caproic acid (example 19D), 0,365 g (1.7 mmol) of H-(L)- [(cyclohexyl)Gly]-N-(2-methoxyethyl)amide, to 0.645 g (1.7 mmol) HBTU and 0.4 ml (3.72 mmol) N-methylmorpholine in 15 ml of acetonitrile was stirred at RT for 16 h, the Reaction mixture was concentrated and the residue is dissolved in ethyl acetate. Then this solution is washed with water, 10% citric acid, water, saturated solution of NaHCO3and saline, dried in the presence of Na2SO4and concentrate. After column chromatography (SiO2C) get the connection specified in the header: RLC Rf(A) = 0,53.

Example 21: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- (phenylmethyl)hexanoyl-L-[(phenyl)Gly]-N-(2-methoxyethyl)amide

By analogy with example 1 and 1.15 g (1.6 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R) -(phenylmethyl)hexanoyl-(L)-[(f is asanoha in the connection header. Treatment and column chromatography (SiO2from D to A) produce the connection specified in the header: TLC Rf(A) = 0,47; tRet(II) = br15.15 min; FAB-MS (M+H)+= 604.

The original connection was obtained as follows.

21A) of Boc-(L)-(phenyl)Gly-N-(2-methoxyethyl)amide

By analogy with example 20B) solution 0,503 g (2 mmol) N-Boc-(L)-phenyl) glycine in 10 ml of methylene chloride is treated consistently, after cooling to a temperature of 0oC, 0,413 g (2 mmol) of DCC and 0,297 g (2.2 mmol) NOWT. After 20 min the mixture was treated for 15 min with a solution 0,172 ml (2 mmol) of 2-methoxyethylamine in 8 ml of methylene chloride. After thorough mixing the mixture at RT and processing the crude product is purified by stirring in a simple ester: TLC Rf(A) = 0,5.

21B) H-(L)-[(phenyl)Gly]-N-(2-methoxyethyl)amide

By analogy with example 20B), and 0.61 g (1,98 mmol) Boc-(L)- [(phenyl)Gly] -N-(2-methoxyethyl)amide are stirred in 10.4 ml of formic acid for 2 hours Specified in the title compound obtained after treatment and subjected to further use without further purification: TLC Rf(B) = 0,3.

21B) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-[(phenyl)Gly]-N-(2 - methoxyethyl)amide

P is ethyl)Caproic acid, 0.4 g (1.92 mmol) of N-(L)-[(phenyl)Gly]-N-(2 - methoxyethyl)amide, 0,728 g (1.92 mmol) of HBTU and 17.4 ml (4.2 mmol) of 0.25 M solution of N-methylmorpholine in acetonitrile was stirred at RT for 22 h Treatment of the reaction mixture with subsequent column chromatography (SiO2, ethyl acetate/hexane, 1/1 - 3/1) results in the connection specified in the header: TLC Rf(A) = 0,63.

Example 22: 5(S)-[(1-methyl-4-piperidinylcarbonyl)amino] -4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A solution of 346 mg (3 mmol) of 1-methyl-4-piperidinol (Fluka, Buchs, Switzerland) in 2 ml of THF is introduced into a solution of 217 mg (0.73 mmol) of triphosgene in 20 ml of THF. The resulting suspension is cooled in an ice bath and then treated to 1.16 ml (8.3 mmol) of triethylamine, after which the resulting mixture was stirred at RT for 30 minutes the suspension is added to a suspension of 500 mg (0,92 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 20 ml of DMF and the mixture is stirred for 2 h in argon atmosphere. The mixture is then poured into ice water and extracted 2 times with ethyl acetate. The organic extracts are washed sequentially with water, saturated sodium bicarbonate solution, water and saline solution, after chertavian insoluble components by suction and washing the residue with a simple ether. TLC Rf(K) = 0,60; tRet(I) = 10,8 min; FAB-MS (M+H)+= 647.

The original connection was obtained as follows.

22A) 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 5 g (8.25 mmol) of 5(S)-(Boc-amino)- 4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 12 in 40 ml of 4 n hydrochloric acid is stirred in dioxane for 2 h in an ice bath. The reaction mixture was evaporated in vacuum and the residue lyophilized from dioxane to obtain specified in the title compound: TLC Rf(B) = 0,18; tRet(I) = 11,3 min; FAB-MS (M+H)+= 506.

Example 23: 5(S)-(3(S)-tetrahydroprotoberberine)-4(S)- hydroxy-6-diclohexal-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

A suspension of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A) in 30 ml of THF is treated at -5oC 1,28 ml of triethylamine, and then 694 mg (4.61 mmol) of 3(S)-tetrahydroprotoberberine [see J. Chromatography 506, 598 (1990)], and the mixture was stirred at RT for 1 h in argon atmosphere. The mixture is then poured into ice water and extracted 3 times with ethyl acetate. EOS is the first solution, then evaporated. Specified in the title compound obtained after boiling the crude product in ethyl acetate, separating the insoluble components by suction and washing the residue with ethyl acetate and simple ether. TLC Rf(B) = 0,74; tRet(I) = 14,0 min; FAB-MS (M+H)+= 620.

Example 24: 5(S)-(2(R,S)-tetrahydroprotoberberine) -4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 23 is listed in the title compound obtained as a mixture of two epimeres that cannot be separated using GHUR on the basis of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide from example 22A), 660 mg (3,68 mmol) racemic tetrahydropyranyloxy-chloride [see Carbohydrate Res. , 4(4), 343 (1967)] and 0,909 ml (6,45 mmol) of triethylamine. TLC Rf(B) = 0,69; tRet(I) = 15.5 min; FAB-MS (M+N)+= 648.

Example 25: 5(S)-(5(S)-2 - oxopentanenitrile)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 22 specified in the title compound is obtained after chromatographic purification on silica gel using system alue ethoxyethyl)amide from example 22A), 345 mg (3 mmol) of 5-(S)-hydroxymethyl-2-pyrrolidone (= (L)-pyroglutamyl - Fluka, Buchs, Switzerland), 297 mg (1 mmol) triphosgene and 1.25 ml (9 mmol) of triethylamine. TLC Rf(K) = 0,50; tRet(-1) = 12,6 min; FAB-MS (M+N)+= 647.

Example 26: 5(S)-(2-methoxyethoxymethyl)-4(S)-hydroxy-6-cyclohexyl-2(R) -[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 23 specified in the header connection receive on the basis of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide from example 22A), 511 mg (3,70 mmol) of 2 - methoxyacetanilide and 0,909 ml (6,45 mmol) of triethylamine. TLC Rf(B) = 0,63; tRet(I) = a 13.9 min; FAB-MS (M+H)+= 608.

Starting material was obtained as follows.

26a) 2 - methoxyethoxymethyl (= 2-methoxyethylamine)

13.3 ml (168 mmol) of 2-methoxyethanol (Fluka, Buchs, Switzerland) is added dropwise at 0-5oC and under nitrogen atmosphere to 100 ml (202 mmol) of a 20% solution of phosgene in toluene, and this mixture is thoroughly stirred at 0oC for 90 min and at RT for 18 h, the Reaction mixture is extracted with water and the organic phase is filtered through cotton and evaporated. IR (CH2Cl2): inter alia 3055 Shir, 2995 Shir, 2935 Shire, the EP 27: 5(S)-[(L)-thiazolidin-4-ylcarbonyl] -4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

A solution of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R) - [(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A) in 12 ml of DMF is treated with RT 270 mg (2.02 mmol) of (D-thiazolidin-4-carboxylic acid (= (L)-tiopronin; Sigma, Buchs, Switzerland), 0.33 ml (2.02 mmol) diethylthiophosphate and of 0.91 ml (of 6.52 mmol) of triethylamine, and the resulting suspension is stirred in an argon atmosphere for 1 h, the Suspension was diluted with 40 ml ethyl acetate and filtered. The residue is dissolved in a 9:1 mixture of methylene chloride and methanol, then evaporated to dryness. The compound obtained as white solid after boiling the residue in ethyl acetate. TLC Rf(B) = 0,72; tRet(I) = 10,5 min; FAB-MS(M+H)+= 621.

Example 28: 5(S)-(4-oxo-4H-1-benzopyran-2-ylcarbonyl)-4(S) -hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide

A solution of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L) -Val-N-(2-methoxyethyl)amide from example 22A) in 18 ml of DMF is treated at RT with the use of 470 mg (2,40 mmol) of 4-oxo - 4H-1-benzopyran-2-carboxylic acid (Aldrich, Steinheim, Germany), of 0.59 ml (3.90 mmol) diethylthiophosphate and 0.90 ml (6,45 mmol) of triethylamine, and the mixture was stirred in the atmosphere a. The organic extracts are washed sequentially with water, saturated sodium bicarbonate solution, water and brine, then evaporated to dryness. The compound obtained as white solid after chromatographic purification on silica gel using methylene chloride/methanol (98: 2) and in boiling diethyl ether. TLC Rf(B) = 0,63; tRet(I) = 15,4 min; FAB-MS (M+H)+= 678.

Example 29: 5(S)-(indolyl-2-ylcarbonyl)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl) amide

By analogy with example 28 specified in the title compound obtained as white solids after boiling in diethyl ether, on the basis of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A), 331 mg (2.03 mmol) of indole-2-carboxylic acid (Fluka, Buchs, Switzerland) and 0,331 ml (2.03 mmol) diethylthiophosphate and 0.90 ml (6,45 mmol) of triethylamine. TLC Rf(B) = 0,75; tRet(I) = 14,4 min; FAB-MS (M+H)+= 651.

Example 30: 5(S)-(methoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 28 specified in the title compound p is(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A), 462 mg (2,63 mmol) methoxycarbonyl-(L)-valine, 0,43 ml and 2.83 mmol) diethylthiophosphate and 1.34 ml (being 9.61 mmol) of triethylamine. TLC Rf(B) = 0,61; tRet(I) = 14,2 min; FAB-MS (M+H)+= 663.

Starting material was obtained as follows.

30A) N-(methoxycarbonyl)-(L)-valine

5,67 g (60 mol) of methylchloroform (Fluka, Buchs, Switzerland) are added to 7.0 g (60 mmol) of L-valine in 100 ml of 2 n NaOH solution and 30 ml of dioxane (resulting in an exothermic reaction), after which this mixture is stirred at RT for 18 h, the Reaction mixture is extracted with methylene chloride and the aqueous phase is acidified with 27 ml of a 4n solution of HCl and again extracted with methylene chloride. Drying and evaporation of the last methylenchloride

phases allow you to receive the specified header connection: tRet(I) = 7,2 min;1H-NMR (200 MHz, CD3OD) as 0.96 (t, J=7 Hz, 6H), of 2.16 (m, 1H), to 3.67 (s, 3H), 4,06 (m, 1H), 7,07 (d, J= 8 Hz, HNpartsthe metering yexchange ratetenny)

Example 31: 5(S)-([N-(L)-thiazolidin-4-ylcarbonyl-(L)-Val] -amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 28 specified in the title compound obtained as white solids after boiling diethyl ether, based on a 0.60 g (1.11 mmol) of 5(S)-s is(to 1.33 mmol) of N-[(L)-thiazolidin-4-ylcarbonyl]-(L)-valine (= (L)-thiopropyl-(L)-valine), 0.25 ml (1,63 mmol) diethylthiophosphate and 0.55 ml (3,91 mmol) of triethylamine. TLC Rf(K) = 0,54; tRet(I) = 11,0 min; FAB-MS (M+H)+= 720.

31a) H-(L)-thiopropyl-(L)-valine

By analogy with example 28 complex benzyl ether (L)-thiopropyl-(L)-valine get from 3,99 g (10.5 mmol) of 4-toluensulfonate complex benzyl ether (L)-valine (Fluka, Buchs, Switzerland), 1,33 g (10.0 mmol) Ü-thiazolidin-4-carboxylic acid (=(L)-tiopronin; Sigma, Buchs, Switzerland), 1.8 ml (11.0 mmol) diethylthiophosphate and 5.6 ml (40.0 mmol) of triethylamine. A solution of 1.37 g of this crude product in 15 ml of methanol is treated with 8.5 ml of 1 n sodium hydroxide solution and the mixture was stirred at RT for 2 h, the Reaction solution is evaporated to half its volume under vacuum and washed with ethyl acetate. The aqueous phase is acidified with 1 N. a solution of hydrochloric acid, saturated sodium chloride solution and extracted 4 times with ethyl acetate. Specified in the title compound is obtained after evaporation of the organic extracts and boiling the residue with simple ether. TLC Rf(K) = 0,54; tRet(III) = 12,2 min; FAB-MS (M+H)+= 233.

Example 32: 5(S)-(benzyloxycarbonyl-(L)-4-[TRANS-hydroxypropyl] -amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methox the society after chromatographic purification on silica gel using the system and To boiling diethyl ether, on the basis of 0.84 g (1.55 mmol) of 5(S)-amino-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl- (L) -Val-N- (2-methoxyethyl)amide from example 22A), 412 mg (1.55 mmol) of TRANS-benzyloxycarbonyl-(L)-4-hydroxyproline (Bachem, Bubendorf, Switzerland), of 0.26 ml (1,63 mmol) diethylthiophosphate and 0.5 ml (3.6 mmol) of triethylamine. TLCf(K) = 0,50; tRet(I) = 13,8 min; FAB-MS(M+H)+= 753.

Example 33: 5(S)-(- [TRANS-4-hydroxypropyl] - amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 700 mg (0,93 mmol) of 5(S)-benzyloxycarbonyl-(L)-4-[transhydrogenase] amino - 4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 32) in 90 ml of methanol hydronaut at RT for 2.5 h in the presence of 140 mg of 10% palladium on coal under hydrogen pressure of 1 ATM. The catalyst is filtered off and the filtrate is evaporated to dryness, and then specified in the title compound obtained as white solids after boiling with diethyl ether. TLC Rf(K) = 0,18; tRet(I) = a 9.9 min; FAB-MS (M+H)+= 619.

Example 34: 5(S)-(2-amino-4-thiazoleacetate-4(S)-hydroxy-6-cyclohexyl-2(R) -[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with preperation, according to 0.60 g (1.11 mmol) of 5(S)-amino-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L) -Val-N-(2-methoxyethyl)amide from example 22A), 211 mg (1,33 mmol) 2-amino-4-thiazolylazo acid (Aldrich, Steinheim, Germany), 0.25 ml (1,63 mmol) diethylthiophosphate and 0.55 ml (3,91 mmol) of triethylamine. TLC Rf(B) a = 0,50; tRet(I) = 10,8 min; FAB-MS (M+H)+= 646.

Example 35: 5(S)-(6-(4-methyl-1-piperazinil)-3 - pyridylcarbonyl)-4(S)-hydroxy-6-cyclohexyl-2(R) - [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 28 specified in the title compound obtained as white solids after boiling with ethyl acetate, based on a 0.60 g (1.11 mmol)-5(S)- amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A), 246 mg (1.12 mmol) of 6-(4-methyl-1-piperazinil)-3 - pyridineboronic acid (receipt see application EP 0385351 A1), 0.2 ml (1,22 mmol) diethylthiophosphate and 0.55 ml (3,91 mmol) of triethylamine. TLC Rf(B) = 0,28;tRet= 10,7 min; FAB-MS (M+N)+= 709.

Example 36: 5(S)-(4-(4-morpholinylmethyl)benzoylamine)-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

By analogy with example 28 specified in the header connection on the S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 22A), 523 mg (2.03 mmol) of the hydrochloride of 4-(4-morpholinylmethyl)benzoic acid (receipt, see Tet. Lett. 32, 7385 (1991)), 0,33 ml (2.02 mmol) diethylthiophosphate and 1.29 ml (which 9.22 mmol) of triethylamine. TLC Rf(B) = 0,60; tRet(l) = 11,1 min; FAB-MS (M+N)+= 709.

Example 37: 5(S)-(O-[4-tetrahydropyranyl] -(L)-lactosamine)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]-hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 28 specified in the title compound obtained as white solids after boiling with ethyl acetate, on the basis of 1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)- Val-N-(2-methoxyethyl)amide from example 22A), 321 mg (1.88 mmol) of O- [4-tetrahydropyranyl]-(L)-lactic acid, 0.33 ml (2.02 mmol) diethylthiophosphate and 1.03 ml (7,38 mmol) of triethylamine. TLC Rf(B) = 0,72; tRet(I) = 14,0 min; FAB-MS (M+H)+= 662.

Starting material was obtained as follows.

37A) O-[4-tattoogallery]-(L)-lactic acid (= 2(S)- (tetrahydropyran-4-yloxy)propanoic acid)

The solution 1,021 g (0,951 ml. d = 1,074; 10 mmol) tetrahydro-2H-Piran-4-ol (Fluka, Buchs, Switzerland) in absolute 1,4-dioxane is treated at a temperature of 65oC 1.6 g (40 mmol) of a 60% aqueous solution of sodium hydride in oil (Fluka, Vinnie 2 h and then cooled to 65oC, and then added dropwise within about 8 min a solution of 1.08 g (0,863 ml. d = amount of 1, 258; 10 mmol) of R(+)-2-chloropropionic acid (Fluka, Buchs, Switzerland) in absolute 1,4-dioxane. The resulting brown suspension was diluted with dioxane so that the final reaction mixture contained 55 ml of dioxane, and the mixture is then heated for 3 h under reflux, stirring. The mixture is then stirred at room temperature for 14 h In the resulting brown suspension is added dropwise 40 ml of water for 2 min and the resulting yellow solution evaporated to dryness in HV. The residue is dissolved in 200 ml of water and the aqueous solution extracted twice, in each case, using 250 ml and 150 ml of ethyl acetate. The organic phase is washed once with 100 ml of water. All the aqueous phases are combined and acidified (pH 1) 4 N. hydrochloric acid. Thus obtained solution is saturated with sodium chloride and extracted twice with 300 ml of ethyl acetate in each case. The organic phase is washed three times with 150 ml of saturated solution of sodium chloride. Then all an ethyl acetate extracts are combined, dried in the presence of magnesium sulphate, filtered and evaporated to dryness in HV and 30oC. the Residue (yellow oil) purified by distillation from the ball is inania receive in the form of a colorless oil, which, when defending cures to obtain colorless crystals that melt at a temperature 33,7 - 67,6oand containing 0.13 mol (1,30%) water; []D20= -46,7 1,0o(C= 1,035; CHCl3).

Example 38: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p - benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)AMI

By analogy with example 1 indicated in the header connection receive on the basis of 1.29 g (1,63 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- [(p-benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide and 1.03 g (3,26 mmol) of three-hydrate TBAF. TLC Rf(M) = 0,58; tRet(I) = 16,9 min

Starting material was obtained as follows.

38A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val - N-(2-methoxyethyl)amide

By analogy with example 1B) is indicated in the title compound obtained as a colourless resin after chromatographic purification on silica gel using as eluent a mixture of hexane and ethyl acetate (1:1), according to 1.14 g (1.8 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(p-benzyloxyphenyl)methyl] Caproic acid, 313 mg (1.8 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) min; FAB-MS (M+H)+= 790.

38b) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3 (R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-he

By analogy with example 1H), 1.13 g (3,70 mmol) of 5(S)- [1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-it (example 2B), dissolved in 4.8 ml of THF and 0.75 ml of 1,3-dimethyl-3,4,5,6 - tetrahydro-2(1H)-pyrimidinone, deprotonated at -75oC with the help of 7.25 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (15 min) 1.2 g (3.7 mmol) of p-benzyloxybenzaldehyde (example 1G) in 2 ml of THF. Column chromatography (SiO2, hexane/ethyl acetate, 2: 1) allows to obtain the purified compound indicated in the title: TLC Rf(D) = 0,30; tRet(I) = 28,2 min; FAB-MS (M+H)+= 502.

38b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p - benzyloxyphenyl) methyl] hexanoic acid

By analogy to example 1i), 1.4 g (2,79 mmol) of 5(S)-[1(S)- (Boc-amino)-2-phenylethyl] -3(R)-[(p-benzyloxyphenyl)methyl] dihydrofuran-2- (3H)-she's in 45 ml of dimethoxyethane and 23 ml of water hydrolyzing with 11 ml of 1M solution of lithium hydroxide. Then one stripped off partially the mixture is then poured into a mixture of ice, 137 ml us. solution of NH4Cl, 11 ml of a 10% aqueous citric acid solution and 56 ml of methylene chloride with methanol is added to dissolve the precipitated solid precipitate. The aqueous phase is extracted with 2 portions mate the>and evaporated: tRet(I) = 24,0 min; FAB-MS (M+N)+= 520.

38g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(p-benzyloxyphenyl)methyl] hexanoic acid

1.4 g (2,69 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2R-[(p-benzyloxyphenyl) methyl] Caproic acid, 2.9 ml of DMF was stirred at RT for 18 h with 1,87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. The reaction mixture was poured into ice water and the mixture extracted with 3 portions of ethyl acetate; the combined organic phases are washed with 10% citric acid solution, water and saline, dried in the presence of Na2SO4and evaporated. Get the oil. Then carry out the hydrolysis of complex functions salelologa ether oil, at RT, using 2.2 g of potassium carbonate in 63 ml of methanol/THF/H2O, 3:1:1, and the reaction mixture was partially evaporated at RT. The aqueous residue was poured into 10% citric acid solution and ice, after which the mixture is extracted with 3 portions of ethyl acetate; the organic phase is washed twice with water and once with saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2D) of the crude product allows you to get the connection specified in the header: TLC Rfxifei)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)-amide

Hydrogenation of a solution of 718 mg (1.06 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R) -[p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide from example 38 in 50 ml of methanol at RT for 3 h in the presence of 150 mg of 10% Pd/C under hydrogen pressure of 1 ATM results, after filtering off the catalyst and evaporation of the filtrate, specified in the title compound as an amorphous solid: TLC Rf(hexane/ethyl acetate, 2:1) = 0,29; tRet(I) = 12,8 min; FAB-MS (M+H)+= 586.

Example 40: (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(p-isobutoxide)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A suspension consisting of 585 mg (1 mmol) of 5(S) -(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 39 and 1.22 g of cesium carbonate in 50 ml of dioxane and stirred at RT for 16 h under nitrogen atmosphere, and then treated with 2.7 ml of isobutylamine (Fluka, Buchs, Switzerland) and heated at 80oC for 3 h before until TLC monitoring will show the complete absence of any of the starting materials. Finally, the reaction mixture is diluted with methylene chloride and the precipitate is filtered off. The filtrate is evaporated and get the connection specified in the header, after chromatographic purification on the Etat/hexane. TLC Rf(L) = 0,5; tRef(I) = 17,1 min; FAB-MS (M+H)+= 642.

Example 41: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-(2 - pyridyloxy)phenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 40 is listed in the title compound is obtained after chromatographic purification on silica gel using methylene chloride/methanol (97:3) as eluent and crystallization from ethyl acetate, from 65 mg of 5(S)- (Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 39, 137 mg of cesium carbonate and 3 ml of 2-picolylamine (selected from hydrochloric salt (Fluka, Buchs, Switzerland) solution of NaHCO3). TLC Rf(L) = 0,4; tRet(l) = 11,7 min; FAB-MS (M+N)+= 677.

Example 42: 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(n-(3-pyridyloxy)phenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A suspension consisting of 585 mg (1 mmol) of 5(S)-(Boc-amino)- 4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxyphenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide from example 39 and 1.22 g of cesium carbonate, stirred at RT under nitrogen atmosphere, and then treated with 4.0 g of 3-picolylamine [selected from hydrochloric salt (Fluka, Buchs, Switzerland) a solution of NaHCO3] and heated at 85oC for 6 h P is Loiret with methylene chloride and the precipitate is filtered off. The filtrate is evaporated to obtain the connection specified in the header, in the form of an amorphous solid after chromatographic purification on silica gel using methylene chloride/THF (2: 1) as eluent and lyophilization from dioxane. TLC Rf(L) = 0,5; tRet(I) = 11.5 min; FAB-MS (M+H)+= 677.

Example 43: 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

A solution consisting of 90 mg (0,154 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide from example 39 in 5 ml of a mixture of dioxane/DMF (1:1), treated at 0oC 100 mg (0.31 mmol) of cesium carbonate, and then 0.01 ml (0.15 mmol) under the conditions. After stirring at RT for 14 h under nitrogen atmosphere, the reaction mixture was poured into ice water and extracted with methylene chloride. The organic extracts are washed with saturated sodium bicarbonate solution and brine, filtered through cotton and evaporated. Specified in the title compound is obtained after chromatographic purification on silica gel using methylene chloride/methanol (19: 1) as eluent and lyophilization from dioxane. TLC Rf(methylene chloride/methanol 19:1) = 0,27; tRet(I) = 14.6; FAB-MS (M+H)+= 600 is xitil)amide

A solution consisting of 165 mg of 5(S)-(Boc-amino)-4 (S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3,4 - methylenedioxyphenyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide, Android 4.04 ml of abs. DMF is treated 127,4 mg of TBAF and the reaction mixture stirred at RT for 21 h Slightly turbid, yellowish solution is poured into 30 ml of water and the mixture extracted with ethyl acetate. The organic phase is washed so that it became neutral, sequentially with saturated sodium bicarbonate solution and brine, and dried in the presence of sodium sulfate. Specified in the title compound was dissolved in methylene chloride and precipitated with hexane. TLC Rf(A) = 0,42; FAB-MS (M+N)+= 614.

Starting material was obtained as follows.

44a) 3,4-methylenedioxybenzyl

In an argon atmosphere and at 0oC 15,04 ml of thionyl chloride is added dropwise over 25 min to 10,82 g of 3,4-methylenedioxybenzyl alcohol (Fluka, Buchs, Switzerland) and 48 g of diisopropylaminoethanol (base polymer: polystyrene, cross-linking with 2% of divinylbenzene and diisopropylaminomethyl; (Fluka, Buchs, Switzerland) in 200 ml of absolute ether. After stirring at 0oC for 1.5 h the mixture is filtered with suction and the filtrate is concentrated on RE, and then inania. TLC Rf(hexane/ethyl acetate, 4: 1) = 0,47;1H-NMR (200 MHz, CDCl3): 6,95 is 6.7 (m, 3H); 5,97 (s, 2H); 4.53-in (s, 2H).

B) 3,4-methylenedioxyaniline

11,65 g of 3,4-methylenedioxyaniline in 128 ml of abs. acetone is treated 49,7 g of sodium iodide, stirred at RT for 2.5 h in an argon atmosphere, excluding light, and this mixture is diluted with 1.5 l of simple ether, after which the mixture is washed with 10% sodium thiosulfate solution (600 ml) and brine. Specified in the title compound is obtained after drying in the presence of sodium sulfate and remove solvent. The compound is crystallized from ether/hexane, melting point 51oC. TLC Rf(hexane/ethyl acetate, 4:1) = 0,43;1H-NMR (360 MHz, CDCl3): 6,93-6,77 (m,2H); 6,77-only 6.64 (m,1H); 5,95 (s,2H); of 4.44 (s, 2H).

V) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(3,4 - methylenedioxyphenyl)methyl]dihydrofuran-2-(3H)-he

Under nitrogen atmosphere a solution of 500 mg of 5(S)-[1(S)-(Boc-amino)-2 - phenylethyl]dihydrofuran-2-(3H)-it (getting see example 2B) in 2 ml of abs. THF and 0.33 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) is cooled to -75oC and treated with internal temperature below -70oC is 3.21 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany), after which the mixture was stirred at -75oC for 20 THF, and during this period the internal temperature does not exceed -70oC. the mixture is Then thoroughly stirred at -75oC for 1 h Then 0,611 ml of propionic acid and 0,611 ml of water successively added, using a syringe with-75-70oC. During this procedure, the temperature was raised to -30oC. the mixture is Then diluted with 35 ml of ethyl acetate, followed by stirring with 10 ml of 10% citric acid solution for 5 min in cold (ice water/water cooling). The aqueous phase is separated and the organic phase washed sequentially with saline, saturated sodium bicarbonate solution and again with saline. The combined aqueous phase re-extracted 2 times with ethyl acetate, and the combined organic phases are dried in the presence of sodium sulfate and concentrate. Specified in the title compound obtained as brownish oil. Cleaning perform column chromatography on silica gel (eluent D). TLC Rf(D) = 0,38; FAB - MS (M+N)+= 440.

G) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4 - methylenedioxyphenyl)methyl]hexanoic acid

A solution of 278 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl-3(R)- [(3,4-methylenedioxyphenyl)methyl] dihydrofuran-2-(3H)-she of 10.25 ml of dimethyl ether ethylenglycol is more at RT for 3 h, dilute with ethyl acetate and THF and washed in a separating funnel to obtain a neutral solution using a mixture of 31 ml us. solution of NH4Cl and 2.6 ml of 10% citric acid solution, followed by washing with salt solution and water. Specified in the title compound, which is subjected to further processing without further purification, are obtained after drying in the presence of Na2SO4and removal of the solvent. FAB-MS(M+H)+= 458.

44D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(3,4-methylenedioxyphenyl)methyl] hexanoic acid

A solution of 271 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(3,4-methylenedioxyphenyl)methyl] Caproic acid, 2.13 ml of DMF is treated, with stirring, 338 mg of imidazole and 415 mg of tert - butyldimethylchlorosilane. After stirring at RT for 20 h the reaction solution was poured into ice water and the mixture extracted with ethyl acetate; the organic phase is washed with 10% citric acid solution and brine. Get the crude product which is dissolved in 7,13 ml of methanol and 2.75 ml of THF, after which the resulting solution was treated at RT with a solution of 485 mg of potassium carbonate 2.75 ml of water. The reaction mixture was stirred at RT for 2 hours, the horse, the mixture is extracted with ethyl acetate. The organic phase is washed with cold saline solution. After drying in the presence of sodium sulfate, the solvent evaporated and the residue chromatographic on silica gel (eluent C) obtaining specified in the connection header. TLC Rf(C) = 0,27; FAB-MS (M+N)+= 572.

44e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(3,4-methylenedioxyphenyl)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

A mixture of 120 mg of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3,4-methylenedioxyphenyl)methyl] Caproic acid, 87,6 mg of HBTU and 40.2 mg of H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B), 1.97 ml of 0.25 M solution of NMM in acetonitrile was stirred at RT for 19 h in argon atmosphere. The solution is concentrated to half its volume by RE, diluted with cold ethyl acetate and washed successively with a solution of 10% citric acid, water, us. a solution of NaHCO3and finally brine. Specified in the title compound, which is subjected to further processing without further purification, are obtained after drying in the presence of sodium sulfate and remove solvent. TLC Rf(D) = 0,21; FAB-MS (M+N)+= 728.

Example 45: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2R)-[(3,4-acid)methyl] hexanoyl-(L)-Val-N-(2-IU acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 3,38 ml of abs. DMF desilicious using 113,6 mg of TBAF obtaining specified in the connection header. Cleaning is carried out by chromatography 2 times on silica gel (eluent A, THF and methanol). Specified in the title compound is recrystallized from methylene chloride/hexane. TLC Rf(A) = 0,37; FAB-MS (M+N)+= 630.

45a) 3,4-dimethoxybenzoic

By analogy with example 44a) specified in the title compound is obtained from 10 g of 3,4-dimethoxybenzyl alcohol (Fluka, Buchs, Switzerland) and 46.2 g of diisopropylaminoethanol (polymer basis) and to 4.62 g of thionyl chloride in 200 ml of absolute ether. TLC Rf(hexane/ethyl acetate, 4:1) = 0,31;1H-NMR (200 MHz, CdCl3): 7,0 - 6,87 (m, 2H); PC 6.82 (d,1H); 4,56 (s,2H); from 3.9 (s,3H); a 3.87 (s,3H).

45) 3,4-dimethoxybenzamide

By analogy with example b) specified in the title compound is obtained from 6,185 g of 3,4-dimethoxybenzaldehyde and 24,19 g of sodium iodide in 62 ml of abs. of acetone. TLC Rf(hexane/ethyl acetate, 4:1) = 0,40;1H-NMR (200 MHz, CDCl3): to 6.95 (DD, 1H); to 6.88 (d,1H); 6.75 in (d,1H); 4,47 (s,2H); a 3.87 (s,3H); 3,86 (s,3H).

V) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(3,4 - acid)methyl] dihydrofuran-2-(3H)-he

By analogy with example V) 1 g 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-it (getting see example 2B) in 4 ml of abs. THF diproton the-tetrahydro-2(1H)-pyrimidone] (DMPU) and alkylate 911 mg of 3,4 - dimethoxybenzaldehyde. Chromatography on silica gel (eluent D, and J) results specified in the header of the pure compounds. TLC Rf(C) = 0,42; FAB-MS (M+N)+= 455.

45g) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4 - acid) methyl] hexanoic acid

By analogy with example g) 778 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl-3(R)- [(3,4-acid)methyl] dihydrofuran-2-(3H)-she 27,67 ml dimethoxyethane and 13,91 ml of water hydrolyzing with 6,83 ml of 1M solution of lithium hydroxide, getting mentioned in the title compound, which is subjected directly to further processing. TLC Rf(C) = 0,07.

45d) 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl - 2(R)- [(3,4-acid)methyl] hexanoic acid

By analogy with example 44D) 804 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(3,4-acid)methyl] Caproic acid in 5,94 ml DMF similarbut in the presence 946,6 mg of imidazole 1,162 g of tert - butyldimethylchlorosilane. Complex silloway ester in the crude product split at RT for 2 h in a mixture consisting of 19,61 ml of methanol, 7,56 ml of THF, 7,56 ml of water and 1,334 g of potassium carbonate. Specified in the title compound purified chromatographically (2 times) on silica gel (eluent D, C, J, and C). TLC Rf(C) = 0,27; FAB-MS (M+N)+= 557.

E) 5(S)-(Boc-what BR>
By analogy with example 44th) 109.9 mg of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3,4-acid)methyl] Caproic acid, 78,1 mg of HBTU and 35,9 mg of H-(L)-Val-N- (2-methoxyethyl)amide (receipt see example 1B), 1.75 ml of 0.25 M solution of NMM/CH3CN is subjected to interaction with obtaining specified in the connection header. TLC Rf(A) = 0,39; FAB-MS (M+N)+= 744.

Example 46: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3 - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 44, 300 mg of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3 - methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide at 6.63 ml of abs. DMF desilicious using 217,7 ml TBAF obtaining specified in the connection header. Cleaning is carried out by chromatography on silica gel (eluent a and methanol) or deposition of the substance of cold ethyl acetate. TLC Rf(A) = 0,32; FAB-MS (M+N)+= 600.

46a) 3-methoxybenzamide

By analogy with example b) specified in the title compound is obtained from 2 ml of 3-methoxybenzylamine (Fluka, Buchs, Switzerland) and 9,72 g of sodium iodide in 23 ml of abs. of acetone. TLC Rf(hexane/ethyl acetate, 2,5:1) = 0,71;1H-NMR (200 MHz, CDCl3): 7,20 (m,1H); 7,0-6,87 (m,2H); is 6.78 (DD, 1H); was 4.42 (s,2H); and 3.8 (s,3H).

46B) 5(S)-[1(S)-(Boc-amino) -2-phenylethyl] dihydrofuran-2-(3H)-it (see getting example 26) in 3 ml of abs. THF deprotonated (-75oC) using 9,62 ml of 1M solution of bis(tri-methylsilyl)lithium amide in THF, adding is 0.998 ml [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) and alkylate 1.22 g of 3-methoxybenzylidene. Chromatography on silica gel (eluent E) results specified in the connection header. TLC Rf(hexane/ethyl acetate, 2,5:1) = 0,32; FAB-MS (M+N)+= 426.

V) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3 - methoxyphenyl)methyl] hexanoic acid

By analogy with example g) 1,315 g 5(S)-[1(S)-(Boc - amino)-2-phenylethyl-3(R)-[(3-methoxyphenyl)methyl] dihydrofuran-2- (3H)-she's in to 49.9 ml dimethoxyethane and 25,16 ml of water hydrolyzing with 12,36 ml of 1M solution of lithium hydroxide, getting mentioned in the title compound, which is subjected directly to further processing. TLC Rf(S) = 0,09. FAB-MS (M+N)+= 444.

G) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(3-methoxyphenyl)methyl] hexanoic acid

By analogy with example 44D) 1.3 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl-2(R)-[(3-methoxyphenyl)methyl] Caproic acid in 13 ml of DMF similarbut in the presence of 1,646 g of imidazole 1,987 g of tert - butyldimethylchlorosilane. The group of complex salelologa ester in the crude product split at RT for 2 h in the MCA is cidaut chromatography on silica gel (eluent E,D and C). TLC Rf(D) = 0,06; FAB-MS (M+N)+= 558.

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl -2(R)-[(3-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 44th) 200 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(3-methoxyphenyl)methyl] Caproic acid and 68.6 mg of H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) to 3.36 ml of 0.25 M solution of NMM/CH3CN is subjected to interaction with 149,4 mg HBTU, receiving specified in the header connection. TLC Rf(C) = 0,20; FAB-MS (M+N)+= 714.

Example 47: 5(S)-(Boc-amino) -4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

< / BR>
337 mg (0,379 mmol) of 5(S)-(Boc-amino)-4(S)-(tert.- butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 7,28 ml of abs. DMF is treated 244 ml of TBAF and the reaction mixture stirred at RT for 20 h in an argon atmosphere. The reaction mixture is diluted with about 50 ml of ethyl acetate and the mixture is successively washed with water, saturated sodium bicarbonate solution and saline. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate in those who on the results desired connection, specified in the header, which crystallizes. Additional product is obtained by purification of the mother liquor on silica gel (eluent, ethyl acetate: methanol, 9: 1). Melting point 141-143oC TLC Rf(ethyl acetate) = 0,16; FAB-MS (M+N)+= 660. GHUR tRet= 14,59 min (gradient II). IR (KBr) = inter alia, 1687, 1651, 1622, 1525, 1495 and 1172 cm-1. 1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m, 5H), 6.78, and 6,63 (each d, each 1H), a 4.03 (d,1H), 3,85, 3,81, and of 3.80 (each s, each 3H), of 1.32 and 1.26 (each s, total 9H from Boc), 0,82 (pseudo t, 6H).

Starting material was obtained as follows.

47A) 2,3,4-trimethoxybenzoic

In the atmosphere of argon, 5 g (24,47 mmol) of 2,3,4 - trimethoxybenzyl alcohol (Aldrich, Steinheim, Germany) dissolved 13.9 ml of abs. of methylene chloride, and this solution is treated 0,278 ml of pyridine. 3,05 ml of thionyl chloride in 6,94 ml of abs. the methylene chloride is added dropwise to this solution, slightly cooling (ice/water) for 20 minutes During this procedure, the internal temperature was raised to approximately 18-23oC. the Mixture is subjected to interaction within 45 min, after which a weak-yellow solution was poured into ice-cold water. After phase separation the organic phase is washed once with 1 N. a solution of sulfuric acid and water. After drying the deposits 93-95oC/0.07 mm RT.CT.) obtaining specified in the connection header.1H-NMR (220 MHz, CDCl3): 7,05 (d, 1H), 6,65 (d,1H), br4.61 (s,2H), of 3.97 (s,3H), 3,85 (s,3H). GHUR tRet= 8,1 min (gradient II).

47b) 2,3,4-trimethoxybenzoate

46,64 g (215,2 mmol) of 2,3,4-trimethoxybenzaldehyde in 466 ml of abs. acetone was treated with 156,7 g (4,86 equivalent) of sodium iodide and the mixture is stirred at RT for 2,75 hours, excluding light. The reaction mixture is treated with approximately 3 l (cold) ether and the organic phase washed 1 time 10% solution of thiophosphate sodium and 2 times salt solution (both solutions are cold). The combined aqueous phase re-extracted with simple ether. The combined organic phases are dried in the presence of sodium sulphate and evaporated to RE at a temperature of about 30oC. the Residue, representing the target of the connection specified in the header, again dried in HV and subjected to further processing in the form of a crude product.1H-NMR (200 MHz, CDCl3): 7.03, and 6,59 (each d, each 1H), 4,47 (s,2H), 4,05, 3,85, and of 3.84 (each s, each 3H).

47b) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(2.3.4-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-he

The solution 1,368 g (4,48 mmol) of 5(S)-[1(S)-(Boc-amino-2-peneliti(1H)-pyrimidone] (DMPU) is cooled to -75oC in an argon atmosphere and treated dropwise at the internal temperature below -70oC for about 20 min 8,78 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany). After 15 min the mixture was added dropwise over about 15 min a solution of 1.38 g (1 equivalent) 2,3,4 - trimethoxybenzaldehyde 2.5 ml of abs. THF, and the mixture is subjected to interaction with -75oC in the course of 2.25 hours To process the reaction mixture is subjected to interaction with a rate of 1.67 ml of propionic acid and 1.67 ml of water, and the temperature was raised to 0oC. the mixture is Then poured on 20 ml of (cold) 10% citric acid solution and add approximately 50 ml of cold ethyl acetate. After stirring for 5 minutes the phases are separated. The organic phase is washed sequentially with saline, saturated sodium bicarbonate solution and again with saline. The combined aqueous phase re-extracted 2 times with ethyl acetate, and the combined organic phases are dried in the presence of sodium sulfate and concentrate. The residue after removal of solvent chromatographic on silica gel (hexane:ethyl acetate, 3: 1) to obtain specified in the connection header. GHUR tRet= 16,49 min (gradient II). FAB-MS (M+N)+

G) 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl) methyl] hexanoic acid

The solution 1,354 g (2,685 mmol) of 5(S)-[1(S)-(BOC-amino-2-phenylethyl]-3(R)-[(2,3,4 - trimethoxyphenyl)methyl] dihydrofuran-2-(3H)-she 43,36 ml dimethoxyethane and 21,86 ml of water is treated at RT with a 10.74 ml of 1M solution of lithium hydroxide in water. Then the reaction mixture was stirred for 2 h, transferred into a separating funnel, diluted with 132 ml of a saturated solution of ammonium chloride and 11 ml of a 10% aqueous citric acid solution (both cold), followed by extraction with ethyl acetate and a small amount of THF. Specified in the title compound, which being dried in HV and further processed without additional purification, obtained after washing of the organic phase (cold) salt solution and drying in the presence of Na2SO4TLC Rf(C) = 0,03. MS (M-H2O)+= 485.

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) - 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoic acid

The solution 1,308 g (2,597 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2R-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid, 1,443 g (20,776 mmol) of imidazole and 1,816 g (11,686 mmol) of tert-butyldimethylchlorosilane and this mixture is extracted with ethyl acetate; the organic phase is washed with cold 10% citric acid solution and brine. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and evaporated to RE at a temperature of about 30oC. the Obtained product is dissolved in 34,51 ml of methanol and 11,82 ml of THF, after which the resulting solution was treated at RT with a solution of 2.08 g of potassium carbonate in 11,82 ml of water. The reaction mixture was stirred at RT for 2.5 h, concentrated at a temperature of about 30oC to half its volume and treated with ethyl acetate and (cold) 10% citric acid solution and the phases are separated. The organic phase is washed with 2 times (cold) salt solution. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The remainder chromatographic on silica gel (hexane: ethyl acetate, 1:1 and then 1:1,5) obtaining specified in the connection header. TLC Rf(J) = 0,02. FAB-MS (M+N)+= 618. IR (KBr) = inter alia, 1712, 1495, 1366, 1101 and 836 cm-1. 1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m,5H), 6,84 and 6.67 (each d, each 1H), 6,23 and 5.55 (each d, total 1H of NH), 3,86, 3,81, and of 3.80 (each s, each 3H), what ethylcellulose) -6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl) amide

A mixture of 250 mg (0,405 mmol) of 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid, 168, 8mm ml (0,445 mmol) and HBTU 77,55 mg (0,445 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) in 3.8 ml of 0.25 M solution of NMM in acetonitrile (2.35 equivalent) stirred at RT for 21 h in argon atmosphere. The reaction mixture is concentrated on a RE at a temperature of about 30oC and the residue is dissolved in ethyl acetate; this solution is washed successively with a solution of 10% citric acid, water, us. a solution of NaHCO3and, finally, a saline (all cold). The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The crude product (specified in the header of the connection) is subjected to further processing without purification. TLC Rf(A) = 0,57. FAB-MS (M+N)+= 774. GHUR tRet= 21,68 min (gradient II). IR (KBr) = inter alia, 1711, 1653, 1495, 1468, 1100 and 836 cm-1. 1NMR (CD3OD) = inter alia, to 7.3, and 7.1 (m,5H), 6,79 and 6,65 (each d, each 1H), 5,93 and to 5.57 (each d, total 1H of NH), a 3.87, 3,83 and of 3.80 (each s, each 3H), at 3.35 (s,2H), of 1.30 and 1.20 (each s, total 9H from Boc), is 0.96 (s,9H), of 0.90 and 0.87 (each 3H), of 0.18 and 0.16 (each s, each 3H).

Alternatively,1994)].

I) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl - 2(R)-[(2,3,4-tomatometer)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

1 g (e 2.06 mmol) of 5(S)- [1(S)-(Boc-amino)-2 - phenylethyl-3(R)-[(2,3,4-trimethoxyphenyl)methyl] dihydrofuran-2-(3H)- she (obtained according to example 47b) and 2.51 g (7 equivalents) of H-(L)-Val-N-(2-methoxyethyl)amide (obtained in accordance with example 16) is subjected to interaction with the 70oC for 18 h 0,354 ml (3 equivalents) of acetic acid in a sealed glass tube. The mixture is cooled and the residue is extracted with ethyl acetate, and the organic phase is washed successively 1 N. a hydrochloric acid solution, water and brine. After drying in the presence of sodium sulfate and removal of solvent the residue is recrystallized from ethanol/water. The compound obtained is identical to the connection specified in the header of example 47.

Another alternative method of obtaining the compound of example 47 is as follows.

S) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)AMI

500 mg (1,03 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl-3(R)- [(2,3,4-trimethoxyphenyl)methyl] dihydrofuran-2-(3H)-she (obtained according to example 47b) and 538,5 mg (3 equivalents) of H-(L)-Val - N-(2-methox is (1 equivalent) of 2-hydroxypyridine in a sealed glass tube. The residue is dissolved in 4 ml of ethanol and poured into 50 ml of water, after which the resulting mixture was stirred for 2 hours, the Crystalline precipitate is filtered off with suction, washed with water and dried. The compound obtained is identical to the connection specified in the header of example 47.

Alternative and similar to that outlined in example 47b) specified in the header of this example, the connection can also be obtained using 2,3,4-trimethoxybenzylamine (instead of 2,3,4-trimethoxybenzaldehyde). 2,3,4-Trimethoxybenzylamine obtained as follows.

I) 2,3,4-trimethoxybenzylamine

2,04 g (10 mmol) of 2,3,4-trimethoxybenzyl alcohol in 30 ml of absolute toluene is treated 0,258 ml (0.32 equivalent) of pyridine and the solution is cooled to a temperature of approximately 4oC using ice water. To the solution are added dropwise 0,951 ml trichromate phosphorus in 5 ml of absolute toluene at the same temperature and for 30 min and the solution stirred at the same temperature for 45 minutes, the Reaction mixture was diluted with simple ether and the whole mixture was poured into ice-cold water, followed by stirring the mixture for 5 minutes After separation of the phases the organic phase is washed with water, salt, RA is the first phase in the presence of sodium sulphate her concentrate and residual solvents are removed from the residue under high vacuum for 1 h Received the connection specified in the header, without purification, is subjected to further processing.1H-NMR (200 MHz, CDCl3): 7,05 (d, 1H), 6,65 (d, 1H), 4,55 (s,2H), 4,07, 3,88 and 3.85 (each s, each 3H).

Example 48: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(3,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 44, 191 mg of 5(S)-(Boc - amino)-4(8)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3,4,5 - trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 4.6 ml of abs. DMF desilicious with 159 mg of TBAF obtaining specified in the connection header. Cleaning is carried out by chromatography on silica gel (eluent A), followed by dissolving in dioxane and lyophilization. TLC Rf(A) = 0,26; FAB-MS (M+N)+= 660.

Starting material was obtained as follows.

48A) 3,4,5-trimethoxybenzamide

By analogy with example b) specified in the title compound is obtained from 5 g of 3,4,5-trimethoxybenzylamine (Fluka, Buchs, Switzerland) and 16,89 g of sodium iodide in 40 ml of abs. of acetone. TLC Rf(hexane/ethyl acetate, 4:1) = 0,27;1H-NMR (360 MHz, CDCl3): 6,60 (s,2H); of 4.44 (s,2H), 3,86 (s,6H), 3,83 (s,3H).

B) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(3,4,5 - trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-he

By analogy with the use of the -75oC) using 6.42 per ml of 1M solution of bis(trimethylsilyl)amide lithium in THF, adding to 0.66 ml [1,3-dimethyl - 3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) and alkylate 1,008 g 3,4,5-trimethoxybenzaldehyde. Chromatography on silica gel (eluent, hexane/acetone, 3: 1) results specified in the connection header. TLC Rf(hexane/acetone, 3:1) = 0,22; FAB-MS (M+N)+= 485.

48V) 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(3,4,5-trimethoxyphenyl)methyl] hexanoic acid

By analogy with example g) 1,097 g 5(S)-[1(S)-(Boc-amino)-2-phenylethyl-3(R)- [(3,4,5-trimethoxyphenyl)methyl] dihydrofuran-2-(3H)-she 36,48 ml dimethoxyethane and 18,39 ml of water hydrolyzing with 9,03 ml of 1M solution of lithium hydroxide, getting mentioned in the title compound, which is subjected to further processing without additional purification.

48g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(3,4,5-trimethoxyphenyl)methyl] hexanoic acid

By analogy with example 44D) 1,526 g 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4,5 - trimethoxyphenyl)methyl] Caproic acid in 15,16 ml DMF similarbut in the presence of 1,683 g of imidazole 2,11 g of tert - butyldimethylchlorosilane. Complex silloway ester in the crude product split at RT for 2.5 h in a mixture consisting of the 40.3 ml of methanol, to 13.8 ml is agile (solvents: hexane, C and J). TLC Rf) = 0,39; FAB-MS (M+N)+= 618.

D) 5(S)-(Boc-amino)-4(S) - (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[3,4,5 - trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

By analogy with example 44th) 202 mg of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(3,4,5 - trimethoxyphenyl)methyl] Caproic acid and 62.6 mg of H-(L)-Val-N- (2-methoxyethyl)amide (receipt see example 1B) of 3.07 ml of 0.25 M solution of NMM/CH3CN are interacting with to 136.4 mg HBTU, then from 24.8 mg of HBTU, getting mentioned in the title compound, which after 20 hours the reaction is subjected to further processing without additional purification. TLC Rf(A) = 0,32; FAB-MS (M+N)+= 774.

Example 49: 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(2,4-acid)methyl]hexanoyl-(L) -Val-N-(2-methoxyethyl)amide

599 mg (0,805 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2,4-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide 15.5 ml of abs. DMF is treated 508 mg (1,61 mmol) TBAF, and the reaction mixture stirred at RT for 20 h in an argon atmosphere. The reaction mixture is diluted with approximately 80 ml of ethyl acetate and the mixture is successively washed with water, saturated sodium bicarbonate solution and saline. United water f is concentrated to about 30 ml per RE. During this procedure, specified in the title compound precipitated in pure form. It is filtered off by suction, washed with hexane and dried to constant weight. TLC Rf(A) = 0,28; FAB-MS (M+N)+= 630. GHUR tRet= 14,79 min (gradient II). IR (KBr) = inter alia, 3463, 3340, 3305, 1685, 1648, 1620 and 1524 cm-1.1NMR (CD3OD) = inter alia, 7,29-to 7.09 (m,5H), 6.90 to (d,1H), 6,46 (d,1H), 6.35mm (DD,1H), 4,01 (d,1H), 3,80 and 3.75 (each s, each 3H), 3,30 (s,3H), of 1.35 (s,9H), or 0.83 (pseudo t, 6H).

Starting material was obtained as follows.

49a) 2,4-dimethoxybenzamide

2 g (11,77 mmol) of 2,4 - dimethoxybenzyl alcohol (Aldrich, Steinheim, Germany) dissolved in 30 ml of abs. of toluene, and this solution is treated with 0.3 ml of pyridine. Light the solution is cooled to a temperature of approximately 4oC and to this solution is added dropwise to 1.12 ml (0,992 equivalent) PBr3in 6 ml of toluene for 30 minutes the Mixture is subjected to interaction within 45 min, after which the reaction solution was poured into ice water and extracted with simple ether. After phase separation the organic phase is washed once with water, saturated sodium bicarbonate solution and saline (all cold). The combined aqueous phase re-extracted with simple ether. The joint body is C. In toluene solution, which still contains the specified header connection, immediately subjected to further use. TLC (hexane:ethyl acetate, 1:1), decomposition.

B) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(2,4 - acid)methyl] dihydrofuran-2-(3H)-he

A solution of 3.57 g (11.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2- (3H)-it (getting see example 2B) in 12 ml of abs. THF and 2.35 ml (1.65 equivalents) [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) is cooled to -75oC in an argon atmosphere and treated dropwise at the internal temperature below -70oC for about 30 min to 22.9 ml (1.96 equivalent) 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany). After 15 min the mixture was added dropwise over about 15 min, 25 ml of toluene containing about 1 equivalent of 2,4-dimethoxybenzamide, and the mixture is subjected to interaction at -70oC for 2 hours To the reaction mixture add 4,36 ml of propionic acid and 4,36 ml of water and the temperature was raised to 0oC. the mixture is Then diluted with 200 ml of (cold) of ethyl acetate and stirred for 5 min with 60 ml of (cold) 10% citric acid. After mixing, the phases are separated. The organic phase is washed with placentas is under sodium sulfate and concentrated. Specified in the title compound emit flash chromatography on silica gel (E). TLC Rf) = 0,24; FAB-MS (M+N)+= 455. GHUR tRet= 16,85 min (gradient II). IR (CH2Cl2) = inter alia, 3429, 1769, 1712, 1613 and 1506 cm-1.1H-NMR (CDCl3) = inter alia, 7,34-7,10 (m,5H), 6,98 (d,1H), 6,45-of 6.29 (m, 2H). or 4.31 (TD,1H), 3,78, and 3,71 (each s, each 3H), is 3.08 and 2,66 (each DD, each 1H), of 1.35 (s,9H).

49b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4-acid) methyl] hexanoic acid

The solution was 1.58 g (3,47 mmol) of 5(S)-[1(S)- (Boc-amino-2-phenylethyl]-3(R)-[(2,4 - acid)methyl] dihydrofuran-2-(3H)-she's in 56 ml of dimethyl ether of ethylene glycol and 28.2 ml of water is treated at RT 13,87 ml of 1M solution of lithium hydroxide in water. Then the reaction mixture was stirred for 1.75 h, then the reaction mixture was diluted with ethyl acetate in a small amount of THF and washed first with a mixture consisting of 170,6 ml of saturated solution of ammonium chloride and 14.25 ml of 10% citric acid solution (both cold), and then brine. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of Na2SO4and evaporated to RE at a temperature of about 30oC. the Residue, representing specified in the header the P>o
C. TLC Rf(D) = in the beginning. FAB-MS (M+N)+= 474. GHUR tRet= 14,34 min (gradient II). IR (KBr) = inter alia, 3420, 3350, 2818, 1686, 1518 and 1508 cm-1.1H-NMR (CD3OD) = inter alia, 7,30-to 7.09 (m,5H), 6,94 (d,1H), 6,47 (d,1H), 6,37 (DD, 1H), of 3.78 and 3.75 (each s, each 3H), of 1.33 (s,9H).

G) 5(S)-(Boc-amino)-4(S)-(tert - butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,4-acid)methyl] hexanoic acid

A solution of 1.5 g (3,17 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl-2R-[(2,4-acid)methyl] Caproic acid, 1,76 g (25,36 mmol) of imidazole and 2,22 g (14,26 mmol) tert - butyldimethylchlorosilane in 16 ml of abs. DMF was stirred at RT for 20 h in an argon atmosphere.

The reaction mixture was poured into ice water and the mixture extracted with ethyl acetate; the organic phase is washed with cold 10% citric acid solution and brine. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and the solvent is removed on RE at a temperature of about 30oC. the oil Obtained is dissolved in 42,1 ml of methanol and 14.4 ml of THF, after which the resulting solution was treated at RT with a solution of 2.5 g of potassium carbonate in 14.4 ml of water. The reaction mixture was stirred at RT for 2 h, concentrated in tempemail 10% citric acid solution and salt solution (both cold). The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and evaporated. Chromatography on silica gel (D) to receive specified in the title compound in purified form. TLC Rf(C) = 0,34. FAB-MS (M+N)+= 588. GHUR tRet= 20,24 min (gradient II). IR (KBr) = inter alia, 1712, 1654, 1614, 1588, and 1507 cm-1.1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m,5H), 6,98 (d,1H), 6,50 (d,1H), 6,40 (DD,1H), 3,80 and 3.76 (each s, each 3H), of 1.31 (9H), of 0.93 (s,9H), of 0.14 and 0.11 (each s, each 3H).

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2,4-acid)methyl]hexanoyl-(L)- Val-N-(2-methoxyethyl)amide

A mixture of 497 mg (0,845 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- [(2,4-acid)methyl] Caproic acid, 352 mg (0,929 mmol) HBTU and 162 mg (0,929 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) in 7,94 ml of 0.25 M solution of NMM in acetonitrile (2.35 equivalent) stirred at RT for 20 h in an argon atmosphere. The reaction mixture is concentrated on a RE at a temperature of about 30oC and the residue is dissolved in ethyl acetate; this solution was washed us. a solution of NaHCO3and a salt solution. The combined aqueous phase re-extracted with ethyl acetate. Put the frame in the connection header is actually in its pure form. TLC Rf(J) = 0,25. FAB-MS (M+N)+= 744. GHUR tRet= 21,55 min (gradient II). IR (CH2Cl2) = inter alia, 3434, 1703, 1667, 1506 and 838 cm-1.1H-NMR (CD3OD) = inter alia, 7,31-7,11 (m,5H), 6,91 (d,1H), 6,50 (d,1H), 6,37 (DD,1H), 3,84 and 3.76 (each s, each 3H), and 3.31 (s, 3H), of 1.30 (s, 9H), were 0.94 (s,9H), and 0,83 0,85 (each d, each 3H), of 0.16 and 0.15 (each s, each 3H).

Example 50: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(2-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

311 mg (0,436 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2-methoxyphenyl)methyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide 8.4 ml of abs. DMF is treated with 275 mg (0,871 mmol) TBAF, and the reaction mixture stirred at RT for 21 h in argon atmosphere. The mixture is diluted with approximately 60 ml of ethyl acetate and everything is washed successively with a saturated solution of sodium bicarbonate and saline. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and concentrated to 10 ml on RE at a temperature of about 30oC. During this procedure, specified in the title compound precipitated in pure form. It is filtered by suction, washed with hexane and dried overnight in HV. TLC Rf(ethyl acetate) =NMR (CD3OD) = inter alia, 7,28-7,06 (m, 6H), of 7.00 (d,1H), to 6.88 (d,1H), 6,76 (t,1H), 3,81 (c,3H), 3,48 (c,3H), of 1.33 (s,9H), 0,81 (pseudo t, 6H).

Starting material was obtained as follows.

50A) 2-methoxybenzylidene

Within about 30 min of 16.8 ml of thionyl chloride are added dropwise to 10 ml of 2-methoxybenzamido alcohol (Fluka, Buchs, Switzerland) and 53,76 g diisopropylaminoethanol (polymer basis: see example 44a) in 200 ml of absolute ether. After stirring at 0oC for 1.5 h the mixture is filtered with suction and the filtrate is concentrated on RE, and then in HV. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 6:1). TLC Rf(hexane/ethyl acetate, 4:1) = 0,5;1H-NMR (200 MHz, CDCl3): 7,42-7,24 (m,2H), 7,08-6,84 (m,2H), 4,68 (c,2H), 3,9 (c,3H).

50B) 2-methoxybenzamide

2 g of 2-methoxybenzylamine in 22 ml of abs. acetone is treated with 9.3 g of sodium iodide and the mixture is stirred at RT overnight, then diluted with 250 ml of simple ether and all of this is washed with 10% sodium thiosulfate solution and brine. Specified in the title compound is obtained after drying in the presence of sodium sulfate and remove solvent. The connection is subjected to further processing without additional purification. TLC Rf(hexane/Atila)-2-phenylethyl] -3(R)-[(2-methoxy-phenyl)methyl] dihydrofuran-2-(3H)-he

A solution of 1 g (3,275 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-it (getting see example 2B) in 4 ml of abs. THF and of 0.66 ml [1,3-dimethyl - 3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) (1.67 equivalent) is cooled to -75oC in an argon atmosphere and treated dropwise at the internal temperature below -70oC and for 30 min 6.42 per ml (1.96 equivalent) 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany), after which the mixture is stirred for 15 minutes dropwise within 10 min add a solution of 812 mg (3,275 mmol) of 2-methoxybenzylidene in 2 ml of THF and the mixture is subjected to interaction at -70oC for 2 hours Then 1,22 ml of propionic acid and 1.22 ml of water are successively added to the solution, increasing to 0oC. the Reaction mixture is diluted with 50 ml of (cold) ethyl acetate, followed by stirring with 20 ml of (cold) 10% citric acid solution for 5 min, followed by separation of the phases. The organic phase is washed with brine, saturated sodium bicarbonate solution and again with saline, dried in the presence of sodium sulfate and concentrate. Specified in the title compound emit flash chromatography on silica gel (hexane: ethyl acetate, 3:1). TLC Rf(hexane:ethyl acetate = 3:1) = 0,54; MS M3) = inter alia, 7,38-7,13 (m,5H), 7,20 (m,1H), was 7.08 (d,1H), 6.87 in (t,1H), for 6.81 (d,1H), 3,74 (s,3H), of 1.34 (s,9H).

50g) 5(S)-(Boc-amino)-4(S) -hydroxy-6-phenyl-2(R)-[(2-methoxyphenyl)methyl]hexanoic acid

A solution of 474 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(2-methoxyphenyl)methyl] dihydrofuran-2-(3H)-she's in 18 ml of dimethoxyethane and 9,07 ml of water is treated dropwise at RT of 4.45 ml of 1M solution of lithium hydroxide. Then the reaction mixture was stirred at RT for 3 h, diluted with ethyl acetate and THF and washed in a separating funnel to obtain a neutral solution using a mixture consisting of 54,78 ml us. solution of NH4Cl and 4,58 ml of 10% citric acid solution, followed by washing with salt solution and water. Specified in the title compound, which is subjected to further processing without further purification, are obtained after drying in the presence of Na2SO4and removal of the solvent. TLC Rf(hexane:ethyl acetate, 2,5:1) = 0,15.

50D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2-methoxyphenyl)methyl] hexanoic acid

A solution of 500 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2R- [(2-methoxyphenyl)methyl] Caproic acid in 5 ml of DMF is treated with stirring 614 mg of imidazole and 796 mg of tert-butyldimethylchlorosilane. After displacement the volume; the organic phase is washed with 10% citric acid solution and brine. The group of complex salelologa ester in the crude product split at RT for 2 h in a mixture consisting of to 13.29 ml of methanol, 5,13 ml of THF, 904 mg of potassium carbonate and 5,13 ml of water. The reaction mixture is concentrated to half its volume of RE at a temperature of about 30oC and the residue diluted with ethyl acetate. The organic phase is washed with 10% citric acid solution and salt solution (all cold). The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and the residue chromatographic on silica gel (eluent: hexane:ethyl acetate, 3:1 and 1:1) to obtain specified in the connection header. TLC Rf(hexane:ethyl acetate, 2,5:1) = 0,12. FAB-MS (M+H)+= 558.

50e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A mixture of 250 mg (0,448 mmol) of 5(S)-(Boc - amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2 - methoxyphenyl)methyl] Caproic acid, 187 mg (0,493 mmol) HBTU and 86 mg (0,493 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) in 4.2 ml of 0.25 M solution of NMM in acetonitrile (2.35 equivalent) mix the 30oC and the residue is dissolved in ethyl acetate; this solution was sequentially washed with 10% citric acid solution, us. a solution of NaHCO3and a salt solution (all cold). The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and the solvent is removed on RE. The remainder consists of specified in the connection header is actually in its pure form. TLC Rf(hexane:ethyl acetate, 1:2) = 0,29. FAB-MS (M+N)+= 714. GHUR tRet= 21,66 min (gradient II). IR (CH2Cl2) = inter alia, 3435, 1704, 1667, 1495 and 836 cm-1.

1H-NMR (CD3OD) = inter alia, 7,29-7,10 (m, 6N), 7,02 (d, 1H), 6,91 (d, 1H), 6,80 (t, 1H), 3,86 (c, 3H), 3,30 (c, 3H), 1,31 (c, 9H), 0,93 (c, 9H), of 0.85 (d, 6N), of 0.16 and 0.15 (each s, each 3H).

Example 51: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(2,3-dimethyl-4-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

323,5 mg (0,436 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3-dimethyl-4 - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide 8.4 ml of abs. DMF is treated 280,7 mg (0,872 mmol) TBAF, and the reaction mixture stirred at RT for 20 h in an argon atmosphere. The mixture is diluted with approximately 80 ml of ethyl acetate and everything is washed successively with water, NASA is by ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The obtained gel-like product chromatographic on silica gel (hexane:ethyl acetate, 1: 2). The fractions containing the product group and concentrate. The residue is dissolved in dioxane and lyophilizers, thus receiving the connection specified in the header. TLC Rf(hexane:ethyl acetate, 1:2) = 0,18; FAB-MS (M+N)+= 628. GHUR tRet= 15,52 min (gradient II). IR (KBr) = inter alia, 1688, 1650, 1619, 1519 and 1261 cm-1.1H-NMR (CD3OD) = inter alia, 7,31-7,10 (m, 5H), 6.87 in and 6,63 (each d, each 1H), a 4.03 (d, 1H), 3,75, 2.20 2,11 (each s, each 3H), of 1.35 (s, 3H), 0,83 (pseudo t, 6N).

Starting material was obtained as follows.

51A) of 2,3-dimethyl-4-methoxybenzylidene

For about 25 min 1G (6,016 mmol) of 2,3-dimethyl-4-methoxybenzylthio alcohol (Aldrich, Steinheim, Germany) and 4.8 g of diisopropylaminoethanol (polymer basis: see example 44a) in 21 ml of absolute ether is treated dropwise at 0 to 5oC using 0,482 ml of thionyl chloride. After the reaction the mixture is filtered with suction and the solvent and excess reagent are removed. The remainder, representing the target of the connection specified in the header, subject) dalnas is 9, 1485, 1466 and 1107 cm-1.1H-NMR (200 MHz, CDCl3): 7,14 (d, 1H), 6,69 (d, 1H), with 4.64 (c, 2H), 3,82, 2,34 and 2.18 (each s, each 3H).

51B) of 2,3-dimethyl-4-methoxybenzamide)

838,6 mg (of 4.54 mmol) of 2,3-dimethyl-4-methoxybenzylamine 8.5 ml of abs. acetone is treated 3,328 g (22,1 mmol) of sodium iodide and the mixture is stirred at RT for 15 h, excluding light. The resulting suspension is dark brown handle 100 ml simple diethyl ether and the resulting solution was washed with 10% sodium thiosulfate solution. Specified in the title compound as a yellowish solid obtained after drying in the presence of sodium sulfate and remove solvent. The connection is subjected to further processing without additional purification. TLC Rf(hexane/ethyl acetate, 4:1) = 0,63; IR (CH2Cl3) = inter alia, 1610, 1495, 1120 and 820 cm-1.1H-NMR (200 MHz, CDCl3): 7,17 and 6,65 (each d, each 1H), to 4.52 (s, 2H), 3,82, 2,23 and 2.18 (each s, each 3H).

51B report) 5 (S)-[1(S)-(Boc-amino)-2-phenylethyl] -3(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl] dihydrofuran-2-(3H)-he

The solution 1,248 g (4,087 mmol) of 5(S)-[1(S)- (Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-it (getting see example 2B) in 5 ml of abs. THF and 0,823 ml (6,825 mmol) of [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) is cooled to -75oC is the super 17 min 8 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany). After another 15 min dropwise within 10 min add solution 1,128 g (4,087 mmol) of 2,3-dimethyl-4-methoxy-benzylidene in 3 ml of abs. THP, and all this put together in -75oC for 2 h and Then 1.5 ml of propionic acid and 1.5 ml of water are successively added to the solution, increasing to 0oC. the Reaction mixture was poured into 35 ml of (cold) 10% citric acid solution and then adding to the mixture of approximately 70 ml of (cold) ethyl acetate. After stirring for 5 minutes the phases are separated. The organic phase is washed sequentially with saline, saturated sodium bicarbonate solution and again with saline, dried in the presence of sodium sulfate and concentrate. The residue after removal of solvent chromatographic on silica gel (hexane:ethyl acetate, 2:1). Specified in the title compound obtained as a colorless foam. TLC Rf(hexane:ethyl acetate = 2:1) = 0,37; GHUR tRet= 17,83 min (gradient II) FAB-MS (M+N)+= 453;. IR (CH2Cl) = inter alia, 3428, 1769, 1712 and 1495 cm-1.1H-NMR (CDCl3) = inter alia, 7,38-was 7.08 (m, 5H), 6,86 and 6,62 (each d, each 1H), 3,78 (3H), 3,21 and 2.16 (each DD, each 1H), 2,19 and 2.13 (each s, each 3H), of 1.35 (s,N).

51G) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3 - DIMET the Tyl-4-methoxyphenyl)methyl] dihydrofuran-2- (3H)-she 35,8 ml dimethoxyethane and 18 ml of water is treated at RT of 8.8 ml of a 1M solution of lithium hydroxide in water. Then the reaction mixture was stirred for 2.5 hours the Mixture is transferred into a separating funnel and diluted to 108.5 ml us. solution of NH4Cl and 9 ml of 10% citric acid solution (both cold), then extracted with ethyl acetate and a small amount of THF. Specified in the title compound, which is subjected to further processing without additional purification, obtained after washing of the organic phase (cold) salt solution and drying in the presence of Na2SO4. TLC Rf(hexane:ethyl acetate, 1:1) = at the start. FAB-MS (M+N)+= 472. IR (KBr) = inter alia, 1724, 1666, 1527 and 1169 cm-1.1H-NMR (CDCl3) = inter alia, 7,31-7,11 (m, 5H), 6,93 and 6.68 (each d, each 1H), 3,76 (s, 3H), 3,23 and 2,59 (each DD, each 1H), 2.21 and a 2.12 (each s, each 3H), 1.27mm (s,N).

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- -6-phenyl-2(R)-[(2,2-dimethyl-4-methoxyphenyl)methyl] hexanoic acid

The solution 1,153 g (from 2.445 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6 phenyl-2R-[(2,3-dimethyl-4-methoxyphenyl)methyl] Caproic acid, 1,372 g (20,05 mmol) of imidazole and 1,709 g (11.0 mmol) of tert-butyldimethylchlorosilane 8.7 ml of abs. DMF was stirred at RT for 18 h in an argon atmosphere. The reaction mixture was poured into ice water and the mixture extracted with ethyl acetate; the organic phase is prtraceroute with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and evaporated to RE at a temperature of about 30oC. the Obtained product is dissolved in 28.8 ml of methanol and 11.2 ml of THF, after which the resulting solution was treated at RT with a solution 1,962 g of potassium carbonate in 11.2 ml of water. The reaction mixture was stirred at RT for 2.25 hours, concentrated at a temperature of about 30oC to half its volume and the residue is treated with ethyl acetate and (cold) 10% citric acid solution and the phases are separated. The organic phase is washed 2 times with saline. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The remainder chromatographic on silica gel (hexane:ethyl acetate, 1:1 and then 3:1) to obtain specified in the connection header. TLC Rf(hexane:ethyl acetate, 1:1) = 0,42. FAB-MS (M+N)+= 586. IR (KBr) = inter alia, 1711, 1485, 1260 and 1107 cm-1.1H-NMR (CD3OD) = inter alia, 7,30-7,06 (m, 5H), 6,91 and 6,65 (each d, each 1H), 6,00 and 5,41 (each d, total 1H of NH in), 3.75 (s, 3H), 2.21 and a 2.12 (each s, each 3H), 1.31 and to 1.21 (each with just N of Boc), 0,89 (s, N), of 0.12 and 0.08 (each s, each 3H).

E) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-(o)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3-dimethyl-4 - methoxyphenyl)methyl] Caproic acid, 232.5 m mg (0,613 mmol) and HBTU 106.8 mg (0,613 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) in 5.3 ml of 0.25 M solution of NMM in acetonitrile (2.4 equivalents) was stirred at RT for 2.25 hours in argon atmosphere. The reaction mixture is concentrated on a RE at a temperature of about 30oC and the residue treated with ethyl acetate; an ethyl acetate solution is washed successively 10% citric acid solution, us. a solution of NaHCO3and, finally, a saline (all cold). The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The crude product chromatographic twice on silica gel (hexane:eteltetet, 1:2 and 1:1) to obtain specified in the connection header. TLC Rf(hexane:ethyl acetate, 1:1) = 0,16. FAB-MS (M+N)+= 742. GHUR tRet= 22,41 min (gradient II). IR (CH2Cl2) = inter alia, 3434, 1701, 1667, 1499 and 1165 cm-1.1H-NMR (CD3OD) = inter alia, to 7.3, and 7.1 (m, 5H), 6,85 and 6,64 (each d, each 1H), 5,59 and 5,61 (each d, total 1H of NH in), 3.75 (s, 3H), 2,16 and 2.02 (each s, each 3H), 1.31 and 1.20 of each, just N of Boc), of 0.95 (s, N), and 0,66 0,68 (each d, each 3H), of 0.17 and 0.16 (each s, each 3H).

Example 52: 5(S)-(Boc-amino)-4(8)-hydroxy-6-phenyl-2(R)- [(2,4,5-trimethoxyphenyl is to obtain out of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide in absolute DMF using TBAF. [Starting material for 2,4,5-trimethoxybenzene Deputy can be purchased from Fluka, Buchs, Switzerland, in the form of 2,4,5-trimethoxybenzaldehyde, from which the corresponding alcohol produced as an intermediate connection by restoring using sodium borohydride].

Example 53: 5(R)-(Boc-amino)-4(8)-hydroxy-6-phenyl-2(R)-[(2,4,6 - trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)AMI

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino) -4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,4,6 - trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in absolute DMF using TBAF. [Starting material for 2,4,6-trimethoxyaniline Deputy can be purchased from Fluka, Buchs, Switzerland, in the form of 2,4,6-trimethoxybenzaldehyde, from which the corresponding alcohol produced as an intermediate connection by restoring using sodium borohydride].

Example 54: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(5,6,7,8-tetrahydro-1-naphthyl) methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- [(5,6,7,8-tetrahydro-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)am what I get from tetralin by chloromethylpyridine; see also J. Org. Chem. 43, 2167 (1978) for instructions].

Example 55: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,5 - acid)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(2,5-acid)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide in absolute DMF using TBAF. [Source substance for 2.5-dimethoxybenzidine Deputy can be purchased from Fluka, Buchs, Switzerland, in the form of 2.5-dimethoxybenzyl alcohol].

Example 56: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,6 - acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(2,6-acid)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in absolute DMF using TBAF. [Starting material for 2,6-dimethoxyaniline Deputy, 2,6-dimethoxybenzyl alcohol, derived from 2,6-dimethoxybenzoate by restoring using lithium aluminum hydride in abs. THF. Methyl 2,6-dimethoxybenzoate derived from 2,6-dimethoxybenzoic acid (Fluka, Buchs, Switzerland) by interacting with dimethylsulfate in acetone is 6-phenyl-2(R)- [(4-methoxy-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(4 - methoxy-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in absolute DMF using TBAF. [Starting material to obtain naphthylethylene Deputy, 1-methyl bromide-4 - methoxynaphthalene, is obtained from 1-methoxynaphthalene (Fluka, Buchs, Switzerland) synthesized by using the I2/Br2in CHCl3exposing the resulting bromide Grignard reaction and processing CO2with the formation of the corresponding acid; by reacting the latter with lithium aluminum hydride, with the formation of 1-hydroxymethyl-4-methoxynaphthalene (recovery) and the interaction of the latter with PBr3to obtain the target substance (see Can. J. Chem. 59, 2629 (1981))].

Example 58: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4 - cyano-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(4-cyano-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in absolute DMF using TBAF. [1-methyl bromide-4-cyanonaphthalene, the source material for side 4-cyanonaphthalene chain, get allir is about bromoacetophenone with the formation of bromatology acid, recovery which then results in carbinol, from which the corresponding cenocoeliinae get using copper cyanide (I) of this cyanocobalamine get the precursor to the side chain of 1-methyl bromide-4-cyanonaphthalene using the traditional method, using PBr3(see Can. J. Chem. 59, 2629 (1981))].

Example 59: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-fluorescent-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 44 specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(4-fluorescent-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in absolute DMF using TBAF. [Starting material for obtaining side 4-formattitle chain, 1-methyl bromide-4-fornatale, obtained by recovery of 4-fluoro-1-naphthoic acid (Aldrich, Steinheim, Germany) using lithium aluminum hydride and subsequent interaction with PBr3(see Can. J. Chem. 59, 2629 (1981))].

Example 60: 5(S)-(Boc-amino)-4(S)- hydroxy-6-cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

A solution of 178 mg (0,204 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-V 21 PM The reaction mixture is diluted with about 30 ml of ethyl acetate and the mixture is successively washed with water, saturated sodium bicarbonate solution and saline. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulfate and concentrate. The remainder chromatographic on silica gel (ethyl acetate). The fractions containing the product are pooled, concentrated, dissolved again in a small amount of dioxane and lyophilizers obtaining specified in the connection header. IR (CH2Cl2) = inter alia, 3432, 1708, 1681, 1670, 1495, 1167 and 1099 cm-1. FAB-MS (M+H)+= 666. GHUR tRet= 16,49 min (gradient II).1H-NMR (CD3OD) = inter alia, to 6.80 and 6,63 (each D. each 1H), 4.09 to (d, 1H), 3,86 (s, 3H), 3,80 (SS, 6N), and 3.31 (s, 3H), of 1.42 (s, N), of 0.90 (d, 6N).

Starting material was obtained as follows.

60A) 5(S)-[1 S)-(Boc-amino)-2-cyclohexylethyl]dihydrofuran-2-(3H)-he

15 g (49,12 mmol) of 5(S)-[1(S)-(Boc-amino)-2 - phenylethyl]dihydrofuran-2-(3H)-it (example 2B) was dissolved in 150 ml of methanol, and the solution was treated with 0.75 g of Nishimura catalyst and hydronaut (RT, normal pressure) up until disappear any absorption of hydrogen. The catalyst is filtered off, the connection will get thick, viscous oil. IR (CH2Cl2) = inter alia, 3431, 1774, 1711, 1501 and 1170 cm-1. FAB-MS (M+H)+= 312.1H-NMR (DMSO-d6) = inter alia, to 6.80 (d, 1H), and 4.40 (m, 1H), 3,66 (m, 1H), 2,58 is 2.43 (m, 2H), 2,37 (DD, 1H), and 2.14 (m, 1H), 1.39 in (C, N).

60B) 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl-3(R)-[(2,3,4 - trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-he

A solution of 1.47 g (4,72 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl] dihydrofuran-2-(3H)-she's in 6 ml of abs. THF and 1 ml (1.65 equivalents) [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone] (DMPU) is cooled to -75oC in an argon atmosphere and treated dropwise at the internal temperature below -70oC for about 20 min 9,44 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF (Aldrich, Steinheim, Germany). After 20 min the mixture was added dropwise over approximately 10 min, a solution of 1.45 g (4,72 mmol) of 2,3,4-trimethoxybenzaldehyde (example 47b) in 3 ml of abs. THF, and the mixture is subjected to interaction with -75oC for 2.5 h, the Reaction mixture is subjected to processing of 1.76 ml propionic acid, and then to 1.76 ml of water and the temperature was raised to 0oC. the Reaction mixture is diluted with approximately 70 ml of ethyl acetate and stirred with 30 ml of (cold) 10% citric acid solution. The aqueous phase is separated and the organic phase is washed successively Z re-extracted 2 times with ethyl acetate, and the combined organic phases are dried in the presence of sodium sulfate and concentrate. The residue after removal of solvent chromatographic on silica gel (toluene: ethyl acetate 5:1) to obtain specified in the connection header. GHUR tRet= 19,13 min (gradient II). FAB-MS (M+N)+= 491. IR (CH2Cl2) = inter alia, 3429, 1766, 1711, 1602, 1495, 1165 and 1100 cm-1.1H-NMR (CD3OD) = inter alia, 6,86 (d, 1H), 6,70 (d, 1H), 4,37 (m, 1H), a 3.87, 3,82 and 3,81 (each s, each 3H), 3,37 (m, 1H), 3,13 (DD, 1H), equal to 2.94 (m, 1H), 2,59 (DD, 1H), 1,40 (s, N).

60V) 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- (2,3,4-trimethoxyphenyl)methyl]hexanoic acid

A solution of 600 mg (1,22 mmol) of 5(S)-[1(S)-(Boc-amino-2-cyclohexylethyl]-3(R)-[(2,3,4 - trimethoxyphenyl)methyl] dihydrofuran-2-(3H)-she's in 20 ml of dimethoxyethane and 9.9 ml of water is treated at RT with the help of 4.9 ml of a 1M solution of lithium hydroxide in water. Then the reaction mixture was stirred for 2 h, transferred into a separating funnel, diluted with 60 ml us. solution of ammonium chloride and 5 ml of 10% citric acid solution (both cold), followed by extraction with ethyl acetate and a small amount of THF. Specified in the title compound, which being dried in HV and further processed without additional purification, obtained after washing the B>) = inter alia, 3431, 1710, 1602, 1495, 1165 and 1100 cm-1. FAB-MS (M+N)+= 510. GHUR tRet= 16,13 min (gradient II).

60g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid

A solution of 598 mg (1,175 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-cyclohexyl-2R-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid, process, mixing with 653 mg (9.4 mmol) of imidazole and 822 mg (5,287 mmol) of tert-butyldimethylchlorosilane in 6 ml of abs. DMF. After stirring at RT for 17 h in an argon atmosphere, the reaction mixture was poured into ice water and the mixture extracted with ethyl acetate; the organic phase is washed with cold 10% citric acid solution and brine. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and evaporated. The crude product is dried in HV for about 2 hours, and then dissolved in 15.6 ml of methanol and 5.3 ml of THF, after which the resulting solution is treated 941 mg of potassium carbonate in 5.3 ml of water. The reaction mixture was stirred at RT for about 3 h, concentrated at a temperature of about 30oC to half its volume and treated with ethyl acetate; the organic phase is washed traceroute with ethyl acetate. The combined organic phases are dried in the presence of sodium sulphate and evaporated. The crude product chromatographic on silica gel (hexane:ethyl acetate, 2:1) to obtain specified in the connection header. IR (CH2Cl2) = inter alia, 3436, 1708, 1603, 1494, 1166, 1100 and 837 cm-1. FAB-MS (M+H)+= 624. GHUR tRet= 23,14 min (gradient II).1H-NMR (CD3OD) = inter alia, 6,76 (d, 1H), 6,59 (d, 1H), 6,07 and 5,50 (each d, total 1H, rotamer NH), 3,86, 3,82 and 3,81 (each s, each 3H), 3.75 to is 3.57 (m, 2H), 2.93 which is 2.75 (m, 2H), 2,70 (m, 1H), 1,42 (s, N), 0,87 (C, 6N), of 0.11 and 0.08 (each s, each 3H).

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A mixture of 135 mg (0,265 mmol) 5(8)-(Boc-amino)-4(8)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- [(2,3,4-trimethoxyphenyl)methyl] Caproic acid, 100 mg (0,265 mmol) HBTU and 51 mg (0,291 mmol) H-(L)-Val-N-(2-methoxyethyl)amide (receipt see example 1B) 2.5 ml of 0.25 M solution of NMM in acetonitrile was stirred at RT for 21 h in argon atmosphere. The solution is concentrated to half its volume on RE at a temperature of about 30oC and diluted with cold ethyl acetate; this solution is washed successively with a solution of 10% citric acid, water, us. a solution of NaHCO3and, VCE connection, which is subjected to further processing without purification, is obtained after drying in the presence of sodium sulfate and remove solvent. IR (CH2Cl3) = inter alia, 3434, 1667, 1495, 1166, 1097 and 838 cm-1. FAB-MS (M+H)+= 780. GHUR tRet= 24,79 min (gradient II).1H-NMR (CD3OD) = inter alia, to 6.80 and 5,64 (each d, each 1H), to 5.85 (d, 1H), 3,88, 3,83 and 3,81 (each s, each 3H), of 3.32 (s, 3H), USD 1.43 (s, N), of 0.90 (s, N), 0,13 (d, 6N).

Example 61: 5(S)-(Boc-amino)-4(S)- hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Ala-N- (2-methoxyethyl)amide

By analogy with example 1), 115 mg (0,17 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl] hexanoyl-(L)-Ala-N-(2-methoxyethyl)amide in 5 ml of DMF desilicious using 114 mg (0.36 mmol) and TBAF process. Column chromatography (SiO2, ethyl acetate/hexane, 2:1 - > 3:1 > 100% ethyl acetate) results specified in the title compound: TLCf(A) = 0,42; tRet(II) = 15,4 min; FAB-MS (M+H)+= 578.

Starting material was obtained as follows.

61A) Z-(L)-Ala-N-(2-methoxyethyl)amide

5.0 g (28.5 mmol) of Z-(L)-alanine in 125 ml of methylene chloride activate in a protective gas atmosphere using 6,48 g (of 31.4 mmol) DCC and 4,24 g (of 31.4 mmol) NOWT. In the resulting suspension we use Uchenie 60 hours The reaction mixture was then filtered and the filtrate washed us. a solution of NaHCO3and brine, dried with Na2SO4and evaporated. Boiling the crude product with DIPE and medium pressure chromatography [(phase: LiChroprerSi 60; silica gel for chromatography medium pressure; Merck, Darmstadt, Germany), download in the form of a solution in methylene chloride/methanol, elution with methylene chloride ---> methylene chloride/methanol, 19:1 ---> 92:8] allow to obtain specified in the title compound: TLC Rf(B) = 0.56, tRet(II) = 9,5 minutes

B) H-(L)-Ala-N-(2-methoxyethyl)amide

Hydrogenation of 4.6 g (16.4 mol) of Z-(L)-Ala-N-(2-methoxyethyl)amide in 100 ml of methanol at RT, and reduced pressure in the presence of 1 g of 10% Pd/C results, after separation by filtration of the catalyst, evaporation of the filtrate and filtration of the solution of crude product in methylene chloride through silica gel with 10% methanol in methylene chloride indicated in the title compound: FAB-MS (M+N)+= 147.1H-NMR (200 MHz, CD3OD): a 1.25 (d, J=7 Hz, H3C) to 3.33 (s, H3C-O), 3,3-3,5 (m, HCH2C-CH2).

V) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)- Ala-N-(2-methoxyethyl)amide

L)methyl] Caproic acid (example 12 g) and 42.8 mg (0.29 mmol) of H-(L)-Ala-N-(2-methoxyethyl)amide are dissolved in 2.6 ml of 0.25 M NMM/CH3CN, and the solution process III mg (0.29 mmol) of HBTU. Because GHUR shows that starting material still present after 18 h exposure at RT, add another 1.1 equivalent of HBTU. After 48 h, the reaction mixture was evaporated and the residue treated with ethyl acetate; the solution is thoroughly washed with water, 2 portions of 10% citric acid, water, 2 portions of us. solution of NaHCO3and finally brine. The inorganic phase is extracted twice with ethyl acetate, and the organic phase is dried with Na2SO4and evaporated to give, after column chromatography (SiO2, hexane/ethyl acetate, 2:1 ---> 1:1) as specified in the title compound: TLC Rf(C) = 0,14; tRet(II) = 22,6 minutes

Example 62: 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-2-methoxyethoxy)phenyl]-2(R)- [(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1,21 g (1,41 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-[p-(2-methoxyethoxy)phenyl] -2(R)-[(p - benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example e) in 31 ml of DMF desilicious using 890 mg (2.82 mmol) of TBAF in nitrogen atmosphere. After 18 h at RT the mixture was poured in 430 ml of water and all of it is extracted with 3 portions of ethyl acetate/methanol, about 10: 1. The organic phase is washed with 2 times nagaloka compound: TLC Rf(F) = 0,38; tRet(II) = a 16.4 min; FAB-MS (M+H)+= 750.

Starting material was obtained as follows.

A) 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl] dihydrofuran-2- (3H)-he

Hydrogenation of 3.0 g (7,29 mmol) of 5(S)-[1(S)-(Boc-amino)-2- (p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-it (getting see example 1G) in 100 ml of methanol with 0.6 g of 10% Pd/C results specified in the title compound after separation by filtration of the catalyst and evaporation of the filtrate: tRet(II) = 10,6 minutes

B) 5(S)-[1(S)-(Boc-amino)-2-(n-(2-methoxyethoxy)phenyl)-ethyl] dihydrofuran-2-(3H)-he

3,17 g (9,86 mmol) of 5(S)-[1(8)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-she's in 190 ml of a mixture of DMF/dioxane, 1:1, is treated in nitrogen atmosphere 6.4g (19,7 mmol) Cs2CO3and 2.0 g (9,86 mmol) of 2-methoxyacridine. Because GHUR shows that unreacted 5(S)-[1(S)-(Boc-amino)-2- (p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-he is still after 18 h after exposure at RT, batch add additional 1.2 g of 2-methoxyacridine. As soon as GHUR shows that the reaction is complete, the reaction mixture is poured into 190 ml of ice water and all of it is extracted three times with methylene chloride. The organic phase is washed with water and brine, dried with Na2SO4TES in the title compound: TLC Rf(D) = 0,08; FAB-MS (M+H)+= 380.

B') 2-methoxyaniline

A solution of 10 ml (109 mmol) of 2-chloroethylnitrosourea ether in 205 ml of acetone is treated in portions with the help of 80.1 g (534 mmol) of NaI and the mixture is refluxed for 20 hours the mixture Distribution between the 2 portions of simple ether and brine, drying the organic phase in the presence of Na2SO4and their evaporation (RT, 300 mbar) allow to obtain specified in the header connection:1H-NMR (200 MHz, CDCl3): of 3.25 (t, J=7 Hz, 2H), 3,39 (s, 3H), of 3.65 (t, J=7 Hz, 2H).

V) 5(S)-[1(S)-(BOC-amino)-2-[p-(2-methoxyethoxy)phenyl)ethyl] -3(R)-[(p-benzyloxyphenyl)methyl]dihydrofuran-2-(3H)-he

In nitrogen atmosphere 3.6 g (9,48 mmol) of 5(S)-[1(S)-(BOC-amino)-2-[p-(2-methoxyethoxymethyl)ethyl] dihydrofuran-2-(3H)-she dissolved 17.3 ml of THF and 1.9 ml of DMPU, deprotonated at -70oC using 18,58 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF and the mixture is stirred for 15 min, with subsequent alkylation of 3.07 g (9,48 mmol) p-benzyloxybenzaldehyde (example 1G) in 6 ml THF. After 30 minutes stirring at a temperature of -75oC mixture protonium of 3.53 ml (by 47.4 mmol) of propionic acid and of 3.53 ml of water and heated to a temperature of 0oC. the Reaction mixture was diluted with 95 ml of ethyl acetate and su is the solution. The aqueous phase is re-extracted with 2 portions of ethyl acetate. The organic phase is dried with sodium sulfate and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) and crystallization from ethyl acetate/hexane allow you to get purified the connection specified in the header: TLC Rf(C) = 0,38; tRet(I) = 18,0 min; FAB-MS (M+H)+= 576.

62g) 5(S)-(BOC-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] - 2(R)-[(p-benzyloxyphenyl)methyl]hexanoic acid

of 3.85 g (of 6.68 mmol) of 5(S)-[1(S)-(Boc-amino)-2-[p- (2-methoxyethoxymethyl)ethyl] -3(R)-[(p-benzyloxyphenyl)methyl] dihydrofuran - 2-(3H)-she's in 107 ml of dimethoxyethane and 54 ml of water hydrolyzing in a protective gas atmosphere with the help of 26.5 ml of a 1M solution of lithium hydroxide. The mixture is then stirred at RT for 17 h and treated with chilled on ice with a mixture of 324 ml us. solution of NH4Cl, 27 ml of a 10% aqueous citric acid solution and 134 ml of methylene chloride with methanol is added to dissolve the product. The aqueous phase is separated and extracted with 2 portions of methylene chloride, and the organic phase washed with brine, dried with Na2SO4and evaporated. tRet(I) = 15,8 min; FAB-MS (M+N)+= 594.

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-[p-(2 - methoxyethoxy)phenyl]-2(R) is)phenyl] -2(R)-[(p-benzyloxyphenyl)methyl] Caproic acid in 11 ml of DMF similarbut at RT for 16 h in a protective gas atmosphere with the use of 4.49 g (29,8 mmol) of tert-butyldimethylchlorosilane and 3.6 g (53,1 mmol) of imidazole. The reaction mixture was poured into ice water and the mixture extracted with 3 portions of ethyl acetate; the organic phase washed with 10% citric acid solution, 2 times with water and saline, dried in the presence of Na2SO4and evaporated. The residue is dissolved in 79 ml of methanol and 30 ml of THF, and this solution is treated lower than the 5.37 g K2CO3and 30 ml of water and stirred at RT for 3 h, the Reaction mixture was poured into chilled on ice for 10% citric acid solution, after which the mixture is extracted with 3 portions of ethyl acetate; the organic phase is washed twice with water and once with saline, dried in the presence of Na2SO4and evaporated. Column chromatography (SiO2hexane/ethyl acetate, 1:1) product allows you to get the connection specified in the header: TLC Rf(C) = 0,28; tRet(II) = 20,9 minutes

62e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-[p-(2 - methoxyethoxymethyl] -2(R)-[(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val - N-(2-methoxyethyl)amide

to 1.00 g (1,41 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6- [p-(2-methoxyethoxy)phenyl]-2(R)-[(p-benzyloxyphenyl) methyl]Caproic acid and 270 mg (1.55 mmol) of H-(L)-Val - N-(2-methoxyethyl)amide (example 1B) in 13.5 ml of 0.25 M NMM/CH3CN is subjected to interaction in the atmosphere sasanov washed with water, 2 times 10% citric acid solution, water, 2 times us. a solution of NaHCO2once water and finally once with brine. The aqueous phase is extracted twice with ethyl acetate, and the organic phase is dried Na2SO4and evaporated. Get listed in the header connection. tRet(II) = 22,7 min; FAB-MS(M+H)+= 864.

Example 63: 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl]- 2(R)-[(p-hydroxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenation of a solution of 600 mg (0.80 mmol) of 5(S)-(Boc-amino)- 4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] -2(R)- [(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 62) in 20 ml of methanol in the presence of 200 mg of 10% Pd/C, filtration of the mixture and evaporation yield specified in the header connection: TLC Rf(F) = 0,19; tRet(II) = 12,3 min; FAB-MS (M+H)+= 660.

Example 64: 5(S)-(Boc-amino)-4(S)-hydroxy-6- [p-(2-methoxyethoxy)phenyl] -2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In nitrogen atmosphere, 100 mg (0,152 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-[p-(2 - methoxyethoxy)phenyl] -2(R)-[(p-hydroxyphenyl)methyl] hexanoyl-(L)- Val-N-(2-methoxyethyl)amide (example 63) in 3 ml of DMF/dioxane, 1:1, is treated at 0oC using 98,7 mg (0,303 mmol) Cs2CO3still, then add 6 ál under the conditions and incubated at RT additional 24 h, the Reaction mixture was poured into water and the resulting mixture is extracted with 3 portions of methylene chloride. The organic phase is washed with water and brine, dried with Na2SO4and evaporated. Recrystallization from methylene chloride, a small amount of methanol and DIPE results specified in the title compound: TLC RF(H)=0,47; tRet=14,0 min: FAB-MS(M+H)+= 674.

Example 65: 5(S)-(BOC-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl]- 2(R)-{ [p-(2-methoxyethoxy)phenyl] methyl} hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

In nitrogen atmosphere, 100 mg (0,152 mmol) of 5(S)- (Boc-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] -2(R)- [(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide (example 63) in 3 ml of DMF/dioxane, 1:1, is treated at 0oC 98,7 mg (0,303 mmol) Cs2CO3and 40 mg (0,152 mmol) of 2-methoxyacridine (example b') and the mixture was stirred at RT for 24 hours Because GHUR shows that starting material still present in the mixture, add another 60 mg of 2-methoxyethylamine in 3 portions, and the mixture was stirred at RT for several hours in each case. The deposition of the reaction mixture with 4 ml of ice-cold water, filtration, column chromatography (SiOf(II) = 0,59; tRet(II) = a 13.9 min; FAB-MS (M+H)+= 718.

Example 66: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[4-{2 - methoxy)ethoxy}phenylmethyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 1), 3.7 g (4,84 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[4- { 2-(methoxy)ethoxy}phenylmethyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example a) in 15 ml DMF is subjected to interaction with 3,09 g (9,78 mmol) of three-hydrate TBAF, receiving specified in the header connection. The reaction mixture was poured into water and this mixture is extracted with 4 portions of ethyl acetate. The organic phase is washed us. a solution of NaHCO3, water and saline, dried with Na2SO4and evaporated. Cleaned the connection specified in the header, get after dilution with diethyl ether and filtered. TLC Rf(A) = 0,4; tRet(II) = 15,97 min; FAB-MS (M+H)+= 650.

Starting material was obtained as follows.

66A) 3(R)-[4-benzyloxyphenyl)methyl]-5(S)-[1(S)-(Boc-amino)- 2-cyclohexylethyl]dihydrofuran-2-(3H)-he

By analogy with example 1H), 5.2 g (of 16.7 mmol) of 5(S)-[1(S)-(Boc-amino)-2 - cyclohexylethyl] dihydrofuran-2-it (example 12A), dissolved in 50 ml of THF, deprotonated at -70oC with the use of 33.4 ml of a 1M solution of bis(trumpener 1 g) in 15 ml THF. Adding 6.2 ml (83,02 mmol) of propionic acid and water at -75oC and subsequent processing allow to obtain specified in the title compound after column chromatography (SiO2, hexane/ethyl acetate, 4:1): TLC Rf(hexane/ethyl acetate, 4:1) = 0,27; tRet(II) = 20,41 minutes

B) 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4 - benzyloxyphenyl)methyl]hexanoic acid

2.4 g (4,728 mmol) of 3(R)-[(4-benzyloxyphenyl)methyl]-5(S)-[1(S)-(Boc-amino)-2 - cyclohexylethyl] dihydrofuran-2-it in 10 ml of dimethoxyethane hydrolyzing in a protective gas atmosphere with the help of 9.45 ml of 1M solution of lithium hydroxide. The mixture is then stirred at RT for 17 h and treated with chilled on ice with a mixture of 324 ml us. solution of NH4Cl, 27 ml of a 10% aqueous citric acid solution and 134 ml of methylene chloride with methanol is added to dissolve the product. The aqueous phase is separated and extracted with 2 portions of methylene chloride, and the organic phase washed with brine, dried with Na2SO4and evaporated. The crude product is purified column chromatography (SiO2, eluent C), receiving specified in the header connection. TLC Rf= 0,35; tRet(II) = 17,88 min; FAB-MS (M+H)+= 526.

V) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - College)- 4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] Caproic acid in 288 ml of DMF in turn specified in the header of the connection using a 35.8 g (237,6 mmol) tert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. Column chromatography (SiO2, hexane/ethyl acetate, 4:1 ---> 1:1) of the crude product allows you to get listed in the title compound: TLC Rf(E) = 0,34; tRet(gradient from 75 to 100% (a) (b) within 20 minutes) = 25,06 min; FAB-MS (M+N)+= 526.

66g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A solution of 3 g (to 18.7 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide and 10 g (15.6 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] Caproic acid in 50 ml of DMF is cooled tooC in an ice bath and treated with 2.9 ml (17,2 mmol) diethylthiophosphate (Aldrich; Milwaukee, USA) and then 5.5 ml of triethylamine. After stirring the mixture at RT the reaction mixture was poured into water and the mixture extracted with 3 portions of ethyl acetate. The combined organic phases are washed with water, us. a solution of NaHCO3(2 times) and brine, then dried in the presence of Na2SO4and concentrate under reduced pressure. Specified in the title compound purified column chromatography: (SiO2, eluent C); TLC Rf(A) == 0,56; tRet(II) = 24,82 min; FAB-MS (M+N)+= 796.

D) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - qi is em-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl) amide in 20 ml of methanol hydronaut in the presence of 0.32 g of 10% Pd/C. Specified in the title compound, which is obtained after separation by filtration of the catalyst and evaporation of the filtrate, is subjected to further processing without additional purification; TLC Rf(C) = 0,18; tRet(II) = 21,81 min; FAB-MS (M+N)+= 706.

E) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-{ 2-methoxy)ethoxy} phenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

A solution of 0.75 g (1.06 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(4-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide in 10 ml of dioxane is treated at 1,384 g (of 4.25 mmol) Cs2CO3and after 4 h of 0.79 g (of 4.25 mmol) of 2-methoxyacridine (example b'). After stirring at 80oC for 24 h, the reaction mixture was poured into water and ethyl acetate. After separation of the organic phase the aqueous solution is washed 3 times with ethyl acetate. The combined extracts are washed successively with water, saturated sodium bicarbonate solution and saline. After drying in the presence of sodium sulfate and evaporation under reduced pressure the resulting residue is stirred with hexane and filtered. Column chromatography (SiO2, hexane/acetone, 2:1) results specified in the title compound: TLC )-4(S) -hydroxy-6-cyclohexyl-2(R)-[4-{ 2-methoxy)ethoxy} phenylmethyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide

500 mg (0,909 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-cyclohexyl-2(R)-[4-{ 2-(methoxy)ethoxy} phenylmethyl] hexanoyl- (L)-Val-N-(2-methoxyethyl)amide in 5 ml of DMF is treated at 0oC consistently 0.51 ml (3.65 mmol) of triethylamine and 0.34 g (2,09 mmol) triftoratsetata (see patent US 3852464). After stirring for 10 min the reaction mixture is poured on water and extracted with 3 portions of ethyl acetate. The combined extracts are washed successively with water, saturated sodium bicarbonate solution and saline. After drying in the presence of sodium sulfate and concentration under reduced pressure specified in the title compound is obtained from the residue by treatment with ethyl acetate. TLC Rf(B) = 0,77; tRet(II) = 15,26 min; FAB-MS (M+H)+= 676.

Starting material was obtained as follows.

67a) 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-{2- (methoxy)ethoxy}phenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

2.3 g (3.54 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(4-{2-(methoxy)ethoxy}phenyl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide (example 66) in 25 ml of methylene chloride is treated at 0oC with 25 ml triperoxonane acid. After stirring at RT for 2 h the reaction mixture mpariwa the phase is washed again with saturated aqueous sodium bicarbonate solution and saline solution, then evaporated to dryness. The dry residue is boiled with 100 ml of diethyl ether in the bath to ultrasonic treatment, after which it is filtered off by suction and washed. Specified in the title compound is obtained after drying the filtration residue at RT and in high vacuum. TLC Rf(B) = 0,4; tRet(II) = 10,2 min; FAB-MS (M+H)+= 550.

Example 68: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R) -[(3,4-methylenedioxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60) specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-cyclohexyl-2(R)-[(3,4-methylenedioxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide using TBAF in abs. DMF.

Example 69: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(3,4-acid)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

By analogy with example 60) specified in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl - 2(R)-[(3,4-acid)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide using TBAF in abs. DMF.

Example 70: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(3 - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60), ocassional)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide using TBAF in abs. DMF.

Example 71: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(3,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl - 2(R)-[(3,4,5-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide using TBAF in abs. DMF.

Example 72: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,4 - acid)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl - 2(R)-[(2,4-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide using TBAF in abs. DMF.

Example 73: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(2-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino) -4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(2 - methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide using TBAF in abs. DMF.

Example 74: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy, the hexyl - 2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide using TBAF in abs. DMF.

Example 75: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl - 2(R)-[(2,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-cyclohexyl-2(R)-[(2,4,5-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide using TBAF in abs. DMF.

Example 76: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,4,6 - trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)AMI

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-cyclohexyl-2(R)-[(2,4,6-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide using TBAF in abs. DMF.

Example 77: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(5,6,7,8-tetrahydro-1-methyl)naphthyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl) amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-cyclohexyl-2(R)-[(5,6,7,8-tetrahydro-1-methyl)naphthyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide using TBAF in abs. DMF.

Example 78: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(2,5 - acid)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Example 79: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(2,6 - acid)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl - 2(R)-[(2,6-acid)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide using TBAF in abs. DMF.

Example 80: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4 - methoxy-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(4-methoxy-1-naphthyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl) amide using TBAF in abs. DMF.

Example 81: 5(S)-(Boc-amino)-4(S)- hydroxy-6-cyclohexyl-2(R)-[(4-cyano-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60, indicated in the title compound is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl - 2(R)-[(4-cyano-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide using TBAF in abs. DMF.

Example 82: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-fluoro-1 - naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

By analogy with example 60, fluoro-1-naphthyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide using TBAF in abs. DMF.

Example 83: 5(S)-(3-hydroxy-2-methylphenylethylamine)-4(S)-hydroxy-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val - N-(2-methoxyethyl)amide

150 mg (0,251 mmol) of 5(S)-amino-4(S)- hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide (hydrochloric salt) is dissolved in dichloromethane and the organic phase washed with saturated sodium bicarbonate solution, dried in the presence of sodium sulfate and concentrate. Released Amin stirred at RT for 16 h at 2.36 ml (0.25 M) solution of NMM in acetonitrile together with 105 mg of HBTU (1.1 equivalent) and 42 mg (1.1 equivalents) of 3-hydroxy-2-methylbenzoic acid [obtained in accordance with the work of F. Fringuelli, V. Mancini & A. Taticchi, Tetrahedron 25, 4249 (1969]. The reaction mixture is extracted with cold mixture of ethyl acetate and THF and washed successively 10% citric acid solution, water, us. a solution of NaHCO3and saline, dried in the presence of Na2SO4with the subsequent removal of the solvent and the boiling residue (twice) in diethyl ether. The obtained solid residue is filtered off with suction, washed with diethyl ether and dried, obtaining mentioned in the title compound: FAB-MS (M+N)+= 694; tRet(II) = the remaining 9.08 minutes

Recognize the methyl] hexanoyl-(L)-Val-N-(2 methoxyethyl)amide (hydrochloric salt)

1.5 g of 2.27 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 47) is added in an argon atmosphere rationed to 10 ml chilled on ice 4 n solution of hydrogen chloride in dioxane and the mixture is stirred for 3.5 hours while cooling with ice. The reaction solution quickly drain to remove excess hydrogen chloride, and then frozen and lyophilizers. The lyophilisate is stirred for 1 h in acetone and then filtered off with suction, washed with hexane and dried, thereby obtaining specified in the title compound: FAB-MS (M+N)+= 560; tRet(II) = 7,30 minutes

Example 84: 5(S)-(2-methoxy-1(R,S)- methylethanolamine)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

1.0 g (of 1.84 mmol) of 5(S)-amino-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide (obtained according to example 22A) in 30 ml of THF cooled to a temperature of approximately 7oUsing ice water and treated with 0,909 ml (3.5 equivalents) of triethylamine followed by the addition 563 mg (2 equivalents) of 2-methoxy-1(R, S)- methylethylacetate. Chilled bath removed and the mixture paranromal successively with water, us. a solution of NaHCO3, water and saline, dried in the presence of Na2SO4with the subsequent removal of the solvent and the boiling residue in a simple ether. The precipitate is filtered off and dried, obtaining mentioned in the title compound: FAB-MS (M+N)+= 622; tRet(I) = 14,55 and 14,70 minutes (mixture of diastereoisomers).

Starting material was obtained as follows.

A) 2-methoxy-1(R,S)-metiletilchlorfos

1,00 ml (10.2 mmol) of 1-methoxy-2-propanol (Fluka, Buchs, Switzerland) was slowly injected into a chilled on ice, a solution of 916 mg (1.1 equivalents) of bis (trichloromethyl) carbonate (triphosgene; Fluka, Buchs, Switzerland) in 35 ml of ether using a syringe. At the same time from a dropping funnel is added dropwise 1 ml (1.2 equivalents) of pyridine in 5 ml of ether. Upon completion of the addition the mixture was stirred at RT for 60 min, the Reaction mixture was filtered through cotton wool and the solvent is carefully evaporated (water bath at 35oC). Oily residue (specified in the header of the connection) is subjected to further processing without additional purification.1H-NMR (200 MHz, CDCl3) = inter alia, of 5.05 (m, 1H), 3,30 (s, 3H), of 1.27 (d, 3H).

Example 85: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl]GE is s is obtained from 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)- [(cyclohexyl)Gly] -N-(2-methoxyethyl)amide using TBAF in DMF. FAB-MS (M+N)+= 646; tRet(I) = 17,46 minutes

Starting material was obtained as follows.

85a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)- [(cyclohexyl)-Gly]-N-(2-methoxyethyl)amide

By analogy with example d) specified in the title compound is obtained from 1,128 g (2.0 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] Caproic acid (obtained according to example 12 g), 472 mg (1.1 equivalent) of H-(L)-[(cyclohex-forces)Gly] -N-(2-methoxyethyl)amide (obtained according to example 20B), of 0.36 ml (1.1 equivalent) diethylthiophosphate (Aldrich, Milwaukee, USA) and 0.7 ml (2.5 equivalents) of triethylamine in 10 ml of DMF. FAB-MS (M+N)+= 760; tRet(I) = 24,73 minutes

Example 86: 5(S)-(ethoxy-(L)-Val-amino)-4(S)-hydroxy-6 - cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 27 is indicated in the title compound obtained as a colourless solid, after boiling in a simple ether on the basis of 1.0 g (1,844 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)- [(n-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (obtained according to example 22A), 500 mg (1.4 equivalent) etoxycarbonyl= 677; tRet(I) = 14,68 minutes

Starting material was obtained as follows.

86a) N-(etoxycarbonyl)-(L)-valine

Specified in the header connection receive by analogy with example 30A) of L-valine in 2n NaOH solution and dioxane using ethylchloride (Fluka, Buchs, Switzerland) and subjected to further processing without additional purification.

Example 87: 5(S)-(1,1-dimethyl-2-methoxyethylamine)-4(S) -hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

By analogy with example 26 specified in the header connection receive on the basis of 813 mg (1.5 mmol) of 5(S)-amino-4(S)-hydroxy-6-cyclohexyl-2(R)- [(p-methoxyphenyl)methyl] hexanoyl-(L)-Van-N-(2 - methoxyethyl)amide (obtained according to example 22A), 490 mg (2 equivalents) of (1,1-dimethyl-2-methoxy)ethylchloride and 0.6 ml (2.9 equivalents) of triethylamine. Cleaning is carried out by chromatography on silica gel (eluent: hexane/acetone, 2:1). FAB-MS (M+N)+= 636; tRet(I) = 15,45 minutes

Starting material was obtained as follows.

87a) 1-methoxy-2-methyl-2-propanol

10.8 g (0.1 mmol) of 1-chloro-2-methyl-2-propanol (Lancaster Synthesis, Bischheim, France) in 30 ml of methanol are treated in an argon atmosphere of 20.4 ml of a solution of methoxide three is Arsenii of the reaction the precipitate is filtered off and the solvent is distilled through a Vigreux column, the residue is distilled under normal pressure to obtain specified in the connection header. 1H-NMR (200 MHz, CDCl3) = to 3.33 (s, 3H), 3.15 in (s, 2H), 1,13 (C, 6N). FAB-MS(M+H+= 105 [see also Amer., Soc. 75, 155 (1953)].

B) (1,1-dimethyl-2-methoxy)ethylchloride

770 mg (2,59 mmol) of bis(trichloromethyl)carbonate (triphosgene; Fluka, Buchs, Switzerland) dissolved at RT in 25 ml of ether and the solution treated 737 mg (7,07 mmol) of 1-methoxy-2-methyl-2-propanol dissolved in a small amount of simple ether. The solution is cooled in a bath with ice and slow process of 0.67 ml (8,48 mmol) of pyridine in 3 ml of a simple ester. After complete addition, the ice bath removed and the mixture was stirred at RT for 1 h, the Reaction mixture was filtered through cotton wool and the solvent is distilled at RT. The crude product (specified in the header of the connection) is subjected to further processing without additional purification. IR (CH2CL2) = inter alia 1780, 1210, 1198, 1145 and 1120 cm-1.

Example 88: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4 - biphenylyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

0.21 g (0.276 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(4-biphenylyl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in 4 ml of DMF desilicious in nitrogen atmosphere using racette. The organic phase is washed us. a solution of NaHCO3and brine, dried with Na2SO4and evaporated to obtain specified in the connection header after stirring for DIPE: TLC Rf(B) = 0,55; tRet(II) = 16,5 min; FAB-MS (M+N)+=646.

Starting material was obtained as follows.

A) 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(4-biphenyl)methyl] dihydrofuran-2-(3H)-he

By analogy with example 5g), 5.0 g (to 16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] dihydrofuran-2-(3H)-she dissolved in 24,0 ml THF and 2.8 ml of DMPU, deprotonated at -70oC using the 32.7 ml of 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (-75 -50 ... oC) 6,07 g (24.6 mmol) of 4-biphenylmethanol (Salor, Milwaukee, USA) in 20 ml of THF. Protonation with the help of 6.1 ml (81,9 mmol) of propionic acid and 6.1 ml of water at -75oC, extraction and chromatography medium pressure (gradient: 0-1% ethyl acetate in toluene) to produce specified in the title compound: TLC Rf(D) = 0,57; tRet(II) = 18,8 minutes

88B) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(4-biphenylyl)methyl] hexanoic acid

1.3 g (was 2.76 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(4 - biphenylyl)methyl]dihydrofuran-2-(3H)-she's in 28 ml of dimethoxyethane hydrolyzing using 11 is srabatyvayut chilled on ice with a mixture of 15 ml us. solution of NH4Cl, 80 ml of 10% citric acid solution and methylene chloride. The aqueous phase is separated and extracted twice with methylene chloride. The organic phase is washed with saline, dried in the presence of Na2SO4and evaporated to obtain specified in the title compound: TLC Rf(B) = 0,4; tRet(II) = 16,4 minutes

V) 5(S)-(Boc-amino)-4(S)-(tributyltinhydride)- 6-phenyl-2(R)-[(4-biphenylyl)methyl]hexanoic acid

of 1.23 g (2.51 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl - 2(R)-[(4-biphenylyl)methyl] Caproic acid 25,0 ml of DMF similarbut in a protective gas atmosphere of 1.74 g (11.5 mmol) of tert-butyldimethylchlorosilane and 1.40 g (to 20.6 mmol) of imidazole at RT for 20 h, the Reaction mixture was evaporated and the residue treated with ethyl acetate, the resulting solution washed with saturated sodium bicarbonate solution, water and brine. The aqueous phase is extracted twice with ethyl acetate and the organic phases are dried in the presence of Na2SO4and evaporated. The residue is dissolved in 30 ml of methanol and 7 ml of THF, and this solution is treated with 2.0 g K2CO3and 7 ml of water, then stirred at RT for 1 h, the Reaction mixture was then partially evaporated and the residue diluted with chilled on ice for 10% solution of citric karevym solution dried in the presence of Na2SO4and evaporated. The medium pressure chromatography (gradient: 0-50% ethyl acetate in hexane) to receive the connection specified in the header: TLC Rf(C) = 0.56, tRet(II) = 22,1 minutes

G) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl - 2(R)-[(4-biphenylyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In nitrogen atmosphere 280 mg (0.46 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(4-biphenylyl)methyl] Caproic acid of 4.44 ml of 0.25 M NMM/CH3CN activate using 193 mg (0.51 mmol) of HBTU. After 5 min the mixture was added 90 mg (0.51 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) and mix thoroughly for 20 hours at RT. Processing by analogy with example 1B) and the digestion of the crude product in hexane yield specified in the title compound: TLCf(D) = 0,2; tRet(II) = 22,7 minutes

Example 89: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)- 2(R)-[(4-biphenylyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

1.4 g (1.6 mmol) of 5(S)-(Boc-amino)-4(S)-(tertBUTYLPEROXY)- 6-(p-benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide in 30 ml of DMF desilicious in a protective gas atmosphere with

by using 1.0 g (3.2 mmol TBAF. After 20 h stirring Rea who gt; methylene chloride/methanol, 9:1) and stirring in DIPE allow to obtain specified in the header connection: tRet(II) = 18,0 min; FAB-MS (M+N)+= 752.

The original connection was obtained as follows.

89a) 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] -3(R)-[(4 - biphenylyl)methyl]dihydrofuran-2-(3H)-he

By analogy with example 5g), of 5.55 g (13.5 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] dihydrofuran-2-(3H)-it (getting see example 1G), dissolved in 20,0 ml THF and 2.3 ml of DMPU, deprotonated at -70oC with 27 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (within 1 h) using 5.0 g (a 20.2 mmol) of 4-biphenylmethanol (Salor, Milwaukee, USA) in 16 ml THF.) Protonation with 5.0 ml (67,4 mmol) of propionic acid and 5.0 ml of water at -75oC, extraction and chromatography medium pressure (gradient: 30-50% ethyl acetate in toluene) to produce specified in the title compound: TLC Rf(Q) = 0,15; tRet(II) = 20,0 min

B) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)- [(4-biphenylyl)methyl]hexanoic acid

4,56 g (7.9 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(benzyloxyphenyl)ethyl]-3(R)-[(4-biphenylyl)methyl] dihydrofuran-2-(3H)-she's in 80 ml of dimethoxyethane hydrolized with the use of 31.6 ml of 1M current chilled on ice with a mixture of 43 ml us. solution of NH4Cl, 229 ml of 10% citric acid solution and methylene chloride. The aqueous phase is separated and extracted twice with methylene chloride. The organic phase is washed with saline, dried in the presence of Na2SO4and evaporated. Crystallization from DIPE results specified in the connection header: tRet(II) = 17,9 minutes

V) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p - benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl]hexanoic acid

3,19 g (5.4 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p - benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl] Caproic acid in 55,0 ml DMF similarbut in a protective gas atmosphere 3,71 g (24.6 mmol) of tert-butyldimethylchlorosilane and 3.0 g (to 44.0 mmol) of imidazole at RT for 20 h, the Reaction mixture was evaporated and the residue treated with ethyl acetate, the resulting solution washed with saturated sodium bicarbonate solution, water and brine. The aqueous phase is extracted twice with ethyl acetate and the organic phases are dried in the presence of Na2SO4and evaporated. The residue is dissolved in 64 ml of methanol and 15 ml of THF and this solution is treated with 4.5 g K2CO3and 15 ml of water, then stirred at RT for 1 h Treatment by analogy with example V) and the chromatography medium pressur = 0,7; tRet(II) = 22,7 minutes

G) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p - benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl] hexanoyl-(D-Val-N-(2 - methoxyethyl) amide

In nitrogen atmosphere to 1000 mg (1.44 mmol) of 5(S)-(Boc-amino)- 4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-[(4 - biphenylyl)methyl] Caproic acid, 13.8 ml of 0.25 M NMM/CH3CN activate using 601 mg (1,58 mmol) of HBTU. After 5 min the mixture was added 276 mg (1,58 mmol) H-(L)-Val-N- (2-methoxyethyl)amide (example 1B) and mix thoroughly for 20 h at RT. Processing by analogy with example 1B) and the medium pressure chromatography (gradient 40-60% ethyl acetate in hexane) allow to obtain specified in the title compound: TLC Rf(C) = 0,33; tRet(II) = 23,5 minutes

Example 90: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)- [(4-biphenylyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Hydrogenation of 200 mg (0,265 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)- [(4-biphenylyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 89) in 20 ml of methanol/methylene chloride, 1:1, in the presence of 0.1 g of 10% Pd/C, the separation by filtration of the catalyst and evaporation yield specified in the connection header: tRet(II) = 14,5 min; FAB-MS (M+N)+= 662.

Example 91: 5(S)-(Boc-s nitrogen and while cooling on ice, a solution of 173 mg (0.26 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)- 2(R)-[(4-biphenylyl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide (example 90) in 5 ml of DMF/dioxane, 1: 1, is treated with 170 mg (0.52 mmol) Cs2CO2and 16 μl (0.26 mmol) under the conditions and the mixture was stirred at RT for 20 h followed by the addition of 4.5 ml of ice water, after which the mixture was diluted with water and methylene chloride. The aqueous phase is extracted with 2 portions of methylene chloride. The organic phase is washed with water and brine, dried with Na2SO4and evaporated. Stirring of the residue in hexane results specified in the connection header: tRet(II) = 16,2 min; FAB-MS (M+N)+= 676.

Example 92: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)- [({2'-cyanobiphenyl}4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

In nitrogen atmosphere 2,11 g (2.36 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)- 2(R)-[({ 2'-cyanobiphenyl} -4-yl)methyl] hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide in 49 ml of DMF desilicious using 1,49 g (4.7 mmol) of TBAF. After 20 h stirring, the reaction mixture was treated similarly to example 88. Stirring in hexane allow to obtain specified in the header connection: tRet(II) = 17,4 min; FAB-MS (M+N)+= 777.

Starting material was obtained as follows.

92A) 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]-3(R)-[({2'-cyanobiphenyl} -4-yl)methyl]dihydrofuran-2-(3H)-it (see getting example 1G), dissolved in 22,0 ml THF and 2.4 ml of DMPU, deprotonated at -70oC with the help of 23.5 ml of a 1M solution of bis(trimethylsilyl)amide lithium in THF and alkylate (within 2 hours) with the use of 3.43 g (12.1 mmol) of 4-(methyl bromide)-2'-cyanobiphenyl [96%; regarding the receipt, see, for example, J. Med. Chem. 34, 2525 (1991)] . Protonation using a 4.5 ml of propionic acid and 4.5 l of water at -75oC, extraction, column chromatography (silica gel, hexane/ethyl acetate, 2: 1) and recrystallization from ethyl acetate/hexane yield specified in the title compound: TLC Rf(D) = 0,3; tRet(II) = 19,0 min; FAB-MS (M+H)+= 603.

B) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)- 2(R)-[({2'-cyanobiphenyl}-4-yl)methyl]hexanoic acid (lithium salt)

4.59 g (7.6 mmol) of 5(S)-[1(8)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] -3(R)-[({ 2'-cyanobiphenyl} -4-yl)methyl]dihydrofuran-2-(3H)-she's in 120 ml of dimethoxyethane and 61 ml of water is stirred with 30 ml of 1M solution of lithium hydroxide in water to form a white suspension. After 16 h stirring at RT, the crystals are filtered by suction and washed with dimethoxyethane (obtaining lithium salt specified in the connection header): anal. the calc. for C38H39N2O6Li 2H2O: C 68,87%, H 6,54%, N 4,23%, NGOs evaporated and the residue is treated chilled on ice with a mixture of 340 ml us. solution NH/Cl, 30 ml of 10% citric acid solution and methylene chloride. The aqueous phase is separated and twice extracted with 2 portions of methylene chloride. Washing the organic phases with brine, drying in the presence of Na2SO4and evaporation yield specified in the connection header in the form of the free acid.

V) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-(p-benzyloxyphenyl)-2(R)-[({2'-cyanobiphenyl}-4-yl)methyl]hexanoic acid

4.7 g (7.5 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[({2'-cyanobiphenyl} -4-yl)methyl]Caproic acid (lithium salt) in 8.1 ml of DMF was stirred at RT for 20 h together with 5.2 g (34.6 mmol) of tert-butyldimethylchlorosilane and 4,18 g (to 61.4 mmol) of imidazole, excluding moisture. Because GHUR shows that starting material still present in the solution, add an additional 1,02 g of imidazole and 1.13 g of tert-butyldimethylchlorosilane. After 2 days the reaction mixture is poured on ice water and extracted 3 times with ethyl acetate. The organic phase was washed with 10% citric acid solution, water and saline, dried in the presence of Na2SO4and evaporated. The residue is dissolved in 91 ml of methanol and 34 ml of THF and this solution is treated with 6.2 g of K2CO3and 34 m is ablaut chilled on ice for 10% citric acid solution, followed by extraction with 3 portions of ethyl acetate. The organic phases are washed with 2 portions of water and brine, then dried in the presence of Na2SO4and evaporated. Column chromatography (silica gel:hexane/ethyl acetate, 1:1) allow to obtain the connection specified in the header: TLC Rf(C) = 0,21; tRet(II) = 22,0 minutes

92g) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6- (p-benzyloxyphenyl)-2(R)-[({ 2'-cyanobiphenyl} -4-yl)methyl]hexanoyl- (L)-Val-N-(2-methoxyethyl)amide

In nitrogen atmosphere 2,00 g (2,72 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-[({ 2'- cyanobiphenyl} -4-yl)methyl] Caproic acid, 652 mg (a 4.83 mmol) HOBT, 1.54 g (8,05 mmol) EDC and at 1.17 ml (8,73 mmol) of triethylamine initially introduced in 24 ml of DMF. Then the mixture was added 674 mg (a 3.87 mmol) of H-(L)-Val-N-(2-methoxyethyl)amide (example 1B) and the resulting mixture is stirred thoroughly over night at RT. The reaction mixture is evaporated in a high vacuum, the residue is partitioned between 3 portions of methylene chloride, 10% aqueous citric acid solution, saturated sodium bicarbonate solution and saline. Drying of the organic phase in the presence of Na2SO4their evaporation and recrystallization of the residue from hot mixture of ethyl acetate and hexane allow to obtain specified in the header connection: tRet
Hydrogenation of 1.20 g (1.54 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-benzyloxyphenyl)-2(R)-[({ 2'-cyanobiphenyl}-4 - yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 92) in 40 ml of methanol and 15 ml of THF in the presence of 0.24 g of 10% Pd/C separation by filtration of the catalyst, evaporation and precipitation with DIPE from a concentrated solution in methanol yield specified in the connection header: tRet(II) = 13,7 min; FAB-MS (M+N)+= 687.

Example 94: 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)- [({ 2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl) amide

Under nitrogen atmosphere a solution of 100 mg (0,145 mmol) of 5(S)-(Boc-amino)-4(S)- hydroxy-6-(p-hydroxyphenyl)-2(R)-[({ 2'-cyanobiphenyl}-4-yl)meth - yl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 93) in 3 ml of DMF/dioxane, 1:1, handle, cooling on ice, a 94.6 mg (0.29 mmol) Cs2CO3and 9.0 μl (0,145 mmol) under the conditions, and the mixture was stirred at RT for 20 hours Because GHUR shows that starting material still present in the mixture, add the same amount of Cs2CO3and under the conditions. After stirring over night the reaction mixture was added 2.5 ml of ice water and the resulting suspension was diluted with water and methylene chloride. The aqueous phase is separated and extracted with 24and evaporated. Column chromatography (silica gel: methylene chloride/THF, 15: 1 ---> 4:1) and stirring of the residue in hexane allow you to get the connection specified in the header: TLC Rf(R) = 0,1; tRet(II) = 15.5 min; FAB-MS (M+N)+= 701.

Example 95: 5(S)-(Boc-amino)-4(S)-hydroxy-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-ethoxyethyl) amide

1120 mg (1,42 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-ethoxyethyl) amide in 14 ml of DMF is treated with 920 mg (2,84 mmol) TBAF, and the reaction mixture stirred at RT for 21 h in argon atmosphere. The reaction mixture was poured in cold saline solution and the solid is filtered off. This substance is dissolved in ethyl acetate and the solution washed successively with water, us. a solution of NaHCO3and a salt solution. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of Na2SO4and concentrate at a temperature of about 30oC. the Residue is boiled in diisopropyl ether and filtered off. After separation by filtration is specified in the title compound was washed with hexane and then dried under reduced pressure. methylene chloride) = inter alia, 3431, 2967, 1680, 1494, 1467, 1367, 1275 and 1166 cm-1.1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m, 5H), 6.78, and 6,61 (each d, each 1H), a 4.03 (d, 1H), 3,85, 3,81, and of 3.80 (each s, each 3H), 3.46 in (K, 2N), of 1.32 and 1.26 (each with just N from Boc) and 1.15 (t, 3H), 0,82 (pseudo t, 6N).

Starting material was obtained as follows.

95A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy) -6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-ethoxyethyl) amide

By analogy with example 1B), 1.27 g (2.05 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid (receipt, see example d) and 460 mg of H-(L)-Val-N-(2 - ethoxyethyl)amide in 19.2 ml of 0.25 M NMM/CH3CN is treated with 860 mg of HBTU for 20 h with the formation specified in the connection header. The latter is dissolved in ethyl acetate; the solution is thoroughly washed successively 10% cold citric acid solution, water, us. a solution of NaHCO3and, finally, twice with saline. After drying the organic phase in the presence of sodium sulfate filter and concentrate under reduced pressure. Specified in the title compound purified by medium pressure chromatography (8 bar, methylene chloride/methanol). TLC Rf(A) = 0,5. FAB-MS (M+N)+= 788. IR (methylene chloride example 1B), cleaned the connection, specified in the header, get in the form of oil, after separation by filtration of the catalyst and evaporation of the filtrate, by hydrogenation 6,12 g (19,59 mmol) of Z-(L)-Val-N-(2-ethoxyethyl)amide in 120 ml of methanol at RT, reduced pressure and in the presence of 0.61 g of 10% Pd/C 1H-NMR (200 MHz, CDCl3): to 0.80 and 0.95 (DD, 6N), and 1.2 (t, 3H), 1,35 (W, 2N), of 2.25 (m, 1H), 3,2 (d, 1H), 3.45 points (t, 2H), 3,47 (m, 4H), 7.5 (a Shir, 1H).

V) Z-(L)-Val-N-(2-ethoxyethyl)amide

5,025 g (20 mmol) of Z-(L)-valine dissolved in 20 ml of methylene chloride and this solution is treated at -10 ... -15oC of 2.68 ml (to 20.4 mmol) isobutylphthalate (Fluka; Buchs/Switzerland) and 22.2 ml (20 mmol) of NMM. After stirring the mixture for 15 min in it add in a protective gas atmosphere 2,064 g (23.2 mmol) of 2-ethoxyethylene (Pfaltz &Bauer, Waterbury, USA). The resulting beige suspension is heated to RT and treated with 100 ml of ethyl acetate and 40 ml of water. After separation of the organic phase it is washed with 40 ml of 1 n sodium hydroxide solution and brine (three times). The resulting solution was dried with Na2SO4and evaporated in HV. The residue is boiled in hexane and filtered by suction. Specified in the title compound, which is obtained in this way is subjected to further reaction without additional purification. TLC Rf(A) = 0,4;

Example 96: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(3-methoxypropyl)amide

1.19 g (1,51 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(3-methoxypropyl)amide 14.5 ml of abs. DMF is treated with 980 mg (to 3.02 mmol) TBAF, and the reaction mixture stirred at RT for 22 h in an argon atmosphere. The reaction mixture was poured in cold saline solution and the solid is filtered off. This substance is dissolved in ethyl acetate and the solution washed successively with water, us. a solution of NaHCO2and a salt solution. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of Na2SO4and concentrate at a temperature of about 30oC. the Residue is boiled in diisopropyl ether and filtered off. After separation by filtration is specified in the title compound is dried under reduced pressure. Melting point 131-132oC. TLC Rf(A) = 0,23. FAB-MS (M+N)+= 674. GHUR tRet= 14,88 min (gradient II). IR (methylene chloride) = inter alia, 3430, 2966, 1665, 1494, 1467, 1367, 1275 and 1167 cm-1.1H-NMR (CD3OD) = inter alia, 7,30-7,20 (m, 5H), 6.78, and 6,61 (each d, each 1H), a 4.03 (d, 1H), 3,85, 3,LASS="ptx2">

Starting material was obtained as follows.

96A) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(3-methoxypropyl) amide

By analogy with example 1B), 2,47 g (4.00 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid (receipt, see example d) and 830 mg of H-(L)-Val-N- (3-methoxypropyl)amide in 37,6 ml of 0.25 M NMM/CH3CN react with 1,67 g HBTU for 22 h with the formation specified in the connection header. The latter is dissolved in ethyl acetate; the solution is washed successively 10% cold citric acid solution, water, us. a solution of NaHCO3and, finally, twice with saline. After drying the organic phase in the presence of sodium sulfate filter and concentrate under reduced pressure. Specified in the title compound purified by medium pressure chromatography (8 bar, methylene chloride/methanol). TLC Rf(A) = 0,35; FAB-MS (M+N)+= 788. IR (methylene chloride) = inter alia, 3436, 2932, 1665, 1602, 1494, 1468, 1390, 1367, 1250 and 1165 cm-1.

96b) H-(L)-Val-N-(3-methoxypropyl)amide

By analogy with example 1B), cleaned the connection specified in the header, get in the form of oil, after separation of the filter catalysts of the ri RT, reduced pressure and in the presence of 2,226 g 10% Pd/C: FAB-MS (M+N)+= 189;1H-NMR (360 MHz, DMSO-d6: from 0.76 and 0.87 (DD. 6N), 1,6 (W, 2N), and 1.63 (m, 2H), of 1.84 (m, 1H), 2,9 (m, 1H), 3,1 (m, 2H), 3,22 (c, 3H), and 3.31 (m, 2H), 7,82 (W, 1H).

96v) Z-(L)-Val-N-(3-methoxypropyl)amide

By analogy with example 1A), 20 g (of 79.6 mmol) of Z-(L)-valine 250 ml of CH3CN and 20.5 ml of 95% NMM (175,1 mmol) is treated 9,00 ml (87,55 mmol) 3-methoxypropylamine (Fluka; Buchs, Switzerland). In the resulting thick suspension add a 33.2 g (87,55 mmol) HBTU and thoroughly stirred at RT for 22 h, the Reaction mixture was evaporated and the residue is dissolved in ethyl acetate; this solution is extracted with water, 2 times with 10% citric acid solution, water, 2 times with saturated sodium bicarbonate solution and saline. The aqueous phase is extracted with two portions of ethyl acetate, and the organic phase is dried with Na2SO4and evaporated. Crystallization from ethyl acetate/hexane results specified in the title compound: TLCf(G) = 0,41; tRet(II) = up 11,86 min; FAB-MS (M+N)+= 323.

Example 97: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)- [(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(3-ethoxypropan)amide

0.97 g (1.57 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]gets for 18 h in an argon atmosphere. The reaction mixture was dissolved in ethyl acetate and the resulting solution washed successively with water, us. a solution of NaHCO3and a salt solution. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of Na2SO4and concentrate at a temperature of about 30oC. the Residue is purified column chromatography (silica gel, C). TLC Rf(A) = 0,44. FAB-MS (M+N)+= 688. GHUR tRet= 15,43 min (gradient II).1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m, 5H), 6.78, and 6,61 (each d, each 1H), 4,0 (d, 1H), 3,85, 3,81, and of 3.80 (each s, each 3H), and 3.7 (m, 1H), 3,53 (m, 1H), 3,45 (kV, 2N) and (m, 2H), 3,17 (m, 3H), 2,85-2,7 (mm, 5H), 1.93 and-1,6 (m, 5H), of 1.32 and 1.26 (each with just N of Boc), 0,85 (pseudo t, 6N).

Starting material was obtained as follows.

97a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (3-ethoxypropan)amide

By analogy with example 1B), 1,235 g (2.00 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid (receipt, see example d) and 445 mg of H-(L)-Val-N- (3-ethoxypropan)amide in 18.8 ml of 0.25 M NMM/CH3CN handle 0,835 g HBTU for 22 h with the formation specified in the header sedimentological 10% cold citric acid solution, water, us. a solution of NaHCO3and, finally, twice with saline. After drying the organic phase in the presence of sodium sulfate filter and concentrate under reduced pressure. Specified in the title compound purified column chromatography (silica gel, methylene chloride/methanol, 99:1). TLC Rf(C) = 0,32; tRet(II) = 22,58 min; FAB-MS (M+N)+= 802.

97B) H-(L)-Val-N-(3-ethoxypropan)amide

By analogy with example 1B), cleaned the connection specified in the header, get in the form of oil, after separation by filtration of the catalyst and evaporation of the filtrate, by hydrogenation of 6.2 g (18.4 mmol) of Z-(L)-Val-N-(3-ethoxypropan)amide in 120,0 ml of methanol at RT, reduced pressure and in the presence of 0.62 g of 10% Pd/C1H-NMR (200 MHz, CDCl3): of 0.8 and 0.97 (DD. 6N), and 1.2 (t, 3H) and 1.3 (W, 2N), and 1.8 (m, 2H), 2,25 (m, 1H), 3,2 (d, 1H), 3,38 (m, 2H), of 3.45 (m, 4H), 7,55 (W, 1H).

V) Z-(L)-Val-N-(3-ethoxypropan)amide

5,025 g (20 mmol) of Z-(L)-valine dissolved in 20 ml of methylene chloride and this solution is treated at -10 ... -15oC of 2.68 ml (to 20.4 mmol) isobutylphthalate and 2.2 ml (20 mmol) of NMM. After stirring the mixture for 15 min in it add in a protective gas atmosphere 2,78 ml (23.2 mmol) of 3-ethoxypropylamine. The resulting beige suspension is heated to RT and processing the IDA sodium and salt solution (three times). The resulting solution was dried with Na2SO4and evaporated in HV. The residue is boiled in hexane and filtered by suction. Specified in the title compound, which is obtained in this way is subjected to further reaction without additional purification. TLC Rf(C) = 0,35;1H-NMR (200 MHz, CDCl3): 0,95 (DD, 6N), and 1.2 (t, 3H), of 1.75 (m, 2H), 2,1 (m, 1H), 3,3-3,55 (m, 7H), 3,93 (DD, 1H), 5,1 (s, 2H), 5,4 (W, 1H), 6,55 (W, 1H), 7,35 (s, 5H).

Example 98: 5(S)-(Boc-amino)-4(S)-hydoxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-[3-(n-propyloxy)propyl]amide

1.4 g (1,71 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-[3-(n-propyloxy)propyl] amide in 16.0 ml of abs. DMF is treated 1,17 g TBAF and the reaction mixture stirred at RT for 18 h in an argon atmosphere. The reaction mixture was poured into a mixture of brine and ice and the insoluble matter is filtered off. The residue is dissolved in ethyl acetate and the resulting solution washed successively with water, us. a solution of NaHCO3and a salt solution. The combined aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried in the presence of Na2SO4and concentrate at a temperature of about 30oC. the Residue to the N)+= 702. GHUR tRet= to 16.31 min (gradient II).1H-NMR (CD3OD) = inter alia, 7,30-7,10 (m, 5H), 6.78, and 6,61 (each d, each 1H), 4,0 (d, 1H), 3,85, 3,81, and of 3.80 (each s, each 3H), and 3.7 (m, 1H), 3,54 (m, 1H), 3.43 points (t, 2H), 3,37 (t, 2H), 3.15 in (m, 2H), 2,9-2,63 (mm, 5H), of 1.93 (m, 1H), 1,82-1,5 (m, 6N), of 1.32 and 1.26 (each with just N of Boc), 0,85 (pseudo t, 6N).

Starting material was obtained as follows.

98A) 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-[3-(n-propyloxy)propyl] amide

By analogy with example 1B), 1,235 g (2.00 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] Caproic acid (receipt, see example d) and 497 mg of H-(L)-Val-N-[3-(n-propyloxy)propyl] amide in 18.8 ml of 0.25 M NMM/CH3CN handle 0,835 g HBTU for 22 h with the formation specified in the connection header. After concentration of the suspension dissolve it in cold ethyl acetate and the resulting solution was thoroughly washed successively 10% cold citric acid solution, water, us. a solution of NaHCO3and, finally, twice with saline. After drying the organic phase in the presence of sodium sulfate filter and concentrate under reduced pressure. Specified in the header of the connection behaviour is FAB-MS (M+N)+= 816.

B) H-(L)-Val-N-[3-(n-propyloxy)propyl]amide

By analogy with example 1B), cleaned the connection specified in the header, get in the form of oil, after separation by filtration of the catalyst and evaporation of the filtrate, by hydrogenation of 6.3 g (17,48 mmol) of Z-(L)-Val-N-[3-(n-propyloxy)propyl] amide in 120,0 ml of methanol at RT, reduced pressure and in the presence 0,63 g 10% Pd/C1H-NMR (200 MHz, CDCl3): 0.8 in (d, 3H), of 0.9 and 0.97 (DD, 6N), 1,25 (W, 2H), 1,4 (m, 2H), 1,78 (m, 2H), 2,25 (m, 1H), 3,2 (d, 1H), 3,38 (m, 4H), 3,5 (m, 2H), 7.5 (a Shir, 1H).

V) Z-(L)-Val-N-[3-(n-propyloxy)propyl]amide

5,025 g (20 mmol) of Z-(L)-valine dissolved in 20 ml of methylene chloride and this solution is treated at -10 ... -15oC of 2.68 ml (to 20.4 mmol) isobutylphthalate and 2.2 ml (20 mmol) of NMM. After stirring the mixture for 15 min in it add in a protective gas atmosphere of 2.72 ml (23.2 mmol) of 3-(n-propyloxy)propylamide (Tokyo Kasei Organic Chemicals, Tokyo, Japan). The resulting beige suspension is heated to RT and treated with 100 ml of ethyl acetate and 40 ml of water. After separation of the organic phase it is washed with 40 ml of 1N. a solution of sodium hydroxide and brine (three times). The resulting solution was dried with Na2SO4and evaporated in HV. The residue is boiled in hexane and filtered by suction. Specified in C Rf(C) = 0,6;1H-NMR (200 MHz, CDCl3): 0,92 (m, N), and 1.6 (m, 2H), of 1.75 (m, 2H), 2,1 (m, 1H), 3,35 (m, 4H), 3,5 (m, 2H), 3,93 (DD, 1H), 5,1 (c, 2H), 5,4 (W, 1H), 6,5 (W, 1H), 7,35 (c, 5H).

Example 99: 5(S)-(3-hydroxy-2 - methylphenylsiloxane)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)- [({2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

Specified in the header connection receive by analogy with one of the methods described in the above examples.

Example 100: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[({ 2'- cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

Specified in the header connection receive by analogy with one of the methods described in the above examples.

Example 101: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)- [({2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2 - methoxyethyl)amide

Specified in the header connection receive by analogy with one of the methods described in the above examples.

Example 102: 5(S)-(p-nitrobenzenesulfonamide)-4(S)-hydroxy - 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

to 1.00 g (1,67 mmol) of 5(S)-amino-4(S)-hydroxy - 6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl)amide (hydrochloric salt) (example 83A) is dissolved is of Ulfat sodium and concentrate. Released Amin stirred at 0oC for 17 h in 25 ml of pyridine along with 475 mg (1.25 equivalents) of 4-nitrobenzenesulfonamide (Fluka, Buchs, Switzerland). After adding another 285 mg (0.75 equivalent) of 4-nitrobenzenesulfonamide mixture is subjected to further interaction at RT for 3 h, the Reaction mixture was concentrated. The oily residue is dissolved in cold ethyl acetate and the solution washed successively 10% citric acid solution, brine, us. a solution of NaHCO3and saline, dried in the presence of Na2SO4and the solvent is removed. The resulting crystalline residue is crystallized from ethyl acetate /hexane, filtered off with suction, washed with hexane and dried, obtaining mentioned in the title compound: FAB-MS (M+N)+= 745; melting point 195-198oC; tRet= 10,45 minutes

Example 103: 5(S)-(p-aminobenzenesulfonamide)-4(S)-hydroxy-6 - phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N- (2-methoxyethyl) amide

200 mg (0,268 mmol) of 5(S)-(p-nitrobenzenesulfonamide)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (example 102) dissolved in 6 ml of methanol and 1 equivalent of acetic acid. After dobavileny solution share throughHyflo Super Cel filter additive based on kieselguhr (diatomaceous earth); (Fluka, Buchs, Switzerland). The solution concentrate. The resulting crystalline residue is again crystallized from methanol/hexane, filtered off with suction and washed with hexane, getting mentioned in the title compound: FAB-MS (M+H)+= 715; melting point 200-206oC; tRet(II) = 9,14 minutes

Example 104: 5(S)-[o-methyl-(p-nitrobenzenesulfonyl)amino] -4(S)- hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N- (2-methoxyethyl)amide

Specified in the header connection receive by analogy with one of the methods described in the above examples.

Example 105: 5(S)-[o-methyl-(p-aminobenzenesulfonamide)amino] - 4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide

Specified in the header connection receive by analogy with one of the methods described in the above examples.

Example 106: Capsules

Crystalline 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2-(2,3,4 - trimethoxyphenyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (active substance) grind (particle size of approximately from 1 to 100 μm) with a conventional paddle mixer (aprimitive, USA; also obtained from Emkalyx, France; trademark of BASF) in the same way traditional pulverized with a mixer and fine fraction is separated by sieving using a sieve (0.5 mm) and then used as described below. 16,00 g sesame oil initially introduced in chemical beaker followed by the addition of 1.20 g of powdered active substance, of 1.20 g of the fine fractionPluronic F 68 and 1.20 g of hydroxypropylmethylcellulose (cellulose HP-M-603 from Shin-Etsu Chemicals Ltd., Tokyo, Japan), stirring the mixture in the mixer (IKA-Werk, Germany), which is connected with a toothed stirrer (diameter 46 mm) (stirring speed 2000 rpm). After 20 minutes of mixing at the specified speed get the suspension pasty consistency, which is used to fill hard gelatin capsules (20 x 40 m; R. P. Scherer AG, Eberbach, Germany).

Example 107: Capsules (II)

The following components (g) process, as described below, with the aim of obtaining 10,000 capsules each containing 100 mg of active compound (for example, 5(S)-(Boc-amino)-4(S)- hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenyl)hexanoyl-(L)-Val-N- (2-methoxyethyl)amide):

Active connection - 1000

Pluronic F 68 - 1000

Hydroxypropylmethyl initially introduced into the heated reactor (Fryma) andPluronicPluronic F 68 fall asleep there. The reactor is heated to 60oC andPluronicPluronic F 68 distributed by stirring the mixture for approximately 2 h). The mixture is cooled to a temperature of approximately 30oC, mixing and homogenizing the mixture. The hypromellose and active connection type and distribute in oily mass, mixing and homogenizing (approximately 1 hour). The suspension, which has a pasty consistency, used for filling hard gelatin capsules (size 0, for example, from Elanco or Parke-Davies (Caprogel) or soft gelatin capsules (length 20 mm; R. P. Scherer AG, Eberbach, Germany) using traditional equipment.

Example 108: Gelatin solution

Aqueous solution, sterilized by filtration and containing as active compound is one of compounds of formula I mentioned in the previous examples, along with 20% cyclodextrins as solubilization mixed under aseptic conditions, and when heated with a sterile gelatin solution containing phenol as preservative, so that 1.0 ml of solution has the following composition, mg:

Active connection - 3,0

Gelatin - 150,0

Phenol - 4,7

Distillirovanna is in for injections

5 mg of one of the compounds of formula I mentioned in the previous examples, as active compounds, dissolved in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrins as solubilization. The solution is sterilized by filtration and used in aseptic conditions to fill in 2 ml ampoules, after which it is frozen and lyophilizers. Before using the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological sodium chloride solution. The solution is used for intramuscular or intravenous administration. This composition can also be used for filling dual-chamber syringes are single use only.

Example 109: Nasal spray

500 mg powder (< 5.0 µm) powder of one of the compounds of formula I mentioned in the previous examples, as the active compounds suspended in a mixture of 3.5 ml of Myglyol 812and 0.08 g of benzyl alcohol. This suspension is introduced into a container fitted with a metering valve. to 5.0 g of Freon 12, which is under pressure due to the valve, is introduced into the container. "Freon" is dissolved in a mixture of Myglyol/benzyl alcohol by shaking. This container with the spray contains approximately 100 is the following process for the preparation of 10,000 tablets, each of which contains 100 mg of active compound, g:

Active connection - 1000

Corn starch - 680

Colloidal silicic acid - 200

Magnesium stearate - 20

Stearic acid - 50

Sodium salt carboxymethylamino starch - 250

Water - as required

A mixture of one of the compounds of formula I mentioned in the previous examples, as active compounds, 50 g of corn starch and the colloidal silicic acid is treated with starch paste consisting of 250 g of corn starch and 2.2 kg of demineralized water, with the formation of the wet mass. It passed through a sieve with mesh size of 3 mm and dried in the dryer fluidized bed at 45oC for 30 minutes the Dried granulate is pressed through a sieve with mesh size of 1 mm, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, magnesium stearate, stearic acid and sodium salt carboxymethylamino starch, and then pressed into tablets slightly dome-shaped.

Example 111: Pharmacokinetics in dogs

Composition: Capsules from example 106

The experiment: use two Soucek breed of short-legged hound (Ciba-Geigy, Sissein). In Vimala experiment. Give food again at 8 h after the start of the experiment. Each bitch give 2 capsules, which together contain 1.2 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4 - trimethoxyphenyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide (active substance), which corresponds to an average dose of approximately 100 mg/kg of body weight. The blood from the saphenous vein paws collected in heparinised tubes at different times after administration of the drug.

To analyze the concentration of drugs in plasma, heparinized blood is centrifuged (4000 x g, 20 min) and the plasma is withdrawn and mixed with an equal volume of acetonitrile. The mixture was incubated on ice for 30 minutes Protein precipitate seized by centrifugation (10000 x g, 5 min) and the supernatant centrifuged again. The concentration of the active substance in the final supernatant determined using obremenitve GHUR: analysis GHUR carried out on an analytical column Nucleosil C18 (5 μm) size 125 x 4.6 mm (Macherey &Nagel, düren, Germany), using as mobile phase of 50% acetonitrile and 0.1% triperoxonane acid in water. The flow rate is 1 ml/min. under these conditions, the detection limit is 0.1 μm. Active ingredient detect ultraviolet absorbance at ing concentrations by comparison with standard curves. Standard curves obtained by analysis GHUR plasmas dogs that have a known added concentration of the active substance, and of plasmas, which are treated similarly to sample processing, using for this purpose the above-mentioned stage.

Results see table. 2 (in PL. 2 - the table of values - values are given in ng/mg).

Example 112: Synergistic effect obtained by combining 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4 - trimethoxyphenyl)methyl] hexanoyl-(L)-Van-N-(2-methoxyethyl)amide (compound from example 47) with indinavir or saquinavir in experiments using cell lines

The activity of the individual compounds and compositions of the compounds mentioned in the title of example, in co-culture cell line CEM-SS and permanently infected cell line H9/HIV-I/IIIB determined using the method described above in connection with the description of pharmacological properties. The measurement result is expressed as the percent reduction in the activity of the reverse transcriptase (RT). The results are presented in table. 3 and 4; the results of measurements that confirm the manifestation of synergism, are underlined:

a) compositions with saquinavir (see tab. 3);

b) composition with indinavir: (see tab. 4).

Therefore, a synergistic effect is also found when the experiment using human mononuclear peripheral blood cells.

1. Connection pissy alkoxycarbonyl), in which the moiety of the lower alkoxy is not substituted or substituted by one or more radicals selected independently of one another from halogen, lower alkoxy or pyrrolidinyl, which is not substituted or substituted by one or more radicals selected independently of one another from oxo or hydroxyl, lower alkanoyl, which is not substituted or substituted by piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, diazolidinyl, thiazolium, indolium, 4H-1-benzopyranyl, piperidinyloxy, tetrahydropyranyloxy or tetrahydrofurane, which in each case is not substituted or substituted by one or more substituents, selected independently of one another from oxo, hydroxyl, amino, lower alkyl and lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, arylcarbamoyl, which is replaced by heterocyclyl or morpholine-lower alkyl, phenyl-lower alkanoyl, which is substituted by hydroxyl, lower

the alkyl and arylsulfonyl; the remainder, which is linked via a carbonyl group of the amino acids valine and which N-allerban on the amino group with the lowest alkoxycarbonyl;

R2- cyclohexyl or phenyl which is not substituted or substituted by one or more radicals selected e pyridyl bound via a carbon atom in the ring, and lower alkoxy-lower alkoxy;

R3- cyclohexyl, cyclohexenyl, phenyl, naphthyl or tetrahydronaphthyl, which is not substituted or substituted by one or more radicals selected independently of one another from phenyl, cyanophenyl, phenyl-lower alkyl, halogen, cyano, hydroxyl, lower alkoxy, phenyl-lower alkoxy, pyridyl-lower alkoxy, where the pyridine is linked via a carbon atom in the ring, a lower alkoxy-lower alkoxy, lower alkylenedioxy and phenyl-lower alkanesulfonyl, which is not substituted or substituted in the phenyl radical by one or more radicals selected independently of one another from halogen;< / BR>
R4- lower alkyl, cyclohexyl or phenyl;

R5is lower alkyl;

n = 1 or 2

or its salt, provided that there is at least one salt-forming group.

2. The compound of formula I under item 1, wherein R1- acyl radical selected from lower alkoxy-lower alkanoyl, lower alkoxy-lower alkanoyl, which is replaced by the moiety of the lower alkoxy, one or more times by halogen, lower alkoxy or pyrrolidinyl, which is not substituted or is substituted by oxo, N-lower alkoxycarbonyl-piperidinyl-lower alkanoyl, pirila on the nitrogen atom, aminothiazoline-lower alkanoyl, thiazolyl-lower alkanoyl, indolyl-lower alkanoyl, 4H-1-benzopyranyl - lower alkanoyl, which is substituted by oxo, N-lower alkylpiperidines-lower alkanoyl, tetrahydropyranyloxy-lower alkanoyl, tetrahydropyranyloxy-lower alkanoyl, morpholinyl-lower alkylbenzene, lower alkyldimethylbenzylammonium, phenyl-lower alkanoyl, which is substituted by hydroxyl and lower alkyl and which has one hydroxyl substituent and one lower alkyl substituent in each case on the phenyl ring, and phenylsulfonyl, which is substituted by an amino or nitro, or its salt, provided that there is at least one salt-forming group.

3. The compound of formula I under item 1, wherein R2and R3there are the following combinations: R2=phenyl and R3=cyanophenyl; R2=phenyl and R3=2,4-differenl; R2=phenyl and R3=4-lower alkoxyphenyl; R2=4-(lower alkoxy-lower alkoxy)phenyl, and R3=4-(phenyl-lower alkoxy)phenyl; R2= cyclohexyl and R3= 4 - lower alkoxyphenyl; R2=phenyl and R3=phenyl; R2=phenyl and R3=4-[(pyridine-2-yl or pyridin-3-yl)-lower alkoxy]phenyl; R2
2
= phenyl and R3=2,3,4-tri-lower alkoxyphenyl, or its salt, provided that there is at least one salt-forming group.

4. The compound of formula I under item 1, wherein R1choose from ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-cryptgetkeyparam, 2-(methoxy)ethoxycarbonyl, 2-methoxy-1-(R,S) - methylethanolamine, 1,1-dimethyl-2-methoxyethoxymethyl, 5(S)-2-oxopropylidene, 1-ethoxycarbonylpyrimidine-4-yl-carbonyl, TRANS-(L)-4-hydroxyproline, N-(benzyloxycarbonyl)-TRANS-(L)-4-hydroxyproline, (L)-thiazolidin-4-ylcarbonyl, indole-2-ylcarbonyl, 4H-1-benzopyran-2-ylcarbonyl, N-metilprednisolone, tetrahydropyran-2-(R,S)-ylcarbonyl, O-(tetrahydropyran-4-yl)-(L)-lactol (2(S)-(tetrahydropyran-4-yloxy)propionyl), 3(S)-tetrahydropyranyloxy, 2-aminothiazol-4-lacetera, 6-(4-methylpiperazin-1-yl)pyridine-3-ylcarbonyl, 4-(morpholine-4-ylmethyl)-benzoyl, N-methoxycarbonyl-(L)-poured, N-[(L)-thiazolidin-4-ylcarbonyl] -(L)-valil, 3-hydroxy-2-methylbenzene, 4-nitrobenzenesulfonyl, 4-aminobenzenesulphonyl, 2-methyl-4-nitrobenzenesulfonyl and 4-amino-2-methylbenzenesulfonyl, R2and R3selected from cyclohexyl, cyclohexen-1-yl, phenyl, 4-biphenylyl, 2-C the Nile, trimethoxyphenyl, 4-(2-methoxyethoxy)phenyl, 3,4-methylenedioxyphenyl, 4-(pyridine-2-or pyridine - 3-ylethoxy)phenyl, 4-methoxy-2-ftoheia, 4-fluoro-2-methoxyphenyl, 4-methoxy-2-hydroxyphenyl, 4-methoxy-2,3-dimetilfenil, 4-(2-phenylethyl)phenyl, 2-ftoheia, 4-hydroxyphenyl, acid, 5,6,7,8-tetrahydro-1-naphthyl, 4-ptomaphila, 4-cyanonaphthalene, 4-lower alkoxymethyl and 4-(2,6-dichlorobenzenesulfonyl)phenyl, R4- isopropyl, cyclohexyl or phenyl, R5is ethyl or methyl and n = 2 or 1, or its salt, provided that there is at least one salt-forming group.

5. The compound of formula I under item 1, which is selected from the following compounds:

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(p-benzyloxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-cyanophenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(o-forfinal)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-{[p-(2-phenylethyl) phenyl]methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-{ [n-(2,6-dichlorobenzenesulfonyl)phenyl]methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-guide)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-isobutoxide)-2R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-(phenylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-{ [(1-ethoxycarbonylpyrimidine-4-yl)carbonyl] amino} 4(S)-hydroxy-6-cyclohexyl-2(R) - [(p-methoxyphenyl)methyl]hexanoyl -(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-cyclohexylmethyl)hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-(4-methoxyphenyl)-2(R)-[cyclohexen-1-ylmethyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoyl-(L)-Vak-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-hydroxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-[(cyclohexyl)Glu]-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-[(phenyl)Glu]-N-(2-methoxyethyl)amide;

5(S)-(3(S)-tetrahydroprotoberberine)-5-(S)-hydroxy-6-cyclohexyl-2-(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(2(R, S)-tetrahydroprotoberberine)-4-(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(5(S)-oxopentanenitrile)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(2-methoxyethoxymethyl)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-((L)-thiazolidin-4-ylcarbonyl)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(4-oxo-4H-1-benzopyran-2-ylcarbonyl)-4-(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(indolyl-2-ylcarbonyl)-4-(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(methoxycarbonyl-(L)-Val-N-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-([N-((L)-thiazolidin-4-ylcarbonyl-(L)-Val] -amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(benyl-(L)-Val-N-(2-methoxyethyl)amide;

5(2) - ((L)-[TRANS-4-hydroxypropyl] amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(2-amino-4-thiazoleacetate)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(6-(4-methyl-1-piperazinil)-3-pyridylcarbonyl)-4-(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(4-(4-morpholinylmethyl)benzoylamine)-4-(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(O[4-tetrahydropyranyl] -(L)-lactosamine)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-hydroxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

(S)-(BOC-amino-4(S)-hydroxy-6-phenyl-2(R)-[(p-isobutoxide)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[p-(2-pyridyloxy)phenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-what phenyl-2(R)-[(3,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4,5-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,4,6-trimethoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(5,6,7,8-tetrahydro-1-naphthyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,5-acid)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,6-acid)methyl] -(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-methoxy-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-cyano-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-fluorescent-1-naphthyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

5(S)-(BOC-amino)-4(S)-hydroxy-6-[p-(2-methoxyethoxy)phenyl] -2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide; and

5(S)-(BOC-amino)-4(S)-hydroxy-6-[(n-(2-methoxyethoxy)phenyl] -2(R)-{[p-(2-methoxyethoxy)phenyl]methyl}hexanoyl-(L)-Val-N-(2-methoxyethyl)amide;

or its salt, provided that there is at least one salt-forming group.

6. The compound of formula I under item 1, which is selected from the following compounds:

5(S)-(2-methoxy-1(R, S)-methylethanolamine)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-[(cyclohexyl)Gly]-N-(2-methoxyethyl)amide,

5(S)-(etoxycarbonyl-(L)-Val-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(1,1-dimethyl-2-methoxyethylamine)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(4-biphenylyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide.

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2 (who phenyl)-methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[({ 2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-[({ 2'-cyanobiphenyl}-4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

5(S)-(BOC-amino)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-[({2'-cyanobiphenyl}-4-yl)-methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide and

5(S)-(3-hydroxy-2-methylphenylsiloxane)-4(S)-hydroxy-6-(p-methoxyphenyl)-2(R)-[({ 2'-cyanobiphenyl} -4-yl)methyl]hexanoyl-(L)-Val-N-(2-methoxyethyl)amide,

or its salt, provided that there is at least one salt-forming group.

7. Pharmaceutical preparation having antiviral activity and containing the compound of formula I in an effective amount or its pharmaceutically used salt according to any one of paragraphs.1 to 3 together with a pharmaceutically used by the media.

8. Composition active substances, characterized in that it comprises a compound of the formula I according to one of paragraphs.1 - 5 or its pharmaceutically acceptable salt in combination with an additional substance with antiviral activity, where the molar ratio of the compounds of formula I and the additional compound is in the range 8:1 to 1:2.

9. Composition p is-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide, and b) one or both of the active compounds saquinavir and indinavir.

10. Pharmaceutical drug with antiviral activity comprising an effective amount of the composition under item 8, possessing antiviral activity, together with a pharmaceutically acceptable carrier.

11. Pharmaceutical drug under item 10, characterized in that it is a combination of (a) compounds of formula I, having the designation 5(S)-(BOC-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4 trimethoxyphenyl)methyl] hexanoyl-(L)-Val-N-(2-methoxyethyl)amide, together with b) one or both of the active compounds saquinavir and indinavir.

12. The method of obtaining the compounds of formula I under item 1, in which condense the acid of formula II

R1-OH

or its reactive derivative,

where R1has the same meaning as in the compounds of formula I,

with aminoguanidinium formula III

< / BR>
or its reactive derivative,

where n and the radicals have the meanings given for compounds of formula I, with free functional groups, with the exception of those that participate in the reaction, are present, if necessary, in protected form in the original substances of the formulae II and III,

and the .10 and 11.

 

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