KR100486051B1 - Antivirally Active Heterocyclic Azahexane Derivatives - Google Patents

Abstract

The salts of the compounds of formula I * or at least one salt forming group, if present, are described.

<Formula I *>

Where

R ₁ is lower alkoxycarbonyl,

R ₂ is sec- or tert-lower alkyl or lower alkylthio-lower alkyl,

R ₃ is phenyl unsubstituted or substituted by one or more lower alkoxy groups, or C ₄ -C ₈ cycloalkyl,

R ₄ is substituted or unsubstituted by lower alkyl or phenyl-lower alkyl and has from 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ). Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom, having from 5 to 8 ring atoms,

R ₅ is one of the groups described for R ₂ independently of R _2,

R ₆ is lower alkoxycarbonyl independently of R ₁ .

These compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit good pharmacokinetic properties.

Description

Antivirally Active Heterocyclic Azahexane Derivatives

According to the WHO estimates, more than 20 million people are currently infected with HIV-1 or HIV-2, the "human immunodeficiency virus." Almost without exception, infected patients develop prevalent stages of the immune system known as "acquired immunodeficiency syndrome or AIDS" through preliminary stages such as ARDS. In the case of an overwhelming number, this disease will soon kill infected patients.

Inhibitors of reverse transcriptase, an enzyme that converts retroviral RNA into DNA, such as 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI) and also trisodium phosphonoformate , Ammonium-21-tungstenato-9-antimonate, 1-β-D-ribofuranooxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine, and also adriamycin Has been used until now mainly to treat retroviral diseases such as AIDS. In addition, T4 cell receptors, which are present on specific cells of the body's immune system and serve to immobilize infectious viral particles and introduce them into these cells, resulting in infection, for example, as recombinant molecules or molecular fragments Attempts have been made to introduce the goal, which is to block the binding site of the virus so that the virion can no longer bind to the cell. Compounds that prevent viruses from passing through cell membranes in other ways, such as polymannoacetate, are also used.

The first so-called retroviral aspartate protease inhibitors allowed for the inhibition of this infection were saquinavier (N-tert-butyl-decahydro-2- [2 (R) -hydroxy-4-phenyl-3 ( S)-[[N-2-quinolylcarbonyl-L-asparaginyl] amino] butyl]-(4aS, 8aS) -isoquinoline-3 (S) -carboxamide (Ro 31-8959)) . Other compounds have since been subsequently accepted (Merck and Ribbonavir).

Many other inhibitors of the retroviral aspartate protease, an enzyme that functions as follows, are currently under development.

For AIDS viruses, HIV-1 and HIV-2, and corresponding viruses in other retroviruses, such as cats (FIV) and monkeys (SIV), for example, the core protein of the virus is HIV-protease and the like. Mature by proteolysis with aspartate protease. If there is no maturation by hydrolysis, infectious viral particles cannot form. The maturation stage induced by the protease due to the central role of the aspartate protease such as HIV-1 or HIV-2 protease in the maturation of the virus and based on, for example, experimental results on infected cell culture. Effectively inhibiting is expected to inhibit the assembly of mature virions in vivo. Thus, suitable inhibitors can be used for the treatment.

It is an object of the present invention to have high antiviral activity against many viral strains, including strains that have high inhibitory activity against viral replication in cells and are resistant to known compounds such as saquinavier, ritonavir and indinavir, and in particular It is to provide novel compounds having good pharmacokinetic properties such as advantageous pharmaceutical properties such as high bioavailability and high blood concentration and / or high selectivity.

Azahexane derivatives according to the invention are the compounds of formula (I) or salts thereof if at least one salt forming group is present.

Where

R ₁ is lower alkoxycarbonyl,

R ₂ is sec- or tert-lower alkyl or lower alkylthio-lower alkyl,

R ₃ is phenyl unsubstituted or substituted by one or more lower alkoxy groups, or C ₄ -C ₈ cycloalkyl,

R ₄ is substituted or unsubstituted by lower alkyl or phenyl-lower alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ) Phenyl or cyclohexyl, each substituted at the 4-position by an unsaturated heterocyclyl having 5 to 8 ring atoms, bonded via a ring carbon atom,

R ₅ is one of the groups described for R ₂ independently of R _2,

R ₆ is lower alkoxycarbonyl independently of R ₁ .

These compounds have surprisingly good and surprisingly positive pharmaceutical properties, as detailed below, and the synthesis is relatively simple.

Unless otherwise indicated, the above and the following general terms have the following meanings within the scope of the present invention.

The term "lower" refers to a group of carbon atoms containing up to 7 carbon atoms, preferably up to 4 carbon atoms, which group is not branched or branched more than once.

Lower alkyl and C ₁ -C ₄ -alkyl are especially tert-butyl, sec-butyl, isobutyl, n-butyl, isopropyl, n-propyl, ethyl and methyl.

When referring to a plurality of compounds, salts, etc., one compound, one salt, and the like are encompassed.

All asymmetric carbon atoms present, such as, for example, carbon atoms bonded to R ₂ and R ₅ groups, are (R)-, (S)-or (R, S) -stereo arrays, preferably (R)- Or (S) -stereo arrays, with (S) -stereo arrays being preferred for carbon atoms having R ₂ and / or R ₅ in the compounds of formula (I). Thus, the compounds may exist in the form of isomeric mixtures or in the form of pure isomers, preferably in the form of enantiomerically pure diastereomers.

Lower alkoxycarbonyl is preferably C ₁ -C ₄ -alkoxycarbonyl, in which the alkyl group is branched or unbranched, in particular ethoxycarbonyl or methoxycarbonyl.

sec- and tert-lower alkyl are in particular sec-butyl, tert-butyl or isopropyl.

Lower alkylthio-lower alkyl is especially methylthiomethyl.

Phenyl unsubstituted or substituted by one or more lower alkoxy groups is especially phenyl unsubstituted or substituted by one to three alkoxy groups, in particular methoxy. In the case where three methoxy substituents are present, in particular in the 2,3,4-position of the phenyl ring, in the case where one methoxy group is present, the substituents are in particular in the 2-, 3-position, more particularly It is in the 4-position. Unsubstituted phenyl is preferred.

C ₄ -C ₈ cycloalkyl is especially cyclopentyl or more particularly cyclohexyl.

As R ₃ , phenyl is preferred over cyclohexyl.

Substituted or unsubstituted by lower alkyl or phenyl-lower alkyl and comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ); In phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom having 8 ring atoms, the corresponding heterocyclyl has the following meanings in particular:

Unsaturated heterocyclyl bonded via a ring carbon atom is 5 to 8 containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ). Having a ring atom and unsubstituted or substituted by lower alkyl, in particular methyl or by phenyl-lower alkyl, where the lower alkyl group is unbranched or branched, in particular 1-methyl-1-phenylmethyl One of the following groups bonded via a carbon atom: thienyl (= thiophenyl); Oxazolyl; Thiazolyl; Imidazolyl; 1,4-thiazinyl; Triazolyl unsubstituted or in particular substituted with 1-methyl-1-phenylethyl or preferably with tert-butyl, especially with methyl, for example 1-, 2-, or 4- (methyl or tert-butyl) -triazol-3-yl; With tetrazolyl, for example 1-methyl-1-phenylethyl, or preferably unsubstituted or especially substituted by lower alkyl such as 1-methyl-1-phenylethyl or preferably tert-butyl or especially methyl Is 2H-tetrazol-5-yl substituted by tert-butyl or especially lower alkyl such as methyl, or 1H-tetrazol-5-yl substituted by tert-butyl or especially methyl; Pyridinyl; Pyrazinyl; And pyrimidinyl; More particularly 2- or 3-thienyl (= thiophen-2-yl or thiophen-3-yl); Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or in particular substituted in 2-position with 1-methyl-1-phenylethyl or preferably with tert-butyl or especially with methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-2-yl; Pyridin-3-yl; Pyridin-4-yl; Or pyrazin-2-yl.

R ₄ is preferably phenyl substituted at the 4-position by unsaturated heterocyclyl, wherein the unsaturated heterocyclyl is selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO ₂ ) Heterocyclic having 5 to 8 ring carbon atoms, including 1 to 4 heteroatoms, which are bonded through a ring carbon atom and substituted or unsubstituted by lower alkyl or phenyl-lower alkyl, heterocyclyl is preferably Has the meaning defined as preferred above.

The compound of formula (I) preferably has formula (Ia) in which the definition of the group is as described above.

Salts are especially pharmaceutically acceptable salts of compounds of formula (I).

Such salts are for example by compounds of formula (I) having a basic R ₄ -CH ₂ -bearing nitrogen atom, preferably by inorganic acids, such as hydrochloric acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or by strong organic sulfonic acid, sulfuric acid or phosphoric acid Or N-substituted sulfamic acid (preferably pKa <1) as an acid addition salt. Another salt may be present when a basic heterocyclyl group such as pyridyl is in R ₄ . Such salts are in particular acid addition salts with organic or inorganic acids, in particular pharmaceutically acceptable salts. Suitable inorganic acids are, for example, hydrochloric acid such as hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids include, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2-hydroxybutyl acid, gluconic acid , Glucose monocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids such as glutamic acid, aspartic acid, N Methylglycine, acetylaminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphate, glucose-6-phosphate, glucose-1-phosphate, fructose Lactose-1,6-diphosphoric acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2 -Carboxylic acid, 3,4,5-trimethoxybenzoic acid, 2- Oxybenzoic acid, 2-acetoxybenzoic acid, 4-amino-salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, glucuronic acid, galacturonic acid, methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 , 2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenesulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfate, N-cyclohexyl sulfamic acid , N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protic acid, such as ascorbic acid.

If a negatively charged group is present in R ₄ , for example tetrazolyl, the salt may be, for example, a metal salt such as an alkali metal or alkaline earth metal salt (such as sodium, potassium, magnesium or calcium salts) or ammonia or a suitable organic. Bases such as ammonium salts with amines such as tertiary monoamines such as triethylamine or tri (2-hydroxyethyl) -amine, or heterocyclic bases such as N-ethyl-piperidine Or N, N'-dimethylpiperazine.

For isolation or purification, it is also possible to use pharmaceutically unsuitable salts such as picrates or perchlorates, for example. Only pharmaceutically acceptable salts or free compounds (optionally in the form of pharmaceutical compositions) can be used for the treatment and are therefore preferred.

In view of the deep linkage between the novel compounds in free form and salt compounds, including salts which can be used, for example, in the purification of new compounds or as intermediates in the identification of new compounds, all references above and below to free compounds Is to be understood to encompass the corresponding salts as appropriate for convenience.

Compounds of formula (I) have important pharmaceutical properties. They have activity against antiretroviral activity, in particular HIV-1 and HIV-2 viruses, which are believed to be the cause of AIDS, and surprisingly have a synergistic effect when used with other compounds that have activity against retroviral aspartate protease. Compounds of formula (I) are inhibitors of retroviral aspartate proteases, in particular inhibitors of aspartate proteases of HIV-1 or HIV-2, and thus prevent retroviral diseases such as AIDS or preliminary steps thereof (eg ARDS). Suitable for treatment. Compounds of formula (I) show activity against the corresponding animal retrovirus, for example SIV (monkey) or FIV (cat).

Compounds of formula (I) are surprisingly particularly advantageous and have cell tests against various viral strains, including viral strains that are resistant to other protease inhibitors, for example very high antigens in MT2-cells. Good pharmacokinetic properties such as viral activity, high bioavailability, high selectivity and especially high blood concentrations (even for oral administration).

The inhibitory action of the compounds of formula (I) on the proteolytic activity of HIV-1 protease can be demonstrated, for example, according to known procedures (AD Richards et al., J. Biol. Chem. 265 (14), 7733-7736 ( 1990). In this case, the inhibition rate for the activity of the HIV-1 protease (manufactured by S. Billich et al., J. Biol. Chem. 263 (34), 17905-17908 (1990)) is a gag precursor protein as substrate analogue. Icosapeptide (RRSNQVSQNYPIVQNIQGRR; synthetic substrate of HIV-1 protease; one known method (see J. Schneider et al., Cell 54, 363-368 (1988)) Measured in the presence of peptide synthesis). This substrate and its cleavage product are analyzed by high performance liquid chromatography (HPLC).

Test compounds are dissolved in dimethyl sulfoxide. Enzyme testing is performed by adding to the test mixture a solution in which the inhibitor is appropriately diluted in 20 mM β-morpholinoethanesulfonic acid (MES) buffer (pH 6). The test mixture consists of the Icosapeptides (122 μM) in 20 mM MES buffer, pH 6.0. 100 μl is used as a test batch. The reaction is initiated by adding 10 ml of HIV-1 protease solution and terminated after incubating for 1 hour at 37 ° C. by adding 10 μl of 0.3 M HClO ₄ . After centrifuging the sample at 10,000 xg for 5 minutes, 20 μl of the supernatant obtained was subjected to a 125x4.6 mm Nucleosil C18-5μ HPLC column (Macherey & Nagel, Dueren, FRG based on silica gel coated with C ₁₈ alkyl chains). Loaded on the reverse phase). Uncleaved Icosapeptides and their cleavage products are eluted from the column at a flow rate of 1 ml / min for 15 minutes in the following gradient: 100% eluent 1 → 50% eluent 1 + 50% eluent 2 (for Excipient 1: 10% acetonitrile, 90% H ₂ O, 0.1% trifluoroacetic acid (TFA); eluent 2: 75% acetonitrile, 25% H ₂ O, 0.08% TFA). Eluted peptide fragments are quantified by measuring the peak height of the cleavage product at 215 nm.

Compounds of formula (I) exhibit inhibitory activity in the nanomolar (nM) range, which preferably has an IC ₅₀ value (IC ₅₀ = concentration at which the activity of HIV-1 protease is reduced by 50% compared to that of a control-free inhibitor) Is about 2 x 10 ^-7 to 5 x 10 ^-9 M, preferably 5 x 10 ^-8 to 5 x 10 ^-9 M.

Other experiments for determining inhibitory activity against HIV-proteases (see Matayoshi et al., Science 247, 954-958 (1990), modified herein), are briefly summarized as proteases (tablets: Leuthardt et al., FEBS Lett. 326, 275). -80 (1993)) assay buffer at room temperature [20 mM MES pH 6.0, 200 mM NaCl, 1 mM dithiothreitol, 10 μΜ fluorescent substrate SC4400 {4- (4-dimethylaminophenylazo) benzoyl-γ- 0.01% containing aminobutyryl-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-EDANS (EDANS = 5- (2-aminoethylamino) -1-naphthalenesulfonic acid), Neosystem Laboratoire, France} Polyethylene glycol (average molecular weight 6000-8000 Da)] was incubated in 100 [mu] l. The reaction is stopped by adding 900 μl of 0.03 M HClO ₄ . HIV-1 protease activity is determined by measuring the increase in fluorescence at λex = 336, λem = 485 nm. The IC ₅₀ value of the compound of formula I is determined as the concentration of compound required to inhibit protease activity by 50% in the assay. Values were obtained from computer-generated graphs from relevant data at at least five concentrations of the compound of formula (I), with three determinations per concentration.

Further tests may demonstrate that the compounds of formula (I) protect cells by preventing or at least slowing the infection of cells normally infected by HIV. For this test, MT-2-cells infected with HIV-1 / MN are used. MT-2 cells have been transformed with HTLV-1 (leukemia-inducing virus) and its serial producers and are therefore particularly sensitive to the cytopathogenic effects of HIV. MT-2 cells can be obtained from Dr. Douglas Richman through the National Institutes of Health (NIH), the NIAID, AIDS Division, and the AIDS Research and Reference Reagent Program (J. Biol. Chem. 263, 5870-5875 ( 1988) and Science 229, 563-566 (1985). MT-2 cells are cultured in RPMI 1640 medium (Gibco, Scotland; RPMI contains a glutamine deficient amino acid mixture) supplemented with calf serum, glutamine and standard antibiotics inactivated by 10% heat treatment. In all cases the cells used for infection and also viral stock solutions (HIV-1 / MN) are free of mycoplasms. Viral stock solutions are prepared from cell culture supernatants of the permanently infected cell line H9 / HIV-1 / MN, which are lined with Robert Gallo (NIH), the NIAID, the AIDS Division, and the AIDS Research and Reference Reagent Program. Robert Gallo) (see Science 224, 500-503 (1984) and Science 226, 1165-1170 (1984)). The appropriate concentration of HIV-1 / MN virus stock solution (determined by titration to MT-2 cells) was 4.2 × 10 ⁵ TCID50 / ml (TCID50 = tissue culture infection dose = dose infecting 50% of MT-2 cells) )to be. In order to determine the inhibitory activity of the compounds of formula (I), MT-2 multiplied by 2 × 10 ⁴ exponential function to 2800 TCID50 of HIV-1 / MN in 50 μl of each corresponding test compound in culture medium and 100 μl of culture medium. Cells were added and applied to 50-ul culture medium in 96-well microtiter plates (with round base). After incubation for 4 days (37 ° C., 5% CO ₂ ), 10 μl samples of supernatant were taken from each well and transferred to another 96-well microtiter plate and stored at −20 ° C. (if needed). To measure virus-associated reverse transcriptase activity, 30 μl of reverse transcriptase (RT) cocktail is added to each sample. Reverse transcriptase cocktail is 50 mM Tris (α, α, α-tris (hydroxymethyl) methylamine, Ultra pur, Merk, Germany), pH 7.8, 75mM KCl, 2mM dithiothreitol, 5mM MgCl ₂ , 0.1% Noni Det P-40 (cleaner; from Sigma, Switzerland), 0.8 mM EDTA, 10 μg / ml poly-A (from Pharmacia, Uppsala, Sweden) and 0.16 μg / ml oligo (T) (= pdT (12-18), Sweden Pharmacia from Uppsala) contains a "template primer" and, if necessary, the mixture is filtered through a 0.45 mm Acrodisc filter (Gelman Science Inc., Ann Arbor, USA). It is stored at -20 ° C. Prior to testing, 0.1% (v / v) of [alpha- ³² P] dTTP is added to an aliquot of the solution to obtain 10 μCi / ml of radioactivity.

After mixing, the plates are incubated at 37 ° C. for 2 hours and then 5 μl of the reaction mixture is transferred to DE81 paper (Whatman, one filter per well). The dried filter is washed three times for 5 minutes with 300 mM NaCl / 25 mM trisodium citrate, once with ethanol and once again dried in air. Radioactivity on the filter is measured with a Matrix Packard 96-well counter (Packard, Zurich, Switzerland). The ED ₉₀ value is calculated and defined as the concentration of the test compound that reduces the RT activity by 90% compared to the control without the test compound.

Preferred compounds of formula (I) show ED ₉₀ (90% inhibition of viral replication) at concentrations of 10 ⁻⁷ to 10 ⁻⁹ M, in particular 5 × 10 ⁻⁹ to 10 ⁻⁹ M.

Thus, compounds of formula I are suitable for very effectively delaying HIV-1 replication in cell culture.

To determine their pharmacokinetic properties, the compounds of formula I are dissolved in dimethyl sulfoxide (DMSO) at a concentration of 240 mg / ml. The resulting solution is diluted to 1:20 (v / v) with 20% (w / v) hydroxypropyl-β-cyclodextrin aqueous solution to obtain a test compound concentration of 12 mg / ml. This solution is briefly treated with ultrasound and then orally administered to BALB / c mouse females (Bomholtgarden, Copenhagen, Denmark) by artificial tube feeding at a dose of 120 mg / kg. Animals are killed after a period of time (eg, 30 minutes, 60 minutes, 90 minutes and 120 minutes) after administration and the plasma is stored in heparinized test tubes. Blood is centrifuged (12000 x g, 5 min) to separate plasma. The same volume of acetonitrile is added to the plasma to remove the protein. The mixture is mixed using a vortex mixer and left at room temperature for 20 to 30 minutes. The precipitate is pelleted by centrifugation (12000 x g, 5 minutes) and the concentration of test compound is determined by reverse phase high performance liquid chromatography (HPLC).

HPLC analysis of the samples obtained according to the above method was performed using a 125 x 4.6 mm Nucleosil® C ₁₈ -column (silica derivatized with a carbon group having 18 carbon atoms) using a 2 cm long preparative column of the same column material. Gel-based reversed phase product, Macherey & Nagel, Duren, Germany). This test consists of the following linear acetonitrile / water gradient (0.05% trifluoroacetic acid in each case): 20% acetonitrile to 100% acetonitrile 20 minutes, then 100% acetonitrile 5 minutes, then 1 minute and Perform regression to initial state for 4 min rebalance. Flow rate is 1 ml / min. Under these conditions, the compound of formula I obtained in Example 1 has a residence time of about 15.5 minutes and a detection limit of 0.1 to 0.2 μM. Test compounds are detected by UV absorbance measurements at 255 nm. Peaks are identified by retention time and UV spectrum appears between 205 and 400 nm. Concentration is determined by an external standard method, the peak height is used to determine the concentration compared to the standard curve. Standard curves are obtained through similar HPLC analysis of mouse plasma, which already knows the concentration of the test compound involved and which has been treated in the manner described above.

In this experiment, the compound of formula (I) has a much higher plasma concentration than ED ₉₀ determined in the cell experiment, for example, up to 8000 times higher than ED ₉₀ after 30 minutes, and up to 10500 times higher than ED ₉₀ after 90 minutes. And a preferred plasma concentration is from 0.1 μM to 25 μM, in particular from 1 to 25 μM 30 minutes after oral administration, and the plasma concentration from 90 minutes after oral administration is from 0.5 to 35 μM, in particular from 1 to 35 μM.

Similarly, in dogs, the concentration in the blood of a compound of formula (I), for example the title compound of Example 46, can be measured using, for example, a formulation according to Example 63 or Example 64. For example, 92-100 mg / kg of compound administered via gavage is used, and then the concentration in the blood is measured, for example, 1, 2, 3, 4, 6, 8 and 24 hours after administration. Also here concentrations in the blood can be observed in the μM range.

In particular, surprisingly high bioavailability (high plasma concentration) and surprisingly good ED ₉₀ in cell experiments together give the compounds of the invention an unprecedented value. Activity against inhibitors of the retroviral aspartate protease, which have already appeared tolerate, is still possible and there is a further important advantage of the compounds according to the invention.

This can be demonstrated, for example, by the following or similar test: Inhibitor-resistant HIV-1 protease mutants are cloned as follows. HIV-protease mutants are freely available through infectious clone pNL4-3 ("NIH AIDS reference and reagent program") through PCR-supported mutagenesis and cloning; the original reference is A. Adachi et al., J. Virol ( 1986) 59, 284-91, but of course this can be any other HIV clone or even a clinical material if it is certainly equivalent). In other respects, allogeneic point mutants include only the changes described in the literature with respect to viral resistance to various protease inhibitors. The cloned fragments are only 500 bp in length, for example, and the rest have not changed. Always use mutations in the same clone to ensure direct equivalence, which will not be the case for direct comparisons of clinical samples or direct comparisons of other HIV clones. In transient DNA transfection assays, proviruses produced in human T4-positive cells (HeLaT4) also show a decrease in inhibitory activity when compared to wild-type virus, meaning increased resistance. This system is used as a transient DNA transfection system for 1) identifying possible cross resistance of protease variants to various protease inhibitors, and 2) testing to establish the performance and schematic resistance of new inhibitor candidates.

For example, in the transfection system described above, 1- [4- (pyridin-2-yl) phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N -Methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane (Example 46) has an IC ₉₀ of less than 30 nM, which is practically useful in Saoffavier (Hoffmann-LaRoche, Better in vitro performance, 5 (S)-(tert-butoxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R)-(2,3,4- Trimethoxyphenylmethyl) -hexanoyl- (L) -valyl-N- (2-methoxy-ethyl) -amide (= Racinavier, EP 0 708 085 (published April 24, 1996, originally Ciba) Activity against resistant variants (45l / 76F strain) established against Gaigi AG, owned by Nopartis AG, is comparable to saquinavir and indinavir (Merck & Co., Inc., see below). Or better than the activity of ritonavir (Abbott, see below) 10 nM saquinavier, ritona compared to other strains (eg, 46 l / 47 V / 50 V (VX478)). Caused more potent activity than fish and indinavir (not quantified) Instead of the strains described above, "in the name of Richard Axel and Paul Maddon in the NIH AIDS reference and reagent program Any human T4-positive cell, such as HeLa T4 cells deposited and available therefrom, can be used.

In principle, suitable mutations for this test system for resistance are known (eg 48V / 90M strains (Saquinavier resistance): Jacobsen, H., Yasargil, K., Winslow, DL, Craig, JC, Krohn) , A., Duncan, IB, & Mous, J. Virology 206, 527 (1995); Merch Mutationen (multiple dogs, for example 71V / 82T / 84V): Condra, JH, Schlief, WA, Blahy, OM, Gabryelski , LJ, Graham, DJ, Quintero, JC, Rhodes, A., Robbins, HL, Roth, E. Shivaprakash, M., & et al. Nature 374, 569 (1995); Abbott 82V / 84A strain: Markowitz, M., Mo, H., Kempf, DJ, Norbeck, DW, Bhat, TN, Erickson, JW, & Ho, DDJ Virol. 69, 701 (1995).

When determining antienzymatic activity against numerous human aspartate proteases according to known methods (see, eg, Biochem. J. 265, 871-878 (1990)), the compounds of formula (I) may be High selectivity to retroviral aspartate protease. For example, the inhibition rate constant (IC ₅₀ ) for the compound of formula (I) for cathepsin D in the test is at least 10 μM, in particular at least 25 μM. In this test the IC ₅₀ for human cathepsin D is measured at pH 3.1. This test is performed following known procedures using substrate KPIQF * NphRL (Jupp, RA, Dunn, BM, Jacobs, JW, Vlasuk, G., Arcuri, KE, Veber, DF, S. Perow, DS, Payne , LS, Boger, J., DeLazlo, S., Chakrabarty, PK, TenBroeke, J., Hangauer, DG, Ondeyka, D., Greenlee, WJ and Kay, J .: Statins for Various Aspartate Proteases Selectivity of the substrate inhibitor, see Biochem. J. 265: 871-878 (1990)).

The compounds of formula (I) may be used alone or in other pharmaceutical active substances (or salts thereof, if at least one salt former is present) which is active against retroviruses, in particular HIV, eg HIV-1 or HIV-2. In combination (either as a fixed mixture of corresponding compositions or as a mixture or separate compositions of individual compounds administered sequentially at staggered times), in particular inhibitors of reverse transcriptases, in particular nucleoside analogs, in particular 3′-azido-3 '-Deoxythymidine (= dozibudine = RETROVIR®, Burroughs-Wellcome), 2', 3'-dideoxycytidine (= salcitabine = HIVID®, Hoffmann-LaRoche), 2 ', 3'-dideoxyinosine (= didanosine = VIDEX®, Bristol-Myers-Squibb) or (2R, cis) -4-amino-1- (2-hydroxymethyl-1,3-oxathiolane- 5-yl)-(1H) -pyrimidin-2-one (= lamivudine, Glaxo), in particular d4C = 2 ', 3'-didehydro-2', 3'-dideoxycytidine, d4T = 2 ', 3'-didehydro-2', 3'-dideoxythymidine (= stavudine = ZERIT®) or 2 ', 3'-dideoxyinosine (= ddlno = DZI = didanosine = VIDEX®); Or non-nucleoside analogs, for example 11-cyclopropyl-5,11-dihydro-4-methyl- (6H) -dipyrido [3,2-b; 2 ', 3'-e]-[ 1,4] diazepine-6-one, and one or more (especially one or two) of retroviral aspartate proteases, in particular other inhibitors of HIV (eg HIV-1, HIV-2), in particular It may be administered in combination with (a) to (h) and salts thereof, if salt forming groups are present:

a) European Patent 0 346 847 (published December 20, 1989) and European Patent 0 432 695 (published June 19, 1991; corresponding patents of US Pat. No. 5,196,438 (published March 23, 1993)); One of the inhibitors described, in particular the compound Ro 31-8959 (= Saquinavier, Hoffman-LaRoche),

b) one of the inhibitors described in European Patent 0 541 168 (published May 12, 1993; corresponding patent of US Pat. No. 5,413,999), in particular compound L-735,524 (= indinavir = CRIXIVAN; Merck & Co., Inc .),

c) one of the inhibitors described in European Patent No. 0 486 948 (published May 27, 1992; corresponding patent of US Pat. No. 5,354,866), in particular compound ABT-538 (= ritonavir, Abbott),

d) compound KVX-478 (or VX-478 or 141W94; Glaxo Wellcome, Vertex and Kissei Pharmaceuticals),

e) compound AG-1343 (Agouron),

f) compound KNI-272 (Nippon Mining),

g) compound U-96988 (Upjohn), and / or

h) Compound BILA-2011 BS (= Parinavier, Boehringer-Ingelheim).

i) compound 5 (S)-(tert-butoxycarbonylamino) -4 (S) -hydroxy-6-phenyl-2 (R)-(2,3,4-trimethoxyphenylmethyl) -hexa Noyl- (L) -valyl-N- (2-methoxy-ethyl) -amide (= Racinavier, EP 0 708 085 (published April 24, 1996, originally filed by Ciba-Geigy AG, Nofar) Owned by tisge).

In addition, the compounds of formula (I) can be used to prevent, inhibit and treat infections of retroviruses, in particular HIV (eg HIV-1, HIV-2), in cell culture, especially in cell culture of lymphocyte cell lines of warm-blooded animals. This is of great commercial value because it is particularly advantageous in very important cell cultures, for example producing certain antibodies, vaccines or messenger materials such as interleukin and the like.

Finally, the compounds of formula (I) can be used as reference materials, for example as HPLC standards or as reference materials for animal model comparisons, in experiments with different aspartate protease inhibitors, for example with respect to the concentrations in the blood obtained. have.

In the preferred groups of formula (I) mentioned below, the definitions of substituents may be used from the general definitions provided above for convenience (for example, to replace more general definitions by the most specific definitions or those described as being particularly preferred), Preferred in each case are the definitions described above as preferred or provided as examples.

Preferred

R ₁ is lower alkoxycarbonyl, in particular methoxycarbonyl or ethoxycarbonyl,

R ₂ is isopropyl, sec-butyl (preferably (S) -configuration), or tert-butyl,

R ₃ is phenyl or else cyclohexyl,

R ₄ is thienyl (= thiophenyl) bonded via a ring carbon atom; Oxazolyl; Thiazolyl; Imidazolyl; 1,4-thiazinyl; Triazolyl unsubstituted or in particular substituted by 1-methyl-1-phenylethyl or preferably by tert-butyl, especially by methyl, for example 1-, 2-, or 4- (methyl or tert -Butyl) -triazol-3-yl; With tetrazolyl, for example 1-methyl-1-phenylethyl, or preferably unsubstituted or especially substituted by lower alkyl such as 1-methyl-1-phenylethyl or preferably tert-butyl or especially methyl Is 2H-tetrazol-5-yl substituted by lower alkyl such as tert-butyl or especially methyl, or 1H-tetrazol-5-yl substituted by methyl; Pyridinyl; Pyrazinyl; And pyrimidinyl; In particular 2- or 3-thienyl (= thiophen-2-yl or thiophen-3-yl); Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or in particular substituted in 2-position with 1-methyl-1-phenylethyl or preferably with tert-butyl or especially with methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-2-yl; Pyridin-3-yl; Pyridin-4-yl; Or phenyl substituted at the 4-position with one of pyrazin-2-yl,

R ₅ is isopropyl, sec-butyl (preferably (S) -configuration), tert-butyl or methylthiomethyl,

R ₆ is a compound of formula (I) which is lower alkoxycarbonyl, in particular methoxycarbonyl or ethoxycarbonyl, in particular a compound of formula (Ia) or a salt thereof (if present with a salt forming group), in particular a pharmaceutically acceptable salt thereof.

More preferably,

R ₁ is methoxycarbonyl or ethoxycarbonyl,

R ₂ is isopropyl, sec-butyl or tert-butyl,

R ₃ is phenyl,

R ₄ is 2- or 3-thienyl (thiophen-2-yl or thiophen-3-yl); Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or in particular substituted at 2-position by 1-methyl-1-phenylethyl or preferably tert-butyl or particularly methyl; Or 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-2-yl; Pyridin-3-yl; Pyridin-4-yl; Or phenyl substituted at the 4-position by pyrazin-2-yl, particularly 4- (thiazol-2-yl) -phenyl; 4- (thiazol-5-yl) -phenyl; 4- (pyridin-2-yl) -phenyl; Or 4- (2-methyl-tetrazol-5-yl) -phenyl,

R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl,

R ₆ is methoxycarbonyl or ethoxycarbonyl,

Provided that R ₄ is 2- or 3-thienyl (= thiophen-2-yl or thiophen-3-yl); Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or substituted in the 2-position with 1-methyl-1-phenyl-ethyl or preferably with tert-butyl or especially with methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-3-yl; Pyridin-4-yl; Or a phenyl in which the 4-position of the phenyl ring is substituted by pyrazin-2-yl, at least one of the two groups R ₂ and R ₅ is tert-butyl or (if at least one salt forming group is pharmaceutically Acceptable salts thereof).

Particularly preferred is

R ₁ is methoxycarbonyl or ethoxycarbonyl,

R ₂ is isopropyl, sec-butyl or tert-butyl,

R ₃ is phenyl,

R ₄ is 4- (thiazol-2-yl) -phenyl; 4- (thiazol-5-yl) -phenyl; 4- (pyridin-2-yl) -phenyl; Or 4- (2-methyl-tetrazol-5-yl) -phenyl,

R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl,

R ₆ is a compound of formula I which is methoxycarbonyl or ethoxycarbonyl or a salt thereof (pharmaceutically acceptable if at least one salt forming group is present).

Very preferred are the compounds of formula (I) or the salts thereof (preferably pharmaceutically acceptable).

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L) -tert-louisyl) amino] -6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L) -tert-louisyl) amino] -6-phenyl-2-azahexane,

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane,

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane,

1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxy Carbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane,

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L)- Valeryl) amino] -6-phenyl-2-azahexane,

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane,

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S) -N -(N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, or

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 (S ) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane.

Especially preferred are the compounds of formula (I) described in the examples or their pharmaceutically acceptable salts if there are at least one salt forming group.

Salts of compounds of formula I and of these compounds having at least one salt forming group are prepared by known methods, for example as follows.

a) A hydrazine derivative of formula III is added to an epoxide of formula IV *, preferably formula IV, wherein the free functional groups, except those participating in the reaction, are present in protected form, if necessary), removing any protecting groups Or

b) condensing an amino compound of formula (V *), in particular of formula (V), with an acid of formula (VI) or a reactive acid derivative thereof, wherein the free functional groups, except for Remove the protector from, or

c) condensing an amino compound of formula (VII *), in particular of formula (VII), with an acid of formula (VIII) or a reactive acid derivative thereof (where free functional groups are present in protected form Remove the protector from, or

d) the substituents R ₁ and R ₆ pairs and R ₂ and R ₅ pairs are in each case two identical groups as defined for the compound of formula I and R ₃ and R ₄ as defined for the compound of formula I To prepare a compound of formula (I), condensation of a diamino compound of formula (IX *), in particular of formula (IX), with an acid of formula (VIIIa) or a reactive acid derivative thereof (where Present in protected form), or

e) reacting an imino compound of formula (I '*), in particular formula (I') with a compound of formula (X), wherein the free functional groups are present in protected form or,

f) reacting an imino compound of formula (I ′ *), in particular of formula (I ′), with an aldehyde of formula (X *), wherein the free functional groups, except those participating in the reaction, are present in protected form, if necessary) and removing any protecting groups An isomeric mixture obtained by converting a compound of formula (I) having at least one salt forming group obtained according to any one of the methods a) to f) And / or convert the compound of formula I according to the invention into another compound of formula I according to the invention.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as described for the compound of Formula I,

R ₁ ′ and R ₂ ′ are as defined for R ₁ and R ₆ in Formula I, respectively for R ₂ and R ₅ , with R ₁ and R ₆ pairs and R ₂ and R ₅ pairs in each case Is the same group.

X is a leaving group.

The above method is described in more detail below with reference to preferred embodiments.

In the following description of the preparation of the individual methods and starting materials, unless otherwise indicated, the groups R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined for the compounds of formula I, preferred In each case it is a definition that is presented as preferred.

Method a) (addition of amines to epoxides)

In the hydrazine derivatives of formula III, the amino groups participating in the reaction preferably have free hydrogen atoms, but this may have been induced to increase the reactivity of the hydrazine derivatives.

Epoxides of formula IV allow the final addition of hydrazine derivatives to proceed preferentially.

In the starting materials, functional groups to avoid reactions, especially carboxyl, amino and hydroxy groups, can be protected with suitable protecting groups (conventional protecting groups) commonly used for the synthesis of peptide compounds and for the synthesis of cephalosporins, penicillins, nucleic acid derivatives and sugars. have. These protecting groups may already be present in the precursor and protect the functional groups associated with unnecessary side reactions such as acylation, etherification, esterification, oxidation, solvolysis and the like. In some cases, protecting groups may also allow the reaction to proceed selectively, for example stereoselectively. Easily removable, ie can be removed under physiological conditions, for example by solvolysis, reduction, photolysis or enzymes, without undesirable side reactions. Although groups similar to protecting groups may be present in the final product, the compounds of formula (I) having protected functional groups may have greater metabolic stability or pharmacokinetic properties that are in some other way superior to the corresponding compounds having free functional groups. The above and below protecting groups are referred to in their true sense when the group is not present in the final product.

The protection of functional groups by such protecting groups, protecting groups themselves, and protecting group removal reactions are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry" (published by Pleunm Press in London and New York, 1973), Th. W. Greene, "Protective Groups in Organic Synthesis" (Willey, New York, 1981), "The Peptides" (vol. 3, edited by E. Gross and J. Meienhofer, published by Academic Press, London and New York, 1981), " Methoden der organischen Chemie "(Methods of Organic Chemistry; Houben Weyl, 4th edition, 15 / I, Georg Thieme Verlag, Stuttagart 1974), HD Jakubke and H. Jescheit," Aminosaeuren, Peptide, Preteine "(Amino Acids, Peptides and Proteins), Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and Jochen Lehmann "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (The Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974 have.

The carboxyl groups are protected, for example, in the form of ester groups which can be selectively cleaved under mild conditions. Carboxyl groups protected in esterified form are preferably esterified by lower alkyl groups branched at the 1-position of the lower alkyl group or substituted with suitable substituents at the 1- or 2-position of the lower alkyl group.

Protected carboxyl groups esterified with lower alkyl groups are for example methoxycarbonyl or ethoxycarbonyl.

The protected carboxyl group esterified with a lower alkyl group branched at the 1-position of the lower alkyl group is for example tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl.

The protected carboxyl group esterified with a lower alkyl group substituted at the 1- or 2-position of the lower alkyl group by a suitable substituent is for example 1 or 2 aryl groups (where aryl is for example lower alkyl (e.g. tert- Lower alkyl, e.g. tert-butyl, lower alkoxy (e.g. methoxy), hydroxy, halogen (e.g. chlorine) and / or phenyl unsubstituted or substituted one, two or three times by nitro Arylmethoxycarbonyl, for example benzyloxycarbonyl, benzyloxycarbonyl (eg 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl) substituted by the above substituents, diphenyl Methoxycarbonyl or diphenylmethoxycarbonyl substituted by such substituents (e.g. di- (4-methoxyphenyl) methoxycarbonyl) and other lower alkyl groups, where the lower alkyl groups are 1- or 2 Substituted with an appropriate substituent in the position) Carboxyl, for example 1-lower alkoxy-lower alkoxycarbonyl (e.g. methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl), 1-lower alkylthio- Lower alkoxycarbonyl (eg 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl), aroylmethoxycarbonyl (where the aroyl group is substituted by, for example, halogen (eg bromine) or Unsubstituted benzoyl), for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl (eg 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2- Iodoethoxycarbonyl), and also 2- (trisubstituted silyl) -lower alkoxycarbonyl, wherein the substituents are independently of each other substituted by lower alkyl, lower alkoxy, aryl, halogen and / or nitro or Unsubstituted aliphatic, araliphatic, cycloaliphatic, or aromatic hydrocarbon groups, for example the Substituted or unsubstituted lower alkyl group, such as phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl (e.g. 2-tri-lower alkylsilylethoxycar Carbonyl, for example 2-trimethylsilylethoxycarbonyl) or 2- (di-n-butylmethylsilyl) ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl (eg triphenylsilylethoxycarbon Bonyl.

In addition, the carboxy group is protected as an organosilyloxycarbonyl group. Organic silyloxycarbonyl groups are, for example, tri-lower alkylsilyloxycarbonyl groups (eg trimethylsilyloxycarbonyl).

The protected carboxyl group is preferably tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxy Carbonyl.

Protected amino groups can be protected, for example, in the form of acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino groups or as azido groups.

In the corresponding acylamino groups, acyl is substituted with, for example, lower carboxylic acids having up to 18 carbon atoms, in particular lower alkancarboxylic acids unsubstituted or substituted by halogen or aryl, or halogen, lower alkoxy or nitro or the like. Or an unsubstituted benzoic acid, or preferably an acyl group of carbonic acid semiester. Such acyl groups are, for example, lower alkanoyls (eg formyl, acetyl, propionyl or pivaloyl), halo-lower alkanoyls (eg 2-haloacetyl, eg 2-chloro-, 2- Bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl) benzoyl unsubstituted or substituted by halogen, lower alkoxy or nitro or the like (e.g. benzoyl , 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl), lower alkoxycarbonyl, preferably lower alkoxycarbon branched at the 1-position of the lower alkyl group or suitably substituted at the 1- or 2-position Carbonyl (e.g. tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl), 1, 2 or 3 aryl groups (where aryl is e.g. lower alkyl e.g. tert-lower alkyl, e.g. Tert-butyl), lower alkoxy (e.g. methoxy), hydroxy, halogen (e.g. chlorine) and / or nitro Arylmethoxycarbonyl, such as mono- or polysubstituted or unsubstituted phenyl, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenyl- Methoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is preferably benzoyl unsubstituted or substituted by, for example, halogen (e.g., bromine) ), For example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl (eg, 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbon Carbonyl), 2- (trisubstituted silyl) -lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl (e.g. 2-trimethylsilylethoxycarbonyl) or 2- (di- n-butylmethylsilyl) ethoxycarbonyl, or 2-triarylsilyl-lower alkoxycarbonyl (e.g. triphenylsilylethoxy Cycarbonyl).

In arylmethylamino groups, for example mono-, di- or especially tri-arylmethylamino groups, aryl groups are especially unsubstituted or substituted phenyl groups. Examples of such groups are benzyl-, diphenylmethyl- or especially trityl-amino, or very particularly 1-aryl-lower alkylmethylamino, wherein the lower alkyl group is preferably branched at the 1-position, eg For example, 1-methyl-1-phenyl-ethylamino.

In the etherified mercaptoamino group, the mercapto group is in particular substituted arylthio or aryl-lower alkylthio (where aryl is for example lower alkyl (eg methyl or tert-butyl), lower alkoxy (eg methoxy) , Phenyl unsubstituted or substituted by halogen (eg chlorine) and / or nitro, for example in the form of 4-nitrophenylthio.

In 2-acyl-lower alk-1-enyl groups that can be used as amino protecting groups, acyl is, for example, the corresponding group of lower alkanecarboxylic acid; Counterparts of benzoic acid unsubstituted or substituted by lower alkyl (eg methyl or tert-butyl), lower alkoxy (eg methoxy), halogen (eg chlorine) and / or nitro; Or in particular the counterparts of carbonate semiesters (such as carbonate lower alkyl semiesters). Corresponding protecting groups are in particular 1-lower alkanoyl-lower alk-1-en-2-yl (eg 1-lower alkanoyl-prop-1-en-2-yl, for example 1-acetyl-prop -1-en-2-yl) or lower alkoxycarbonyl-lower alk-1-en-2-yl (e.g. lower alkoxycarbonyl-prop-1-en-2-yl, e.g. 1- Oxycarbonyl-prop-1-en-2-yl).

The silylamino group is for example a tri-lower alkyl-silylamino group (eg trimethylsilylamino or tert-butyldimethylsilylamino). In addition, the silicon atoms of the silylamino groups can only be substituted by two lower alkyl groups (eg methyl groups) and by the amino or carboxyl groups of the second molecule of formula (I). Compounds having such protecting groups can be prepared, for example, using the corresponding chlorosilanes, for example dimethylchlorosilane, as silylating agents.

Amino groups can be protected by conversion to protonated forms. Suitable corresponding anions are mainly anions of strong inorganic acids, such as sulfuric acid, phosphoric acid or hydrofluoric acid, such as chlorine or bromine anions, or organic sulfonic acids such as p-toluenesulfonic acid.

Preferred amino protecting groups are lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl, 1-methyl-1-phenyl- Ethyl and lower alkoxycarbonyl-lower alk-1-en-2-yl.

The hydroxyl group is protected by an acyl group, for example lower alkanoyl (eg 2,2-dichloroacetyl) substituted by halogen (e.g. chlorine) or acyl groups of carbonic acid semiesters as mentioned for particularly protected amino groups Can be. Preferred hydroxy protecting groups are, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. Hydroxy groups can also be tri-lower alkylsilyls (e.g. trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl), ether groups that can be easily removed (e.g. alkyl groups, e.g. tert-lower alkyl, e.g. tert-butyl), oxa- or thia-aliphatic or -alicyclic (especially 2-oxa- or 2-thia-aliphatic or -alicyclic), hydrocarbon groups (e.g. 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 5 to 7 ring atoms Having 2-oxa- or 2-thia-cycloalkyl (eg 2-tetrahydrofuryl or 2-tetrahydropyranyl) or a corresponding thia analog, and 1-phenyl-lower alkyl (eg benzyl, diphenylmethyl or Trityl, where the phenyl group is halogen, for example chlorine, lower alkoxy (eg methoxy), and / or It may be protected by a may be substituted by a Trojan)).

The hydroxy and amino groups present adjacent to each other in the molecule are, for example, a methylene group, for example an unsubstituted or substituted alkylidene, eg substituted by a divalent protecting group such as one or two lower alkyl groups or oxo or the like. For example, lower alkylidene (eg isopropylidene), cycloalkylidene (eg cyclohexylidene), carbonyl group or benzylidene.

In this context, protecting groups (eg carboxyl protecting groups) are in particular polymer carriers which are bonded to the functional groups (eg carboxyl groups) to be protected in such a way that they can be easily removed, for example suitable for Merifield synthesis. It should be understood as a carrier. Examples of such suitable polymer carriers are, in particular, polystyrene resins which are weakly crosslinked by copolymerization with divinylbenzene and which have a suitable bridge former for reversible bonding.

The addition of the compound of formula III to the epoxide of formula IV is preferably carried out under reaction conditions commonly used to add nucleophiles to the epoxide.

The addition is especially in aqueous solution and / or polar solvents such as alcohols such as methanol, ethanol, isopropanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide or phenolic ( Eg in the presence of phenol) and also under anhydrous conditions, in a nonpolar solvent (such as benzene or toluene), or in a benzene / water emulsion, optionally an acidic or basic catalyst (such as an alkali hydroxide solution such as sodium hydroxide solution). ), Or in the presence of a solid catalyst (e.g. aluminum oxide) doped with hydrazine, in an ether (e.g. diethyl ether), typically at a temperature from about 0 ° C to the boiling point of the reaction mixture, preferably Is at temperatures up to the reflux point at 20 ° C., optionally under elevated pressure, for example in a bomb tube (in this case exceed the boiling point measured at atmospheric pressure). And / or under an inert gas such as nitrogen or argon, each of the two compounds of formula III and formula IV being for example in a molar ratio of 1: 1 to 1: 100, in particular 1: 1: 1: 10, more preferably in excess of a molar ratio of 1: 1 to 1: 3.

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Method b) (formation of amide bonds)

In the starting materials of the formulas (V) and (VI), the functional groups are protected independently of one another by one of the protecting groups mentioned in process a), except for groups which participate in the reaction or do not react in the reaction conditions.

Compounds of formula VI include free carboxyl groups or exist in the form of reactive acid derivatives thereof, for example in the form of derived active esters or reactive anhydrides, or in the form of reactive cyclic amides. Reactive acid derivatives may be formed in situ.

Activated esters of compounds of the formula (VI) having terminal carboxyl groups are especially unsaturated esters at the carbon linking the groups to be esterified, for example esters of vinyl esters, for example vinyl esters (for example corresponding esters with vinyl acetate Obtainable by exchange reaction; activated vinyl ester method), carbamoyl ester (e.g., by treatment of the corresponding acid with isoxazolium reagent; 1,2-isoxazolium method or Woodward method ), Or 1-lower alkoxyvinyl ester (for example obtained by treating the corresponding acid with lower alkoxyacetylene; ethoxyacetylene method), or an amidino-type ester (e.g., N, N'-disubstituted amidinoester) (For example, the corresponding acid may be substituted with a suitable N, N'-disubstituted carbodiimide (e.g., N, N'-dicyclohexylcarbodiimide or Obtained by treatment with N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide); or a carbodiimide method), or an N, N-disubstituted amidinoester (e.g., a corresponding acid Obtainable by treatment with N, N-disubstituted cyanamides; cyanamide process), suitable aryl esters, in particular phenyl esters appropriately substituted with electron withdrawing substituents (e.g. Condensing agents (e.g. N with 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldazophenol) Obtained by treatment in the presence of N′-dicyclohexylcarbodiimide) activated aryl ester process), cyanomethyl ester (eg by treatment of the corresponding acid in the presence of base with chloroacetonitrile); Cyanomethyl ester method), unsubstituted or substituted (eg nitro Substituted thioesters (especially phenylthioesters) (e.g., the corresponding acids are unsubstituted or substituted (e.g. nitro substituted) with thiophenols using the anhydride method or the carbodiimide method. Activated thiol ester methods), or in particular amino esters or amido esters (e.g., the corresponding acid is converted to an N-hydroxyamino compound or an N-hydroxyamido compound, for example N-hydride). Roxy-succinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, 1-hydroxybenzotria Obtainable by treating with sol or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, for example according to the anhydride method or the carbodiimide method; Activated N-hydroxy ester method). For example, internal esters, γ-lactones may also be used.

The anhydrides of the acids are symmetric or preferably mixed anhydrides of these acids, for example inorganic anhydrides, for example acid halides (especially acid chlorides), including anhydrides (for example the corresponding acids are thionyl chloride, phosphorus, phosgene or Obtainable by treatment with oxalyl chloride; acid chloride method), azide (for example, by passing the corresponding hydrazide from the corresponding acid ester and treating it with nitrous acid; azide method), carbonate semiester (e.g. Anhydrides containing carbonate lower alkyl semiesters, in particular chloroformic acid methyl esters (e.g., the corresponding acids are treated with chloroformic acid lower alkyl esters or 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinolines Mixed O-alkylcarboxylic acid anhydride methods) or dihalogenated (especially dichlorolated) phosphoric acid-containing anhydrides (e.g. The reaction can be obtained by treatment with phosphorus oxychloride; phosphorus oxychloride method), anhydrides including other phosphoric acid derivatives (e.g., phenyl N-phenylphosphoramidochlorate, or sulfonic anhydride and / or lacase) Obtainable in the presence of beautification depressant additives (e.g., N-hydroxybenzotriazole) or in the presence of cyanophosphonic acid diethyl ester) or anhydrides containing phosphoric acid derivatives, or anhydrides containing organic acids (e.g., mixed with organic carboxylic acids) Anhydrides) (e.g., by treating the corresponding acid with a substituted or unsubstituted lower alkane- or phenyl-lower alkanecarboxylic acid halide (e.g. phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride) Mixed carboxylic acid anhydride methods or organic sulfonic acid-containing anhydrides (e.g., salts of the corresponding acids (e.g. alkali metal salts). Obtainable by treatment with a ride such as lower alkane- or aryl- such as methane or p-toluene-sulfonyl chloride; mixed sulfonic anhydride process; And symmetric anhydrides (such as obtainable by condensation of the corresponding acids in the presence of carbodiimide or 1-diethylaminopropene; symmetric anhydride methods).

Suitable cyclic amides are in particular aromatic five-membered diazascle-containing amides (e.g. imidazole-based, e.g. imidazole-containing amides) (e.g. the corresponding acid is converted to N, N'-carbonyldiimidazol). Obtainable by treatment; imidazole method) or pyrazole (e.g. 3,5-dimethylpyrazole) containing amide (e.g., treated with acetylacetone to obtain through acid hydrazide; pyrazoleide method) to be.

As mentioned above, derivatives of carboxylic acids used as acylating agents can also be formed in situ. For example, N, N'-disubstituted amidinoesters are suitable N, N'-disubstituted carbodiimides (e.g., N, N'-dicyclohexylcarbodiimide or especially N- (3-dimethylaminopropyl). ) -N'-ethylcarbodiimide) can be formed in situ by reacting a mixture of the acid used as the acylating agent and the starting material of formula (V). In addition, the aminoesters or amidoesters of the acids used as the acylating agents may react the mixtures of the corresponding acids and amino starting materials with N, N'-disubstituted carbodiimides (e.g., In the presence of N, N'-dicyclohexylcarbodiimide) and N-hydroxyamine or N-hydroxyamide (eg N-hydroxysuccinimide), a suitable base (eg 4) -Dimethylaminopyridine). In addition, in situ activation can be achieved by using N, N, N ', N'-tetraalkyluronium compounds (e.g., O-benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluoro Phosphate, O- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (1,8-diazabicyclo [5.4 .0] -undec-7-ene (1,5-5) with or without), or O- (3,4-dihydro-4-oxo-1,2,3-benzotriazolin-3- 1) -N, N, N ', N'-tetramethyluronium tetrafluoroborate). Finally, the phosphate anhydride of the carboxylic acid of formula VI is used in the presence of sulfonic anhydride (e.g. 4-toluenesulfonic anhydride) with an alkylphosphate amide (e.g. hexamethylphosphate triamide) and a salt (e.g. tetrafluoroborate, e.g. Sodium tetrafluoroborate) or other derivatives of hexamethylphosphate triamide (e.g. benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluoride) are preferably racemizing agents (e.g. N-hydroxybenzotriazole) can be prepared by reacting in situ.

The amino groups of the compounds of the formula (V) participating in the reaction preferably have at least one reactive hydrogen atom, especially when the carboxy, sulfonyl or phosphoryl groups reacting with them are in reactive form, It can be derivatized by reaction with phosphites such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite. In addition, derivatives of such compounds having amino groups are carbamoyl halides or isocyanates, for example, in which the amino group participating in the reaction is substituted by halocarbonyl (eg chlorocarbonyl) or modified in the form of isocyanate groups, respectively. to be.

Condensation to form amide bonds is described, for example, in the standard literature, "Houben-Weyl, Methoden der organischen Chemie", 4th edition, Volume 15 / II (1974), Volume IX (1955), E 11 ( 1985); Georg Thieme Verlag, Stuttgart, "The Peptides" (edited by E. Gross and J. Meienhofer), Volumes 1 and 2, Academic Press, London and New York (1979/1980), or M. Bodansky, "Principles of Peptide Synthesis "Springer-Verlag, Berlin, 1984).

Condensation of the free carboxylic acid with a suitable amine can be carried out in the presence of one of the usual condensers, or of carboxylic anhydrides or carboxylic acid halides (e.g. chlorides) or activated carboxylic acid esters (e.g. p-nitrophenyl esters). Can be preferably used. Examples of common condensing agents are carbodiimides, for example diethyl-, dipropyl- or dicyclohexyl-carbodiimide, or in particular N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, Other suitable carbonyl compounds (e.g. carbonylimidazole), 1,2-oxazolum compounds (e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert -Butyl-5-methylisoxazolium perchlorate), or a suitable acylamino compound (e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), N, N, N ', N '-Tetraalkyluronium compounds such as O-benzotriazol-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate or in particular O- (1,2-dihydro- 2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) (1,8-diazabicyclo [5.4.0] undec-7-ene- ( 1,5-5) or else activated phosphoric acid derivatives (e.g. diphenylphosphoryl azide, Diethylphosphoryl cyanide, phenyl-N-phenylphosphoroamidochlorate, bis (2-oxo-3-oxazolidinyl) phosphinic chloride or 1-benzotriazolyloxytris (dimethylamino) phosphonium hexa Fluorophosphate).

If desired, organic bases, preferably tertiary amines, for example tri-lower alkylamines, in particular ethyldiisopropylamine, more particularly triethylamine and / or heterocyclic bases, for example 4 -Dimethylaminopyridine or preferably N-methylmorpholine or pyridine is added.

Condensation of the active esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is typically in the presence of an organic base, such as a simple tri-lower alkylamine (such as triethylamine or tributylamine), or one of the organic bases. Under normal conditions. If desired, additionally, condensing agents as described in connection with the free carboxylic acids are used.

Condensation of acid anhydrides and amines can be carried out (for example with sulphates, if necessary), for example in the presence of inorganic carbonates such as ammonium carbonate, or alkali metal carbonates or hydrogen carbonates such as sodium carbonate or potassium carbonate or hydrogen carbonate. have.

Carboxylic acid chlorides, for example, chlorocarboxylic acid derivatives derived from the acid of formula VI, may be used if desired in the presence of the corresponding amine, preferably in the presence of an organic amine such as the tri-lower alkylamine or heterocyclic base described above. Condensation in the presence of an alkali metal hydroxide such as hydrogen sulfate or hydroxide, preferably sodium hydroxide.

Condensation is inert, aprotic and preferably anhydrous solvents or solvent mixtures, such as carboxylic acid amides such as formamide or dimethylformamide, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride or chlorobenzene, Temperature or elevated temperatures as necessary in ketones (e.g. acetone), cyclic ethers (e.g. tetrahydrofuran or dioxane), esters (e.g. ethyl acetate), or nitrile (e.g. acetonitrile), or mixtures thereof, For example at about -40 ° C to about + 100 ° C, preferably at about -10 ° C to about + 70 ° C, and when arylsulfonyl esters are used, also at + 100 ° C to + 200 ° C, in particular At 10 ° C. to 30 ° C., if necessary, under an inert gas (eg nitrogen or argon) atmosphere.

Aqueous, for example alcoholic solvents such as ethanol, or aromatic solvents such as benzene or toluene can also be used. In addition, when alkali metal hydroxide exists as a base, acetone can also be added as needed.

Condensation is also carried out according to a technique known as solid phase synthesis by R. Merrifield, for example in Angew. Chem. 97, 801-812 (1985), Naturwissenschaften 71, 252-258 (1984), or R.A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131-5135 (1985).

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Method c) (formation of amide bonds)

In the starting materials of the formulas (VII) and (VIII), the functional groups are protected independently of one another by one of the protecting groups mentioned in process a) except for groups which participate in the reaction or do not react in the reaction conditions.

This method is similar in its entirety to that shown in method b), but the compound of formula VII is used in place of the compound of formula V and the compound of formula VIII is used in place of the compound of formula VI.

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Method d) (formation of amide bonds)

In the acid of the formula VIIIa suitable for the introduction of the same acyl group and the starting material of the formula IX, or in the reactive derivatives thereof, the functional group which does not participate in the reaction or does not react in the reaction conditions is determined by one of the protecting groups mentioned in the method a). Protected independently of each other.

Preferred starting compounds of formula (IX) which can be protected by protecting groups are compounds of formula (II) which are set forth below in the paragraphs relating to the starting compounds.

This method is similar in its entirety to that shown in method b), but the compound of formula IX is used in place of the compound of formula V and the compound of formula VIIIa is used in place of the compound of formula VI.

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Method e) (alkylation of a second nitrogen atom)

In the starting materials of the formulas I 'and X, or in reactive derivatives thereof, the functional groups which do not participate in the reaction or do not react in the reaction conditions are protected independently from each other by one of the protecting groups mentioned in the method a).

Leaving group X is in particular a hydroxy group which is esterified with a strong inorganic acid or an organic acid, for example hydroxy, strong organic sulfonic acid (e.g., inorganic acids such as hydrochloric acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid) Eg lower alkanesulfonic acid which is unsubstituted or substituted by halogen (e.g. fluorine) or aromatic sulfonic acid (e.g. unsubstituted or lower alkyl (e.g. methyl), halogen (e.g. bromine) and / or) A nucleophilic leaving group selected from hydroxy esterified with nitro-substituted benzenesulfonic acids such as methanesulfonic acid, p-bromotoluenesulfonic acid or p-toluenesulfonic acid, or hydroxy esterified with hydrazonic acid.

Substitution occurs under conditions of primary or secondary nucleophilic substitution.

For example, one of the compounds of formula X (where X is a highly polar leaving group of the electron shell, for example iodine) is a polar protic solvent (e.g. acetone, acetonitrile, nitromethane, dimethyl sulfoxide or Dimethylformamide). The reaction can be carried out in water as a solubilizer, optionally in an admixture with an organic solvent, such as ethanol, tetrahydrofuran or acetone. Substitution may be carried out at reduced or elevated temperatures, if desired, for example at about −40 ° C. to about 100 ° C., preferably at −10 ° C. to about 50 ° C. atmosphere, if necessary, in an inert gas (eg nitrogen or argon) atmosphere. Is performed in

Method e) is not successful in all cases and is less preferred because it is often possible under special conditions.

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Method f) (Reducible Alkylation of Second Amino Group)

In the starting materials of the formulas I 'and X *, or in reactive derivatives thereof, the functional groups which do not participate in the reaction or do not react in the reaction conditions are protected independently from each other by one of the protecting groups mentioned in the method a).

Reactive derivatives of compounds of formula (I) are for example corresponding disulphite adducts or in particular semiacetals or ketals of compounds of formula (X *) with alcohols (eg lower alkanols), compounds of formula (X *) and mertopanes (eg lower Alkanesulfide). Preference is given to free aldehydes of formula (X *).

Reductive alkylation is carried out at atmospheric pressure or 0.1 to 10 megapascals (in the presence of a catalyst, particularly preferably a precious metal catalyst (e.g. platinum or in particular palladium), or a heavy metal catalyst (e.g. Raney nickel) which is bonded to a carrier material such as carbon ( Hydrogenated at a pressure of MPa) or using a hydride complex (e.g. borohydride, in particular alkali metal cyanoborohydride, for example sodium cyanoborohydride), an appropriate acid, preferably relatively Reduction in the presence of a weak acid (e.g. lower alkanecarboxylic acid or in particular sulfonic acid, e.g. p-toluenesulfonic acid), can be carried out in conventional solvents, e.g. alcohol (e.g. methanol or ethanol) or ether (e.g. cyclic ether). , For example tetrahydrofuran), preferably in the presence or absence of water.

The protecting group can be liberated according to the method described below entitled "Removing the protecting group".

Removal of protector

Removal of protecting groups, such as carboxy-, amino- and hydroxy protecting groups, which are not constituents of the final desired product of formula (I) can be carried out in a manner known per se, for example, by solvolysis, in particular hydrolysis, alcoholic decomposition or The use of acid hydrolysis or by reduction, in particular by hydrocracking or by chemical reduction, or by photolysis, is carried out step by step or simultaneously as necessary, in which case enzymatic methods may also be used. Removal of protecting groups is described, for example, in the "protecting groups" section of the standard treatment mentioned above.

For example, protected carboxy, for example tert-lower alkoxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyl or lower alkoxy or lower alkylthio substituted at the 2-position by a trisubstituted silyl group Lower alkoxycarbonyl substituted at the 1-position or unsubstituted or substituted diphenylmethoxycarbonyl may be appropriately added with a nucleophilic compound such as phenol or anisole, such as formic acid, hydrochloric acid or trifluoroacetic acid. It can be converted to free carboxy by treating with acid. Carboxy may also be liberated from lower alkoxycarbonyl by bases such as hydroxides such as alkali metal hydroxides such as NaOH or KOH. Unsubstituted or substituted benzyloxycarbonyl can be liberated by hydrocracking, for example, with hydrogen in the presence of a metal hydrogenation catalyst such as a palladium catalyst. In addition, benzyloxycarbonyl, which is suitably substituted, for example 4-nitrobenzyloxycarbonyl, is also typically a hydrogen generating agent capable of generating hydrogen with the metal, for example an acid, preferably a suitable carboxyl. Lower alkancarboxylic acids, for example unsubstituted or substituted by hydroxy, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or Tartaric acid, or in the presence of an alcohol or thiol, preferably with the addition of water, for example an alkali metal dithionite such as sodium dithionite or a reducing metal such as zinc, or chromium (II) such as chromium (II) chloride It can be reduced and converted to the free carboxy by treating with a reducing metal salt such as a salt. By treating with a reducing metal or metal salt as described above, 2-halo-lower alkoxycarbonyl (after converting the 2-bromo-lower alkoxycarbonyl group to the corresponding 2-iodo-lower alkoxycarbonyl group as necessary) or aroylmeth The oxycarbonyl can also be converted to the free carboxy. Aroylmethoxycarbonyl can be liberated by treatment with a nucleophilic, preferably salt forming reagent such as sodium thiophenolate or sodium iodide. 2- (trisubstituted silyl) -lower alkoxycarbonyls, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyls, also provide fluoride anions in the presence of macrocyclic polyethers ("crown ethers") as needed Fluoride of an organic quaternary base in the presence of a hydrofluoric acid salt (e.g., an alkali metal fluoride such as sodium fluoride or potassium fluoride), or an aprotic polar solvent (e.g. dimethyl sulfoxide or N, N-dimethylacetamide) Examples: conversion to free carboxy by treatment with tetra-lower alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride such as tetraethylammonium fluoride or tetrabutylammonium fluoride. Carboxy protected as organic silyloxycarbonyl (eg tri-lower alkylsilyloxycarbonyl such as trimethylsilyloxycarbonyl) is treated in a conventional manner, for example with water, alcohol or acid or as described above. By treatment with fluoride it can be separated by solvent addition. The esterified carboxy can also be enzymatically isolated using, for example, an esterase or a suitable peptidase such as trypsin.

Protected amino groups are released in a known manner in different ways depending on the nature of the protecting group, preferably by solvation or reduction. Lower alkoxycarbonylamino (e.g. tert-butoxycarbonylamino) may be used in the presence of an acid, for example an inorganic acid such as hydrogen halide (e.g. hydrogen chloride or hydrogen bromide), sulfuric acid or phosphoric acid, preferably hydrogen chloride, or strong In the presence of an organic acid, for example trihaloacetic acid or formic acid such as trifluoroacetic acid, a polar solvent such as water or ether (preferably cyclic ether such as dioxane) or nitrile (e.g. acetonitrile), 2 -Halo-lower alkoxycarbonylamino can be separated (with the conversion of the 2-bromo-lower alkoxycarbonylamino group as necessary after the conversion of the 2-iodo-lower alkoxycarbonylamino group), or directly It can be dissolved in liquid organic carboxylic acid such as formic acid and separated, and aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino is, for example, aqueous. It can be separated by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as acetic acid. Aroylmethoxycarbonylamino can also be isolated by treatment with nucleophilic, preferably salt forming reagents (eg sodium thiophenolate) and 4-nitrobenzyloxycarbonylamino is alkali metal dithionite (eg sodium Dithionite). Substituted or unsubstituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2- (trisubstituted silyl) -lower alkoxycarbonylamino (e.g. 2-tri-lower alkylsilyl-lower alkoxycarbonyl The amino may be separated by a suitable acid, for example formic acid or trifluoroacetic acid, and the unsubstituted or substituted benzyloxycarbonylamino may be treated with hydrogen in the presence of a suitable hydrogenation catalyst such as, for example, platinum or palladium catalysts. And substituted or unsubstituted triarylmethylamino or formylamino, for example, in the presence of water, for example, in the presence of an inorganic acid (e.g. hydrochloric acid) or an organic acid (e.g. formic acid, acetic acid or Trifluoroacetic acid) and an amino group protected in silylamino form, for example hydrolysis or alcohol The amino group protected by 2-haloacetyl (eg 2-chloroacetyl) can be treated with thiourea in the presence of a base or a thiolate salt such as an alkali metal thiolate of thiourea. After treatment, the resulting substitution product can be liberated by solvolysis (eg alcoholic decomposition or hydrolysis) Amino is polar, with or without water, at temperatures from 0 ° C. to 100 ° C., in particular at reflux. Liberated from trifluoroacetylamino by hydrocracking with a base such as an alkali metal hydroxide or carbonate (eg Na ₂ CO ₃ or K ₂ CO ₃ ) in a solvent (eg alcohol, eg methanol). The amino groups protected by 2- (trisubstituted silyl) -lower alkoxycarbonyls, such as -tri-lower alkylsilyl-lower alkoxycarbonyls, are associated with the glass of the correspondingly protected carboxyl groups. It may also be converted to the free amino group by treating a salt of hydrofluoric acid which gives the anion of the fluoride as described above, eg a 1-aryl-lower alkylmethyl protecting group wherein the lower alkyl group is preferably branched at position 1, e. For example, 1-methyl-phenyl-ethyl can be removed in the presence of a strong acid such as sulfuric acid (for example 80% sulfuric acid) in an aqueous solution, particularly at a preferred temperature of -10 ° C to 30 ° C, especially about 0 ° C. Similarly, silyl groups such as trimethylsilyl bonded directly to heteroatoms such as nitrogen can be removed using fluoride ions.

The amino protected in the form of an azido group can be reduced to a catalytic hydrogenation reaction, for example by treating hydrogen in the presence of a hydrogenation catalyst (e.g., platinum oxide, palladium or Raney nickel), or the mercapto compound ( Example: dithiothreitol or mercaptoethanol), or reduced to a free amino by treatment with zinc in the presence of an acid (eg acetic acid) or the like. The catalytic hydrogenation reaction is preferably at about 20-25 ° C. in an inert solvent such as a halogenated hydrocarbon such as methylene chloride or water or a mixture of water and an organic solvent such as alcohol or dioxane, or Performed by cooling or heating.

Hydroxy groups protected by suitable acyl groups, by tri-lower alkylsilyl groups, or by substituted or unsubstituted 1-phenyl-lower alkyl are similarly liberated with correspondingly protected amino groups. Hydroxy groups protected by 2,2-dichloroacetyl are freed by, for example, basic hydrolysis, and hydroxyl groups protected by tert-lower alkyl or by 2-oxa- or 2-thia-aliphatic or cycloaliphatic hydrocarbon groups It is liberated by acid hydrolysis by treating strong carboxylic acids such as inorganic acids or trifluoroacetic acid, for example. Methylene groups mono- or di-substituted by divalent protecting groups, preferably by lower alkyl, for example lower alkylidene such as isopropylidene, cycloalkylidene such as cyclohexylidene or benzylidene Adjacent hydroxy groups and amino groups protected together by may be liberated in the presence of acid hydrocracking, in particular in the presence of inorganic or strong organic acids. Tri-lower alkylsilyl groups are likewise removed by acid hydrolysis with inorganic acids (preferably hydrofluoric acid) or strong carboxylic acids and the like. 2-halo-lower alkoxycarbonyls can be prepared by using the aforementioned reducing agents, for example reducing metals (eg zinc), reducing metal salts (eg chromium (II) salts) or sulfur compounds (eg sodium dithionite or In particular sodium sulfide and carbon disulfide).

Where several types of protected functional groups are present, the protecting group, if necessary, uses one or more protecting groups simultaneously, e.g. trifluoroacetyl, which is an amino protecting group via a base catalyst, for example K ₂ CO ₃ in methanol / water. And then remove the amino protecting group tert-butoxycarbonyl, for example in dioxane or acetonitrile (with or without water) with HCl or formic acid or the amino protecting group 1-methyl-1 -Phenyl-ethyl can be selectively removed by acid hydrolysis with sulfuric acid or usually by treatment with, for example, trifluoroacetic acid, or hydrogen and a hydrogenation catalyst (such as a palladium on carbon catalyst). Conversely, groups can also be chosen in such a way that they are not separated at the same time but instead are separated in the desired order to obtain corresponding intermediates.

Additional process steps

In further processes carried out as necessary, the functional groups of the starting compound not involved in the reaction can be unprotected or can be protected by one or more protecting groups, for example specified in method a). The protecting groups retained in the final product may be separated in whole or in part by any of the methods mentioned in the paragraph entitled "Removal of protecting groups".

Salts of compounds of formula (I) having salt forming groups can be prepared by known methods. For example, acid addition salts of compounds of formula I can be obtained, for example, by treatment with an acid or a suitable anion exchange reagent.

Salts can be converted to the free compounds by conventional means, such as by treating with a suitable basic agent.

Stereoisomeric Mixtures For example, mixtures of diastereomers can be separated into the corresponding isomers by known methods according to suitable separation procedures. For example, mixtures of diastereomers can be separated into individual diastereomers by fractional crystallization, chromatography, solvent distribution, and the like. Such separation can be carried out in one step of the starting material or with the compound of formula (I) itself.

In the compounds of formula (I), wherein R ₂ is phenyl, the phenyl group is used in particular in the presence of heavy metal oxides (eg rhodium / platinum mixed oxides), for example using a Nishimura catalyst, preferably alcohols (eg methanol or In a polar solvent such as ethanol), it may be hydrogenated by catalytic hydrogenation at a temperature of 0 ° C. to 80 ° C., in particular 10 ° C. to 40 ° C., at a preferred hydrogen pressure of 1 to 10 atm, preferably at about atmospheric pressure. have.

In compounds of formula I, wherein R ₄ is 4-tetrazol-5-ylphenyl, lower alkyl groups such as methyl are lower alkyl halides or lower alkyl arylsulfonates (e.g. lower alkyl iodides or lower alkyltoluenesulfonates, e.g. For example, methyl iodide or tert-butyl iodide), preferably cyclic ethers (such as dioxane) and N, N-di-lower alkyl-lower alkancarboxylic acid amides (such as dimethylform In the presence of cesium carbonate in the mixture of amides) and can be converted by reacting at a preferred temperature of -10 ° C to 40 ° C, in particular 0 ° C to about 30 ° C.

In compounds of formula I, wherein R ₄ is 4- (1- or 2-phenyl-lower alkyl, for example 1- or 2- (1-methyl-1-phenylethyl) -tetrazol-5-yl) phenyl, The phenyl-lower alkyl group (preferably 1-methyl-1-phenylethyl) may be removed by treatment with a strong inorganic acid such as sulfuric acid in aqueous solution, preferably at a temperature of -20 ° C to 30 ° C, for example 0 ° C. .

Common process conditions

All processes presented herein can be carried out under known reaction conditions, but preferably under the conditions specifically described above, in the absence or generally presence of a solvent or diluent (preferably these solvents or diluents are used reagents) Inert to, and a solvent for), the presence of a catalyst, condensing or neutralizing agent, for example an ion exchanger (e.g. cation exchanger, for example H ⁺ form), depending on the reaction and / or the nature of the reactants or In the absence, at room temperature, at room temperature or at elevated temperatures, for example from about -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example -80 ° C to -60 ° C, at room temperature, -20 At 40 ° C. to 40 ° C. or at the boiling point of the solvent used, under atmospheric pressure or in a closed container, optionally under pressure and / or in an inert atmosphere (eg argon or nitrogen atmosphere). The.

For all starting materials and intermediates, salts may be present when there are salt forming groups. Salts may also be present during the reaction of such compounds if the reaction is not affected.

In all reaction steps, any isomeric mixtures formed are individual isomers, such as diastereomers or enantiomers, or any desired isomeric mixtures, such as racemates or diastereomeric mixtures, for example " Additional process steps can be separated similarly to the method described under the heading "Additional process steps".

In certain cases, such as hydrogenation, stereoselective reactions can be carried out, for example, so that individual isomers can be more easily obtained.

Unless otherwise specified in the description of each process, solvents that can be selected as suitable for a particular reaction include, for example, water, esters (e.g. lower alkyl-lower alkanoates, e.g. diethyl acetate), ethers ( Examples are aliphatic ethers such as diethyl ether, or cyclic ethers such as tetrahydrofuran, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol, 1- or 2-propanol ), Nitrile (e.g. acetonitrile), halogenated hydrocarbons (e.g. methylene chloride), acid amides (e.g. dimethylformamide), base (e.g. heterocyclic nitrogen bases, e.g. pyridine), carboxylic anhydride (Such as lower alkanoic anhydrides such as acetic anhydride), cyclic, linear or branched hydrocarbons (such as cyclohexane, hexane or isopentane) or mixtures of these solvents, such as aqueous solutions. Such solvent mixtures can also be used for workup, for example, chromatography or partitioning.

The present invention uses a compound which can be obtained as an intermediate in any step as starting material and performs the remaining steps or the process is stopped in any step or the starting material is produced under reaction conditions or in the form of a reactive derivative or salt. Or a compound obtainable according to the process of the present invention relates to a form of a process which is prepared under process conditions and further processed in situ, which is described as being preferred, particularly particularly preferred, and more particularly preferred and / or Preference is given to using starting materials which give rise to compounds described as very particularly preferred.

The preparation of the compounds of formula (I) is preferably carried out analogously to the methods and processes set forth in the examples.

The compounds of formula (I) and salts thereof can also be obtained in the form of hydrates or in crystalline form containing a solvent used for crystallization.

Pharmaceutical composition:

The present invention relates to a pharmaceutical composition containing a compound of formula (I *), in particular a compound of formula (I), most particularly a compound of formula (Ia).

The pharmaceutically acceptable compounds of the present invention can be used to prepare pharmaceutical compositions in admixture form, for example, containing an effective amount of the active ingredient or comprising a substantial amount of a pharmaceutically acceptable carrier, inorganic or organic, solid or liquid. Can be.

The invention also relates to a retroviral protease, in particular retroviral aspartate, which comprises a compound of formula (I *) or a pharmaceutically acceptable salt thereof in an amount effective to inhibit the retroviral protease, together with at least one pharmaceutically acceptable carrier. For administration to incubated animals, especially humans, for the treatment and inhibition of diseases susceptible to inhibition of proteases such as HIV-1 or HIV-II gag proteases, such as retroviral diseases (such as AIDS or its predecessors). It relates to suitable pharmaceutical compositions.

The pharmaceutical composition according to the present invention is enteric, for example nasal, rectal or oral administration, to a warm-blooded animal (human and animal), containing an effective dose of a pharmaceutically active ingredient alone or in combination with a substantial amount of a pharmaceutically acceptable carrier, Or for parenteral administration, eg intramuscular or intravenous administration. The dose of active ingredient depends on the type of animal, body weight, age and individual condition, individual pharmacokinetic data, disease to be treated, dosage form and the like.

The present invention relates to a method for treating a virus caused by a virus, in particular a retrovirus, in particular AIDS or a previous stage, wherein a therapeutically effective amount of a compound of formula (I *) or a pharmaceutically acceptable salt thereof is used as said disease, In particular, AIDS, or one of its predecessors, is administered to a warm-blooded animal, such as a human, in need of treatment at a dose effective for treating the disease. Preferred dosages for administration to a constant temperature animal, in particular a human weighing about 70 kg, are from about 3 mg to about 3 g, preferably from about 10 mg to about 1.5 g, for example from about 50 mg to 1000 mg per person per day, Preferably, for example, it is divided into three single doses in 1 of the same size. Typically children receive half of the adult dose.

The pharmaceutical composition contains about 1% to about 95%, preferably about 20% to about 90% of the active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dosage form, for example in the form of ampoules, vials, suppositories, coated tablets, tablets or capsules.

The pharmaceutical composition of the present invention is prepared by known methods such as solubilization, lyophilization, mixing, granulation or sugar preparation.

Solutions of the active ingredient and also suspending agents and in particular aqueous isotonic solutions or suspensions are preferably used, for example in the case of lyophilized compositions containing the active ingredient alone or in combination with a carrier (eg mannitol) before use. It can be made into a solution or a suspension. The pharmaceutical composition may be sterilized and / or may contain excipients such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, osmotic salts and / or buffers, or acids (eg, citric acid). And a known method such as a conventional solubilization or lyophilization method. The solution or suspension may be a viscosity enhancing material (e.g. sodium carboxymethylcellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose (e.g. cellulose HPM603), silica gel, dextran, polyvinylpyrrolidone or gelatin) And the like.

Suspensions in oils contain vegetable, synthetic or semisynthetic oils as common oil components for injection. Oils of this kind are, in particular, long-chain fatty acids having 8 to 22 carbon atoms, in particular 12 to 22 carbon atoms as the acid component, for example lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid. , A liquid fatty acid ester containing margaric acid, stearic acid, arachidic acid, benhenic acid, or a corresponding unsaturated acid, for example oleic acid, elideic acid, erucic acid, brasidic acid or linoleic acid, and if necessary antioxidant For example, vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene may be added. The alcohol component of this fatty acid ester has up to 6 carbon atoms and is mono- or polyvalent, for example monovalent, divalent or trivalent alcohols such as methanol, ethanol, propanol, butanol or pentanol or its Isomers, especially glycols and glycerol. Thus, examples of fatty acids that may be mentioned include ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethyleneglycerol trioleate available from Gattefosse, Paris), "Miglyol 812" ( Triglycerides of C ₈ -C ₁₂ saturated fatty acids available from Huels AG, Germany, in particular vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, soybean oil and, in particular, peanut oil and sesame oil.

Preparation of the injectable compositions is carried out in conventional manner such as filling in ampoules or vials and sealing containers under sterile conditions.

Oral pharmaceutical compositions can be obtained by combining the active compounds with a solid carrier material, granulating the obtained mixture as necessary and adding suitable excipients as necessary, followed by processing into tablets, coated skin cores or capsules. It is also possible to incorporate the active compounds into plastic carriers which release or diffuse the active ingredient in a metered manner.

Suitable carriers are in particular fillers such as sugars such as lactose, saccharose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starch pastes For example, a paste of corn starch, wheat starch, rice starch or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone) and (or ), If desired, disintegrants (e.g., starch and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof, e.g. sodium alginate). Excipients are preferably flow regulators and lubricants such as silicic acid, talc, stearic acid or salts thereof (eg magnesium stearate or calcium stearate) and / or polyethylene glycol. The coating cores are provided with suitable coatings and in particular for the preparation of concentrated sugar solutions containing gum arabic, active, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or coating solutions in suitable organic solvents, or enteric coatings. Suitable cellulose preparations are used, for example solutions of ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

Capsules are hard gelatin capsules and also soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Hard capsules contain the active compound in the form of granules containing, for example, fillers (e.g. lactose), binders (e.g. starches) and / or lubricants (e.g. talc or magnesium stearate) and, if necessary, stabilizers. can do. In capsules, the active compounds are preferably dissolved or suspended in stable oil excipients (e.g. fatty oils, paraffin oil or liquid polyethylene glycols) and stabilizers and / or antimicrobials may likewise be added. Such oils which may be mentioned include in particular long chain fatty acids as acid components, for example long chain fatty acids containing 8 to 22, in particular 12 to 22 carbon atoms (e.g. lauric acid, tridecyl acid, myristic acid, penta). Liquid fatty esters containing decyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids such as oleic acid, oleic acid, erucic acid, brasidic acid or linoleic acid If necessary, antioxidants such as vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene may be added. Mono- or polyhydric, for example mono, di or trihydric alcohols with carbon atoms, for example methanol, ethanol, propanol, butanol or pentanol or isomers thereof, in particular ethylene or propylene glycol and glycerol to be. Thus, examples of fatty acid esters that may be mentioned include ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethyleneglycerol trioleate available from Gattefosse, Paris), "Miglyol 812 "(Triglycerides of C ₈ -C ₁₂ saturated fatty acids available from Huels AG, Germany), in particular vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, peanut oil, soybean oil and especially sesame oil. Paraffin oils may also be used: stabilizers (e.g. emulsifiers, wetting agents or surfactants), binders (e.g. starch pastes using corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth , Methylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose (preferably), sodium carboxymethylcellulose, cyclodextrin ( And / or polyvinylpyrrolidone) and / or antibacterial agents Suitable emulsifying agents, in particular, nonionic surfactants of the oleic acid, fatty acid dihydralcohol ester type (e.g. sorbitan monolaurate, monool Latex, monostearate or monopalmitate, sorbitan tristearate or -trioleate, polyoxyethylene adducts of fatty acid polyhydric alcohol esters such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate Laterates, monopalmitates, tristearates or trioleates), polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyoxyethylene glycol (300 or 400) stearate, polyethylene glycol-2000-stearate), in particular Pluronic® (Wyandotte Chem. Corp .; Ethylene oxide-propylene oxide block polymer of the German trade name BASF) or Synperonic® (ICI) type. If the active ingredient is not soluble in the oil, the active ingredient is in the form of a suspension and the active substance preferably has a particle size of about 1 to 100 mm. Such suspensions can be used on their own, ie without capsules.

Dyestuffs or pigments may be added to tablets or coating coatings and capsule shells to identify or label different doses of active compound.

<Starting substance>

The present invention also relates to novel starting materials and / or intermediates and methods for their preparation. It is preferred that the starting materials used and the reaction conditions chosen produce the compounds described as preferred.

In the preparation of all starting materials, free functional groups which do not participate in the reaction may be in unprotected form or in protected form, for example they may be protected by the abovementioned protecting groups under method a). Those protecting groups may be removed in a suitable number of times by the reaction described in the paragraph entitled "Removing of protecting groups".

The starting materials of process a) are known or, if new, can be prepared according to known methods. For example, the compound of formula III can be prepared from hydrazine or a suitable derivative thereof, and formula IV can be prepared from suitable amino acids or analogs thereof having, for example, one of the aforementioned side chains R ₃ .

The compounds of formula III, for example, known methods or a) alkylation a compound of the formula or part of X in formula (A) as described in method e) the compound of Formula XI is prepared from hydrazine by the introduction of the protecting group according to -R ₄ (wherein R ₄ is as defined for the compound of formula (I) to form a suitable carbonyl compound of formula (X *) or a reactive derivative thereof, as defined in method f) Reacting with a free amino group or an acylated derivative thereof to reduce the resulting hydrazone to produce a hydrazine derivative of formula XII wherein the groups of all mentioned compounds are as defined above and do not participate in the reaction. The functional groups in the reagent are protected if necessary), if necessary, the R ₇ protecting group is removed and the method b) under the conditions mentioned in method b) above; Obtained by condensation with an acid of formula VI or an acid derivative thereof.

Formula XI

Wherein R ₇ is hydrogen or the amino protecting group described under method b), in particular tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, aryl-lower alkoxycarbonyl, for example benzyloxycarbonyl Or 9-fluorenyl-methoxycarbonyl, or one of the acylamino protecting groups mentioned above, in particular trifluoroacetyl.

[Formula XII]

As defined in method f) above, the carbonyl compound of formula (X *) or a reactive derivative thereof suitable for the introduction of a group of sub-formula (A) used in the preparation of the compound of formula (XII) is an aldehyde or a reactive derivative thereof, and Its reactive carbonyl group after reaction with the compound and subsequent reduction is a component of one of the groups of sub-formula A described above.

The reaction of the carbonyl compound and the compound of formula (XI), which yields the corresponding hydrazone, is preferably carried out under the conditions normally used for the reaction of the carbonyl compound with the amine, preferably from 0 ° C. to the reflux temperature of the reaction mixture, preferably Preferably polar in the presence or absence of an acid catalyst such as carboxylic acid such as formic acid or acetic acid or sulfonic acid such as p-toluenesulfonic acid at a temperature of from 20 ° C. to the reflux of the reaction mixture. Organic solvents, for example ethers such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic acid amides such as dimethylformamide, or esters or aqueous solutions such as ethyl acetate, preferably in methanol .

A compound of formula XII * is obtained.

Wherein R ₄ and R ₇ are as defined for the compound of formula XII.

The reduction of the resulting hydrazone of formula XII * is preferably carried out by hydrogenation with hydride complexes in the presence of a suitable catalyst or in the presence of an acid. Suitable catalysts for hydrogenation include metals such as nickel, iron, cobalt or ruthenium, or precious metals or oxides thereof such as palladium or rhodium or oxides thereof, optionally for example suitable carriers such as barium sulfate, It is applied to aluminum oxide or carbon (activated carbon) or in the form of a backbone catalyst such as Raney nickel. Commonly used solvents for catalytic hydrogenation are, for example, water, alcohols such as methanol or ethanol, esters such as ethyl acetate, ethers such as dioxane, chlorinated hydrocarbons such as dichloromethane, such as dimethylformamide Carboxylic acids such as carboxylic acid amide or glacial acetic acid or mixtures of such solvents. The hydrogenation is carried out in conventional apparatuses preferably at a hydrogen pressure of 10 ° C. to 250 ° C., in particular room temperature to 100 ° C. and preferably 1 to 200 bar, in particular 1 to 10 bar. For reduction with hydride complexes, in particular borohydrides such as alkali metal cyanoborohydrides such as sodium cyanoborohydride, preferably mixtures thereof with alcohols or water such as methanol or ethanol Among them, it is preferable to add a weak acid such as sulfonic acid such as p-toluenesulfonic acid or carboxylic acid such as acetic acid (see, eg, Tetrahedron 49, 8605-8628 (1993)).

In addition, under conditions similar to those mentioned in method f), as defined in method f), alkylation can be effected by directly reducing the compound of formula XI with a compound of formula X * or a reactive derivative thereof.

Particularly preferred conditions for the preparation of compounds of formula (XI) are described in J. Chem. Soc. Perkin I. 1712 (1975).

In addition, the compound of formula III is condensed with, for example, the acid of formula VI or acid derivative thereof mentioned in method b) under the conditions mentioned in method b), where R ₇ is hydrogen Which may be obtained by removing a protecting group when R ₇ is a protecting group) to produce a compound of formula III *, which is subjected to the conditions similar to those mentioned for the reduction of hydrazone of formula XII * Reduced to a compound of formula III.

Wherein groups are as defined for compounds of formula (I).

The compounds of formula (III *) may also be prepared from the corresponding compounds of formula (III ′) defined as described below under conditions similar to those described above for the reaction of carbonyl compounds of formula (X *) with hydrazine of formula (XI). Hydrazones of formula III * are produced by reaction with a compound of formula X * as defined.

In addition, the compound of formula IV can for example reduce the amino acid of formula XIII to produce an aldehyde of formula XIV, which is subsequently reacted with an aldehyde compound, preferably a sulfur lide compound, To form an epoxide, remove the protecting group R ₈ (the free amino compound produced when R ₈ is hydrogen may be stable in the form of an acid addition salt), and finally the amino group of the resulting compound described in method b). Acylated with an acid of formula (VIII), where the groups are as defined for formula (VIII), under suitable conditions similar to one.

Wherein R ₈ is hydrogen or in particular the amino protecting group mentioned in method a), in particular tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, aryl-lower alkoxycarbonyl, for example benzyloxycarr Carbonyl or 9-fluoroenyl-methoxycarbonyl, or one of the acylamino protecting groups mentioned in process a) above, in particular trifluoroacetyl, R ₃ is as defined for compounds of formula (I).

In the formula, the group is as defined last.

In the formula, the group is as defined at the end.

The reduction of the corresponding aldehyde of formula XIV to the amino acid of formula XIII is carried out, for example, by reduction of the corresponding alcohol and subsequent oxidation of the aldehydes mentioned.

Reduction to an alcohol (a free compound or a compound N-protected by R ₈ with the following formula XIII *) following the introduction of a protecting group, as described in (method a)), for example, diborane or sodium borohydride A hydride complex such as a lead is used to hydrogenate the acid halides or other activated carboxylic acid derivatives mentioned in process b) under the conditions mentioned for the hydrogenation of the hydrazone obtained from the compound of formula XII. Subsequent oxidation of the resulting alcohol is carried out at halogenated hydrocarbons such as, for example, dichloromethane, and / or acyclic or tetra at inert solvents, for example, at -80 to 0 ° C, for example at -78 to -50 ° C. By oxidizing the hydroxy group with a sulfoxide, such as dimethyl sulfoxide, in the presence of a reagent that activates the hydroxy group, such as carboxylic acid chloride (e.g. oxalyl chloride), in a cyclic ether such as hydrofuran, or, for example, from -50 to Water, organic solvents (e.g., halogenated solvents such as methylene chloride, dimethylformamide) in the presence or absence of basic amines (e.g. tri-lower alkylamines such as triethylamine) at 100 ° C, preferably -10 to 50 ° C. and the like carboxylic acid amides, dimethylsulfoxide and the like or di-lower alkyl sulfoxide) during heteroaryl, such as pyridine / SO ₃ from the base and a clicking Outside by oxidizing with chromic acid or a derivative thereof, such as pyridinium chromate or tert-butyl chromate, dichromomate / sulfuric acid, sulfur trioxide in the presence of nitrous acid, pyrrolusite or selenium dioxide, or for example (contact tube Metallic silver at about 200 to 400 ° C. by catalytic dehydrogenation in the presence of copper, chromium copper or zinc oxide, followed by rapid cooling. It may also be oxidized to 2,2,6,6-tetramethyl-piperidine-1-oxyl in the presence of NaOCl (see Anelli et al. Org. Synth. 69, 212 (1990)).

Wherein groups are as defined for compounds of formula XIII.

In addition, the direct reduction of aldehydes of amino acids is partially at -100 to 0 ° C, preferably at -70 to -30 ° C, for example in nonpolar solvents such as hydrocarbon or aromatic compound solvents such as toluene. Hydrogenated in the presence of a poisonous palladium catalyst, or a lower alkyl ester such as ethyl ester and a hydride complex such as borohydride such as sodium borohydride, or preferably aluminum Hydrides, for example, after reduction using lithium aluminum hydride, lithium tri (tert-butoxy) aluminum hydride or in particular diisobutylaluminum hydride, for example -20 to 60 ° C, preferably Semicarbazide hydrochlora in aqueous solvent system at an temperature of 10-30 ° C., for example alcohol / water such as ethanol / water React with an acid salt of the corresponding semicarbazone such as id to produce the corresponding semicarbazone, and the resulting semicarbazone is reacted with an inert solvent, for example at a temperature of from -30 to 60 ° C, preferably from 0 to 30 ° C. For example, after reaction with a reactive aldehyde such as formaldehyde in a polar organic solvent, for example, a carboxylic acid amide such as dimethylformamide, the above optionally used at a temperature of -40 to 50 ° C, preferably -10 to 30 ° C. By reaction with an acid, for example, an inorganic strong acid such as hydrogen halide, in an aqueous solution in the presence of a solvent. The corresponding ester is reacted with the corresponding carboxylic acid, for example ethanol, for example -50 to 50 ° C., preferably -10 to 20, similarly to the conditions used in the condensation described in process b). At a temperature of &lt; RTI ID = 0.0 &gt; C &lt; / RTI &gt; obtained by reaction with an inorganic acid halide such as, for example, thionyl chloride in a mixture of aromatic and alcoholic solvents such as mixtures of toluene and ethanol.

The preparation of compounds of formula (XIV) is described in J. Chem. Org. Chem. 47, 3016 (1982) or [J. Org. Chem. 43, 3624 (1978), under similar conditions to the reaction conditions mentioned.

Sulphides suitable for converting compounds of formula (XIV) to epoxides of formula (XV) are, for example, dialkylsulfonium methylides such as dimenylsulfonium methylide, alkyl such as methyl- or phenyl-dimethylaminosulfonium methylide Or dialkylsulfonium methylide, such as phenyl-dialkylaminosulfonium methylide, or dimethyl- or diethylsulfonium methylide.

Such sulfur illide compounds may be prepared by the corresponding sulfonium or sulfoxonium salts and bases (eg, hydrogenation) in bipolar aprotic solvents or ethers such as dimethyl sulfoxide or ethers such as tetrahydrofuran or 1,2-dimethoxyethane. Sodium) in situ and react with a compound of formula XIV. The reaction is usually carried out at room temperature, for example, cooling below -20 ° C or with gentle heating, for example below 40 ° C. The sulfides, sulfinamides or sulfoxides produced at the same time are removed in later aqueous workup.

Reaction with sulphurous sulphide is described in J. Org. Chem. 50, 4615 (1985), in a particularly preferred manner similar to the conditions mentioned.

In addition, the compounds of formula XV have a corresponding halo such as chloromethyl-trimethylsilane in an inert solvent such as dioxane or diethyl ether at a temperature of from 0 to 50 ° C., for example from room temperature to about 40 ° C. After reacting a tri-lower alkylsilylmethyl Grignard compound prepared from methylsilane with a compound of formula (XIV) as defined above, for example, a Lewis acid such as BF ₃ is used to remove the silyl group and Resulting in any amino protecting group R ₈ at temperatures from -50 ° C to reflux, in particular from 0 to 30 ° C, preferably halogenated hydrocarbons such as ethers such as diethyl ether or dichloromethane or Remove in mixture, if necessary again acylate and generate with the introduction of amino protecting group R ₁₂ as defined above The double bond is added at a reflux temperature of the mixture at −20 ° C. to a mixture, for example, an inert solvent such as a halogenated hydrocarbon such as dichloromethane, or an alcohol such as methanol, a lower alkanoyl such as acetonitrile. In nitrile, water or mixtures thereof, it is preferably obtained by oxidation with a percarboxylic acid (for example in the form of a magnesium salt) such as m-chloroperbenzoic acid or monoperphthalic acid to produce the oxirane.

The compounds of formula IV also start directly with commercially available alcohols of formula XIII ^* as defined above, which are commercially available, and the alcohols are formulated with an acid of formula VIII or a reactive derivative thereof as defined in method c) and the conditions mentioned therein. And reacting at, and if necessary, introducing a protecting group as described in method a) and removing it with a suitable recovery as described previously in the section entitled "Removing of the protecting group" to obtain a compound analogous to the compound of formula XIII ^* Wherein the position of R ⁸ occupies the corresponding acyl group obtained from the acid of formula VIII, and the resulting compound is oxidized under similar conditions as those mentioned for the oxidation of alcohols of formula XIII ^* to the corresponding aldehydes of formula XIV * To produce a compound, and this aldehyde, for example, to a compound of formula (XIV) As described for the conversion to, for example, the conversion to the compound of formula IV is carried out using an Ilide compound.

Wherein groups are as defined.

The starting materials of the processes b), c) and d) are known or may be prepared according to their own known method if they are new: For example, the compound of formula V is of formula XII wherein R ₇ Protecting groups, and the remaining groups may be prepared from suitable hydrazine derivatives of the formula (V) as defined for compounds of formula (V) and suitable epoxides of formula (IV), wherein the group is as defined for compounds of formula (I) Method b); Compounds of formula VII are suitable hydrazine derivatives of formula III, wherein groups are as defined for compounds of formula I and formula XV, wherein R ₇ is a protecting group and the remaining groups are defined for compounds of formula I As shown) (method c); In addition, compounds of formula (IX) are analogous to process a), suitable hydrazine derivatives of formula (XII) wherein R ₇ is hydrogen and the remaining groups are as defined for compounds of formula (I) and formula (XV) R ₈ is a protecting group and the remaining groups may be prepared from suitable epoxides of the same as defined for compounds of formula (I) (method d), optionally as described under the heading “a removal of the protecting group” And protecting groups R ₇ and R ₈ are preferably as defined above in the definition of compounds of formulas XI and XIII, respectively.

Compounds of formula (I ′) wherein the substituents are as defined above include, for example, compounds of formula (III ′) described in method b) in which any functional groups present without participation in the reaction Can be protected as described and can be liberated again after the reaction with a compound similar to that described in process b).

Wherein groups are as defined for compounds of formula (I).

The compound of formula III ′ reacts an acid of formula VI or a reactive acid derivative thereof, in which group is as defined above, with a compound of formula XI in a manner similar to that described for the reaction of compound of formula XII with formula VI And, if necessary, by removing the protecting group R ₇ according to one of the methods described under the heading "removing a protecting group".

The two amino protecting groups present may be the same or different.

The amino protecting group used is, for example, the amino protecting group described in method a) above. Preference is given to corresponding compounds wherein the protecting group is selected from those described as preferred for R ₇ and R ₈ in the compounds of formulas XI and XIII, respectively.

Protected compounds of formula (I) are, for example, from compounds of formulas (III) and (IV) in which the functional group may be protected with a protecting group, as described in method a) above, for example according to one of the methods mentioned above. Are manufactured.

Aldehydes suitable for the introduction of the acids of the formulas VI, VII and VIIIa and the compounds of the formula X and of the sub-formula A used in the preparation of the compounds of the formula XII can be prepared according to methods known per se if not already known. have.

The preparation of the acid of formula VI is carried out in the presence of dioxane, in particular in the presence of dioxane, in particular in aqueous alkali metal hydroxide solution, for example under similar conditions as described for the acylation in process b). For example, in aqueous sodium hydroxide solution, derivatives of lower alkoxycarboxylic acids suitable for the introduction of lower alkoxycarbonyl groups, for example corresponding pyrocarboxylic acid di-lower alkyl esters (particularly pyrocarboxylic acid dimethyl esters; Swiss Buchs) From Aldrich, Inc.) or preferably haloformic acid lower alkyl esters, such as chloroformic acid lower alkyl esters (especially chloroformic acid methyl esters, Fluka, Buchs, Switzerland) with an amino acid of formula XVI.

Wherein R ₅ is as defined for the compound of formula VI.

Thus, the compound of formula VIII can be obtained by reacting a derivative of lower alkylcarboxylic acid suitable for the introduction of lower alkylcarbonyl groups with an amino acid of formula XVII, wherein the compound of formula VIIIa is obtained by reacting an amino acid of formula XVIII Can be.

Wherein R ₂ is as defined for the compound of formula (I).

Wherein R ₂ ′ is as defined for the compound of formula VIII ′.

The amino acids of the formulas XVI, XVII and XVIIII are known or can be prepared according to methods known per se. They are preferably in the (S) -form (relative to α-carbon atoms).

Compounds of formula IV can be prepared by condensing a compound of formula XIX as defined above with a compound of formula XVIII as defined above. Condensation with an acid of formula (VIII) or an acid derivative thereof is carried out under conditions similar to those mentioned in process e) above. A compound of formula XX is obtained.

Wherein R ₁ and R ₂ are as defined for the compound of formula (I).

Hydroperoxide, hydrogen peroxide or peroxy acid, for example in an inert solvent such as diethyl ether or in a chlorinated hydrocarbon such as chloroform or dichloromethane at a preferred temperature of -20 to 50 ° C. Epoxidation with oxygen, or preferably chemically bound oxygen, in perbenzoic acid, performic acid, peracetic acid, monoperoxyphthalic acid, pertungstic acid or in particular m-chloroperbenzoic acid results in a compound of formula IV as defined above. Create

The starting material of formula (XIX) is preferably in formula XIV (wherein R ₃ is phenyl and R ₈ is a protecting group) in an inert solvent such as diethyl ether at a preferred temperature of −65 to 0 ° C. Grignard reagent, in particular methyltrisilylmethyl Grignard reagent (ClMgCH ₂ Si (CH ₃ ) ₃ , which introduces a methyl group) into a compound of chloromethyltrimethylsilane ( And hydroxy and trimethylsilyl groups, for example, with boron trifluoride, in an ether such as diethyl ether at a preferred temperature of -20 to 30 ° C., and at the same time Remove the protecting group R ₈ (particularly when the tert-butoxycarbonyl protecting group has been removed), or thereafter removing the protecting group as described under the heading "removing the protecting group". Is obtained.

In addition, methyltriphenylphosphonium bromide or iodide in the presence of a strong base such as sodium amidide at a temperature of −90 to 0 ° C. starting from formula XIV wherein R ₃ is phenyl and R ₈ is a protecting group After using a suitable witting reagent such as, it may be synthesized by removing the protecting group R ₈ according to the conditions mentioned under the heading "removing the protecting group".

Compounds of formula (X ^* ) are known or may be prepared according to methods known per se, for example according to the following:

Using a compound of formula XXI, it has 5 to 8 ring atoms and has 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ). Suitable solvents, in particular dimethyl acetamide, at preferred temperatures of 80 ° C. to a boiling point, for example about 150 ° C., of unsaturated heterocycles, unsubstituted or substituted with lower alkyl or phenyl-lower alkyl, in particular with thiazole or thiophene In the presence of an alkali metal lower alkanoate, such as potassium acetate, in a N, N-di-lower alkyl-lower alkanoyl-amide, such as tetrakis (triphenylphosphine) palladium, as a catalyst Compounds of ^* , in particular 4- (thiazol-5-yl) -benzaldehyde or 4- (thiophen-2-yl) -benzaldehyde.

Wherein Hal is halogen, in particular bromine or chlorine.

Alternatively, the corresponding di-lower alkylacetals (see, eg, J. Org. Chem. 56, 4280 (1991)), starting from the compound of formula XXI as defined last, for example Obtained by reacting 4-bromobenzaldehyde with ortho formic acid trimethyl ester in an alcohol such as methanol in the presence of an acid such as bromobenzaldehyde dimethylacetal (e.g., p-toluenesulfonic acid (which can also be used in the form of a hydrate) Can be obtained). The resulting 4-halo-benzaldehyde di-lower alkylacetal is then reacted with magnesium in the presence of a catalytic amount of iodine in a suitable solvent, for example an ether such as tetrahydrofuran, at a preferred temperature of 0 to 70 ° C. After conversion to the Grignard reagent of formula (XXII), it is reacted in the presence of 1,3-bis (diphenylphosphino) propane nickel (II) chloride as catalyst in an ether such as tetrahydrofuran ( In a particularly preferred variant of the process (adding a suitable hydride complex, in particular diisobutylaluminum hydride, dissolved in a hydrocarbon such as hexane for example), it is added at the desired temperature of 0 to 60 ° C. Reaction with the compound yields the corresponding aldehyde compound of formula X ^* .

Wherein Hal is halogen, in particular bromine or chlorine, and Z is lower alkyl.

[Formula XXIII]

Wherein R ₉ has 5 to 8 ring atoms, 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl (-SO-) and sulfonyl (-SO _2- ), and lower alkyl Or an unsaturated heterocycle unsubstituted or substituted with phenyl-lower alkyl, and Hal 'is chlorine or especially bromine.

A compound of formula X ^* : 4- (thiazol-2-yl) -benzaldehyde, 4- (pyridin-2-yl or -3-yl) -benzaldehyde or 4- (pyrazin-2-yl) -benzaldehyde Particularly preferred compounds of the general formula (XXIII) in the preparation are 2-bromothiazole, 2- or 3-bromopyridine or 2-chloropyrazine.

Compounds of formula X ^* (wherein R ₄ is 4- (tetrazolin-5-yl) -phenyl) may be prepared by the reaction of 4-cyanobenzaldehyde in a suitable alkali metal such as lithium chloride in a suitable solvent such as 2-methoxyethanol. In the presence of a halide, it can be obtained by reacting with an alkali metal azide, such as sodium azide, preferably at boiling point. Preferably in a suitable acid, such as methanesulfonic acid and a suitable solvent such as toluene to reflux under a phenyl-lower alkyl halide or, preferably, 2-phenyl-propene, and the like phenyl-by reaction with a lower alkene, one of the corresponding Formula X ^* Or 2-phenyl-lower alkyl compound is obtained. At a preferred temperature of about 0 ° C. to about 30 ° C. in the presence of a suitable solvent, such as dioxane and alkali metal carbonates such as potassium carbonate or in particular cesium carbonate, and lower alkyl halides such as iodide such as methyl iodide Reaction with id or bromide gives a compound of formula X ^* substituted in the tetrazole ring by lower alkyl or phenyl-lower alkyl, in particular 4- (1-methyl-tetrazol-5-yl) benzaldehyde.

Compounds of formula (X) contain aldehyde groups from the corresponding compounds of formula (X ^* ) to hydroxymethyl groups (eg lithium lithium hydride in ethanol in the presence of lithium chloride in diglycol or sodium borohydride in ethanol) , Using a hydride complex such as diisoamylborane and sodium borohydride in tetrahydrofuran) and then, by standard methods, halogenated such as organic or inorganic strong acids such as hydrogen chloride, hydrogen bromide or hydrogen iodide. Hydrogen acids, or strong organic sulfonic acids, for example, unsubstituted or substituted, for example, halo-substituted lower alkanesulfonic acids such as fluoro-substituted or aromatic sulfonic acids, for example lower alkyl such as methyl, such as bromine Benzenesulfonic acids, such as methanesulfonic acid, unsubstituted or substituted by halogen, and / or nitro, by introduction of group X by esterification with p-bromo-toluenesulfonic acid or p-toluenesulfonic acid, or hydrazoic acid. For example, by reaction with an inorganic acid halide such as thionyl or phosphoryl halide (eg chloride, bromide or iodide), the halogen group X can be introduced or the remaining compounds of formula It can be obtained by reacting with other suitable organic or inorganic acids such as strong organic sulfonic acids (used as acid chlorides for example).

In addition, starting materials (in particular compounds of formula IV ^* , V ^* , VII ^* , IX ^* and (I ′) ^* ) can be prepared analogously to the process mentioned in EP 0 521 827 or EP 0 672 448, or Available from the references mentioned therein, or they may be known or prepared according to known methods, or are commercially available.

The preparation of starting materials for the preparation of compounds of formula (I) is preferably carried out analogously to the processes and process steps mentioned in the examples.

Particular preference is given to the starting materials according to the invention, in which case the meanings mentioned in the definitions for the compounds of the formula (I) apply in each case unless the group is specifically defined.

(1) a compound of formula XX wherein R ₁ is methoxycarbonyl or ethoxycarbonyl and R ₂ is tert-butyl;

(2) a compound of formula IV wherein R ₁ is methoxycarbonyl or ethoxycarbonyl and R ₂ is tert-butyl;

(3) a compound of formula III ^* , in particular a compound wherein R ₅ is tert-butyl and R ₆ is methoxycarbonyl or ethoxycarbonyl,

(4) a compound of formula XII,

(5) a compound of formula XII ^* ,

(6) a compound of formula III,

(7) a compound of formula V,

(8) a compound of formula VII,

(9) a compound of formula IX,

(10) a compound of formula X,

(11) 4- (1-methyl-tetrazol-5-yl) benzaldehyde, 4- (thiazol-2-yl) benzaldehyde, 4- (pyridin-2-yl or 3-yl) benzaldehyde, 4- (pyrazine A compound of formula X ^* selected from 2-yl) benzaldehyde, 4- (thiazol-5-yl) benzaldehyde and 4- (thiophen-2-yl) benzaldehyde,

(12) a compound of Formula XXIV

In which R ₁₃ and R ₁₄ is a different amino protecting group selected from those mentioned in process a), in particular a tert-lower alkoxycarbonyl or acylamino protecting group such as tert-butoxycarbonyl, in particular trofluoroacetyl, preferably R ₁₃ silver Trifluoroacetyl and R ₁₄ is tert-butoxycarbonyl (these compounds are compounds of formula (IX) protected at two amino groups),

(13) a compound of formula XXV

Wherein R ₁₄ is an amino protecting group as defined in compounds of formula XXIV, in particular tert-butoxycarbonyl,

(14) a compound of Formula XXVI,

Wherein R ₁₅ is an amino protecting group, in particular tert-butoxycarbonyl, the remaining groups being as defined for the compound of formula (I),

(15) 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -N- (tert-butoxycarbonyl ) Amino-2-N- [N-methoxycarbonyl- (L) -tert-silyl] amino-6-phenyl-2-azahexane (pharmaceutically active intermediate).

When salt-forming groups are present, the compounds mentioned in (1) to (15) as starting materials may also be in the form of salts.

The following examples illustrate the present invention without limiting it.

Temperature is expressed in degrees Celsius (° C.). If no temperature is specified, the reaction is carried out at room temperature. The R _f value indicating the ratio of the osmotic development of the material to the osmotic material at the front end of the eluent is determined on a thin film of silica gel (Merck, Darmstadt, Germany) by thin layer chromatography (TLC) using the solvent system mentioned in each case. Is measured.

HPLC gradient used:

HPLC _20-100 20% → 100% a) in b) for 20 min

HPLC _{20-100 (12 ′)} 20% → 100% a) in b) for 12 min, then 100% a) for 8 min

HPLC _5-60 5% → 60% in b) for 15 min a)

Eluent a): acetonitrile + 0.05% TFA, eluent b): water + 0.05% TFA.

Column (250 × 4.6 mm) packed with “reverse phase” material C18-Nucleosil (5 μm average particle size, silica gel covalently induced with octadecylsilane, Mecherey & Nagel, Duren, Germany). Detection by UV-absorbance at 254 nm. Retention time (t _Ret ) is expressed in minutes. Flow rate 1 ml / min.

Other abbreviations used have the following meanings.

abs. Anhydrous (indicating solvent is anhydrous)

anal. Elemental analysis

Boc. tert-butoxycarbonyl

calc. Theory

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene- (1,5-5)

TLC thin layer chromatography

DIPE Diisopropyl Ether

DMF Dimethylformamide

DPPP [1,3-bis (diphenylphosphino) propane] nickel (II) chloride (Aldrich, Milky Wow, USA)

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

Ether diethyl ether

FAB-MS Fast Atomic Impact Mass Spectroscopy

sat. Saturated

HOAc acetic acid

HOBT 1-hydroxy-benzotriazole

HPLC high performance liquid chromatography

Huenig base N-ethyldiisopropylamine

MeOH Methanol

min min

NMM N-methylmorpholine

Pd / C Charcoal Palladium

Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium

Iso-PrOH Isopropanol

The ratio of osmotic development to the eluent shear in R _f TLC

SiO ₂ silica gel

m.p. Melting point

Brine saturated sodium chloride solution

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

                               (Distilled sodium / benzophenone phase)

TPTU O- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

p-TSA p-toluenesulfonic acid

Sources of some amino acids used as starting materials:

-(2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane (J. Org. Chem. 50, 4615 (1985)

-(2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane (European patent application EP 0 521 827, page 78, example 16d)

-N-methoxycarbonyl- (L) -valine (see Preparation Example of Chem. Lett. 705 (1980))

-N-ethoxycarbonyl- (L) -valine (see Preparation Example J. Org. Chem. 60, 7256 (1995))

-N-methoxycarbonyl- (L) -iso-leucine (see Preparation Example of Chem. Lett. 705 (1980))

<Example 1>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- Valeyl) amino] -6-phenyl-2-azahexane

N-methoxycarbonyl- (L) -valine (excluding EP 0 604 368, see Example 2b) without water, 735 mg (4.20 mmol), 1548 mg (8.07 mmol) EDC and 654 mg (4.844 mmol) HOBT Was added in 10 ml of DMF. 1.13 ml (8.07 mmol) of TEA were added to the white suspension and the mixture was stirred at room temperature for 30 minutes. Then 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl- dissolved in 1 ml of DMF. 595 mg (1.62 mmol) of 2-ahexane was added and the mixture was stirred overnight to terminate the reaction. The reaction mixture was concentrated by evaporation and the resulting oil was dissolved in methylene chloride and washed with 10% citric acid solution, saturated NaHCO ₃ solution and brine. The aqueous phase was extracted twice with methylene chloride and the combined organic phases were filtered through cotton wool and concentrated by evaporation. Column chromatography (SiO ₂ , CH ₂ Cl ₂ / MeOH / H ₂ O / HOAc 85: 13: 1.5: 0.5) and precipitation from DI solution in concentrated solution to methylene chloride gave the title compound, TLC: R _f = 0.57 ( CH ₂ Cl ₂ / MeOH / H ₂ O / HOAc 85: 13: 1.5: 0.5), HPLC _20-100 : t _Ret = 13.0, FAB-MS (M + H) ⁺ = 683.

Starting material was prepared as follows.

1a) 4- (thiazol-5-yl) -benzaldehyde

In a cylinder tube, 3.7 g (20 mmol) of 4-bromobenzaldehyde (Fluka, Buchs, Switzerland), 6.64 ml (93 mmol) of thiazole, 2.94 g of potassium acetate and Pd (PPh ₃ ) in 50 ml of dimethylacetamide ₄ 1.16 g (1 mmol) of the mixture was stirred at 150 ° C for 12 h. The reaction mixture was concentrated by evaporation. Water was added to the residue and the mixture was extracted three times with methylene chloride. The organic phase was filtered through cotton wool, concentrated by evaporation, chromatography (SiO ₂ , hexanes / ethyl acetate 1: 2) to give the title compound: HPLC _20-100 : t _Ret = 11.4, ¹ H-NMR (CD ₃ OD) δ 9.98 (s.HCO), 9.03 (s.H (2) ^thiazole ), 8.32 (s.H (4) ^thiazole ), 7.95 and 7.85 (2d. J = 8, 2H each) , Also the signal of additional hydrate (≒ 12%): 8.92 (s. H (2) ^thiazole ), 8.15 (s. H (4) ^thiazole ), 7.62 and 7.53 (2d. J = 8, 2H each). , 5.54 (s. HC (OH) ₂ ).

1b) N-1- (tert-butoxycarbonyl) -N-2-{[4-thiazol-5-yl) -phenyl] -methylidene} -hydrazone

A solution of 1.22 g (6.45 mmol) of 4- (thiazol-5-yl) -benzaldehyde and 1.12 g (6.14 mmol) of tert-butyl carbazate (Fluka, Buchs, Switzerland) in 40 ml of ethanol at 80 ° C Stir for 12 hours. 60 ml of water at 0 ° C. was added to cool and crystallized to give the title compound: melting point 170 to 171 ° C., HPLC _20-100 : t _Ret = 13.5.

1c) N-1- (tert-butoxycarbonyl) -N-2- [4-thiazol-5-yl) -benzyl] -hydrazine

Under nitrogen atmosphere, 20.4 g (67.2 mmol) of N-1- (tert-butoxycarbonyl) -N-2-{[4-thiazol-5-yl) -phenyl] -methylidene} -hydrazone To 120 ml was added 4.67 g (70.7 mmol, 95%) of sodium cyanoborohydride. Thereafter, a solution of 12.8 g (67.2 mmol) of p-toluenesulfonic acid monohydrate (pH 3 to 4) in 120 ml of THF was added dropwise thereto. After 7 h, water and ethyl acetate were added, the aqueous phase was separated and extracted two more times with ethyl acetate. The organic phase was washed with brine, saturated NaHCO ₃ solution and brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation. 80 ml of dichloroethane and 80 ml of 1 N NaOH solution (foam) were added to the resulting viscous oil, and the mixture was boiled under reflux for 7 hours. The reaction mixture was cooled down and diluted with methylene chloride and water. The aqueous phase was separated and extracted twice with methylene chloride. The organic phase was dried (Na ₂ SO ₄ ), concentrated by evaporation and chromatographed (SiO ₂ , hexane / ethyl acetate 2: 1). Stir in hexane and give the title compound: mp 93-95 ° C., TLC: R _f = 0.12 (hexane / ethyl acetate 2: 1), elemental analysis (C ₁₅ H ₁₉ N ₃ O ₂ S) theory. C 58.99, H 6.27, N 13.76, S 10.50, found C 58.98, H 6.34, N 13.64, S 10.66, HPLC _20-100 : t _Ret = 10.1

1d) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6 -Phenyl-2-azahexane

1.21 g (4.6 mmol) and N-1- (tert-butoxycarbonyl) -N-2 (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane in 25 ml of iso-PrOH A suspension of 1.4 g (4.6 mmol) of-[4- (thiazol-5-yl) -benzyl] -hydrazine was heated with boiling overnight. The reaction mixture was cooled down and water was added. The supernatant was decanted from the separated oil, the oil was dried in vacuo, chromatographed (SiO ₂ , methylene chloride / methanol 30: 1) and the title compound was produced: TLC: R _f = 0.2 (methylene chloride / Methanol 30: 1), HPLC _20-100 : t _Ret = 17.2.

1e) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] in 100 ml of formic acid A solution of 1.14 g (2.0 mmol) of -6-phenyl-2-azahexane was stirred at room temperature for 3 hours and then concentrated by evaporation. Saturated NaHCO ₃ solution and methylene chloride were added to the residue, the aqueous phase was separated and extracted twice with methylene chloride. The organic phase was treated with brine, filtered through cotton wool and concentrated by evaporation to afford the title compound which was used directly in the next step.

<Example 2>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino] -5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S)-[N- (N-methoxy) in 5.6 ml of DMF 344 mg of carbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane and 191 μl (1.74 mmol) of NMM were added to N-methoxycarbonyl- (L) -valine in 2.9 ml of DMF. To 122 mg (0.696 mmol) and 173 mg (0.58 mmol) TPTU were added and the mixture was stirred at rt for 16 h. The reaction mixture was poured into iced water, stirred for 30 minutes and filtered. The residue was column chromatographed (SiO ₂ , methylene chloride / THF 4: 1) and stirred in ether to give the title compound: melting point 134 to 135 ° C., HPLC _20-100 : t _Ret = 14.0, FAB-MS (M + H) ⁺ = 697.

Starting material was prepared as follows.

2a) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S)-(trifluoroacetyl) Amino-6-phenyl-2-azahexane

5.32 g (20.5 mmol) and N-1- (tert-butoxycarbonyl) (2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane in 95 ml of iso-PrOH A suspension of 5.7 g (18.6 mmol) of -N-2- [4-thiazol-5-yl) -benzyl] -hydrazine (Example 1c) was terminated by heating for 8 hours. After cooling, the reaction mixture was partially concentrated by evaporation, left at 0 ° C. and then crystallized to give the title compound which was suction filtered and dried: TLC: R _f = 0.39 (methylene chloride / THF 10: 1) , HPLC _20-100 : t _Ret = 16.5: FAB-MS (M + H) ⁺ = 565. Hang again with (2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane in iso-PrOH and column chromatography (SiO ₂ , methylene chloride / THF 15: 1) As a result, additional products could be obtained from the mother liquor.

2b) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl- 2-azahexane

100 ml of 1N K ₂ CO ₃ solution was added to 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino- in 100 ml of methanol. 5.646 g (10.0 mmol) of 5 (S)-(trifluoroacetyl) amino-6-phenyl-2-azahexane was added dropwise and the mixture was stirred at 70 ° C. for 15 hours. Methanol chloride and water were added, the aqueous phase was separated and extracted twice with methylene chloride. The organic phase was washed twice with water, dried (Na ₂ SO ₄ ) and concentrated by evaporation to afford the title compound: elemental analysis (C ₂₅ H ₃₂ N ₄ O ₃ S (0.53H ₂ O) theory. C 62.80, H 6.97, N 11.72, S 6.71, H ₂ O 2.00, found C 63.2, H 7.01, N 11.57, S 6.49, H ₂ O 1.98, HPLC _20-100 : t _Ret = 11.5.

2c) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-meth Methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Under nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl- (L) -tert-leucine (Example 2e), 2.59 g (13.5 mmol) of EDC and 1.22 g (9.0 mmol) of HOBT were added to 20 ml of DMF. In water. After 15 minutes, 3.79 mL (27 mmol) of TEA was added and 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxy) in 41 ml of DMF. A solution of 2.11 g (4.5 mmol) of carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane was added dropwise. After 3 hours, the reaction mixture was concentrated by evaporation. The resulting oil was dissolved in ethyl acetate and a small amount of THF and washed twice with water, saturated NaHCO ₃ solution, twice with water and brine. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (Na ₂ SO ₄ ) and concentrated by evaporation. Crystallization from column chromatography (SiO ₂ , methylene chloride / THF 5: 1) and ethyl acetate / DIPE gave the title compound, HPLC _20-100 : t _Ret = 16.0: FAB-MS (M + H) ⁺ = 640.

2d) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L)- tert-louisyl) amino-6-phenyl-2-azahexane

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycar 742 mg (1.16 mmol) of bonyl- (L) -tert-leusil) amino-6-phenyl-2-azahexane and 12 ml of formic acid were stirred at room temperature for 7 hours and then concentrated by evaporation. Saturated NaHCO ₃ solution and ethyl acetate were added to the residue, the aqueous phase was separated and extracted with ethyl acetate. The organic phase was treated with water and brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation to afford the title compound which was used directly in the next step.

2e) N- (methoxycarbonyl)-(L) -tert-leucine

23.5 ml (305 mmol) of methyl chloroformate (L) -tert-leucine (= 2 (S) -amino-3, in a mixture of 252 ml (504 mmol) of 2N aqueous sodium hydroxide solution and 80 ml of dioxane To a solution of 20 g (152 mmol) of 3-dimethyl-butyric acid = (L) -α-tert-butylglycine, from Buchs Fluka, Switzerland was added over 20 minutes and the reaction solution was heated at 60 ° C. for 14 hours. . After cooling to room temperature, the reaction solution was washed twice with methanol chloride. The aqueous phase was acidified to pH 2 with 4 N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic extracts were dried (Na ₂ SO ₄ ), concentrated by evaporation and the product started to solidify. The solidified solid was immersed in hexane to give the title compound in the form of a white powder: melting point 106-108 ° C.

<Example 3>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy- (5S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert -Louisyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 4.8 ml of DMF 292 mg of carbonyl- (L) -tert-louisyl) amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM were added N-methoxycarbonyl- (L in 2.5 ml of DMF. ) 3.5 g of tert-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU were added and the mixture was stirred at rt for 14 h. The reaction mixture was poured into 0.2 liters of ice water, stirred for 45 minutes and filtered. The residue was column chromatographed (SiO ₂ , methylene chloride / ethanol 20: 1) and crystallized from ethyl acetate / ether / hexane to give the title compound, melting point 207-209 ° C., TLC: R _f = 0.25 (methylene chloride / Ethanol 20: 1), HPLC _20-100 : t _Ret = 14.7: FAB-MS (M + H) ⁺ = 711.

<Example 4>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 4.8 ml of DMF 292 mg of carbonyl- (L) -tert-louisyl) amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM were added N-methoxycarbonyl- (L in 2.5 ml of DMF. ) -Iso-leucine was added to 113 mg and 149 mg (0.50 mmol) of TPTU, and the mixture was stirred at room temperature for 14 hours and worked up similarly to Example 3 to obtain the title compound, melting point 139 to 141 ° C., TLC: R _f = 0.7 (methylene chloride / methanol 10: 1), HPLC _20-100 : t _Ret = 14.6: FAB-MS (M + H) ⁺ = 711.

Example 5

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 4.8 ml of DMF 292 mg of carbonyl- (L) -tert-louisyl) amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM were added N-methoxycarbonyl- (L in 2.5 ml of DMF. To 116 mg) -S-methylcysteine and 149 mg (0.50 mmol) of TPTU, the mixture was stirred at room temperature for 5 hours and worked up similarly to Example 3 to give the title compound, TLC: R _f = 0.4 ( Methylene chloride / methanol 10: 1), HPLC _20-100 : t _Ret = 13.6 FAB-MS (M + H) ⁺ = 715.

Starting material was prepared as follows.

5a) N-methoxycarbonyl- (L) -S-methylcysteine

After ice cooling, 16.8 g (177.5 mmol) of chloroformic acid methyl ester was added to 150 ml of 2N aqueous sodium hydroxide solution and 18 ml of dioxane to S-methyl- (L) -cysteine ((S) -2-amino-3-methylmer Captopropionic acid, Fluka, Buchs, Switzerland) was added dropwise to a solution of 12.0 g (88.8 mmol), and the mixture was stirred at 70 ° C. overnight to terminate the reaction. The reaction mixture was diluted with 150 ml of methylene chloride, the aqueous phase was separated, acidified with 1N HCl and extracted three times with ethyl acetate. Dry (Na ₂ SO ₄ ) and concentrate the ethyl acetate phase by evaporation to afford the title compound, FAB-MS (M + H) ⁺ = 194.

<Example 6>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) -amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 5.6 ml of DMF 344 mg of carbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane (Example 2d) and 191 μl (1.74 mmol) of NMM were added to N-ethoxycarbonyl- (L in 2.9 ml of DMF. ) -Valine (EP 0 604 368, Example 9a) was added to 132 mg (0.7 mmol) and TPTU 173 mg (0.58 mmol), and the mixture was stirred overnight at room temperature and worked up similarly to Example 3 to give the title compound. Obtained, TLC: R _f = 0.45 (methylene chloride / THF 4: 1), HPLC _20-100 : t _Ret = 14.7, FAB-MS (M + H) ⁺ = 711.

<Example 7>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 213 mg (1.13 mmol) of N-methoxycarbonyl- (L) -tert-leucine (Example 2e), 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT were added in 18 ml of DMF. Put in. After 15 minutes, 627 μl (4.5 mmol) of TEA and 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N 0.75 mmol of methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane was added. After 2 h, water and ethyl acetate were added, the aqueous phase was separated and extracted twice more with ethyl acetate. The organic phase was washed twice with water, saturated NaHCO ₃ solution and water and brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography (SiO ₂ , methylene chloride / THF 5: 1) and crystallization from ether gave the title compound: melting point _200-201 ° C., HPLC _20-100 : t _Ret = 14.0, FAB-MS (M + H ) ⁺ = 697.

Starting material was prepared as follows.

7a) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-meth Methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under a nitrogen atmosphere, 2.66 mg (15.2 mmol) of N-methoxycarbonyl- (L) -valine, 5.46 g (28.5 mmol) of EDC and 2.57 g (19 mmol) of HOBT were dissolved in 42 ml of DMF. 7.9 ml (57 mmol) of TEA were added and after 20 minutes 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarb in 85 ml of DMF A solution of 4.46 g (9.5 mmol) of carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane (Example 2b) was added dropwise. After 1.5 hours, the reaction mixture was worked up similarly to Example 2c. Crystallization from THF / ether gave the title compound, melting point _114-115 ° C., HPLC _20-100 : t _Ret = 15.1. FAB-MS (M + H) ⁺ = 626.

7b) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L)- Valyl) amino-6-phenyl-2-azahexane

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycar 1.25 mg (2.0 mmol) of carbonyl- (L) -valyl) amino-6-phenyl-2-azahexane and 18 ml of formic acid were reacted similarly to Example 2d to give the title compound, HPLC _20-100 : t _Ret = 10.0.

<Example 8>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 213 mg (1.13 mmol) N-ethoxycarbonyl- (L) -valine in 18 ml DMF and 627 μL (4.5 mmol) TEA, 431 mg (2.25 mmol) EDC and 304 mg HOBT ( 2.25 mmol) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L ) -Valyl) amino-6-phenyl-2-azahexane (Example 7b) was reacted with 0.75 mmol to give the title compound, melting point 243 to 244 ° C., HPLC _20-100 : t _Ret = 14.0. FAB-MS (M + H) ⁺ = 697.

Example 9

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 5.8 ml of DMF 0.6 mmol of carbonyl- (L) -valyl) amino-6-phenyl-2-azahexane and 198 μL (1.8 mmol) of NMM were added to 136 mg of N-methoxycarbonyl- (L) -isoleucine in 3 ml of DMF. 0.72 mmol) and 179 mg (0.60 mmol) of TPTU, and the mixture was stirred for 14 hours at room temperature and worked up similarly to Example 3 to obtain the title compound, TLC: R _f = 0.59 (methylene chloride / THF 3 : 1), HPLC _20-100 : t _Ret = 14.0 FAB-MS (M + H) ⁺ = 697.

<Example 10>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 5.6 ml of DMF 0.58 mmol of carbonyl- (L) -valyl) amino-6-phenyl-2-azahexane and 191 μL (1.74 mmol) of NMM were subjected to N-methoxycarbonyl- (L) -S-methylcysteine in 2.9 ml of DMF. Example 5a) was added to 134 mg (0.696 mmol) and 173 mg (0.58 mmol) TPTU and the mixture was stirred at room temperature for 15 hours and worked up similarly to Example 3 to give the title compound, TLC: R _f = 0.17 (Methylene chloride / THF 4: 1), HPLC _20-100 : t _Ret = 13.0 FAB-MS (M + H) ⁺ = 701.

<Example 11>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 4.8 ml of DMF 0.5 mmol of carbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane and 165 μL (1.5 mmol) of NMM were added to N-methoxycarbonyl- (L) -tert-leucine in 2.5 ml of DMF. (Example 2e) To 113.5 mg (0.60 mmol) and 149 mg (0.50 mmol) of TPTU was added and the mixture was stirred at room temperature for 14 hours. Ice water and ethyl acetate were added, the aqueous phase was separated and extracted with ethyl acetate. The organic phase was washed twice with water and brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography (SiO ₂ , ethyl acetate) and crystallization from ethyl acetate / ether / hexanes gave the title compound: TLC: R _f = 0.42 (methylene chloride / ethanol 10: 1), HPLC _20-100 : t _Ret = 14.8, FAB-MS (M + H) ⁺ = 711.

Starting material was prepared as follows.

11a) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-meth Methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane

Under a nitrogen atmosphere, 1.36 g (7.2 mmol) of N-methoxycarbonyl- (L) -iso-leucine, 2.59 g (13.5 mmol) EDC and 1.22 g (9 mmol) HOBT were dissolved in 20 ml of DMF. After 30 minutes, 3.79 ml (27 mmol) of TEA were added and 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxy) in 40 ml of DMF. A solution of 2.11 g (4.5 mmol) of carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane (Example 2b) was added dropwise. After 3 hours, the reaction mixture was worked up similarly to Example 3 to obtain the title compound, melting point 163 to 166 ° C., elemental analysis (C ₃₃ H ₄₅ N ₅ O ₆ S) (0.14H ₂ O) theory. C 61.71, H 7.11, N 10.90, S 4.99, H ₂ O 0.39, found C 61.61, H 7.10, N 10.79, S 4.76, H ₂ O 0.4, HPLC _20-100 : t _Ret = 16.0, FAB-MS (M + H) ⁺ = 640.

11b) 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L)- Iso-Louisyl) amino-6-phenyl-2-azahexane

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycar 320 mg (0.50 mmol) and 6 ml of formic acid were reacted analogously to Example 2d to obtain the title compound, which was directly used for the next step.

<Example 12>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl- (L) -valine, 288 mg (1.5 mmol) and HOBT 135 mg (1.0 mmol) in 2 ml of DMF and 418 μL of TEA were added. 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino5 (S) -N- (N-methoxycarbonyl- (L) in 5 ml of DMF Reaction with 0.5 mmol of iso-leusil) amino-6-phenyl-2-azahexane gave the title compound, melting point 202-204 DEG C, HPLC _20-100 : t _Ret = 14.0. FAB-MS (M + H) ⁺ = 697.

Example 13

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- Iso-Louisyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 175 mg (0.92 mmol) of N-methoxycarbonyl- (L) -isoleucine in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA, 332 mg (1.7 mmol) of EDC and HOBT 156 mg (1.15 mmol) was added to 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-meth) in 5.2 ml of DMF. Reaction with 0.578 mmol of oxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane (Example 11b) gave the title compound, melting point _213-216 ° C., HPLC _20-100 : t _Ret = 14.7. FAB-MS (M + H) ⁺ = 711.

<Example 14>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 175 mg (0.92 mmol) N-ethoxycarbonyl- (L) -valine in 2.5 ml DMF and 483 μL (3.47 mmol) TEA, 332 mg (1.7 mmol) EDC and 156 mg HOBT ( 1.15 mmol) was added to 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarboxyl) in 5.2 ml of DMF. Reaction with 0.578 mmol of carbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane (Example 11b) gave the title compound, melting point _200-203 ° C., HPLC _20-100 : t _Ret = 14.6 . FAB-MS (M + H) ⁺ = 711.

<Example 15>

1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarb in 4.8 ml of DMF Carbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane (Example 11b) 0.5 mmol and NMM 165 μl (1.5 mmol) were added N-methoxycarbonyl- (L) in 2.5 ml of DMF. -S-methylcysteine (Example 5a) was added to 116 mg (0.60 mmol) and 149 mg (0.50 mmol) TPTU, and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added, the aqueous phase was separated and further extracted twice with ethyl acetate. The organic phase was washed twice with water and brine, dried (Na ₂ SO ₄ ) and partially concentrated by evaporation. Crystallization from ether gave the title compound: melting point 179-181 ° C., TLC: R _f = 0.67 (methylene chloride / ethanol 10: 1), HPLC _20-100 : t _Ret = 13.6, FAB-MS (M + H) ⁺ = 715.

<Example 16>

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane

Under argon atmosphere, 2.58 mg (13.7 mmol) of N-methoxycarbonyl- (L) -tert-leucine and 4.09 g (13.7 mmol) of TPTU were dissolved in 15.5 ml of DMF, and 5.7 ml (24.8 mmol) of a base base Was added while cooling and the mixture was stirred for 10 minutes. Then 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2- in 15.5 ml of DMF. 2.29 g (6.20 mmol) of azahexane were added and the mixture was stirred at rt for 16 h. The pale yellow reaction solution was poured into iced water, ethyl acetate was added and the mixture was stirred for 30 minutes. The aqueous phase was separated and extracted twice more with ethyl acetate. The organic phase was washed twice with water, saturated NaHCO ₃ solution and brine twice, dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography (SiO ₂ , hexane / ethyl acetate 1: 3) and crystallization from methylene chloride / DIPE gave the title compound: TLC: R _f = 0.18 (hexanes / ethyl acetate 1: 3), HPLC _{20-100 (12 ')} : t _Ret = 11.0, FAB-MS (M + H) ⁺ = 711. [?] ^0. (C = 0.6, ethanol) = -46 ° C.

Starting materials were prepared as follows.

16a) 4- (thiazol-2-yl) -benzaldehyde

Under argon, 9.2 g (379 mmol) magnesium was placed in 84 ml THF and heated to 60 ° C. A solution of 82.6 g (357 mmol) of 4-bromobenzaldehyde dimethyl acetal (refer to J. Org. Chem. 56, 4280 (1991)) in 677 ml THF was added dropwise to the solution for 30 minutes The mixture was further stirred at boiling temperature for 40 minutes. After cooling the Grignard solution and tilting the dropping funnel, 31.7 ml (338 mmol) 2-bromothiazole (Flucka, Buchs, Switzerland) in 1.68 liters of THF and 5.39 g (9.95 mmol) of DPPP red Was added dropwise to the suspension for 30 minutes. The mixture was stirred at rt for 12 h, an additional 5.39 g of DPPP was added, and the mixture was stirred for an additional 7 h. 840 ml of water were added and the mixture was stirred for 10 minutes, THF was evaporated off using a rotary evaporator and the residue was stirred for 1.5 h in 1.0 liter of ether and 340 ml of 2N HCl. The aqueous phase was separated off and extracted twice with ethyl acetate. The organic phase was washed twice with 0.5 N HCl, water, saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and evaporated to concentration. Chromatography (SiO ₂ , hexanes / ethyl acetate 4: 1) and immersion in hexanes gave the title compound. TLC: R _f = 0.21 (hexane / ethyl acetate 3: 1), melting point: 91-92 ° C., Analytical (C ₁₀ H ₇ NOS) requires C 63.47, H 3.73, N 7.40, S 16.94: found C 63.14, H 3.79 , N 7.27, S 17.08, ¹ H-NMR (CDCl ₃ ) δ 10.05 (s, HCO), 8.15 (d, J = 8, 2H), 7.95 (m, 3H), 7.45 (d, J = 3, 1H ).

16b) N-1- (tert-butoxycarbonyl) -N-2-{[4- (thiazol-2-yl) -phenyl] -methylidene} -hydrazone

A solution of 27.6 g (145 mmol) 4- (thiazol-2-yl) benzaldehyde and 19.7 g (149 mmol) tert-butyl carbazate in 920 ml of ethanol was stirred at 80 ° C. for 18 hours. Cool, concentrate by evaporation and stir from DIPE to afford the title compound. TLC: R _f = 0.31 (toluene / ethyl acetate 3: 1), HPLC _20-100 : t _Ret = 14.5.

16c) N-1- (tert-butoxycarbonyl) -N-2- [4- (thiazol-2-yl) -benzyl] -hydrazine

Under a nitrogen atmosphere, 77.6 g (256 mmol) N-1- (tert-butoxycarbonyl) -N-2-{[4- (thiazol-2-yl) -phenyl] -methylidene} -hydrazone Was added to 450 ml of THF and 16.9 g (257 mmol, 95%) of sodium cyanoborohydride were added. A solution of 49.6 g (261 mmol) of p-toluenesulfonic acid monohydrate (pH 3-4) in 450 ml of THF was added dropwise to the solution. After 17 hours, an additional 3.38 g of sodium cyanoborohydride was added and the pH of this mixture was adjusted to 3-4 using p-toluenesulfonic acid monohydrate solution and stirred for 3 hours to complete the reaction. Water and ethyl acetate were added, the aqueous phase was separated off and extracted twice more with ethyl acetate. The organic phase was washed with brine, saturated NaHCO ₃ solution and brine (twice), dried (sodium sulfate) and evaporated to concentrate. The resulting viscous oil was taken up with 300 ml of 1,2-dichloroethane and 300 ml of 1 N NaOH solution was slowly added (bubble generated) and the mixture was boiled at reflux for 3.5 hours. The mixture was cooled and diluted with methylene chloride and water, the aqueous phase was separated off and extracted twice with methylene chloride. The organic phase was dried (sodium sulfate), evaporated to concentrate and chromatographed (SiO ₂ , toluene / acetone 9: 1 → 6: 1). Stir in hexane to afford the title compound. TLC: R _f = 0.3 (hexane / ethyl acetate 3: 2), HPLC _20-100 : t _Ref = 11.1.

16d) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6 -Phenyl-2-azahexane

6.00 g (22.8 mmol) of (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane in 550 ml of iso-PrOH and 5.37 g (17.6 mmol) of N-1- (tert- The solution with butoxycarbonyl) -N-2- [4- (thiazol-2-yl) -benzyl] -hydrazine was heated at boiling point overnight. The reaction mixture was cooled to room temperature, poured into 0.2 liters of water with stirring and cooled with ice. Suction filtration, washing with water and ether and drying gave the title compound. TLC: R _f = 0.36 (hexane / ethyl acetone 3: 2), HPLC _{20-100 (12 ')} : t _Ref = 12.7. Further product can be isolated from the mother liquor by chromatography (SiO ₂ , hexane / acetone 3: 2).

16e) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane

4.3 g (7.56 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert) in 378 ml of formic acid A solution of -butoxycarbonyl) amino] -6-phenyl-2-azahexane was stirred for 3.5 hours (under argon) at room temperature and then evaporated to concentrate. Saturated NaHCO ₃ solution and methyl chloride were added to the residue, the aqueous phase was separated off and extracted twice with methylene chloride. The organic phase was treated with brine, dried (sodium sulfate) and concentrated by evaporation to form the title compound. HPLC _{20-100 (12 ')} : t _Ref = 6.8.

<Example 17>

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl)-(L) -valyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 294 mg of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N in 4.8 ml of DMF -Methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM in 11 ml mg (0.60 mmol) of N-methoxycarbonyl in 2.5 ml of DMF -(L) -t-Leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU were added at 0 ° C. and the mixture was stirred at rt for 18 h. Water and ethyl acetate were added, the aqueous phase was separated off and extracted twice more with ethyl acetate. The organic phase was washed twice with water, saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and concentrated by evaporation. Column chromatography (SiO ₂ , methylene chloride / THF 4: 1) and precipitated from the concentrated solution in methylene chloride using hexanes gave the title compound. HPLC _20-100 : t _Ref = 14.5, FAB MS (M + H) ⁺ = 697.

Starting materials were prepared as follows.

17a) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S)-(trifluoroacetyl) Amino-6-phenyl-2-azahexane

4.8 g (18.5 mmol) of (2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane in 62 ml of iso-PrOH and 3.78 g (12.4 mmol) of N-1 -(tert-butoxycarbonyl) -N-2- [4- (thiazol-2-yl) benzyl] -hydrazine (Example 16c) was heated at a boiling point for 10 hours with no air . The reaction mixture was cooled down, filtered and washed with ether to afford the title compound. Anal (C ₂₇ H ₃₁ N ₄ F ₃ O ₄ S) Theoretical C 57.44, H 5.53, N 9.92, F 10.09, S 5.68: Found C 57.27, H 5.49, N 9.91, F 9.94, S 5.70, HPLC _20-100 : t _Ret = 16.9, FAB MS (M + H) ⁺ = 565. The filtrate can be concentrated by evaporation, column chromatography (SiO ₂ , methylene chloride / THF 25: 1) and stirred from ether / ethyl acetate to further isolate the product.

17b) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl- 2-azahexane

55 ml of 1 NK ₂ CO ₃ solution was added to 3.12 g (5.5 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- () in 55 ml of methanol. tert-butoxycarbonyl) amino-5 (S)-(trifluoroacetyl) amino-6-phenyl-2-azahexane was added dropwise and the mixture was stirred at 70 ° C. for 9 hours. The mixture was cooled and evaporated off about 30 ml of methanol, the aqueous phase was separated off by addition of methylene chloride and water and extracted with methylene chloride, then the organic phase was washed with water, dried (sodium sulfate) and concentrated by evaporation to give the title compound Obtained. HPLC _20-100 : t _Ret = 11.9, FAB MS (M + H) ⁺ = 469.

17c) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-meth Methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under a nitrogen atmosphere, 1.4 g (8.0 mmol) of N-methoxycarbonyl- (L) -valine, 2.87 g (15 mmol) of EDC and 1.35 g (10 mmol) of HOBT were dissolved in 22 ml of DMF. After 45 minutes, 4.2 ml (30 mmol) of TEA was added followed by 2.34 g (5.0 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S)-in 45 ml of DMF. A solution of hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane was added dropwise. After 1.5 h, the reaction mixture was concentrated by evaporation and the residue was taken up in methylene chloride and washed with water, saturated NaHCO ₃ solution, water and brine. The aqueous phase was extracted twice with methylene chloride and the combined organic phases were dried (sodium sulfate), evaporated and concentrated. Column chromatography (SiO ₂ , methylene chloride / ethyl acetate 2: 1) and crystallized from ethyl acetate / ether gave the title compound. Melting point: _178-179 ° C., HPLC _20-100 : t _Ret = 15.8.

17d) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L)- Valyl) amino-6-phenyl-2-azahexane

0.94 g (1.5 mmol) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N -(N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane and 18 ml of formic acid were stirred at room temperature for 6 hours and worked up similarly to Example 2d to give the title compound. Formed. FAB MS (M + H) ⁺ = 526.

Example 18

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 106 mg (0.56 mmol) of N-methoxycarbonyl- (L) -iso-leucine, 201 mg (1.05 mmol) in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA EDC and 95 mg (0.7 mmol) of HOBT 0.35 mmol of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N Reaction with-(N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane to form the title compound. Melting point: 227-229 ° C., HPLC _20-100 : t _Ret = 14.5, FAB MS (M + H) ⁺ = 697.

Example 19

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Similar to Example 7, 106 mg (0.56 mmol) of N-ethoxycarbonyl- (L) -valine, 201 mg (1.05 mmol) of EDC in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA and 95 mg (0.7 mmol) of HOBT was 0.35 mmol of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N Reaction with -methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane to form the title compound. Analytical (C ₃₅ H ₄₈ N ₆ O ₇ S (0.20 H ₂ O)) Theoretical C 60.01, H 6.96, N 12.00, S 4.58, H ₂ O 0.51: Found C 60.07, H 6.78, N 11.93, S 4.70, H ₂ 0 0.52, HPLC _20-100 : t _Ret = 14.6, FAB MS (M + H) ⁺ = 697.

Example 20

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- Valeyl) amino] -6-phenyl-2-azahexane

Similar to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl- (L) -valine, 288 mg (1.5 mmol) of EDC in 2.2 ml of DMF and 418 μl (3.0 mmol) of TEA and 135 mg (1.0 mmol) of HOBT was added to 0.5 mmol of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) in 4.5 ml of DMF. Reaction with -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane to form the title compound. Melting point: _207-210 ° C., HPLC _20-100 : t _Ret = 13.8, FAB MS (M + H) ⁺ = 683.

Example 21

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

Under argon atmosphere, 294 mg of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N in 4.8 ml of DMF Methoxycarbonyl- (L) -iso-rusilyl) amino-6-phenyl-2-azahexane and 165 μl (1.5 mmol) of NMM were charged at 11 ° C. (113.5 mg (0.60 mmol) in 2.5 ml of DMF at 0 ° C. N-methoxycarbonyl- (L) -t-leucine (Example 2e) and 149 mg (0.50 mmol) of TPTU were added and the mixture was stirred at rt for 16 h. Ice water and ethyl acetate were added, the aqueous phase was separated off and extracted with ethyl acetate. The organic phase was washed twice with water and brine, dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ , ethyl acetate) and crystallization from ethyl acetate / ether / hexanes gave the title compound. Anal (C ₃₆ H ₅₀ N ₆ O ₇ S (1.4% H ₂ O)) Theoretical C 59.97, H 7.15, N 11.66, S 4.45: Found C 59.99, H 7.18, N 11.35, S 4.59, TLC: R _f = 0.51 (methylene chloride / THF 3: 1), HPLC _20-100 : t _Ret = 15.2, FAB MS (M + H) ⁺ = 711.

Starting materials were prepared as follows.

21a) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-meth Methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane

Under a nitrogen atmosphere, 938 mg (4.96 mmol) of N-methoxycarbonyl- (L) -isoleucine, 1.78 g (9.3 mmol) of EDC and 838 mg (6.2 mmol) of HOBT were dissolved in 13.7 ml of DMF. I was. After 30 minutes, 2.6 ml (18.6 mmol) of TEA were added, followed by 1.45 g (3.1 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) in 28 ml of DMF. -Hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane (Example 17b) was added dropwise to the solution. After 3 hours, the reaction mixture was concentrated by evaporation and the residue was taken up in ethyl acetate and small amount of THF and washed with water, saturated NaHCO ₃ solution, water and brine. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate and concentrated by evaporation. Column chromatography (SiO ₂ , methylene chloride / THF 5: 1) and stirring from ethyl acetate / DIPE gave the title compound. HPLC _20-100 : t _Ret = 16.3, FAB MS (M + H) ⁺ = 640.

21b) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L)- Iso-Louisyl) amino-6-phenyl-2-azahexane

761 mg (1.2 mmol) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N -(N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane and 12 ml of formic acid were stirred at room temperature for 7 hours and worked up similarly to Example 2d. The title compound was formed.

<Example 22>

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

321 mg (0.60 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N in 5.8 ml of DMF -Methoxycarbonyl- (L) -iso-rusilyl) amino-6-phenyl-2-azahexane (Example 21b) and 182 mg (1.8 mmol) of NMM under 136 in 3 ml of DMF under argon atmosphere To mg (0.72 mmol) N-ethoxycarbonyl- (L) -valine and 178 mg (0.60 mmol) TPTU were added and the mixture was stirred at rt for 15 h. The reaction mixture was poured into iced water, stirred for 30 minutes and filtered. Crystallization from THF with DIPE and hexanes gave the title compound. Melting point: 209 to 211 ° C., HPLC _20-100 : t _Ret = 15.2, FAB MS (M + H) ⁺ = 711.

<Example 23>

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

321 mg (0.60 mmol) of 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N in 5.8 ml of DMF -Methoxycarbonyl- (L) -iso-rusilyl) amino-6-phenyl-2-azahexane (Example 21b) and 182 mg (1.8 mmol) of NMM were 126 in 3 ml of DMF under argon atmosphere. To mg (0.72 mmol) N-methoxycarbonyl- (L) -valine and 178 mg (0.60 mmol) TPTU were added and the mixture was stirred at room temperature for 15 hours and then worked up similarly to Example 3. It was. TLC: R _f = 0.15 (methylene chloride / THF 4: 1), HPLC _20-100 : t _Ret = 14.5, FAB MS (M + H) ⁺ = 697.

<Example 24>

1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

303 mg (0.50 mmol) 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N in 5 ml of DMF 2.5 ml of methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane (Example 21b) and 165 μl (1.5 mmol) of NMM were ice cooled under argon atmosphere. To 116 mg (0.60 mmol) of N-methoxycarbonyl- (L) -S-methylcysteine (Example 5a) and 149 mg (0.50 mmol) of TPTU in DMF were added and the mixture was kept at room temperature for 4 hours. Stirred. The mixture was poured into ice water, stirred for 30 minutes and extracted twice with ethyl acetate. The organic phase was washed twice with water, twice with saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ : methylene chloride / ethanol 20: 1) and stirring from DIPE gave the title compound. TLC: R _f = 0.39 (methylene chloride / methanol 10: 1), HPLC _20-100 : t _Ret = 14.0, FAB MS (M + H) ⁺ = 715.

<Example 25>

1- {4- [2- (1- (methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-5 (S) -2,5 -Bis [N- (N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane

261 mg (1.38 mmol) N-methoxycarbonyl- (L) -t-leucine (Example 2e), 496 mg (2.58 mmol) EDC and 232 mg (1.72 mmol) HOBT without air In 7.5 ml of DMF. After 15 minutes, 0.72 ml (5.17 mmol) of TEA and 585 mg (0.86 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazole- in 3.5 ml of DMF 5-yl] -phenyl} -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-louisyl) amino-6-phenyl- 2-Azahexane hydrochloride was added. After 20 hours, the mixture was evaporated to concentration, water and methylene chloride were added to the residue, the aqueous phase was separated off and extracted two more times with methylene chloride. The organic phase was washed with 10% citric acid solution, saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and concentrated by evaporation. Precipitation from a concentrated solution in ethyl acetate using DIPE / hexanes afforded the title compound. HPLC _20-100 : t _Ret = 17.5, FAB MS (M + H) ⁺ = 814.

Starting materials were prepared as follows.

25a) 4- (tetrazol-5-yl) -benzaldehyde

20.0 g (0.47 mole) of lithium chloride and 20.5 g (0.315 mole) of sodium azide were added to 41.2 g (0.315 mole) of 4-cyano- in 310 ml of methoxyethanol (Flucka, Buchs, Switzerland). It was added to benzaldehyde (Flucka, Buchs, Switzerland) and the mixture was heated at boiling point (under argon atmosphere) for 6 hours. The cooled reaction mixture was poured into 1 liter of ice / 37% HCl 10: 1 and stirred thoroughly to complete the reaction. Filtration and washing with water gave the title compound. Melting point: 180-182 ° C., ¹ H-NMR (DMSO-d ₆ ) δ 10.11 (s, HCO), 8.29 and 8.14 (2d, J = 8, 2H each).

25b) 4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -benzaldehyde

Under a nitrogen atmosphere, a solution of 6.9 g (58 mmol) of 2-phenyl-propene (Flucka, Buchs, Switzerland) and 22 ml of toluene was added to 10 g (57 mmol) in toluene at 44 ml boiling point. To dropwise addition of 4- (tetrazol-5-yl) -benzaldehyde and 1 g (5.7 mmol) methanesulfonic acid, the mixture was stirred at reflux for 1 hour. The cooled reaction mixture was washed twice with saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and concentrated by evaporation to form the title compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.09 (s, HCO), 8.29 and 8.08 (2d, J = 8, 2H each), 7.33 and 7.17 (2m, 5H), 2.17 (s, 6H).

25c) N-1- (tert-butoxycarbonyl) -N-2- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl-methyl Leeden} -Hydrazone

13.0 g (42 mmol) 4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -benzaldehyde and 5.98 g (45.2 mmol) tert- in 300 ml ethanol. Butyl carbazate was stirred at 80 ° C. for 20 hours. The reaction mixture was then evaporated to concentration in half, 420 ml of water were added and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with saturated NaHCO ₃ solution and brine, dried (sodium sulfate) and concentrated by evaporation to form the title compound. HPLC _20-100 : t _Ret = 17.7.

25d) N-1- (tert-butoxycarbonyl) -N-2- {4- [2- (1- (methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -benzyl} Hydrazine

Under nitrogen atmosphere, 11.6 g (28.5 mmol) of N-1- (tert-butoxycarbonyl) -N-2- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazole -5-yl] -phenyl-methylidene} -hydrazone was placed in 140 ml THF and 2.32 g (31.3 mmol, 85%) sodium cyanoborohydride were added. A solution of 5.42 g (28.5 mmol) of p-toluenesulfonic acid monohydrate in 90 ml of THF was added dropwise to the solution. After 4 hours, the mixture was evaporated to concentration, the residue was taken up in ethyl acetate and washed with saturated NaHCO ₃ solution and brine. The aqueous phase was extracted twice with ethyl acetate and the organic phase was dried (sodium sulfate) and evaporated to concentration. The residue was taken up in 250 ml of methanol and 125 ml of THF, 37 g of K ₂ B ₄ O ₇ x H ₂ O in 125 ml of water were added, cooled and the mixture was stirred overnight. The mixture was evaporated using a rotary evaporator to partially concentrate and diluted with methylene chloride and water, then the aqueous phase was separated off and extracted twice with methylene chloride. The organic phase was dried (sodium sulfate) and concentrated by evaporation to form the title compound. HPLC _20-100 : t _Ret = 16.4.

25e) 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxy Carbonyl) amino-5 (S)-(trifluoroacetyl) amino-6-phenyl-2-azahexane

6.05 g (23.4 mmol) of (2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane in 200 ml of iso-PrOH and 9.54 g (23.4 mmol) of N-1 a mixture of-(tert-butoxycarbonyl) -N-2- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -benzyl} -hydrazine Heated at 90 ° C. for 24 h. Concentrate by evaporation, chromatography (SiO ₂ , methylene chloride / ether 20: 1) and crystallize from MeOH to afford the title compound. Anal (C ₃₄ H ₄₀ N ₇ O ₄ F ₃ ) Theoreticals C 61.16, H 6.04, N 14.68: Found C 61.37, H 6.02, N 14.80.

25f) 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxy Carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane

28 ml of 1 NK ₂ CO ₃ solution was dried at 70 ° C. in 1.9 g (2.8 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazole- in 29 ml of methanol. 5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S)-(trifluoroacetyl) amino-6-phenyl-2-azahexane Add dropwise and stir the mixture for 15 hours. After cooling and evaporation to concentrate, methylene chloride and water were added, the aqueous phase was separated off and extracted with methylene chloride. The organic phase was washed with water, dried (sodium sulfate) and concentrated by evaporation to afford the title compound. HPLC _20-100 : t _Ret = 15.1, FAB MS (M + H) ⁺ = 469.

25 g) 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxy Carbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

Without air, 868 mg (4.59 mmol) of N-methoxycarbonyl- (L) -t-leucine (Example 2e), 1.64 g (8.58 mmol) of EDC and 773 mg (5.72 mmol) of HOBT was dissolved in 24.5 ml of DMF. After 15 minutes, 2.39 ml (17.2 mmol) of TEA and 1.64 g (2.86 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol- in 12 ml of DMF 5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane was added. After 20 h the mixture was evaporated to concentration, water and methylene chloride were added to the residue, the aqueous phase was separated off and extracted twice more with methylene chloride. The organic phase was washed with 10% citric acid solution, saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and concentrated by evaporation. Dipping from DIPE gave the title compound. HPLC _20-100 : t _Ret = 18.6, FAB MS (M + H) ⁺ = 743.

25h) 1- {4- [2- (1-Methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2-amino-5 (S ) -N- (N-methoxycarbonyl- (L) -tert-louisyl) amino-6-phenyl-2-azahexane hydrochloride

Under nitrogen atmosphere, 1.37 g (1.84 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydr Roxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane Stirred for 6 days in 64 ml of acetonitrile and 64 ml of aqueous 2N HCl. The reaction mixture was filtered, concentrated by evaporation of the filtrate under high vacuum at room temperature and finally lyophilization from dioxane to afford the title compound. HPLC _20-100 : t _Ret = 14.2, ¹ H-NMR (CD ₃ OD) especially δ 8.10 (d, J = 8, 2H ^arom ), 7.8 (m, 1H ^arom ), 7.53 (m, 2H ^arom ), 7.32 (m, 3H ^arom ), 7.17 (m, 6H ^arom ), 2.23 (s, 2H ₃ C ^{tetrazol protecting group} ).

Example 26

1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane

345.6 mg (0.424 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl]-while cooling 34.5 ml of an aqueous 80% sulfuric acid solution with ice Phenyl} -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2- Added to azahexane. After stirring for 75 minutes, the mixture was poured into 800 ml of ice water and extracted three times with ethyl acetate. The organic phase was washed three times with water and brine, dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ , ethyl acetate / ethanol 8: 1 → 2: 1) afforded the title compound. TLC: R _f = 0.38 (ethyl acetate / ethanol 2: 1), HPLC _20-100 : t _Ret = 12.5, FAB MS (M + H) ⁺ = 696.

Example 27

1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycar Bonyl- (L) -tert-leusil) amino] -6-phenyl-2-azahexane (and 1-methyl-1H-tetrazolyl isomer)

Under nitrogen atmosphere, 100 mg (0.144 mmol) of 1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- ( N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane is dissolved in 1 ml of DMF / dioxane 1: 1 and 1 ml of dioxane at 0 ° C. 73.2 mg (0.224 mmol) Cs ₂ CO ₃ and 6.9 μL (0.111 mmol) methyl iodide in water were added. This mixture was allowed to slowly warm to room temperature overnight and additional 1 equivalent of Cs ₂ CO ₃ and methyl iodide were added. After stirring for an additional 4 hours at room temperature, the mixture was diluted with ethyl acetate and 1 N sodium hydroxide solution. The aqueous phase was separated off and extracted twice with ethyl acetate. The organic phase was washed twice with water and brine, dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ , methylene chloride / ethyl acetate 1: 1 → 1: 2) gave pure title compound A (about 3 parts), followed by 1- [4- (1-methyl-1H-tetrazol-5- Yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert-louisyl) amino] -6-phenyl 2-Azahexane ( B ) (about 1 part) was obtained. A : TLC: R _f = 0.26 (methylene chloride / ethyl acetate 1: 1), HPLC _20-100 : t _Ret = 14.2, FAB MS (M + H) ⁺ = 710. B : TLC: R _f = 0.09 (methylene chloride / ethyl acetate 1: 1), HPLC _20-100 : t _Ret = 13.3, FAB MS (M + H) ⁺ = 710.

Synthesis of Selective Title Compounds

In a nitrogen atmosphere, 14.56 g (77 mmol) of N-methoxycarbonyl- (L) -t-leucine and 22.87 g (77 mmol) of TPTU were diluted with 77 ml of DMF and 37.3 ml (218 mmol) at room temperature. Stir for 30 minutes in Huenig base. The reaction mixture was then transferred to 35.2 mmol of 1- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S)-in 77 ml of DMF. To the 2,5-diamino-6-phenyl-2-azahexane dihydrochloride ice cooled solution was added dropwise. After stirring at room temperature for 15 hours, the reaction mixture was evaporated to some concentration and the residue (about 80 ml) was poured into 5 liters of water, the mixture was stirred for 30 minutes and the crude product was filtered off. It was dissolved in 90 ml of boiling ethanol, 600 ml of DIPE was added and then cooled to afford the title compound. Melting point 191 to 192 ° C, [α] _D = -46 ° C (c = 0.5, ethanol).

Starting materials were prepared as follows.

27a) 4- (2-methyl-2H-tetrazol-5-yl) -benzaldehyde

While ice cooled, a solution of 75.5 g (0.434 mol) of 4- (tetrazol-5-yl) -benzaldehyde (Example 25a) in 550 ml of DMF / dioxane 1: 1 was added to 200 ml of DMF / dioxane. To 179.7 g (1.30 mole) K ₂ CO ₃ in 1: 1 was added dropwise, the mixture was stirred for 30 minutes and then 40 ml (0.64 mole) of methyl iodide was added. The mixture was stirred in an ice bath for 3 hours, and finally at room temperature for 15 hours, the reaction mixture was poured into 2.8 liters of ice water and stirred for 10 minutes, the title compound was filtered off and washed with water. Mp 137-139 ° C., ¹ H-NMR (CD ₃ OD / CDCl ₃ ) d 10.05 (s, HCO), 8.29 and 8.03 (2d, J = 8, 2H each), 4.43 (s, 3H).

27b) N-1- (tert-butyloxycarbonyl) -N-2- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl-methylidene] -hydrazone

75.0 g (0.40 mol) of 4- (2-methyl-2H-tetrazol-5-yl) -benzaldehyde and 56.4 g (0.426 mol) tert-butyl carbazate in 1400 ml of iso-PrOH Stirred for 24 h. 2.2 liters of water was added to the cooled reaction mixture and the mixture was thoroughly stirred to complete the reaction, and the title compound was filtered off and washed with water. Melting point 195-197 ° C., analysis (C ₁₄ H ₁₈ N ₆ O ₂ ) Theoretical C 55.62, H 6.00, N 27.80: Found C 55.50, H 5.93, N 27.61.

27c) N-1- (tert-butyloxycarbonyl) -N-2- [4- (2-methyl-2H-tetrazol-5-yl) -benzyl] -hydrazine

Under a nitrogen atmosphere, 30.0 g (99.2 mmol) N-1- (tert-butyloxycarbonyl) -N-2- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl-methylidene ] -Hydrazone was placed in 350 ml THF and 8.79 g (119 mmol, 85%) of NaCNBH ₃ were added. A solution of 22.6 g (119 mmol) of p-toluenesulfonic acid monohydrate in 175 ml of THF was added dropwise to the solution (→ precipitation). After 2 hours, the solids were filtered off, washed thoroughly with ethyl acetate and discarded. Water and ethyl acetate were added to the filtrate, the aqueous phase was separated off and extracted twice more with ethyl acetate. The organic phase was washed with saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and evaporated to concentration. The resulting crystals were taken up in 417 ml of methanol and 208 ml of THF, and a solution of 127 g (415 mmol) of K ₂ B ₄ O ₇ .4H ₂ O was added dropwise in 417 ml H ₂ O (→ bubble generation). . The mixture was stirred at rt overnight, poured into 2.2 liters of water and extracted three times with ethyl acetate. The organic phase was washed with saturated NaHCO ₃ solution, water and brine, dried (sodium sulfate) and evaporated to concentration. The crude product was combined with material from the same second batch and filtered through silica gel using methylene chloride / THF 10: 1 as eluent. Evaporate to concentrate the volume of the residue to about 0.1 liters and add 150 ml of DIPE to crystalline title compound (alternatively, N-1- (Boc) -N-2- [4- ( 2-methyl-2H-tetrazol-5-yl) -phenyl-methylidene] -hydrazone may be produced by catalytic hydrogenation). Melting point 100-102 ° C., TLC: R _f = 0.47 (methylene chloride / THF 10: 1), ¹ H-NMR (CD ₃ OD) d 8.06 and 7.52 (2d, J = 8, 2H each), 4.42 (s, 3H), 4.00 (s, 2H), 1.44 (s, 9H), HPLC _20-100 : t _Ret = 10.2.

27d) 1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butyloxycar Carbonyl) amino] -6-phenyl-2-azahexane

36.33 g (138 mmol) of (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane and 38.17 g (125 mmol) of N-1- (tert-butyloxycarbonyl) -N -2- [4- (2-methyl-2H-tetrazol-5-yl) -benzyl] -hydrazine was heated in 964 ml of iso-PrOH at 90 ° C. for 20 hours. The crystallized title compound can be separated from the cooled reaction mixture by filtration. After addition of 1.2 liters of water, further product crystallized from the filtrate. Mp 175-178 ° C., TLC: R _f = 0.22 (methylene chloride / ethyl acetate 6: 1), HPLC _20-100 : t _Ret = 16.9.

27e) 1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2 Azahexane dihydrochloride

93 ml of 4N hydrochloric acid solution was added to 20.0 g (35.2 mmol) of 1- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy in 279 ml of THF. To a solution of -5 (S) -2,5-bis [(tert-butyloxycarbonyl) amino] -6-phenyl-2-azahexane. The mixture was stirred at 50 ° C. for 8 h and then slowly concentrated by evaporation (room temperature, high vacuum). The oily residue was taken up three more times in ethanol, evaporated and concentrated again to afford the crystalline title compound. To determine the analytical data, 1 g of crude product was stirred in 6 ml of hot iso-PrOH, 6 ml of DIPE was added, cooled and filtered off. Mp 227-230 ° C., HPLC _20-100 : t _Ret = 7.4, assay (C ₁₉ H ₂₅ N ₇ O.2HCl (+ 0.20H ₂ O)) theory C 51.40, H 6.22, N 22.08, Cl 15.97, H ₂ O 0.81: Found C 51.50, H 6.33, N 22.28, Cl 15.88, H ₂ O 0.80.

<Example 28>

1- {4- [2- (1-Methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2-N- (N-methoxy Carbonyl- (L) -iso-leusil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-louisyl) amino-6-phenyl-2-azahexane

Without air, 7.5 ml of 261 mg (1.38 mmol) of N-methoxycarbonyl- (L) -iso-leucine, 496 mg (2.58 mmol) of EDC and 232 mg (1.72 mmol) of HOBT Dissolved in DMF. After 15 minutes, 0.72 ml (5.17 mmol) of TEA and 585 mg (0.86 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazole- in 3.5 ml of DMF 5-yl] -phenyl} -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-louisyl) amino-6-phenyl- 2-Azahexane hydrochloride (Example 25h) was added. After 20 hours, the mixture was worked up as described in Example 25i. DIPE was used to precipitate from the concentrated solution in methylene chloride to afford the title compound. HPLC _20-100 : t _Ret = 17.5, FAB MS (M + H) ⁺ = 814.

<Example 29>

1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

354 mg (0.435 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl]-while cooling 35 ml of an aqueous 80% sulfuric acid solution with ice Phenyl} -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-silyl) amino-5 (S) -N- (N-methoxycarbonyl- ( L) -tert-Louisyl) amino-6-phenyl-2-azahexane was added. After stirring for 75 minutes, the mixture was worked up similarly to Example 26 to afford the title compound. HPLC _20-100 : t _Ret = 12.6, FAB MS (M + H) ⁺ = 696.

<Example 30>

1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-louis Sil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-leusil) amino-6-phenyl-2-azahexane

Under nitrogen atmosphere, 72 mg (0.103 mmol) of 1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L 0.5 ml of DMF with) -iso-leusil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert-leusil) -amino] -6-phenyl-2-azahexane Was dissolved in and 71 mg (0.217 mmol) of Cs ₂ CO ₃ and 6.9 μl (0.111 mmol) of methyl iodide in 1 ml of dioxane were added at 0 ° C. The mixture was allowed to slowly warm to room temperature overnight and then diluted with ethyl acetate and 1 N sodium hydroxide solution. The aqueous phase was separated off and extracted twice with ethyl acetate. The organic phase is washed twice with water and brine, dried (sodium sulfate) and concentrated by evaporation to additionally add about 20% of 1- [4- (1-methyl-1H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-silyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) The title compound A was obtained, containing -tert-leusil) amino-6-phenyl-2-azahexane ( B ). HPLC _20-100 A : t _Ret = 14.3, HPLC _20-100 B : t _Ret = 13.3, FAB MS (M + H) ⁺ = 710.

<Example 31>

1- {4- [2- (1-Methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2-N- (N-methoxy Carbonyl- (L) -tert-leusil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane

Without air, 128 mg (0.67 mmol) of N-methoxycarbonyl- (L) -t-leucine (Example 2e), 243 mg (1.27 mmol) of EDC and 114 mg (0.84 mmol) of HOBT was dissolved in 2 ml of DMF. After 15 minutes, 0.35 ml (2.5 mmol) of TEA and 286 mg (0.42 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazole- in 1.5 ml of DMF 5-yl] -phenyl} -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl- 2-Azahexane hydrochloride was added. After 20 hours, this mixture was worked up as described in Example 25. Chromatography (SiO ₂ , ethyl acetate / toluene / methylene chloride 2: 1: 1) afforded the title compound. TLC: R _f = 0.22 (methylene chloride / ethyl acetate 1: 1), HPLC _20-100 : t _Ret = 17.3, FAB MS (M + H) ⁺ = 814.

Starting materials were prepared as follows.

31a) 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxy Carbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

With air excluding, 270 mg (1.43 mmol) of N-methoxycarbonyl- (L) -iso-leucine, 513 mg (2.67 mmol) of EDC and 241 mg (1.78 mmol) of HOBT are 7.8 ml Dissolved in DMF. After stirring for 15 minutes, 0.75 ml (5.4 mmol) of TEA and 510 mg (0.89 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetra in 3.7 ml of DMF Zol-5-yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane (Example 25f) Was added. After 20 hours, the mixture was worked up similarly to Example 25g to afford the title compound. HPLC _20-100 : t _Ret = 18.5, FAB MS (M + H) ⁺ = 743.

31b) 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) -hydroxy-2-amino-5 (S ) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane hydrochloride

Under a nitrogen atmosphere, 317 mg (0.43 mmol) of 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5 in 15 ml of acetonitrile and 15 ml of 2N HCl -Yl] -phenyl} -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl Amino-6-phenyl-2-azahexane was stirred at 50 ° C. for 20 hours and worked up similarly to Example 25h to form the title compound. HPLC _20-100 : t _Ret = 14.4.

<Example 32>

1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-silyl) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino] -6-phenyl-2-azahexane

Similar to Example 26, 1- {4- [2- (1-methyl-1-phenyl-ethyl) -2H-tetrazol-5-yl] -phenyl} -4 (S) using 80% sulfuric acid -Hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-silyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl Amino-6-phenyl-2-azahexane was deprotected to form the title compound.

<Example 33>

1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-Louis Sil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane

Similar to Example 30, 1- [4- (tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (in DMF / dioxane L) -tert-Louisyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino] -6-phenyl-2-azahexane to Cs ₂ CO ₃ And methylated with methyl iodide.

<Example 34>

1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-meth Methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane

Under nitrogen atmosphere, 54 mg (0.28 mmol) of N-methoxycarbonyl- (L) -t-leucine and 84 mg (0.28 mmol) of TPTU in 1 ml of DMF and 94 μl (0.85 mmol) of NMM were added. Stir at room temperature for 10 minutes. 175 mg (0.283 mmol) of 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S)-in 2 ml of DMF Amino-2-N- [N-methoxycarbonyl- (L) -tert-leusil] amino-6-phenyl-2-azahexane hydrochloride was added to the solution, and then the mixture was stirred at room temperature overnight. The reaction was completed. The reaction mixture was poured into 40 ml of water and extracted three times with methylene chloride. The organic phase was filtered through cotton, evaporated to concentrate and chromatographed (SiO ₂ , methylene chloride / methanol 25: 1). TLC: R _f = 0.48 (methylene chloride / methanol 19: 1), HPLC _{20-100 (12 ′)} : t _Ret = 11.8, FAB MS (M + H) ⁺ = 752.

Starting materials were prepared as follows.

34a) N-1- (tert-butyloxycarbonyl) -N-2- [N-methoxycarbonyl- (L) -tert-silyl] -hydrazine

In the absence of air, 130 ml of 10.0 g (52.8 mmol) N-methoxycarbonyl- (L) -t-leucine, 11.1 g (58 mmol) EDC and 7.85 g (58 mmol) HOBT Into ethyl acetate and 7.0 ml (63 mmol) NMM were added. After 30 minutes, 7.69 g (58 mmol) tert-butyl carbazate was added and the mixture was stirred at rt for 16 h. The reaction mixture was diluted with 300 ml of ethyl acetate and washed with saturated NaHCO ₃ solution, water and brine. The aqueous phase was back extracted twice with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated by evaporation to form the title compound. ¹ H-NMR (CD ₃ OD) d 3.98 (s, 1 H), 3.66 (s, 3 H), 1.47 and 1.03 (2 s, 2 × 9 H).

34b) [N-methoxycarbonyl- (L) -tert-leusil] -hydrazine

52.8 mmol of N-1- (tert-butyloxycarbonyl) -N-2- [N-methoxycarbonyl- (L) -tert-silyl] -hydrazine in 100 ml of 4N HCl / dioxane Dissolved and stirred for 18 hours at room temperature. The suspension was concentrated by evaporation and the residue was taken up in saturated NaHCO ₃ solution and extracted four times with a large amount of methylene chloride. The organic phase was filtered through cotton and concentrated by evaporation to afford the title compound. ¹ H-NMR (CD ₃ OD) d 3.89 (s, 1 H), 3.66 (s, 3H), 0.99 (s, 9H).

34c) N-1- [N-methoxycarbonyl- (L) -tert-leusil] -N-2- [4- (tetrazol-5-yl) -phenyl-methylidene] -hydrazone

3.0 g (14.8 mmol) of [N-methoxycarbonyl- (L) -tert-leusil] -hydrazine and 2.57 g (14.8 mmol) of 4- (tetrazol-5-yl) in 30 ml of iso-PrOH The solution with) -benzaldehyde (Example 25a) was heated at boiling point for 18 hours. The mixture was cooled down, 100 ml of water were added and the precipitated title compound was filtered off. ¹ H-NMR (CD ₃ OD) d 8.23 (s, 1H), 8.15-7.9 (m, 4H), 4.08 (s, 1H), 3.67 (s, 3H), 1.06 (s, 9H).

34d) N-1- [N-methoxycarbonyl- (L) -tert-silyl] -N-2- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl- Methylidene] -hydrazone

In an autoclave, 3.0 g (8.3 mmol) of N-1- [N-methoxycarbonyl- (L) -tert-leusil] -N-2- [4- (tetrazol-5) in 25 ml of toluene -Yl) -phenyl-methylidene] -hydrazone, 1.2 g of iso-butene and 54 μl of methanesulfonic acid were heated at 110 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution and brine. The aqueous phase was back extracted twice with ethyl acetate and the organic phase was dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ , hexanes / ethyl acetate 1: 1) gave the title compound. TLC: R _f = 0.22 (hexane / ethyl acetate 1: 1), HPLC _{20-100 (12 ')} : t _Ret = 11.1, FAB MS (M + H) ⁺ = 416.

34e) N-1- [N-methoxycarbonyl- (L) -tert-silyl] -N-2- [4- (2-tert-butyl-2H-tetrazol-5-yl) -benzyl] Hydrazine

Under nitrogen atmosphere, 2.00 g (4.81 mmol) of N-1- [N-methoxycarbonyl- (L) -tert-silyl] -N-2- [4- (2-tert-butyl-2H-tetra Zol-5-yl) -phenyl-methylidene] -hydrazone was dissolved in 9 ml of THF and 317 mg (4.8 mmol, 95%) of NaCNBH ₃ were added. A solution of 915 mg (4.8 mmol) of p-toluenesulfonic acid monohydrate in 9 ml of THF was added dropwise to the solution. After 18 hours, ethyl acetate was added and the mixture was washed with saturated NaHCO ₃ solution and brine. The aqueous phase was extracted twice more with ethyl acetate. The organic phase was dried (sodium sulfate) and evaporated to concentrate. The residue was taken up in 20 ml of THF and 20 ml of water, and the mixture which added 6.18 g (20 mmol) of K ₂ B ₄ O ₇ .4H ₂ O was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO ₃ solution and brine. The aqueous phase was extracted twice with ethyl acetate and the organic phase was dried (sodium sulfate) and evaporated to concentration. Column chromatography (SiO ₂ , hexanes / ethyl acetate 1: 2) gave the title compound. TLC: R _f = 0.28 (hexane / ethyl acetate 1: 2), ¹ H-NMR (CD ₃ OD) d 8.07 and 7.53 (2d, J = 8, 2H each), 4.03 (s, 2H), 3.84 (s , 1H), 3.64 (s, 3H), 1.81 and 0.92 (2s, 9H each).

34f) 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -N- (tert-butyloxycarbonyl) -Amino-2-N- [N-methoxycarbonyl- (L) -tert-silyl] amino-6-phenyl-2-azahexane

737 mg (2.80 mmol) of (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane and 1.17 g (2.80 mmol) of N-1- [N-methoxycarbonyl- (L ) -tert-Loisyl] -N-2- [4- (2-tert-butyl-2H-tetrazol-5-yl) -benzyl] -hydrazine was added at 15 ° C. in iso-PrOH at 90 ° C. for 16 hours. Heated. The product can be crystallized and filtered off while adding 100 ml of water. Recrystallization by addition of DIPE / hexane to the concentrated solution in methylene chloride at 0 ° C. gave the title compound. TLC: R _f = 0.34 (CH ₂ Cl ₂ / MeOH 30: 1), HPLC _{20-100 (12 ')} : t _Ret = 12.5.

34 g) 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -amino-2-N- [N-meth Methoxycarbonyl- (L) -tert-silyl] amino-6-phenyl-2-azahexane hydrochloride

Under nitrogen atmosphere, 200 mg (0.293 mmol) of 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -N dissolve-(tert-butyloxycarbonyl) -amino-2-N- [N-methoxycarbonyl- (L) -tert-silyl] amino-6-phenyl-2-azahexane in 2.3 ml THF 1.6 ml of aqueous 2N HCl was added and the mixture was stirred at 50 ° C. for 8 h. The reaction solution was concentrated by evaporation and the residue was taken up several times in ethanol and again concentrated by evaporation (→ title compound). TLC: R _f = 0.08 (CH ₂ Cl ₂ / MeOH 30: 1), HPLC _{20-100 (12 ′)} : t _Ret = 9.9, ¹ H-NMR (CD ₃ OD) d 8.03 and 7.50 (2d, J = 8, 2H each, 7.32 (m, 5H), 4.18 and 3.91 (2d, J = 4, 2H), 3.80 (m, 1H), 3.68 (s, 1H), 3.58 (s, 3H), 3.57 (m , 1H), 3.3-2.9 (m, 4H), 1.81 and 0.75 (2s, 9H each).

<Example 35>

1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert -Louisyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Under nitrogen atmosphere, 54 mg (0.308 mmol) of N-methoxycarbonyl- (L) -valine and 92 mg (0.308 mmol) of TPTU in 1 ml of DMF and 101 μl (0.91 mmol) of NMM were added at room temperature. Stirred for a minute. 190 mg (0.308 mmol) of 1- [4- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S)-in 2 ml of DMF Amino-2-N- [N-methoxycarbonyl- (L) -tert-silyl] amino-6-phenyl-2-azahexane hydrochloride (Example 34g) was added to the solution and the mixture was added at room temperature. Stir overnight to complete the reaction. The reaction mixture was diluted with methylene chloride and washed with brine. The aqueous phase was extracted twice with methylene chloride and the organic phase was filtered through cotton, evaporated to concentrate and chromatographed (SiO ₂ , methylene chloride / methanol 30: 1). TLC: R _f = 0.21 (methylene chloride / methanol 19: 1), FAB MS (M + H) ⁺ = 738.

<Example 36>

1- [4- (2-Methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-Louis Sil) amino-5 (S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

The title compound can be prepared similarly to any of the above and below examples.

<Example 37>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -valyl ) Amino] -6-phenyl-2-azahexane

Without moisture, 455 mg (2.6 mmol) of N-methoxycarbonyl- (L) -valine, 940 mg (4.9 mmol) of EDC and 405 mg (3 mmol) of HOBT were placed in 10 ml of DMF. Heated at 40 ° C. The mixture with 1.1 ml (7.9 mmol) TEA was stirred for another 15 minutes. 500 mg (0.98 mmol) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-aza Hexane hydrochloride was added to the solution and the mixture was stirred at rt overnight. The reaction mixture was concentrated by evaporation under high vacuum, and the residue was dissolved in methylene chloride and washed successively with sodium carbonate solution (No. 1), phosphate buffer solution (pH = 7, No. 2) and brine. After removal of the solvent, the residue was chromatographed on silica gel (eluent: methylene chloride / methanol 15: 1). The product-containing fractions were concentrated and then the title compound was precipitated using DIPE. The product can be lyophilized from dioxane. HPLC _20-100 : t _Ret = 10.06, FAB MS (M + H) ⁺ = 677. ¹ H-NMR (CD ₃ OD, 200 MHz) i.e. 8.58 / m (1H), 7.78 and 7.50 / each d, J = 5 (2 × 2H), 8.0-7.73 / m (2H), 7.33 / m ( 1H), 7.30-7.05 / m (5H), 3.62 and 3.60 / each s (2 × 3H), 1.85 and 1.68 / each m (2 × 1H), 0.76 / 't', J = 4 (6H), 0.65 And 0.58 / each d, J = 4 (2 × 3 H).

Starting materials were prepared as follows.

37a) 4-bromobenzaldehyde dimethyl acetal

21.1 g (114 mmol) of 4-bromobenzaldehyde and 20 ml (182 mmol) of trimethyl orthoformate (both from Flucka, Buchs, Switzerland) are dissolved in 35 ml of methanol and 0.65 g (3.4 mmol) P-toluenesulfonic acid monohydrate was added at room temperature (exothermic reaction). The reaction mixture was stirred for 20 hours at room temperature under nitrogen. The acid was then neutralized using 0.62 ml of 30% sodium methanolate solution in methanol (3.4 mmol), the reaction mixture was concentrated using a rotary evaporator and the residue was distilled off. The title compound was produced in the form of a colorless liquid. TLC: R _f = 0.58 (hexane / ethyl acetate 2: 1). Boiling point 90-92 ° C. (4 mbar). ¹ H-NMR (CDCl ₃ , 200 MHz) 7.50 and 7.32 / each d, J = 9 (2 × 2H), 5.36 / s (1H), 3.31 / s (6H).

37b) 4- (pyridin-2-yl) -benzaldehyde

6.93 g (29.9 mmol) of 4-bromobenzaldehyde dimethyl acetal in 40 ml of THF is a warm (40-50 ° C.) suspension consisting of 0.8 g (31.6 mmol) of magnesium turnings and a small amount of iodine in 10 ml of THF Dropped in The reaction mixture was heated to 65 ° C. and heated at this temperature for about 30 minutes. The mixture is allowed to cool to room temperature and the Grignard reagent is loaded with 4.46 g (28.2 mmol) of 2-bromopyridine and 0.4 g (0.74 mmol) of DPPP (both from Flucka, Switzerland). Was added dropwise (slightly exothermic reaction). After completion of the dropwise addition, the reaction mixture was boiled at reflux for 4 hours, then allowed to cool and 100 ml of water was added. The mixture was concentrated to about 50 ml using a rotary evaporator, diluted with ethyl acetate and extracted three times with 0.1 N hydrochloric acid. The combined HCl extracts were stirred for 20 minutes at room temperature, made basic with concentrated ammonia solution and extracted with methylene chloride. After removal of the solvent, the residue was chromatographed on silica gel (hexane / ethyl acetate 2: 1). The product-containing fractions were concentrated and the desired title compound crystallized on its own. TLC: R _f = 0.22 (hexane / ethyl acetate 2: 1), HPLC _20-100 : t _Ret = 6.08, ¹ H-NMR (CDCl ₃ , 200 MHz): 8.73 / d, J = 5 (2H), 8.16 And 7.97 / each d (2x2H), 7.80 / d, J = 4 (2H), 7.3 / m (1H).

37c) N-1- (tert-butoxycarbonyl) -N-2- {4-[(pyridin-2-yl) -phenyl] -methylidene} -hydrazone

A solution of 2 g (1.05 mmol) 4- (pyridin-2-yl) -benzaldehyde and 1.37 g (1 mmol) tert-butyl carbazate (Flucka, Buchs, Switzerland) in 30 ml of ethanol Was stirred at 80 ° C. for 5 h (after 4 h additional 0.05 equivalents of tert-butyl carbazate was added). The reaction mixture was left to cool and diluted with water to crystallize the desired title compound. TLC: R _f = 0.51 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 8.92. ¹ H-NMR (CDCl ₃ , 200 MHz): 8.68 / m (1H), 8.21 / s (1H), 7.98 / d, J = 9 (2H, Part A of Aromatic AB Systems), 7.85 / s (1H) , 7.8-7.6 / m (4H), 7.22 / m (1H), 1.53 / s (9H).

37d) N-1- (tert-butoxycarbonyl) -N-2- [4- (pyridin-2-yl) -benzyl] -hydrazine

2 g (6.7 mmol) N-1- (tert-butoxycarbonyl) -N-2- {4-[(pyridin-2-yl) -phenyl] -methylidene} -hydrazone in 30 ml of methanol And 0.2 g of 5% Pd / C were hydrogenated for 8 hours under standard pressure at room temperature. The catalyst was filtered off, washed with methanol and the solvent removed. The title compound was produced in the form of a colorless viscous oil, which solidified on drying under high vacuum. TLC: R _f = 0.46 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 6.71. ¹ H-NMR (CDCl ₃ , 200 MHz) i.e .: 8.69 / m (1H), 7.96 and 7.45 / d, J = 2 (2 × 2H), 7.8-7.65 / m (2H), 7.22 / m (1H ), 4.06 / s (2H), 1.47 / s (9H).

37e) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6- Phenyl-2-azahexane

1.06 g (4 mmol) of (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane in 20 ml of iso-PrOH and 1.2 g (4 mmol) of N-1- (tert- A solution of butoxycarbonyl) -N-2- [4- (pyridin-2-yl) -benzyl] -hydrazine was stirred at 80 ° C. for 16 hours. After cooling, the reaction solution was concentrated using a rotary evaporator to precipitate the title compound as a colorless precipitate. Additional product was precipitated by adding water to the mother liquor. TLC: R _f = 0.53 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 13.15. ¹ H-NMR (CD ₃ OD, 200 MHz) i.e .: 8.57 / s (1H), 7.85 and 7.48 / each d, J = 9 (2 × 2H), 8.0-7.7 / m (2H), 7.33 / m ( 1H), 7.3-7.0 / m (6H), 3.91 / s (2H), 3.82-3.55 / m (2H), 3.05-2.45 / m (4H), 1.31 / s (18H).

37f) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane hydrochloride

10 ml of DMF was obtained from 1.43 g (2.54 mmol) of 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy in 30 ml of 4N hydrochloric acid in dioxane (purchased from Aldrich). -5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6-phenyl-2-azahexane was added (exothermic reaction), and the mixture was stirred at room temperature for 2 hours. Solvent was removed, toluene was added to the residue three times and the mixture was concentrated by evaporation. The residue was dissolved in hot methanol and the title compound was precipitated in the form of a resinous precipitate using DIPE / hexanes. Upon drying under high vacuum, a large volume of foam was generated. HPLC _5-60 : t _Ret = 9.87. ¹ H-NMR (CD ₃ OD, 200 MHz) i.e .: 8.78 / d, J = 5 (1H), 8.72 / dxt, J = 2.5 and 7.5 (1H), 8.35 / d, J = 7.5 (1H), 8.1 / dxd, J = 7.5 (1H) each, 8.02 and 7.72 / each d, J = 9 (2 × 2H), 7.45-7.15 / m (5H), 4.27 and 4.15 / angle d, J = 12.5 (2 × 2H ).

<Example 38>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-ethoxycarbonyl- (L) -valyl ) Amino] -6-phenyl-2-azahexane

Similar to Example 37, after workup, 300 mg (0.59 mmol) of 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (10 mg in 10 ml of DMF) S) -2,5-diamino-6-phenyl-2-azahexane hydrochloride (Example 37f), 446 mg (2.36 mmol) N-ethoxycarbonyl- (L) -valine, 679 mg (3.54 Millimol) EDC, 398 mg (2.95 mmol) HOBT and 0.82 ml (5.9 mmol) TEA resulted in the title compound. TLC: R _f = 0.19 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 11.68. FAB MS (M + H) ⁺ = 705.

<Example 39>

1- [4- (pyridin-3-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -valyl ) Amino] -6-phenyl-2-azahexane

Similar to Example 37, 550 mg (1.52 mmol) of 1- [4- (pyridin-3-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2, in 10 ml of DMF, 5-diamino-6-phenyl-2-azahexane, 691 mg (3.94 mmol) N-methoxycarbonyl- (L) -valine, 1.45 g (7.59 mmol) EDC, 614 mg (4.55 mmol) The title compound was produced from HOBT and 1.06 ml (7.59 mmol) of TEA (unlike described in Example 37, the organic phase was washed with saturated sodium bicarbonate, 10% citric acid and brine). TLC: R _f = 0.4 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 9.91. FAB MS (M + H) ⁺ = 677.

Starting materials were prepared as follows.

39a) 4- (pyridin-3-yl) -benzaldehyde

Similar to Example 37b, 6.39 g (29.9 mmol) 4-bromobenzaldehyde dimethyl acetal (prepared from Example 37a) in 150 ml THF, 0.8 g (31.6 mmol) magnesium turnings, 2.77 ml (28.2 mmol) ) Was subjected to the title compound from 3-bromopyridine (Flucka, Buchs, Switzerland) and 0.4 g (0.74 mmol) DPPP. HPLC _20-100 : t _Ret = 5.50, ¹ H-NMR (CD ₃ OD, 200 MHz): 10.04 / s (1H), 8.87 / d, J = 2.5 (1H), 8.58 / dxd, J = about 1.5 and 5 (1H), 8.17 / m ie J = 7.5 (1H), 8.05 and 7.88 / each d, J = 9 (2 × 2H), 7.56 / dxd, J = 7.5 and 5 (1H).

39b) N-1- (tert-butoxycarbonyl) -N-2- {4-[(pyridin-3-yl) -phenyl] -methylidene} -hydrazone

Similar to Example 37c, 4.11 g (22.4 mmol) 4- (pyridin-3-yl) -benzaldehyde and 2.82 g (21.3 mmol) tert-butyl carbazate in 60 ml of ethanol (Switzerland Buchs) Flucka) to give the title compound. HPLC _20-100 : t _Ret = 8.88. ¹ H-NMR (CD ₃ OD, 200 MHz): 8.83 / d, J = 2.5 (1H), 8.53 / d, J = 5 (1H), 8.14 / m or J = 7.5 (1H), 7.97 / s ( 1H), 7.85 and 7.71 / each d, J = 9 (2 × 2H), 7.53 / dxd, J = 7.5 and 5 (1H).

39c) N-1- (tert-butoxycarbonyl) -N-2- [4- (pyridin-3-yl) -benzyl] -hydrazine

Similar to Example 37d, 5.03 g (16.9 mmol) of N-1- (tert-butoxycarbonyl) -N-2- {4-[(pyridin-3-yl) -phenyl] in 120 ml of methanol The title compound was produced from -methylidene} -hydrazone and 0.5 g of 5% Pd / C and the title compound in crude form was used in the next process. HPLC _20-100 : t _Ret = 6.36. ¹ H-NMR (CD ₃ OD, 200 MHz) ie: 7.63 and 7.51 / each d, J = 9 (2 × 2H), 3.97 / s (2H), 1.43 / s (9H).

39d) 1- [4- (pyridin-3-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6- Phenyl-2-azahexane

Similar to Example 37e, after 14 hours at 80 ° C., 3.82 g (12.8 mmol) of N-1- (tert-butoxycarbonyl) -N-2- [4- (pyridin-3-yl) -benzyl The title compound was produced from] -hydrazine and 3.36 g (12.8 mmol) of (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane. Purification was carried out by chromatography on silica gel (hexane / ethyl acetate 1: 2). TLC: R _f = 0.27 (hexane / ethyl acetate 1: 2). HPLC _20-100 : t _Ret = 13.0. ¹ H-NMR (CD ₃ OD, 200 MHz) i.e .: 7.62 and 7.52 / each d, J = 9 (2 × 2H), 7.4-7.0 / m (5H), 3.93 / s (2H), 1.33 and 1.31 / Each s (2 × 9H).

39e) 1- [4- (pyridin-3-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane

1 g (1.88 mmol) 1- [4- (pyridin-3-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) Amino] -6-phenyl-2-azahexane was dissolved in 10 ml of formic acid and the solution was stirred at room temperature for 5 hours. The reaction mixture was evaporated to concentration, the residue was dissolved in methylene chloride and the organic phase was washed with saturated sodium bicarbonate and brine. After removal of the solvent, the title compound in the form of a brown oil was produced, which was used in the next process without further purification.

<Example 40>

1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -valyl ) Amino] -6-phenyl-2-azahexane

Similar to Example 37, 473 mg (0.75 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S in 10 ml of DMF ) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane hydrochloride, 263 mg (1.5 mmol) N-methoxycarbonyl- (L) -valine The title compound was generated from 575 mg (3 mmol) of EDC (Flucka, Buchs, Switzerland), 405 mg (3 mmol) of HOBT (manufactured by Flucka) and 1.7 ml (12 mmol) of TEA. Ethyl acetate was used instead of methylene chloride and worked up similarly to Example 40f. The compound can be lyophilized from dioxane. TLC: R _f = 0.28 (ethyl acetate). HPLC _20-100 : t _Ret = 13.11. FAB MS (M + H) ⁺ = 678.

Starting materials were prepared as follows.

40a) 4- (pyrazin-2-yl) -benzaldehyde

See European Patent No. 0 344 577.

50 ml of THF was poured into 2.72 g (112 mmol) magnesium turnings degreased with hexane and activated with a small amount of iodine and the mixture was heated at 50 ° C. A solution of 4-bromobenzaldehyde dimethyl acetal (prepared according to Example 37a) in 200 ml THF was added dropwise to the mixture in about 30 minutes. First, the reaction was exothermic and the reaction mixture was heated to about 60 ° C. upon completion of the dropwise addition. After an additional 30 minutes of stirring at 60 ° C., the mixture is allowed to cool to room temperature, decanted from untreated magnesium and the resulting solution containing Grignard reagent is 11.45 g in 500 ml of THF over 20 minutes at room temperature. (100 mmol) was added dropwise to a suspension of 2-chloropyrazine (Flucka, Buchs, Switzerland) and 1.6 g of DPPP (Aldrich, Buchs, Switzerland) (slightly exothermic). The mixture was then stirred at rt for 19 h. 250 ml of water were then added to the reaction mixture and the mixture was stirred for 10 minutes. THF was removed in vacuo, 300 ml of ethyl acetate and 100 ml of 2N hydrochloric acid were added to the remaining emulsion and the mixture was stirred for 5 minutes. After separation of the organic phase, the phase was further stirred twice with 100 ml of 0.5 N hydrochloric acid for 5 minutes each. The ethyl acetate phase was washed successively with saturated sodium bicarbonate solution, water and brine and concentrated. The title compound in the form of pale brown crystals was produced. Recrystallization was performed from methylene chloride / hexanes. Melting point 86-88 ° C. TLC: R _f = 0.17 (hexane / ethyl acetate 2: 1). HPLC _20-100 : t _Ret = 11.06. ¹ H-NMR (CDCl ₃ , 200 MHz): 10.12 / s (1H), 9.14 / d, J≤1 (1H), 8.70 / d, J≤1 (1H), 8.60 / t, J≤1 (1H ), 8.22 and 8.03 / each d, J = 9 (2 × 2H).

40b) N-1- (tert-butoxycarbonyl) -N-2- {4-[(pyrazin-2-yl) -phenyl] -methylidene} -hydrazone

Similar to Example 37c, after 5 hours at 80 ° C., 12.4 g (67.3 mmol) 4- (pyrazin-2-yl) -benzaldehyde and 8.5 g (64 mmol) tert-butyl carba in 170 ml of ethanol The title compound was produced from jade (Flucka, Buchs, Switzerland), which crystallized on its own. Melting point 190 to 198 ° C. TLC: R _f = 0.47 (ethyl acetate). HPLC _20-100 : t _Ret = 13.41.

40c) N-1- (tert-butoxycarbonyl) -N-2- [4- (pyrazin-2-yl) -benzyl] -hydrazine

Similar to Example 37d, after hydrogenation at room temperature for 13 hours, 0.6 g (2 mmol) of N-1- (tert-butoxycarbonyl) -N-2- {4-[( The title compound in oil form was produced from pyrazin-2-yl) -phenyl] -methylidene} -hydrazone and 0.15 g of 5% Pd / C. On titration with ether the title compound crystallized. Recrystallized from ethyl acetate / mineral oil ether. Melting point 110-111 ° C. HPLC _20-100 : t _Ret = 9.62. ¹ H-NMR (CD ₃ OD, 200 MHz): 9.09 / s (1H), 8.65 / t, J≤1 (1H), 8.51 /, J≤1 (1H), 8.05 and 7.53 / each d, J = 5 (2 × 2H), 4.00 / s (2H), 1.43 / s, (9H).

40d) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S)-(trifluoroacetyl) amino -6-phenyl-2-azahexane

Similar to Example 37e, 10.5 g (35 mmol) N-1- (tert-butoxycarbonyl) -N-2- [4- (pyrazin-2-yl) -benzyl]-in 150 ml of isopropanol Beige from hydrazine and 11.7 g (45 mmol) of (2R)-[(1'S)-(trifluoroacetyl) amino-2'-phenylethyl] oxirane (European Patent No. 0 521 827, Example 16d) The title compound was produced in the form of crystals. Melting point 194-196 ° C. TLC: R _f = 0.38 (hexane / ethyl acetate 1: 2). HPLC _20-100 : t _Ret = 16.27.

40e) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -amino-6-phenyl-2 Azahexane

11.75 g (21 mmol) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S)-(tri Fluoroacetyl) amino-6-phenyl-2-azahexane was suspended in 500 ml of methanol and 105 ml of K ₂ CO ₃ solution in water at 60 ° C. was added. The mixture was stirred at 75 ° C. for about 3 hours, methanol was evaporated off and the residue was extracted with ethyl acetate. The organic phase was washed once with water and brine each time and concentrated. The title compound was produced in the form of orange-brown crystals, which could be recrystallized from ethyl acetate / mineral oil ether. Melting point 146-148 ° C. TLC: R _f = 0.08 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 11.23.

40f) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxy Carbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

Similar to Example 37, 3.2 g (7 mmol) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxy) in 130 ml of DMF Carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane, 2.54 g (14 mmol) N-methoxycarbonyl- (L) -valine, 5.4 g (28 mmol) EDC ( The title compound was produced from Flucka, Buchs, Switzerland, 3.8 g (28 mmol) of HOBT (Flucka, Buchs, Switzerland) and 7.1 g (70 mmol) of TEA. The reaction mixture was worked up by removing DMF, taking the residue in methylene chloride and washing with water, saturated sodium bicarbonate solution / water 1: 1, 10% citric acid, water and brine. Concentration gave crystallization of the compound. Melting point 218-220 ° C. TLC: R _f = 0.29 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 15.11.

40 g) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -valyl Amino-6-phenyl-2-azahexane hydrochloride

3.4 g (5.5 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy- in 100 ml of 4N hydrogen chloride and 10 ml of methanol in dioxane (manufactured by Aldrich) 2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -valyl) -amino-6-phenyl-2-azahexane was added at room temperature for 2 hours. Stirred. Solvent was removed, dioxane was added twice to the residue and evaporated off. The title compound was produced in the form of a viscous oil, which crystallized upon titration with ether. Melting point 194-198 ° C. TLC: R _f = 0.35 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 9.77.

<Example 41>

1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- [N- (N-methoxycarbonyl- (L) -iso-leusil) amino] -5 (S)-[N- (N-methoxycarbonyl- (L) -valyl) amino] -6-phenyl-2-azahexane

142 mg (0.75 mmol) of N-methoxycarbonyl- (L) -iso-leucine and 223 mg (0.75 mmol) of TPTU in 3 ml of DMF are stirred at room temperature for 10 minutes and then in 3 ml of DMF 473 mg (0.75 mmol) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- A solution of (L) -valyl) amino-6-phenyl-2-azahexane hydrochloride (Example 40 g) and 0.33 ml NMM was added. The mixture was stirred at rt overnight. The reaction mixture was slowly added dropwise to 100 ml of water, worked up, stirred at room temperature for 20 minutes, filtered and isolated from the resulting precipitate. The precipitate was washed with water and taken up in methylene chloride and the organic phase was washed sequentially with water, saturated sodium bicarbonate solution / water 1: 1, water and brine. After removal of the solvent, the residue was immersed in ether to give the title compound in the form of a colorless powder. The compound can be lyophilized from dioxane. TLC: R _f = 0.28 (ethyl acetate). HPLC _20-100 : t _Ret = 13.78. FAB MS (M + H) ⁺ = 692.

<Example 42>

1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- [N- (N-methoxycarbonyl- (L) -tert-leusil) amino] -5 (S)-[N- (N-methoxycarbonyl- (L) -valyl) amino] -6-phenyl-2-azahexane

Similar to Example 41, after workup, 142 mg (0.75 mmol) N-methoxycarbonyl- (L) -t-leucine (Example 2e), 223 mg (0.75 mmol) in 3 ml of DMF ) TPTU (solution A) and 435 mg (0.75 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) -amino-6-phenyl-2-azahexane hydrochloride (Example 40g) and 0.33 ml of NMM (solution B) Resulting in the crystallization of the title compound upon evaporation of the solvent. This compound can be lyophilized from dioxane. TLC: R _f = 0.46 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 13.85. FAB MS (M + H) ⁺ = 692.

<Example 43>

1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -iso -Louisyl) amino] -6-phenyl-2-azahexane

Similar to Example 41, after workup, 132 mg (0.7 mmol) of N-methoxycarbonyl- (L) -iso-leucine and 208 mg (0.7 mmol) of TPTU (solution) in 3 ml of DMF A) and 400 mg (0.7 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- in 3 ml of DMF The title compound was generated from (N-methoxycarbonyl- (L) -iso-leusil) -amino-6-phenyl-2-azahexane hydrochloride (Example 44b) and 0.31 ml (2.8 mmol) of NMM Dipping with ether gave the title compound in crystalline form. Melting point 211-217 ° C. TLC: R _f = 0.41 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 14.49. FAB MS (M + H) ⁺ = 706.

<Example 44>

1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- [N- (N-methoxycarbonyl- (L) -valyl) amino] -5 (S) -[N- (N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane

Similar to Example 41, after workup, 175 mg (1 mmol) N-methoxycarbonyl- (L) -valine, 297 mg (1 mmol) TPTU (Switzerland Buchs) in 4 ml of DMF Flucka) (solution A) and 571 mg (1 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (in 4 ml of DMF) The title compound was produced from S) -N- (N-methoxycarbonyl- (L) -iso-leusil) -amino-6-phenyl-2-azahexane hydrochloride and 0.44 ml (4 mmol) NMM. Dipping with ether can give the title compound in crystalline form. Melting point 205-208 캜. HPLC _20-100 : t _Ret = 13.87. FAB MS (M + H) ⁺ = 692.

Starting materials were prepared as follows.

44a) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxycarbonyl) amino-5 (S) -N- (N-methoxy Carbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane

Similar to Example 37, 2.3 g (5 mmol) of 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert-butoxy in 90 ml of DMF Carbonyl) amino-5 (S) -amino-6-phenyl-2-azahexane (Example 40e), 1.9 g (10 mmol) N-methoxycarbonyl- (L) -iso-leucine, 3.8 The title compound was produced from g (20 mmol) EDC, 2.7 g (20 mmol) HOBT and 5.1 g (50 mmol) TEA. Post-treatment as described in Example 40f. This compound can be recrystallized from ethyl acetate. TLC: R _f = 0.58 (methylene chloride / methanol 10: 1). HPLC _20-100 : t _Ret = 15.68. ¹ H-NMR (CD ₃ OD, 200 MHz) i.e .: 9.08 / s (1H), 8.65 / bs (1H), 8.51 / t, J≤1 (1H), 8.02 and 7.52 / each d, J = 5 ( 2 × 2H), 7.3-7.1 / m (5H), 3.92 / s (2H), 3.62 / s (3H), 1.28 / s (9H), 0.8 / t, J = 5 (3H), 0.73 / d, J = 4 (3H).

44b) 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso -Louisyl) amino-6-phenyl-2-azahexane hydrochloride

Similar to Example 40g, 1- [4- (pyrazin-2-yl) -phenyl] -4 (S) -hydroxy-2- (tert in 60 ml of 4 N hydrogen chloride in dioxane and 10 ml of methanol The title compound was generated from -butoxycarbonyl) amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane, and ether The title compound was crystallized using. Melting point 200-201 캜. HPLC _20-100 : t _Ret = 10.52.

<Example 45>

1- [4- (thiophen-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- Valeyl) amino] -6-phenyl-2-azahexane

Similar to Example 37, 500 mg (1.36 mmol) of 1- [4- (thiophen-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2 in 10 ml of DMF , 5-diamino-6-phenyl-2-azahexane, 620 mg (3.54 mmol) N-methoxycarbonyl- (L) -valine, 1.3 g (6.8 mmol) EDC, 551 mg (4.08 mmol) The title compound was generated from HOBT and 0.95 ml (6.8 mmol) of TEA, which was lyophilized from dioxane. TLC: R _f = 0.51 (methylene chloride / methanol 15: 1). HPLC _20-100 : t _Ret = 15.30. FAB MS (M + H) ⁺ = 682.

Starting material was prepared as follows.

45a) 4- (thiophen-2-yl) -benzaldehyde

(See Heterocycle 31, 1951 (1990)).

3.7 g (20 mmol) 4-bromobenzaldehyde in 50 ml of dimethylacetamide, 9.5 ml (120 mmol) thiophene, 2.94 g (30 mmol) potassium acetate and tetrakis (triphenylphosphine) palladium (Switzerland Buchs) 1.16 g (1 mmol) of Flucka) were placed in a pressure reactor and stirred at 150 ° C. for 16 hours under nitrogen. The reaction mixture was concentrated by evaporation. The residue was dissolved in water and extracted three times with methylene chloride. After removal of the solvent, the residue was subjected to silica gel chromatography (hexane: ethyl acetate 4: 1). The title compound was obtained as a yellow solid. TLC: R _f = 0.36 (hexane / ethyl acetate 4: 1). HPLC _20-100 : t _Ret = 15.26. 1 H-NMR (CD ₃ OD, 200 MHz): 9.98 / s (1H), 7.93 / d and 7.85 / d, J = 9.5 (2 × 2H), 7.60 / d, J = 2.5 (1H), 7.52 / d , J = 5 (1H), 7.17 / dxd, J = 2.5 and 5 (1H).

45b) N-1- (tert-butoxycarbonyl) -N-2- [4-[(thiophen-2-yl) -phenyl] -methylidene] -hydrazone

In a similar manner to Example 37 c, 2.47 g (13.1 mmol) of 4- (thiophen-2-yl) benzaldehyde in 30 ml of ethanol (4.5 hours at 90 ° C.) and tert-butyl carbazate (Switzerland Buchs) From 1.65 g (12.49 mmol) of Flucka, Material, the title compound was obtained as a yellow crystalline form. Melting point: 162 to 165 ° C. HPLC _20-100 : t _Ret = 16.08. ¹ H-NMR (CD ₃ OD, 200 MHz) ia: 7.91 / s (1 H), 1.53 / s (9 H).

45c) N-1- (tert-butoxycarbonyl) -N-2- [4- (thiophen-2-yl) -benzyl] -hydrazine

N-1- (tert-butoxycarbonyl) -N-2- [4-[(thiophen-2-yl) -phenyl] -methylidene] -hydrazone 3.35 g (11.1 mmol) and cyanobonohydra 0.819 g (11.1 mmol) of sodium iodide (Flucka, Buchs, Switzerland) was dissolved in 11 mL of THF (cancer solution), and for 5 hours in 2.11 g (11.1 mmol) of p-toluenesulfonic acid monohydrate dissolved in 11 mL of THF. Added dropwise. The mixture was stirred overnight at room temperature under nitrogen (pH = about 3-4) and then diluted with ethyl acetate. The organic phase was washed again with brine, saturated sodium hydrogen carbonate solution and brine in turn. The organic phase was evaporated to concentration and the residue was dissolved in 13.3 mL of 1N sodium hydroxide solution. 15 ml of methylene chloride were added and the mixture was heated to reflux at bath temperature of 60 ° C. for 3 hours. After separation of the organic phase, this phase was concentrated to dryness by evaporation. The title compound was obtained in the form of a pale yellow oil. HPLC _20-100 : t _Ret = 12.36. ¹ H-NMR (CD ₃ OD, 200 MHz) ia: 3.91 / s (2H), 1.42 / s (9H).

45d) 1- [4- (thiophen-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) -amino]- 6-phenyl-2-azahexane

In a similar manner to Example 37e, 3.39 g (11.1 mmol) of N-1- (tert-butoxycarbonyl) -N-2- [4- (thiophen-2-yl) -benzyl] -hydrazine in 50 ml of isopropanol ) And (2R)-[(1'S) -Boc-amino-2'-phenylethyl] oxirane (see J. Org. Chem. 50, 4615 (1985)), from 2.93 g (11.1 mmol) The solution was cooled to spontaneously crystallize the title compound to afford the title compound. Melting point: 165 to 168 ° C. HPLC _20-100 : t _Ret = 18.84. ¹ H-NMR (CD ₃ OD, 200 MHz) ia: 7.56 / d, J = 9 (2H), 7.5-7.3 / m (4H), 7.3-7.1 / m (5H), 7.08 / dxd, J = 2 And 5 (1H), 3.85 / s (2H), 1.33 / s and 1.32 / s (2 × 9H), respectively.

45e) 1- [4- (thiophen-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane

In a similar manner to Example 39e), 1- [4- (thiophen-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [( Obtain the title compound in the form of a pale yellow oil from 3.16 g (5.57 mmol) tert-butoxycarbonyl) amino] -6-phenyl-2-azahexane, stir at room temperature for 6 hours, and then without further purification Was used. ¹ H-NMR (CD ₃ OD, 200 MHz) ia: 7.62 / d, J = 9 (2H), 7.5 to 7.1 / some m's, loading (9H), 7.09 / dxd, J = 2 and 5 (1H), 3.72 / s (2 H).

<Example 46>

1- [4- (pyridin-2-yl) phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert- Louisyl) amino] -6-phenyl-2-azahexane

Method A:

Water was removed and 10.85 g of N-methoxycarbonyl- (L) -tert-leucine (Example 2e) and 17.1 g of TPTU were placed in 65 ml of DMF. 35.1 mL of Huenig base was added to the white suspension and the mixture was stirred at room temperature for 20 minutes. Then 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2 dissolved in 65 ml of DMF. 13.2 g (26 mmol) of azahexane hydrochloride (Example 37f) were added and the mixture was stirred for 24 hours to complete the reaction (after 20 hours, an additional 5 mL of Hunig's base was added). The reaction mixture was poured into 600 mL of water and the resulting precipitate was filtered and washed with water. The filter residue was dissolved in methylene chloride and washed twice with saturated NaHCO ₃ solution, water and brine. After drying and concentration with sodium sulfate, the resulting foam was immersed in DIPE. This solid was filtered off and dried. The resulting crude product was again dissolved in methylene chloride, treated with activated charcoal, filtered and then precipitated with ether. The resulting title compound was dried in a heated drier at 40 ° C. under high pressure. Melting point: 202-204 ° C., TLC: R _f = 0.38 (ethyl acetate), HPLC _20-100 : t _Ret = 11.81, FAB MS (M + H) ⁺ = 705. Further product can be obtained from the mother liquor after chromatography (SiO ₂ , hexane / ethyl acetate, then ethyl acetate), after crystallization from ether (melting point: 206 to 207 ° C.).

Method B:

In a similar manner to Example 4, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N (N-meth) in 5 ml of DMF. 0.42 g (2.2 of (N-methoxycarbonyl- (L) -tert-leucine) in 5 ml of DMF is added to 1.32 g of methoxycarbonyl- (L) -tert-rusilyl) amino-6-phenyl-2-azahexane. Mmol), TPTU 0.654 g (2.2 mmol) and Hunig's base 840 μl (5 mmol) were added and the mixture was stirred at room temperature for 22 hours and carried out in a similar manner to Example 3 to afford the title compound. .

Starting material was prepared as follows.

46a) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N-Boc-amino-5 (S) -N- (N-methoxycarbonyl- ( L) -tert-Louisyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2- (N-Boc-amino) -5 (S) in 50 ml of DMF. A solution of 3.93 g of -amino-6-phenyl-2-azahexane hydrochloride (Example 47b) was added to 2.58 g (13.6 mmol) of N-methoxycarbonyl- (L) -tert-leucine in 50 ml of DMF, To this mixture was added dropwise a mixture of 4.88 g (25.5 mmol) EDC and 2.3 g (17 mmol) HOBT. After performing the process, the crude product was immersed in methylene chloride / DIPE and filtered and dried to afford the title compound. TLC: R _f = 0.5 (ethyl acetate), HPLC _20-100 : t _Ret = 12.32, FAB MS (M + H) ⁺ = 634.

46b) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -tert -Louisyl) amino-6-phenyl-2-azahexane hydrochloride

In a similar manner to Example 37f), 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N-Boc-amino-5 (S) -N- (N To 4.4 g (6.94 mmol) of -methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane add 130 ml of 4M HCl in dioxane and dilute the mixture with 7 ml of DMF. It was. After 2.75 h the mixture was used. The title compound was obtained. TLC: R _f = 0.44 (methylene chloride / methanol: 9/1), HPLC _20-100 : t _Ret = 8.47, FAB MS (M + H) ⁺ = 534.

A separate method for the preparation of the title compound from Example 46 is as follows.

<Example 46 *>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert -Louisyl) amino] -6-phenyl-2-azahexane

Water was removed and 567 g (3.0 mole) of N-methoxycarbonyl- (L) -tert-leucine (Example 2e) and 891 g (3.0 mole) of TPTU were placed in 3 L of methylene chloride. While cooling on ice, 775 g (6 mol) of Hunig's base was added dropwise and the mixture was stirred for 20 minutes. Then 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2- in 3 l of methylene chloride A suspension of 432 g (1.0 mol) of azahexane trihydrochloride was added to the solution and the mixture was stirred at room temperature overnight to complete the reaction. The reaction mixture was washed with 10 L water, 10 L saturated NHCO ₃ solution and 5 L brine. The aqueous phase was further extracted twice with 5 liters of methylene chloride. The organic phase was dried (Na ₂ SO ₄ ) and concentrated by evaporation. The residue was dissolved in 6 liters of ethyl acetate and filtered through 500 g of silica gel. The column was rinsed with 6 liters of ethyl acetate and the fractions containing the product were concentrated by evaporation. Stir in boiling DIPE / ethanol 49: 1 (9 L, 1 hour), cool and filter to afford the title compound, which can be further purified by recrystallization from ethanol / water (melting point: 207-209 ° C.) ).

Starting material was prepared as follows.

a *) 4- (pyridin-2-yl) -benzaldehyde

11 g of iodine, followed by 200 g of 4-bromobenzaldehyde dimethyl acetal (Example 37a) was added to 317 g (13.0 moles) of magnesium in 3.5 L (nitrogen atmosphere) THF. Once the reaction is initiated (if any, heated), 2540 g of 4-bromobenzaldehyde dimethyl acetal (total 2740 g, 11.8 mol) in 3.5 L of toluene are added dropwise (25 ° C.-30 ° C., 1 hour) The mixture was stirred at rt for 1 h. Next, 1750 g (11.0 mol) of 2-bromopyridine (Flucka, Buchs, Switzerland), 38 g (70 mmol) of DPPP and 330 ml of diisobutylaluminum hydride (20% in hexane) in 3.3 l of THF were added The Grignard reagent was transferred to the dropping funnel of the containing second instrument. At 15-20 ° C., Grignard reagent was added dropwise (45 min). After stirring for 90 minutes at room temperature, the reaction mixture was poured into 10 kg of ice, 1.5 L of concentrated hydrochloric acid and 1.5 kg of citric acid. 1 kg of Hyflo Super Cel was added and the mixture was stirred for 1 hour and then filtered. The residue was washed twice with 2 L of water, 2 L of toluene and finally with 2 L of 1N HCl solution. The first filtrate and wash water were collected. The aqueous phase was separated and extracted twice with 2 parts of toluene filtrate. The resulting organic phase was washed with 2 parts hydrochloric acid containing filtrate. The aqueous phase was collected. 6 L of toluene was added and the mixture was adjusted to pH 8-9 with 4.6 L of sodium hydroxide solution (30% in water). The mixture was filtered through Hiflo (filter based on diatomaceous earth) (Flucka, Buchs, Switzerland). The aqueous layer was separated and extracted twice with 2 L of toluene. The organic phase was washed twice with water, dried (Na ₂ SO ₄ ) and treated with activated carbon. 0.5 kg of silica gel was added, stirred, filtered and evaporated to give the compound of this material (physical data as in Example 37b).

b *) N-1- (tert-butoxycarbonyl) -N-2- [4-[(pyridin-2-yl) -phenyl] -methylidene] -hydrazone

A solution of 1770 g (9.67 mol) of 4- (pyridin-2-yl) -benzaldehyde and 1220 g (9.2 mol) of tert-butyl carbazate (Flucka, Buchs, Switzerland) in 12.5 L of ethanol is 4 hours at boiling Heated. The mixture was cooled to 40 ° C and 6 kg ice was added. After the mixture was filtered and the title compound was washed with 6 L of water, the compound was obtained in pure form (physical data as in Example 37c).

c *) N-1- (tert-butoxycarbonyl) -N-2- [4- (pyridin-2-yl) -benzyl] -hydrazine

Suspension of 1655 g (5.57 mol) of N-1- (tert-butoxycarbonyl) -N-2- [4-[(pyridin-2-yl) -phenyl] -methylidene] -hydrazone in 12 liters of methanol Was hydrogenated at room temperature under normal pressure in the presence of 166 g of 10% Pd / C. The crystals were filtered off and washed with methanol. Solvent was removed. Crystallization from hexanes gave the title compound. Melting point: 74 to 77 ° C.

d *) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino] -6 -Phenyl-2-azahexane

1185 g (4.5 mol) of (2R)-[(1'S)-(tert-butoxycarbonyl) -amino-2'-phenylethyl] -oxirane in 14 l of iso-propanol and N-1- (tert-part A solution of 1230 g (4.1 mol) of oxycarbonyl) -N-2- [4- (pyridin-2-yl) -benzyl] -hydrazine was heated at boiling point for 16 hours. After cooling, 15 kg of ice and 10 L of water were added. The mixture was stirred for 2 hours. The crystals were filtered off and washed with 6 liters of water. Stir twice each in 5 L of ether, filter, wash with 2 L of ether and finally wash with 2 L of ether / tert-butyl methyl ether 1: 1 to afford the title compound. Melting point: 183 to 188 ° C.

e *) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-diamino-6-phenyl-2-azahexane trihydrochloride

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [(tert-butoxycarbonyl) amino]-in 12 liters of THF A solution of 1465 g (2.6 mol) of 6-phenyl-2-azahexane and 4 L of hydrochloric acid (4N in water) was stirred at 50 ° C. for 4 hours. The aqueous phase was separated from the resulting two-part mixture and concentrated by evaporation under reduced pressure. The residue was diluted with 4 L of ethanol, evaporated to dryness, diluted with 4 L of ethanol / toluene 1: 1, concentrated by evaporation, diluted with 4 L of ethanol and again concentrated by evaporation. Stir in 9 L of DIPE and filter to afford the title compound (physical data as in Example 37f).

e * (i): Alternatively, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-di [(tert-butoxycar Bonyl) -amino] -6-phenyl-2-azahexane was prepared as follows.

Under nitrogen atmosphere, 1- [4- (pyridin-2-yl) phenyl] -1-oxo-5 (S) -2,5-di [(tert-butoxycarbonyl) amino in 5 ml of THF (foam) ] 2.1 (2.1 mmol) of a 1.00 M solution of diisobutylaluminum hydride in methylene chloride was slowly added to an ice-cold solution of 200 mg (0.347 mmol) of 4 (S) -hydroxy-6-phenyl-2-azahexane. Added dropwise. After 2 hours, 7 ml of ethyl acetate was added and after 30 minutes, 70 ml of methanol was added. The reaction mixture was allowed to warm to rt and stirred for 2 h. 0.5 ml of water and 5 g of sodium sulfate were added and the mixture was stirred for another hour to complete the reaction. The salts were filtered off and the filtrate was concentrated by evaporation. Medium pressure chromatography (SiO ₂ , hexanes / ethyl acetate 3: 2 then ethyl acetate) afforded the title compound. Melting point: 184 ° C., TLC (hexane / ethyl acetate 1: 1): R _f = 0.26, FAB MS (M + H) ⁺ = 563.

Starting material, 1- [4- (pyridin-2-yl) phenyl] -1-oxo-5 (S) -2,5-di [(tert-butoxycarbonyl) amino] -4 (S) -hydr Synthesis of oxy-6-phenyl-2-azahexane was carried out through the following steps.

Step (1) 4- (Pyridin-2-yl) -benzoic acid methyl ester:

24.0 g (150 mmol) of 4-cyanobenzoic acid methyl ester (Flucka, Buchs, Switzerland) in 150 ml of toluene were placed in an autoclave under an acetylene atmosphere and cobalt acene (= dicyclopentadienylcobalt, Milwaukee, USA) 0.30 g (1.6 mmol) of Aldrich) was added. The mixture was then adjusted to acetylene pressure of 15 atm, heated at 180 ° C. and stirred for 12 hours. After cooling and depressurizing, 9.5 g of activated carbon was added to the dark suspension. The mixture was diluted with 250 ml of toluene, stirred for 30 minutes, filtered and concentrated by evaporation. Crystallization from warm ether by addition of hexanes afforded the title compound. Melting point: 96 ° C., TLC (hexane / ethyl acetate 4: 1): R _f = 0.37, FAB MS (M + H) ⁺ = 214. Additional product can be obtained from the mother liquor by column chromatography (SiO ₂ , hexane / ethyl acetate 19: 1 then 4: 1).

Step (2) 4- (pyridin-2-yl) -benzoic acid:

12.85 g (60.2 mmol) of 4- (pyridin-2-yl) -benzoic acid methyl ester and 67 mL of 1N sodium hydroxide solution in 125 mL of methanol were stirred at room temperature for 6 hours. The resulting solution was partially evaporated to concentration. The aqueous residue was extracted with ethyl acetate and acidified to pH about 1.5 with 2N HCl solution. The title compound was precipitated out, filtered and washed with water. TLC (ethyl acetate): R _f = 0.35, FAB MS (M + H) ⁺ = 200.

Step (3) 4- (pyridin-2-yl) benzoic acid iso-butyloxyformic anhydride:

By removing the air, 6.0 g (30 mmol) of 4- (pyridin-2-yl) -benzoic acid were suspended in 90 mL of THF at −20 ° C., 9.90 mL (90 mmol) of N-methyl-morpholine and isobutyl chloro 4.32 mL (33 mmol) of formate was added. After 30 minutes, the mixture was filtered, washed with a small amount of cold THF, and the filtrate was partially evaporated to concentration. The residue was diluted with methylene chloride, washed with ice water and cold brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation to afford the title compound. ¹ H-NMR (CDCl ₃ ) ia 8.75 (m, 1H), 8.16 (AB, J = 8, 4H), 7.81 (m, 2H), 7.32 (4-wire, J = 5, 1H), 4.16 (d , J = 7, 2H), 2.10 (9-line system, J = 7, 1H), 1.02 (d, J = 7, 6H).

Step (4) 1- (R) -Cyano-2 (S)-(N-tert-butoxycarbonylamino) -3-phenylpropyl [4- (2-pyridyl)]-benzoate:

At 0 ° C., 250 mg (0.9 mmol) of benzyltriethylammonium chloride were added to 2.0 g of potassium cyanide (30 mmol) and 7.5 mL of methylene chloride in 7.5 mL of water. Then, a solution of 6.21 g (24.9 mmol) of Boc- (L) -phenylalanineal in 10 ml of methylene chloride and 4- (pyridin-2-yl) -benzoic acid isobutyloxyformic anhydride in 10 ml of methylene chloride 30 mmol of the solution was added dropwise at the same time. After 20 minutes at 0 ° C., stirring was continued at room temperature for 4 hours and finally the reaction mixture was diluted with methylene chloride / water. The aqueous phase was separated and extracted twice with methylene chloride. The organic phase was washed three times with water and brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography (SiO ₂ , hexanes / ethyl acetate 4: 1 then 2: 1) was carried out to give 1- (R) -cyano-2 (S)-(N-tert-butoxycarbonylamino)- 3-phenylpropyl [4- (2-pyridinyl)]-benzoate and 1- (S) -cyano-2 (S)-(N-tert-butoxycarbonylamino) -3-phenylpropyl [4 A 5: 1 mixture of-(2-pyridinyl)]-benzoate was obtained. TLC (hexane / ethyl acetate 4: 1): R _f = 0.11, FAB MS (M + H) ⁺ = 458, ¹ H-NMR (CDCl ₃ ) ia 5.66 (d, J = 6, 5 / 6H, 1- (R) epimer), 5.53 (m, 1 / 6H, 1- (S) epimer).

1- (R) -cyano-2 (S)-(N-tert-butoxycarbonylamino) -3-phenylpropyl [4- (2-pyridinyl)] which is diastereomerically pure by dipping in DIPE -Benzoate was obtained: Melting point: 140 to 141 ° C.

Step (5) 4- (S) -1,4-di [(tert-butoxycarbonyl) amino] -3 (R)-[4- (pyridin-2-yl) phenyl] -carbonyloxy-5 -Phenyl-1-azapent-1-ene:

1- (R) -cyano-2 (S)-(N-cyano-2 (S)-(N-tert-butoxycarbonylamino) -3-phenylpropyl [4- (2-pyridyl) ] .- benzoate 2.29 g (5.0 mmol) was dissolved in 80 mL methanol, 900 mg (15 mmol) acetic acid and 661.5 mg (5 mmol) tert-butyl carbazate were added 2.3 g Rainey nickel was added The mixture was then hydrogenated The partially precipitated product was dissolved by adding methanol and heating gently The crystals were filtered and the filtrate was evaporated to concentrate The residue was dissolved in ethyl acetate / saturated NaHCO ₃ solution. The aqueous phase was separated and further extracted twice with ethyl acetate The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated by evaporation Medium pressure chromatography (SiO ₂ , hexane / ethyl acetate 4: 1 Then ethyl acetate) to afford the title compound. 195-196 ° C., TLC (hexane / ethyl acetate 1: 1): R _f = 0.39, FAB MS (M + H) ⁺ = 575.

Step (6) 1- [4- (pyridin-2-yl) phenyl] -1-oxo-5 (S) -2,5-di [(tert-butoxycarbonyl) amino] -4 (S)- Hydroxy-6-phenyl-2-azahexane

Under nitrogen atmosphere, 4- (S) -1,4-di [(tert-butoxycarbonyl) amino] -3 (R)-[4- (pyridin-2-yl) phenyl] -carbohydrate in 10 ml of THF. To 862 mg (1.5 mmol) of bonyloxy-5-phenyl-1-azapent-1-ene was added 111 mg (85%, 1.5 mmol) of NaCNBH ₃ . A solution of 290 mg (1.5 mmol) of p-toluene sulfonic acid in 4 ml of THF was added dropwise. After stirring for 2.5 hours, an additional 55 mg of NaCNBH ₃ and 145 mg of p-toluenesulfonic acid in 2 ml of THF were added and the mixture was stirred for another 2.5 hours. The reaction mixture was then poured into 230 ml of a 1% solution of K ₂ B ₄ O ₇ .4H ₂ O in water and stirred overnight to complete the reaction, filtered and washed with water. The residue was dissolved in ethyl acetate. The solution was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to dryness {4- (S) -1,4-di [(tert-butoxycarbonyl) amino] -3 (S)-[4 -(Pyridin-2-yl) phenyl] -carbonyloxy-5-phenyl-1-azapentane: TLC (hexane / ethyl acetate 1: 1): R _f = 0.45}. The resulting foam was dissolved in 25 ml of diethylene glycol dimethyl ether. 250 μl of 7-methyl-1,5,7-triaza-bicyclo [4,4,0] dec-5-ene (Flucka, Buchs, Switzerland) was added and the mixture was heated to 80 ° C. for 1.5 h. It was. The mixture was concentrated by evaporation under high pressure and the residue was dissolved in ethyl acetate / water. The aqueous phase was separated and extracted twice with ethyl acetate. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and evaporated to concentration. Crystallization from DIPE / hexanes afforded the title compound. Melting point: 104-105 ° C., TLC (hexane / ethyl acetate 1: 1): R _f = 0.20, FAB MS (M + H) ⁺ = 577.

<Example 47>

[4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -iso-louis Amino) -6] phenyl-azahexane

Under a nitrogen atmosphere, 0.45 g (1.5 mmol) N-methoxycarbonyl- (L) -iso-leucine, 0.85 g (4.5 mmol) EDC and 0.4 g (3 mmol) HOBT were dissolved in 10 mL DMF. 1.26 ml of TEA was added and stirred for 10 minutes, then 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S)-in 10 ml of DMF. A solution of 0.96 g (1.5 mmol) of N- (N-methoxycarbonyl- (L) -iso-leusil) -amino-6-phenyl-2-azahexane hydrochloride was added dropwise. After 2 hours, the reaction mixture was concentrated by evaporation. The resulting oil was dissolved in methylene chloride and washed twice with water, NaHCO ₃ solution, water and brine. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated to evaporation. The residue was first immersed in DIPE followed by methylene chloride / ether, then filtered and dried to afford the title compound. TLC: R _f = 0.45 (ethyl acetate), HPLC _20-100 : t _Ret = 11.71, FAB MS (M + H) ⁺ = 705.

Starting material was prepared as follows.

47a) 1- [4- (Pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2- (N-Boc-amino) -5 (S) -trifluoroacetyl-amino-6- Phenyl-2-azahexane

In a similar manner to Example 37e), 7 g (23 mmol) of N-1- (tert-butoxycarbonyl) -N-2- [4- (pyridin-2-yl) -benzyl] -hydrazine were added to isopropanol 125 6 g (23 mmol) of (2R)-[(1'S) -trifluoroacetyl-amino-2'-phenylethyl] oxirane in mL were reacted at 80 ° C. to form the title compound. TLC: R _f = 0.33 (methylene chloride / methanol: 1/1), HPLC _20-100 : t _Ret = 12.76, FAB MS (M + H) ⁺ = 559.

47b) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2- (N-Boc-amino) -5 (S) -amino-6-phenyl-2-aza Hexane

In a similar manner to Example 40e, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2- (N-Boc-amino) -5- ( 5.6 g (10 mmol) of trifluoroacetyl-amino) -6-phenyl-2-azahexane were dissolved in 130 mL of methanol, heated to 65 ° C. and converted to the title compound by dropwise addition of 50 mL of an aqueous 1 M potassium carbonate solution. . TLC: R _f = 0.17 (methylene chloride / methanol: 9/1), HPLC _20-100 : t _Ret = 8.50, FAB MS (M + H) ⁺ = 463.

47c) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2N-Boc-amino-5 (S) -N- (N-methoxy-carbonyl- (L ) -Iso-louisyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, 1.06 g (5.6 mmol) of N-methoxycarbonyl- (L) -iso-leucine, 2.01 g (10.5 mmol) and 0.95 g (7 mmol) HOBT in 20 ml of DMF. To the mixture, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2- (N-Boc-amino) -5 (S) -amino-6- in 25 ml of DMF. A solution of 1.62 g (3.5 mmol) of phenyl-2-azahexane was added dropwise. After running the process, the crude product was immersed in DIPE and filtered off. TLC: R _f = 0.59 (ethyl acetate), HPLC _20-100 : t _Ret = 12.52. FAB MS (M + H) ⁺ = 634.

47d) 1- [4- (Pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso -Louisyl) amino-6-phenyl-2-azahexane hydrochloride

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N-Boc-amino-5 (S) -N- (N- To 1.9 g (3 mmol) of methoxycarbonyl- (L) -iso-leusil) amino-6-phenyl-2-azahexane, 40 ml of 4M HCl in dioxane are added and the mixture is diluted with 3 ml of DMF. It was. After 2.5 hours, the mixture was used. The title compound was obtained. TLC: R _f = 0.55 (methylene chloride / methanol: 9/1), HPLC _20-100 : t _Ret = 8.74, FAB MS (M + H) ⁺ = 534.

<Example 48>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxy-carbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, 0.42 g (2.4 mmol) N-methoxycarbonyl- (L) -valine in 10 mL DMF, 0.862 g (4.5 mmol) EDC, 0.405 g (3 mmol) and 1.26 mL TEA To a mixture of 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl in 10 ml of DMF A solution of 0.964 g (1.5 mmol) of-(L) -tert-louisyl) amino-6-phenyl-2-azahexane hydrochloride was added dropwise. After running the process, the crude product was immersed in DIPE and filtered dried. Subsequent column chromatography (SiO ₂ , hexanes / ethyl acetate: 1/1 to 3/1) gave the title compound pure (TLC: R _f = 0.35 (ethyl acetate), HPLC _20-100 : t _Ret = 10.9 FAB MS (M + H) ⁺ = 691.

<Example 49>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxy-carbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, in 0.152 g (0.8 mmol) of N-methoxycarbonyl- (L) -tert-leucine, 0.287 g (1.5 mmol) of EDC, 0.135 g (1 mmol) of HOBT and 3 ml of DMF To a mixture of 0.49 ml of TEA, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-meth) in 3 ml of DMF 0.315 g (0.5 mmol) of oxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane hydrochloride was added dropwise. After running the process, the crude product was subjected to continuous medium pressure column chromatography (SiO ₂ , hexane / ethyl acetate) to afford the title compound. TLC: R _f = 0.35 (ethyl acetate), HPLC _20-100 : t _Ret = 11.05. FAB MS (M + H) ⁺ = 691.

The starting product was prepared as follows.

49a) 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N-Boc-amino-5 (S) -N- (N-methoxy-carbonyl- (L) -Valyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, 2.49 g (14.2 mmol) N-methoxycarbonyl- (L) -valine, 5.1 g (26.6 mmol) EDC, 2.4 g (17.7 mmol) HOBT and 7.45 mL TEA in 50 mL DMF Mixture of (1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2- (N-Boc-amino) -5 (S) -amino- in 50 ml of DMF. A solution of 4.1 g (8.87 mmol) of 6-phenyl-2-azahexane (Example 47b) was added dropwise After performing the process, the crude product was immersed twice in DIPE and filtered to afford the title compound. _f = 0.42 (ethyl acetate), HPLC _20-100 : t _Ret = 11.92.FAB MS (M + H) ⁺ = 620.

49b) 1- [4- (Pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxy-carbonyl- (L)- Valyl) amino-6-phenyl-2-azahexane hydrochloride

In a similar manner to Example 37f), 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N-Boc-amino-5 (S) -N- (N To 3.5 g (5.65 mmol) of methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane 30 ml of 4M HCl was added and the mixture was diluted with 5 ml DMF. After 3.5 hours, the mixture was used. The title compound was obtained. TLC: R _f = 0.53 (methylene chloride / methanol: 9/1), HPLC _20-100 : t _Ret = 8.00. FAB MS (M + H) ⁺ = 520.

<Example 50>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxy-carbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 46, 0.263 g (1.5 mmol) N-methoxycarbonyl- (L) -valine, 0.446 g (1.5 mmol) TPTU and 0.78 mL (4.5 mmol) DBU in 7 mL DMF, and DMF 10 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxycarbonyl- (L) -iso in ml -Louisyl) amino-6-phenyl-2-azahexane 3HCl (Example 47d) was reacted with 0.96 g (1.5 mmol). After performing the process, the title compound was obtained. TLC: R _f = 0.4 (ethyl acetate), HPLC _20-100 : t _Ret = 11.23. FAB MS (M + H) ⁺ = 691.

<Example 51>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxy-carbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, in 0.6 g (3.2 mmol) N-methoxycarbonyl- (L) -iso-leucine, 1.14 g (6 mmol) EDC, 0.54 g (4 mmol) HOBT and 13 ml DMF To a mixture of 1.68 ml of TEA, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-meth) in 12 ml of DMF. A solution of 1.26 g (2 mmol) of toxylcarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane hydrochloride (Example 49b) was added dropwise. After running the process, the crude product was immersed in DIPE and purified by continuous medium pressure column chromatography (SiO ₂ , hexane / ethyl acetate) to afford the title compound. TLC: R _f = 0.32 (ethyl acetate), HPLC _20-100 : t _Ret = 11.04. FAB MS (M + H) ⁺ = 691.

<Example 52>

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxy-carbonyl- (L) -valyl) -amino-5 (S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane

In a similar manner to Example 1, 0.303 g (1.6 mmol) N-ethoxycarbonyl- (L) -valine, 0.575 g (3 mmol) EDC, 0.27 g (2 mmol) HOBT and 0.98 mL TEA in 7 mL DMF To a mixture of 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-amino-5 (S) -N- (N-methoxylcarbonyl in 5 ml of DMF A solution of 0.629 g (1 mmol) of-(L) -valyl) amino-6-phenyl-2-azahexane hydrochloride (Example 49b) was added dropwise. After running the process, the crude product was immersed in DIPE and purified by continuous medium pressure column chromatography (SiO ₂ , hexane / ethyl acetate) to afford the title compound. TLC: R _f = 0.33 (ethyl acetate), HPLC _20-100 : t _Ret = 11.13. FAB MS (M + H) ⁺ = 691.

<Example 53>

1- [4- (Pyrid-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane methylsulfonic acid salt

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxylcarbonyl- (L) -tert -Louisyl) amino-6-phenyl-2-azahexane (Example 46) 210 mg (0.28 mmol) were dissolved in 10 mL of methylene chloride while heating, and 19.5 μL (0.3 mmol) of methanesulfonic acid was added. The title compound was precipitated with ether, filtered and dried at 50 ° C. under reduced pressure. FAB MS (M + H) ⁺ = 705. ¹ H-NMR (CD ₃ OD) (chemical shift of pyridine protons of the free base in the bracket), δ: 8.81 (8.6), 8.65 (7.9), 8.05 (7.35) Further signal of the methyl group of the salt: δ: 2.7 ppm.

<Example 54>

1- [4- (Pyrid-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane hydrochloride salt

1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxylcarbonyl- (L) -tert -Louisyl) amino] -6-phenyl-2-azahexane (Example 46) 70 mg (0.094 mmol) were dissolved in 6 ml of dioxane and 25 [mu] l of 4M HCl solution in dioxane was added. The resulting precipitate was filtered off and dried. FAB MS (M + H) ⁺ = 705. ¹ H-NMR (CD ₃ OD) (chemical shift of pyridine protons of the free base in the bracket), δ: 8.81 (8.6), 8.65 (7.9), 8.36 (7.8), 8.05 (7.35). Atomic analysis of hydrates of the title compound: Cl Found: 4.6%, Theory: 4.63%.

<Example 55>

Gelatin solution

An aqueous solution in which bacteria were filtered, which is one of the compounds of the formula (I) mentioned in the above examples (e.g., the title compound from Example 2) as the active ingredient, containing 20% of cyclodextrin as a solubilizer, was under sterile conditions While heating, it was mixed with a sterile gelatin solution containing phenol as a preservative, and 1.0 ml of this solution had the following components.

Reactive ingredients 3 mg gelatin 150 mg phenol 4.7 mg Distilled water containing 20% of cyclodextrin as solubilizer 1.0 ml

<Example 56>

Sterile Building Materials For Injection

As active ingredient, 5 mg of one species of the compound of the formula (I, for example, the title compound from Example 3) mentioned in the above examples, in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% of cyclodextrin as solubilizer Dissolved. The solution was bacterial filtered and under sterile conditions, 2 ml of ampoule was added, deep cooled and lyophilized. Prior to use, the lyophilizer was dissolved in 1 ml of distilled water or 1 ml of saline. The solution was administered intramuscularly or intravenously. The formulation can also be injected into a dual chamber disposable syringe.

<Example 57>

Nasal spray

500 mg of powder obtained by finely powdering (less than 5.0 mm) one of the compounds of the formula (I) (for example, the compound from Example 4) as mentioned in the above Example was Myoglyol 812 (registered trademark) 3.5 Suspended as an active ingredient in a mixture of ml and 0.08 g of benzyl alcohol. The suspension was injected into a vessel equipped with a metering valve. 50 g of Freon 12 (registered trademark) (dichlorodifluoromethane, registered trademark of DuPont) was injected into the vessel through a valve under pressure. The "freon" was dissolved by stirring in a myglyol / benzyl alcohol mixture. The spray container contains about 100 servings that can be individually administered.

<Example 58>

Film-coated tablets

The following ingredients are used for the preparation of 10,000 tablets each containing 100 mg of the active ingredient.

Active ingredient 1000 g Cornstarch 680 g Colloidal silicic acid 200 g Magnesium stearate 20 g Stearic acid 50 g Carboxymethyl Sodium Starch 250 g water Fill

As an active ingredient, a mixture of the compound of the formula I mentioned in the above examples (for example, the compound of Example 5), 50 g of cornstarch and colloidal silicic acid, together with a starch paste made of 250 g of cornstarch and 2.2 kg of demineralized water Processed to produce a wet material. This material was passed through a sieve of 3 mm in size and dried in a fluid bed drier at 45 ° C. for 30 minutes. The dried granules are passed through a sieve of eye size 1 mm, mixed and compressed with a pre-sieved mixture of 330 g of cornstarch, magnesium stearate, stearic acid and carboxymethyl sodium starch (1 mm sieve) to form a slightly convex tablet. It was.

<Example 59>

Capsule (I)

Compounds from any one of the examples mentioned above (eg, title compound from Example 6) were micronized using a conventional knife mixer (eg, Turmix). Pluronic® F 68 [block polymer of polyethylene and polypropylene glycol, Wyandotte Chem. Corp. Product, also available from Emkalyx, France, a registered trademark of BASF, was likewise micronized using a conventional mixer and the fine contents were removed using a sieve (0.5 mm) and used as follows. 16.00 g of sesame oil are placed in a glass beaker, 1.20 g of finely divided active ingredient, 1.20 g of fine content of Pluronic® F 68 and hydroxypropylmethylcellulose (cellulose cellulose HP-M- from ShinEtsu chemicals Ltd., Tokyo, Japan). 1.20 g was added with stirring using a stirring apparatus (IKA-Werk, FRG) combined with a tooth stirrer (46 mm in diameter) (stirring rate: 2000 revolutions / minute), stirring for 20 minutes at the same speed and kneading. Suspensions of the same density were prepared and injected into hard gelatin capsules (20 × 40 mm, FRG, RP Scherer AG, Eberbach).

<Example 60>

Capsule (II)

To prepare 10,000 capsules containing 100 mg of active ingredient per capsule (any one of the examples mentioned above, for example from the title compound from Example 7), the following components were processed as follows: .

Active ingredient 1000 g Pluronic (registered trademark) F 68 1000 g Hydroxypropylmethylcellulose 1000 g Sesame oil (see Example 10 for the raw ingredients) 1000 g

Sesame oil was placed in a heatable vessel [Fryma] and Pluronic® F 68 was dispersed in the vessel. The vessel was heated to 60 ° C. and spread evenly with stirring Pluronic® F 68 (continued for 2 hours). With homogeneous stirring, the mixture was cooled to about 30 ° C. Hydroxypropylmethylcellulose and the active ingredient were dispersed and distributed in an oily material with homogeneous stirring (about 1 hour). Dough-like suspensions are prepared by hard gelatin capsules (size 0, for example from Elanco or Parke-Davies (Caprogel)) or soft gelatin capsules (20 mm long oval, FRG, Eberbach) P. Scherrer AG), using conventional equipment.

<Example 61>

Dispersion

To prepare a dispersion comprising 120.0 mg of 10 ml of active ingredient (preferably the title compound from Example 46), the following components were processed as follows.

Active ingredient 120.0 mg Klucel (registered trademark) HF [hydroxypropyl cellulose; Hercules Products in Germany] 50.0 mg Tween (registered trademark) 20 (polyoxyethylene sorbitan monolaurate; Flucka, Buchs, Switzerland) 100.0 mg Demineralized water 10.0 ml

Demineralized water was placed in the container. Hydroxypropylcellulose was dispersed with slow stirring using a magnetic stirrer and swollen for 1 hour. Then polyoxyethylene sorbitan monolaurate was added and the mixture was stirred for 5 minutes using a magnetic stirrer. Finally, the active ingredient was added and the mixture was stirred for 15 minutes using a magnetic stirrer.

<Example 62>

Inhibitory Activity on HIV-1-Protease

The IC ₅₀ values given below for the following examples were obtained using the above-mentioned test system in combination with the icosapeptide RRSNQVSQNYPIVQNIQGRR.

Example IC ₅₀ (μM)

1 0.032

2 0.014

3 0.041

4 0.038

5 0.04

6 0.022

7 0.013

8 0.01

9 0.019

10 0.02

11 0.037

12 0.02

13 0.032

14 0.031

15 0.05

16 0.033

17 0.018

18 0.025

19 0.022

20 0.015

21 0.043

22 0.04

23 0.034

24 0.05

25 0.1

26 0.021

27 0.027

27 (1-methyl-1H-tet

Razolyl isomer) 0.051

28 0.083

29 0.014

30 0.054

31 0.171

34 0.072

35 0.058

37 0.029

38 0.085

39 0.012

40 0.021

41 0.032

42 0.015

43 0.037

44 0.029

45 0.012

46 0.026

47 0.04

48 0.031

49 0.02

50 0.028

51 0.034

52 0.034

<Example 63>

Protection of MT-2 Cells Against HIV Infection

In inhibiting infection of MT-2 cells by viral host HIV-1 / MN, the title compound from Example 46, 1- [4- (pyridin-2-yl) phenyl]-, using the above-mentioned test system, was used. 4 (S) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane The following ED ₉₀ values are shown: ED ₉₀ = 0.003 μM

<Example 64>

Blood concentration in rats

The title compound from Example 46, 1- [4- (pyridin-2-yl) phenyl] -4 (S) -hydroxy-, using the test system mentioned above to determine the pharmacokinetics of the compound of formula I 5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L) -tert-silyl) amino] -6-phenyl-2-azahexane was obtained after oral administration of 120 mg / kg. The following blood concentrations were shown in rats.

Plasma concentration (μM) of the compound of Example 46

30 minutes after dosing 90 minutes after dosing 21.83 31.76

<Example 65>

Formulation as Solution (I):

The formulation comprises 100 mg of the title compound from Example 46, 100 mg of racemic lactic acid (90%), cellulose-HP-M-603, silica gel (Aerosil 200) and deionized water (2 g) as active ingredients It was.

Example 66

Formulation as Solution (II):

The formulation included 18.4 mg of the title compound from Example 46, 5 mg of cellulose-HPM-603, 40 mg of N-methylpyrrolidone and less than 1 ml of distilled water as active ingredients.

<Example 67>

Prepared similarly to one of the above mentioned processes:

A) 1- [4- (pyridin-2-yl) phenyl] -4 (R) -hydroxy-5 (S) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane,

B) 1- [4- (pyridin-2-yl) phenyl] -4 (R) -hydroxy-5 (R) -2,5-bis [N- (N-methoxycarbonyl- (L)- tert-louisyl) amino] -6-phenyl-2-azahexane,

C) 1- [4- (pyridin-2-yl) phenyl] -4 (S) -hydroxy-5 (S) -2- [N- (N-methoxycarbonyl- (L) -tert-Louis Sil) amino] -5- [N- (N-methoxycarbonyl- (D) -tert-silyl) amino] -6-phenyl-2-azahexane, or

D) 1- [4- (pyridin-2-yl) phenyl] -4 (S) -hydroxy-5 (S) -2- [N- (N-methoxycarbonyl- (D) -tert-Louis Sil) amino] -5- [N- (N-methoxycarbonyl- (L) -tert-louisyl) amino] -6-phenyl-2-azahexane.

The present invention relates to heterocyclic azahexane derivatives which can be used as substrate isosteres of retroviral aspartate proteases, salts thereof, methods of preparing these compounds and salts thereof, pharmaceutical compositions containing these compounds or these salts, The use of these compounds or salts thereof (alone or in combination with other antiretroviral active compounds) in the treatment or diagnostic treatment of humans or animals or in the manufacture of pharmaceutical compositions.

Claims (26)

A compound of formula (I) or a salt thereof. <Formula I> Where R ₁ is C ₁ -C ₇ alkoxycarbonyl, R ₂ is sec- or tert-lower alkyl or C ₁ -C ₇ alkylthio-C ₁ -C ₇ alkyl, wherein the term “lower” refers to a group having up to 7 carbon atoms, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is unsubstituted or substituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and is 5 to Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having 8 ring atoms, bonded via a ring carbon atom, R ₅ is one of the groups described for R ₂ independently of R _2, R ₆ is a R ₁ is independently C ₁ -C ₇ alkoxycarbonyl. The compound of formula (Ia) or a salt thereof according to claim 1. <Formula Ia> Wherein groups are as defined in claim 1. The method of claim 2, R ₁ is C ₁ -C ₄ alkoxycarbonyl, R ₂ is isopropyl, sec-butyl or tert-butyl, R ₃ is phenyl or cyclohexyl, Thienyl, wherein R ₄ is bonded via a ring carbon atom; Oxazolyl; Thiazolyl; Imidazolyl; 1,4-thiazinyl; Triazolyl unsubstituted or substituted by 1-methyl-1-phenylethyl, tert-butyl, or methyl; Tetrazolyl unsubstituted or substituted by 1-methyl-1-phenylethyl, tert-butyl or methyl; Pyridinyl; Pyrazinyl; And phenyl substituted at the 4-position by one of pyrimidinyl, R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl, A compound of formula (Ia) or a salt thereof, wherein R ₆ is C ₁ -C ₄ alkoxycarbonyl. The method of claim 2, R ₁ is methoxycarbonyl or ethoxycarbonyl, R ₂ is isopropyl, sec-butyl or tert-butyl, R ₃ is phenyl, R ₄ is 2- or 3-thienyl; Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or substituted in the 2-position by 1-methyl-1-phenylethyl, tert-butyl or methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-2-yl; Pyridin-3-yl; Pyridin-4-yl; Or phenyl substituted at the 4-position of the phenyl ring by pyrazin-2-yl, R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl, R ₆ is methoxycarbonyl or ethoxycarbonyl, Provided that R ₄ is 2- or 3-thienyl; Thiazol-5-yl; Thiazol-2-yl; 2H-tetrazol-5-yl unsubstituted or substituted in the 2-position by 1-methyl-1-phenyl-ethyl, tert-butyl, or methyl; 1H-tetrazol-5-yl substituted in the 1-position by methyl; Pyridin-3-yl; Pyridin-4-yl; Or if the 4-position of the phenyl ring is substituted by pyrazin-2-yl, then at least one of the two groups R ₂ and R ₅ is tert-butyl, or a salt thereof. The method of claim 2, R ₁ is methoxycarbonyl or ethoxycarbonyl, R ₂ is isopropyl, sec-butyl or tert-butyl, R ₃ is phenyl, R ₄ is 4- (thiazol-2-yl) -phenyl; 4- (thiazol-5-yl) -phenyl; 4- (pyridin-2-yl) -phenyl; Or 4- (2-methyl-tetrazol-5-yl) -phenyl, R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl, A compound of formula (Ia) or a salt thereof, wherein R ₆ is methoxycarbonyl or ethoxycarbonyl. The method of claim 2, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -iso-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -S-methylcysteinyl) amino- 5 (S) -N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-ethoxycarbonyl- (L) -valyl) amino-5 (S)- N- (N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L) -tert-louisyl) amino] -6-phenyl-2-azahexane, 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane, 1- [4- (thiazol-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 ( S) -N- (N-methoxycarbonyl- (L) -iso-silyl) amino-6-phenyl-2-azahexane, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarbonyl- (L)- Valeryl) amino] -6-phenyl-2-azahexane, 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -valyl) amino-5 (S) -N -(N-methoxycarbonyl- (L) -tert-silyl) amino-6-phenyl-2-azahexane, and 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-2-N- (N-methoxycarbonyl- (L) -tert-leusil) amino-5 (S A compound of formula (Ia) selected from) -N- (N-methoxycarbonyl- (L) -valyl) amino-6-phenyl-2-azahexane, or a pharmaceutically acceptable salt thereof in each case. The compound of claim 2, wherein 1- [4- (thiazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxy A compound of formula (Ia) or a salt thereof, wherein the compound is carbonyl- (L) -tert-silyl) -amino] -6-phenyl-2-azahexane. The compound of claim 2, wherein 1- [4- (2-methyl-2H-tetrazol-5-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N Or a salt thereof.-(N-methoxycarbonyl- (L) -tert-leusil) amino] -6-phenyl-2-azahexane. The compound of claim 2, wherein 1- [4- (pyridin-2-yl) -phenyl] -4 (S) -hydroxy-5 (S) -2,5-bis- [N- (N-methoxycarb) A compound of formula (Ia) or a salt thereof, wherein the compound is carbonyl- (L) -tert-leusil) amino] -6-phenyl-2-azahexane. For the treatment of AIDS or a preliminary step thereof, containing a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt of such a compound having at least one salt forming group together with a pharmaceutically acceptable carrier. Pharmaceutical composition. A pharmaceutical composition for the treatment of AIDS or a preliminary step thereof containing a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt of such a compound having at least one salt forming group. A pharmaceutical composition for the treatment of SIV or FIV, comprising a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt of such a compound having at least one salt forming group. A pharmaceutical composition for the treatment of AIDS or a preliminary step thereof containing a compound of formula (I) according to any one of claims 1 to 9. a) adding a hydrazine derivative of formula III to an epoxide of formula IV, wherein the free functional groups may be present in protected form except for participating in the reaction, or b) condensing the amino compound of formula (V) with an acid of formula (VI) or a reactive acid derivative thereof, wherein the free functional groups can be present in protected form except for participating in the reaction, or c) condensation of an amino compound of formula VII with an acid of formula VIII or a reactive acid derivative thereof (free functional groups may be present in protected form except for participating in the reaction), or d) the substituents R ₁ and R ₆ pairs and R ₂ and R ₅ pairs are in each case two identical groups as defined for the compound of formula I and R ₃ and R ₄ as defined for the compound of formula I To prepare a compound of formula (I), a diamino compound of formula (IX) is condensed with an acid of formula (VIIIa) or a reactive acid derivative thereof (where the free functional groups can be present in protected form, except for participating in the reaction) Remove or e) reacting an imino compound of formula (I ') with a compound of formula (X), where the free functional groups may be present in protected form except for participating in the reaction, or f) reacting an imino compound of formula (I ') with an aldehyde of formula (X *) (the free functional groups may be present in protected form except for participating in the reaction) and removing the protecting groups, above a) to f) Isomer mixtures which can be obtained by converting a compound of formula (I) having at least one salt forming group obtained according to any one of A process for the preparation of a compound of formula (I) or a salt thereof according to claim 1 for separating and / or converting a compound of formula (I) according to the invention to another compound of formula (I) according to the invention. <Formula III> <Formula IV> <Formula V> <Formula VI> <Formula VII> <Formula VIII> <Formula IX> <Formula VIIIa> <Formula I '> <Formula X> <Formula X *> Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as described for the compound of Formula I, R ₁ ′ and R ₂ ′ are as defined for R ₁ and R ₆ in Formula I, respectively for R ₂ and R ₅ , with R ₁ and R ₆ pairs and R ₂ and R ₅ pairs in each case Are the same group X is a leaving group. A compound of formula (XX) or a salt thereof. <Formula XX> In the above formula, R ₁ is methoxycarbonyl or ethoxycarbonyl, and R ₂ is tert-butyl. A compound of formula IV: <Formula IV> Wherein R ₁ is methoxycarbonyl or ethoxycarbonyl, R ₂ is tert-butyl, R ₃ is phenyl unsubstituted or substituted with one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl. A compound of formula III * or a salt thereof. <Formula III *> Wherein R ₄ is 1 to 4 heteroatoms substituted or unsubstituted with C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl Phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom, having 5 to 8 ring atoms, R ₅ is tert-butyl, R ₆ is methoxy- or ethoxycarbonyl. A compound of formula (XII) or a salt thereof. <Formula XII> Wherein R ₄ is 1 to 4 heteroatoms substituted or unsubstituted with C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl Phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom, having 5 to 8 ring atoms, R ₇ is an amino protecting group. A compound of formula XII * or a salt thereof. <Formula XII *> Wherein R ₄ is 1 to 4 heteroatoms substituted or unsubstituted with C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl Phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom, having 5 to 8 ring atoms, R ₇ is an amino protecting group. A compound of formula III: or a salt thereof. <Formula III> Wherein R ₄ is 1 to 4 heteroatoms substituted or unsubstituted with C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl Phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl bonded via a ring carbon atom, having 5 to 8 ring atoms, R ₅ is isopropyl, sec-butyl, tert-butyl or methylthiomethyl, R ₆ is C ₁ -C ₇ alkoxycarbonyl. A compound of formula (V) or a salt thereof. <Formula V> In the above formula, R ₁ is C ₁ -C ₇ alkoxycarbonyl, R ₂ is sec- or tert-lower alkyl or C ₁ -C ₇ alkylthio-C ₁ -C ₇ alkyl, wherein the term “lower” refers to a group having up to 7 carbon atoms, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having from 8 to 8 ring atoms, bonded via a ring carbon atom. A compound of formula VII or a salt thereof. <Formula VII> In the above formula, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having a ring carbon atom, having from 8 to 8 ring atoms, R ₅ is sec- or tert-lower alkyl or C ₁ -C ₇ alkylthio-C ₁ -C ₇ alkyl, wherein the term “lower” refers to a group having up to 7 carbon atoms, R ₆ is C ₁ -C ₇ alkoxycarbonyl. A compound of formula (IX) or a salt thereof. <Formula IX> In the above formula, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having from 8 to 8 ring atoms, bonded via a ring carbon atom. A compound of formula (XXIV) or a salt thereof. <XXIV> In the above formula, R ₁₃ and R ₁₄ are different amino protecting groups from each other, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having from 8 to 8 ring atoms, bonded via a ring carbon atom. A compound of formula XXV or a salt thereof. <Formula XXV> In the above formula, R ₁₄ is an amino protecting group, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having from 8 to 8 ring atoms, bonded via a ring carbon atom. A compound of formula (XXVI) or a salt thereof. <Formula XXVI> In the above formula, R ₁₅ is an amino protecting group, R ₁ is C ₁ -C ₇ alkoxycarbonyl, R ₂ is sec- or tert-lower alkyl or C ₁ -C ₇ alkylthio-C ₁ -C ₇ alkyl, wherein the term “lower” refers to a group having up to 7 carbon atoms, R ₃ is phenyl unsubstituted or substituted by one or more C ₁ -C ₇ alkoxy groups, or C ₄ -C ₈ cycloalkyl, R ₄ is substituted or unsubstituted by C ₁ -C ₇ alkyl or phenyl-C ₁ -C ₇ alkyl and comprises 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, sulfinyl and sulfonyl and 5 Phenyl or cyclohexyl, each substituted at the 4-position by unsaturated heterocyclyl having from 8 to 8 ring atoms, bonded via a ring carbon atom.