Azahexane derivatives as substrate isosters of retroviral asparate proteases

The invention relates to compounds of formula (I): ##STR1## wherein R.sub.1 and R.sub.10 are each independently of the other lower alkoxycarbonyl; either R.sub.2, R.sub.3 and R.sub.4 are each independently of the other C.sub.1 -C.sub.4 alkyl and R.sub.7, R.sub.8 and R.sub.9 are each selected from hydrogen and C.sub.1 -C.sub.4 alkyl, with not more than 2 of the radicals being hydrogen; or R.sub.7, R.sub.8 and R.sub.9 are each independently of the other C.sub.1 -C.sub.4 alkyl and R.sub.2, R.sub.3 and R.sub.4 are each selected from hydrogen and C.sub.1 -C.sub.4 alkyl, with 1 or 2 of the radicals being hydrogen; R.sub.5 is phenyl or cyclohexyl; and R.sub.6 is phenyl or cyanophenyl; or salts thereof; those compounds are inhibitors of retroviral aspartate proteases and are effective, for example, against HIV.

BRIEF DESCRIPTION OF THE INVENTION
 The invention relates to azahexane derivatives having the property of being
 substrate isosteres of retroviral aspartate proteases, to salts thereof,
 to processes for the preparation of those compounds and their salts, to
 pharmaceutical compositions comprising those compounds or their salts, and
 to the use of those compounds or their salts (alone or in combination with
 other antiretrovirally active compounds) in the therapeutic or diagnostic
 treatment of the human or animal body or in the preparation of
 pharmaceutical compositions.
 BACKGROUND TO THE INVENTION
 According to WHO estimates there are clearly more than 20 million people
 infected by HIV-1 or HIV-2. Sooner or later that infection manifests
 itself by way of preliminary stages, such as ARDS, in a manifest disease
 of the immune system which is known as "Acquired Immunodeficiency
 Syndrome" or AIDS. In the overwhelming number of cases the disease sooner
 or later leads to the death of the infected patients.
 Hitherto, the treatment of retroviral diseases, such as AIDS, has involved
 principally the use of inhibitors of reverse transcriptase, an enzyme
 effective in the conversion of retroviral RNA into DNA, such as
 3'-azido-3'-deoxythymidine (AZT) or dideoxyinosine (DDI), and also
 trisodium phosphonoformate, ammonium-21-tungstenato-9-antimonate,
 1-.beta.-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide and dideoxycytidine
 and also adriamycin. Attempts have also been made to introduce into the
 body, for example in the form of a recombinant molecule or molecule
 fragment, the T4-cell receptor which is present in certain cells of the
 defence system of the human body and is responsible for the anchoring and
 introduction of infectious virus particles into those cells and thus for
 their infection, the objective being that binding sites for the virus will
 be blocked so that the virions will no longer be able to bind to the
 cells. Compounds that prevent the virus penetrating the cell membrane in
 some other way, such as polymannoacetate, are also used.
 Also reported are advanced clinical experiments with a hydroxyethylene
 isostere as an inhibitor of HIV-protease,
 N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolyl-carbon
 yl-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (Ro
 31-8959). That compound exhibits an inhibitory action against HIV-protease
 in vitro, suppression of virus replication in cell experiments and, in
 experiments on rodents, blood levels that are still usable are achieved
 even in the case of oral administration (see Roberts, N. A., et al.,
 Biochemical Soc. Transactions 20, 513-516 (1992)); usable blood levels
 have also been achieved in humans (see e.g. G. J. Muirhead et al., Brit.
 J. Clin. Pharmacol. 34, 170P-171 P (1992)). A so-called "surrogate-marker"
 (titre of the CD4-lymphocytes in the blood, the decrease in which in
 untreated patients is a measure of the advance of the AIDS disease) has
 shown initial positive effects in AIDS patients (see "Roche Statement on
 HIV Proteinase Inhibitor (Ro 31-8959) European Trials Results",
 distributed to participants in the 9th International Congress on AIDS in
 Berlin, Jun. 7-11, 1993). A disadvantage of that compound, Ro 31-8959, is
 that it is expensive to synthesise.
 Also under development are a number of further inhibitors of retroviral
 aspartate protease, an enzyme the function of which can be characterised
 as follows:
 In the AIDS viruses, HIV-1 and HIV-2, and other retroviruses, for example
 corresponding viruses in cats (FIV) and apes (SIV), the proteolytic
 maturation of, for example, the core proteins of the virus is brought
 about by an aspartate protease, such as HIV-protease. Without that
 proteolytic maturation, infectious virus particles cannot be formed. Owing
 to the central role of the said aspartate proteases, such as HIV-1- or
 HIV-2-protease, in the maturation of viruses and on the basis of
 experimental results, for example on infected cell cultures, it has become
 plausible that effective suppression of the maturation step brought about
 by that protease will suppress the assembly of mature virions in vivo.
 Corresponding inhibitors can therefore be used therapeutically.
 The aim of the present invention is to provide a novel type of compound
 that is equipped, especially, with a high degree of inhibitory activity
 against virus replication in cells, high anti-viral activity against
 numerous virus strains, including those which are resistant to known
 compounds, such as saquinavir and indinavir, and especially advantageous
 pharmacological properties, for example good pharmacokinetics, such as
 high bioavailabilty and high blood levels, and/or high selectivity.
 FULL DESCRIPTION OF THE INVENTION
 The azahexane derivatives according to the invention are compounds of
 formula I
 ##STR2##
 wherein
 R.sub.1 and R.sub.10 are each independently of the other lower
 alkoxycarbonyl;
 either R.sub.2, R.sub.3 and R.sub.4 are each independently of the other
 C.sub.1 -C.sub.4 alkyl and R.sub.7, R.sub.8 and R.sub.9 are each selected
 from hydrogen and C.sub.1 -C.sub.4 alkyl, with not more than 2 of the
 radicals being hydrogen;
 or R.sub.7, R.sub.8 and R.sub.9 are each independently of the other C.sub.1
 -C.sub.4 alkyl and R.sub.2, R.sub.3 and R.sub.4 are each selected from
 hydrogen and C.sub.1 -C.sub.4 alkyl, with 1 or 2 of the radicals being
 hydrogen;
 R.sub.5 is phenyl or cyclohexyl; and
 R.sub.6 is phenyl or cyanophenyl;
 or salts thereof.
 Those compounds exhibit unexpectedly good and surprisingly positive
 pharmacological properties, as indicated in detail below, and are
 relatively simple to synthesise.
 Unless indicated to the contrary, the general terms used hereinabove and
 hereinbelow preferably have the following meanings within the scope of
 this disclosure:
 The term "lower" indicates a radical having up to and including a maximum
 of 7 carbon atoms, preferably up to and including a maximum of 4 carbon
 atoms, the radicals in question being unbranched or branched one or more
 times.
 Lower alkyl and C.sub.1 -C.sub.4 alkyl are especially tert-butyl,
 sec-butyl, isobutyl, n-butyl, isopropyl, n-propyl, ethyl and especially
 methyl.
 Any reference to compounds, salts and the like in the plural also includes
 a compound, a salt and the like.
 Any asymmetric carbon atoms present, for example the carbon atoms bonded to
 the radicals R.sub.2, R.sub.3 and R.sub.4 and to R.sub.7, R.sub.8 and
 R.sub.9 and the carbon atoms carrying the radical
 [(R.sub.2)(R.sub.3)(R.sub.4)C]-- or [(R.sub.7)(R.sub.8)(R.sub.9)C]-- in
 compounds of formula I, may be in the (R)-, (S)- or (R,S)-configuration,
 preferably in the (R)- or (S)-configuration, the (S)-configuration being
 especially preferred in the case of the carbon atoms carrying the radical
 [(R.sub.2)(R.sub.3)(R.sub.4)C]-- or [(R.sub.7)(R.sub.8)(R.sub.9)C]-- in
 compounds of formula I. Accordingly, the compounds in question may be in
 the form of isomeric mixtures or in the form of pure isomers, preferably
 in the form of pure diastereoisomers.
 Lower alkoxycarbonyl is preferably C.sub.1 -C.sub.4 alkoxycarbonyl wherein
 the alkyl radical may be branched or unbranched, and is especially
 ethoxycarbonyl or more especially methoxycarbonyl.
 As R.sub.5, phenyl is preferred to cyclohexyl.
 Cyanophenyl is preferably 4-, 3- or especially 2-cyanophenyl.
 The compounds of formula I preferably have the formula Ia
 ##STR3##
 wherein the radicals are as defined.
 Salts are especially the pharmaceutically acceptable, non-toxic salts of
 compounds of formula I.
 Such salts are formed, for example, by compounds of formula I with their
 basic imino group as acid addition salts, preferably with inorganic acids,
 for example hydrohalic acids, such as hydrochloric acid, sulfuric acid or
 phosphoric acid, or with strong organic sulfonic, sulfo or phospho acids
 or N-substituted sulfamic acids (preferably: pKa&lt;1).
 For the purposes of isolation or purification it is also possible to use
 pharmaceutically unacceptable salts, for example perchlorates. Only the
 pharmaceutically acceptable salts or the free compounds of formula I are
 used therapeutically and they are therefore preferred.
 The compounds of formula I have valuable pharmacological properties. They
 have anti-retroviral activity, especially against the viruses HIV-1 and
 HIV-2 which are regarded as causes of AIDS, and surprisingly exhibit
 synergistic effects in combination with other compounds that are active
 against retroviral aspartate proteases. The compounds of formula I are
 inhibitors of retroviral aspartate proteases, especially inhibitors of the
 aspartate protease of HIV-1 or also HIV-2 and are therefore suitable for
 the treatment of retroviral diseases, such as AIDS or its preliminary
 stages (e.g. ARDS). Compounds of formula I also exhibit activity against
 corresponding animal retroviruses, such as SIV (in apes) or FIV (in cats).
 Compounds of formula I exhibit, surprisingly, especially advantageous and
 important pharmacological properties, for example a very high antiviral
 activity in cell tests against various virus strains, including those
 which are resistant to other protease inhibitors, for example in
 MT2-cells, good pharmacokinetics, such as high bioavailability, high
 selectivity and, especially, high blood levels (even in the case of oral
 administration).
 The inhibitory action of the compounds of formula I on the proteolytic
 activity of HIV-1-protease can be shown, for example, analogously to the
 method described by A. D. Richards et al., J. Biol. Chem. 265(14),
 7733-7736 (1990). In that method the inhibition of the action of
 HIV-1-protease (prepared in accordance with S. Billich et al., J. Biol.
 Chem. 263(34), 17905-17908 (1990)) is measured in the presence of the
 icosapeptide RRSNQVSQNYPIVQNIQGRR SEQ ID NO:1, a synthetic substrate of
 HIV-1-protease, prepared by peptide synthesis in accordance with known
 procedures, see J. Schneider et al., Cell 54, 363-368 (1988)), which
 contains as substrate analogue one of the cleavage sites of the
 gag-precursor protein (natural substrate of HIV-1-protease). That
 substrate and its cleavage products are analysed by high performance
 liquid chromatography (HPLC).
 The test compound is dissolved in dimethyl sulfoxide. The enzymatic test is
 carried out by adding suitable dilutions of the inhibitor in 20 mM
 .beta.-morpholinoethanesulfonic acid (MES) buffer pH 6.0 to the test
 mixture. That mixture consists of the above-mentioned iscosapeptide (122
 .mu.M) in 20 mM MES-buffer pH 6.0. 100 .mu.l are used per test batch. The
 reaction is started by the addition of 10 ml of HIV-1-protease solution
 and is stopped after one hours incubation at 37.degree. C. by the addition
 of 10 .mu.l of 0.3M HClO.sub.4. After centrifugation of the sample at
 10,000.times.g for 5 minutes, 20 ml of the resulting supernatant are
 applied to a 125.times.4.6 mm Nucleosil.RTM. C18-5m-HPLC column
 (reversed-phase material supplied by Macherey & Nagel, Duren, FRG, based
 on silica gel that has been charged with C.sub.18 alkyl chains). The
 uncleaved icosapeptide and its cleavage products are eluted from the
 column by means of the following gradient: 100% eluant 1.fwdarw.50% eluant
 1+50% eluant 2 (eluant 1: 10% acetonitrile, 90% H.sub.2 O, 0.1%
 trifluoroacetic acid (TFA); eluant 2: 75% acetonitrile, 25% H.sub.2 O,
 0.08% TFA) for 15 minutes, throughflow rate 1 ml/min. The quantification
 of the eluted peptide fragments is carried out by measuring the peak
 height of the cleavage product at 215 nm.
 Compounds of formula I exhibit inhibitory actions in the nanomolar range;
 they preferably exhibit IC.sub.50 values (IC.sub.50 =that concentration
 which brings about a 50% reduction in the activity of HIV-1-protease in
 comparison with a control without inhibitor) of approximately
 9.times.10.sup.-8 to 4.times.10.sup.-8 M.
 An alternative method (see Matayoshi et al., Science 247, 954-958 (1990),
 here modified) of determining the inhibitory action against HIV-1-protease
 may be described briefly as follows: the protease (purification: see
 Leuthardt et al., FEBS Lett. 326, 275-80 (1993)) is incubated at room
 temperature in 100 .mu.l of assay buffer (20 mM MES pH 6.0; 200 mM NaCl; 1
 mM dithiothreitol; 0.01% polyethylene glycol (average molecular weight
 6000 to 8000 da) with 10 .mu.M fluorogenic substrate SC4400
 (4-(4-dimethylaminophenylazo)benzoyl-.gamma.-aminobutyryl-Ser-Gln-Asn-Tyr-
 Pro-Ile-Val-Gln-EDANS, SEQ ID NO:2,
 (EDANS=5-(2-aminoethylamino)-1-naphthalenesulfonic acid); Neosystem
 Laboratoire, France). The reaction is discontinued by the addition of 900
 .mu.l of 0.03M HClO.sub.4. The HIV-1-protease activity is determined by
 measuring the increase in fluorescence at .lambda.ex=336, .lambda.em=485
 nm. The IC.sub.50 values of compounds of formula I are determined as the
 concentration of the compound that is necessary to inhibit the protease
 activity in the assay by 50%. The numerical values are obtained from
 computer-generated graphs from data relating to at least 5 concentrations
 of the compound of formula I in question with threefold determination per
 concentration.
 In a further test it can be shown that compounds of formula I protect cells
 normally infected by HIV from such an infection or at least slow down such
 an infection. For this test, MT-2-cells infected with HIV-1/MN are used.
 MT-2-cells have been transformed with a continuous producer of HTLV-1 (a
 virus causing leukaemia); they are therefore especially sensitive to the
 cytopathogenic effect of HIV. MT-2-cells can be obtained via the AIDS
 Research and Reference Reagent Program, Division of AIDS, NIAID, NIH from
 Dr. Douglas Richman (see J. Biol. Chem. 263, 5870-5875 (1988) and also
 Science 229, 563-566 (1985)). The MT-2-cells are cultured in RPMI
 1640-medium (Gibco, Scotland; RPMI comprises an amino acid mixture without
 glutamine) supplemented with 10% heat-inactivated foetal calf serum,
 glutamine and standard antibiotics. In all cases the cells, and also the
 virus stock solution used for the infection (HIV-1/MN), are free of
 mycoplasms. The virus stock solution is prepared as a cell culture
 supernatant of the permanently infected cell line H9/HIV-1/MN, which can
 likewise be obtained via the AIDS Research and Reference Program, Division
 of AIDS, NIAID, NIH from Dr. Robert Gallo (see also Science 224, 500-503
 (1984) and Science 226, 1165-1170 (1984)). The titre of the HIV-1/MN virus
 stock solution (determined by titration onto MT-2-cells) is
 4.2.times.10.sup.5 TCID50/ml (TCID50=Tissue Culture Infective Dose=dose
 that infects 50% of the MT-2-cells). In order to measure the
 infection-inhibiting action of the compounds of formula I, 50 .mu.l of the
 test compound in question in culture medium and 2800 TCID50 of HIV-1/MN in
 100 .mu.l of culture medium are added to 2.times.10.sup.4 exponentially
 growing MT-2-cells which have been applied in 50 .mu.l of culture medium
 to 96-well microtitre plates (having a round base). After 4 days'
 incubation (at 37.degree. C., 5% CO.sub.2) a 10 .mu.l sample of the
 supernatant is taken from each well, transferred to a further 96-well
 microtitre plate and (if necessary) stored at -20.degree. C. In order to
 measure the activity of the virus-associated reverse transcriptase, 30
 .mu.l of reverse transcriptase (RT) cocktail are added to each sample. The
 reverse transcriptase cocktail consists of 50 mM Tris
 (.alpha.,.alpha.,.alpha.-tris(hydroxymethyl)methylamine, Ultra pur, Merck,
 Germany) pH 7.8; 75 mM KCl, 2 mM dithiothreitol, 5 mM MgCl.sub.2 ; 0.1%
 Nonidet P40 (detergent; Sigma, Switzerland), 0.8 mM EDTA, 10 .mu.g/ml
 Poly-A (Pharmacia, Uppsala, Sweden) and 0.16 .mu.g/ml oligo(T)
 (=pdT(12-18), Pharmacia, Uppsala, Sweden) as "template primer"--if
 desired, the mixture is filtered through a 0.45 mm Acrodisc filter (Gelman
 Sciences Inc., Ann Arbor, USA). It is stored at -20.degree. C. Prior to
 the test, 0.1% (v/v) [alpha-.sup.32 P]dTTP is added to aliquots of the
 solution in order to establish a final radioactivity of 10 .mu.Ci/ml.
 After mixing, the plate is incubated for 2 hours at 37.degree. C. 5 .mu.l
 of the reaction mixture are transferred to DE81 paper (Whatman, one filter
 per well). The dried filters are washed three times for 5 minutes with 300
 mM NaCl/25 mM trisodium citrate and then once with ethanol and again dried
 in the air. The radioactivity on the filters is measured in a Matrix
 Packard 96-well counter (Packard, Zurich, Switzerland). The ED.sub.90
 values are calculated and are defined as the concentration of the test
 compound that reduces the RT activity by 90% in comparison with a control
 without test compound.
 Compounds of formula I here exhibit preferably an ED.sub.90, that is to say
 a 90% inhibition of virus replication, at concentrations of from 10.sup.-8
 to 10.sup.-9 M, especially from 5.times.10.sup.-9 to 10 .sup.-9 M.
 Accordingly, compounds of formula I are suitable for the highly effective
 retardation of the replication of HIV-1 in cell cultures.
 In the determination of the anti-enzymatic activity against numerous human
 aspartate proteases in accordance with known methods (see, for example,
 Biochem. J. 265, 871-878 (1990)), compounds of formula I exhibit a high
 selectivity towards the retroviral aspartate protease of HIV, especially
 HIV-1. For example, the inhibition constant (IC.sub.50) for compounds of
 formula I in the test against cathepsin D is more than 25 .mu.M. The
 IC.sub.50 against human cathepsin D in that test is measured at pH 3.1.
 The test is carried out in accordance with known procedures using the
 substrate KPIQF*NphRL (see Jupp, R. A., Dunn, B. M., Jacobs, J. W.,
 Vlasuk, G., Arcuri, K. E., Veber, D. F., S. Perow, D. S., Payne, L. S.,
 Boger, J., DeLazio, S., Chakrabarty, P. K, TenBroeke, J., Hangauer, D. G.,
 Ondeyka, D., Greenlee, W. J. and Kay, J.: The selectivity of statine-based
 inhibitors against various human aspartic proteases. Biochem. J. 265:
 871-878 (1990)).
 In order to determine their pharmacokinetics, the compounds of formula I
 are dissolved in dimethyl sulfoxide (DMSO) in a concentration of 240
 mg/ml. The resulting solutions are diluted 1:20 (v/v) with 20% (w/v)
 aqueous hydroxypropyl-.beta.-cyclodextrin solution in order to obtain a
 concentration of the test compound in question of 12 mg/ml. The resulting
 solution is treated briefly with ultrasound and administered orally to
 female BALB/c mice (Bomholt-garden, Copenhagen, Denmark) by artificial
 tube feeding at a dose of 120 mg/kg. At fixed times (for example 30, 60,
 90, 120 min) after administration, mice are sacrificed and the plasma
 stored in heparinised test tubes. The blood is centrifuged
 (12,000.times.g, 5 min) and the plasma removed. The plasma is
 deproteinised by the addition of an equal volume of acetonitrile. The
 mixture is mixed using a vortex mixer and and left to stand at room
 temperature for 20 to 30 minutes. The precipitate is pelleted by
 centrifugation (12,000.times.g, 5 min), and the concentration of the test
 compound is determined by reversed phase high performance liquid
 chromatography (HPLC).
 The HPLC analysis of the samples obtained in accordance with the method
 described above is carried out on a 125.times.4.6 mm Nucleosil.RTM.
 C.sub.18 -column (reversed-phase material supplied by Macherey & Nagel,
 Duren, Germany, based on silica gel derivatised with carbon radicals
 having 18 carbon atoms), using a 2 cm long preliminary column of the same
 column material. The test is carried out with the following linear
 acetonitrile/water gradient (in each case in the presence of 0.05%
 trifluoroacetic acid): 20% acetonitrile to 100% acetonitrile for 20 min;
 then 5 min 100% acetonitrile; then returning to the initial conditions for
 1 min and 4 min reequilibration. The flow rate is 1 ml/min. Under those
 conditions the compound of formula I from Example 1, for example, has a
 retention time of about 15.5 minutes, and its detection limit is 0.1-0.2
 .mu.M. The test compound is detected by UV absorption measurement at 255
 nm. Peaks are identified by the retention time and the UV spectrum between
 205 and 400 nm. The concentrations are determined by the external standard
 method; the peak heights are obtained for determining the concentrations
 by comparison with standard curves. The standard curves are obtained by
 analogous HPLC analysis of mouse plasma that contains known concentrations
 of the test compound in question and that has been worked up in accordance
 with the method described above.
 In that experiment compounds of formula I produce plasma concentrations far
 above the ED.sub.90 determined above in the cell experiment, for example
 from 0.5 to 7 .mu.M, especially from 1 to 7 .mu.M, after 30 minutes and
 from 1 to 6 .mu.M after 90 minutes; for example, the compound of formula I
 from Example 1 exhibits a plasma level of 6.33 .mu.M 30 minutes after oral
 administration, and 5.35 .mu.M after 90 minutes.
 In particular, the combination of high bioavailability (high plasma
 levels), which is surprising on its own, and the unexpectedly excellent
 ED.sub.90 in the cell experiment makes the compounds of the present
 invention valuable in an unforeseen way.
 In the determination of the anti-enzymatic activity against numerous human
 aspartate proteases in accordance with known methods (see, for example,
 Biochem. J. 265, 871-878 (1990)), compounds of formula I exhibit a high
 selectivity towards the retroviral aspartate protease of HIV, especially
 HIV-1.
 The compounds of formula I can be used alone or in combination (as a set
 combination of corresponding compositions or as a combination of
 individual compounds or individual compositions in a time-staggered
 sequence) with other substances (or salts thereof provided that at least
 one salt-forming group is present) that are effective against
 retroviruses, especially HIV, such as HIV-1 or HIV-2; especially with
 inhibitors of reverse transcriptase, more especially nucleoside analogues,
 especially 3'-azido-3'-deoxypyrimidine (=zidovudine=.RTM.RETROVIR,
 Burroughs-Wellcome), 2',3'-dideoxycytidine (=zalcitabine=.RTM.HIVID,
 Hoffmann-LaRoche), 2',3'-dideoxyinosine (=didanosine=.RTM.VIDEX,
 Bristol-Myers-Squibb) or
 (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-
 one (=lamivudine, Glaxo) or non-nucleoside analogues, such as
 11-cyclopropyl-5,11-dihydro-4-methyl-(6H)-dipyrido[3,2-b;
 2',3'-e]-[1,4]diazepin-6-one; or with one or more (especially one or also
 two) other inhibitors of retroviral aspartate proteases, especially
 aspartate proteases of HIV, such as HIV-1 and HIV-2, especially
 a) one of the inhibitors mentioned in EP 0 346 847 (published on Dec. 20,
 1989) and EP 0 432 695 (published on Jun. 19, 1991; corresponds to U.S.
 Pat. No. 5,196,438, published on Mar. 23, 1993), especially the compound
 designated Ro 31-8959 (=saquinavir; Hoffmann-LaRoche);
 b) one of the inhibitors mentioned in EP 0 541 168 (published on May 12,
 1993; corresponds to U.S. Pat. No. 5,413,999), especially the compound
 designated L-735,524 (=indinavir=.RTM.CRIXIVAN; Merck & Co., Inc.);
 c) one of the inibitors mentioned in EP 0 486 948 (published on May 27,
 1992; corresponds to U.S. Pat. No. 5,354,866), especially the compound
 designated ABT-538 (=ritonavir; Abbott);
 d) the compound designated KVX-478 (or VX-478 or 141W94; GlaxoWellcome,
 Vertex and Kissei Pharmaceuticals)
 e) the compound designated AG-1343 (Agouron);
 f) the compound designated KNI-272 (Nippon Mining);
 g) the compound designated U-96988 (Upjohn); and/or
 h) the compound designated BILA-2011 BS (=palinavir; Boehringer-Ingelheim),
 or in each case a salt thereof provided that salt-forming groups are
 present.
 The compounds of formula I can also be used in the prevention, control and
 treatment of retrovirus infections, especially HIV, such as HIV-1 or
 HIV-2, in cell cultures, especially cell cultures of lymphocyte cell
 lines, from warm-blooded animals, which is advantageous especially in the
 case of very valuable cell cultures that produce, for example, specific
 antibodies, vaccines or messenger substances, such as interleukins and the
 like, and are therefore of great commercial value.
 Finally, the compounds of formula I can be used as standards in
 experiments, for example as HPLC standards or as standards for the
 comparison of animal models in respect of different aspartate protease
 inhibitors, for example in respect of the blood levels achievable.
 In the groups of preferred compounds of formula I mentioned below, it is
 possible where expedient (for example in order to replace more general
 definitions by more specific definitions or, especially, by definitions
 described as being preferred) to use definitions of substituents from the
 general definitions given above; in each case preference is given to the
 definitions described above as being preferred or given as examples.
 Preference is given to compounds of formula I, especially of formula Ia,
 wherein
 R.sub.1 and R.sub.10 are each independently of the other lower
 alkoxycarbonyl;
 either R.sub.2, R.sub.3 and R.sub.4 are each independently of the other
 C.sub.1 -C.sub.4 alkyl and R.sub.7, R.sub.8 and R.sub.9 are each selected
 from hydrogen and C.sub.1 -C.sub.4 alkyl, but not more than one of the
 radicals may be hydrogen;
 or (preferably) R.sub.7, R.sub.8 and R.sub.9 are each independently of the
 other C.sub.1 -C.sub.4 alkyl and R.sub.2, R.sub.3 and R.sub.4 are each
 selected from hydrogen and C.sub.1 -C.sub.4 alkyl, but not more than one
 of the radicals may be hydrogen;
 R.sub.5 is phenyl or cyclohexyl; and
 R.sub.6 is phenyl or cyanophenyl;
 or salts thereof.
 Greater preference is given to compounds of formula I, especially of
 formula Ia, wherein
 R.sub.1 and R.sub.10 are each independently of the other tert-butoxy- or
 especially ethoxy- or more especially methoxy-carbonyl;
 either R.sub.2, R.sub.3 and R.sub.4 are each independently of the other
 methyl and R.sub.7, R.sub.8 and R.sub.9 are each selected from hydrogen
 and methyl, but not more than one of the radicals may be hydrogen;
 or (preferably) R.sub.7, R.sub.8 and R.sub.9 are each independently of the
 other methyl and R.sub.2, R.sub.3 and R.sub.4 are each selected from
 hydrogen and methyl, but not more than one of the radicals may be
 hydrogen;
 R.sub.5 is phenyl; and
 R.sub.6 is phenyl or 2-cyanophenyl;
 or salts thereof.
 Greatest preference is given to the compounds of formula I mentioned in the
 Examples, or pharmaceutically acceptable salts thereof provided that at
 least one salt-forming group is present.
 The compound of formula I having the name
 1-(4-biphenylyl)-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)-amino-4(S)-hydrox
 y-5(S)-N-(N-methoxycarbonyl-(L)-valyl)-amino-6-phenyl-2-azahexane
 ##STR4##
 or a pharmaceutically acceptable salt thereof, is especially preferred.
 Special preference is given also to the compound of formula I having the
 name
 1-(4(2-cyanophenyl)phenyl)-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)-amino-4
 (S)-hydroxy-5(S)-N-(N-methoxycarbonyl-(L)-valyl)-amino-6-phenyl-2-azahexane
 , or a pharmaceutically acceptable salt thereof.
 Very special preference is given also to the compound of formula I having
 the name
 1-(4-biphenyl)-4(S)-hydroxy-5(S)-2,5-bis[N-(N-methoxycarbonyl-(L)-tert-leu
 cyl)-amino]-6-phenyl-2-azahexane, or a pharmaceutically acceptable salt
 thereof.
 The compounds of formula I and salts of those compounds having at least one
 salt-forming group are prepared according to processes known per se, for
 example as follows:
 a) a hydrazine derivative of formula
 ##STR5##
 wherein the radicals R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are as
 defined for compounds of formula I, is added to an epoxide of formula
 ##STR6##
 wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as
 defined for compounds of formula I, free functional groups with the
 exception of those participating in the reaction being, if necessary, in
 protected form, and any protecting groups are removed, or
 b) an amino compound of formula
 ##STR7##
 wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
 R.sub.6 are as defined for compounds of formula I, is condensed with an
 acid of formula
 ##STR8##
 or with a reactive acid derivative thereof, wherein the radicals R.sub.7,
 R.sub.8, R.sub.9 and R.sub.10 are as defined for compounds of formula I,
 free functional groups with the exception of those participating in the
 reaction being, if necessary, in protected form, and any protecting groups
 are removed, or
 c) an amino compound of formula
 ##STR9##
 wherein the radicals R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and
 R.sub.10 are as defined for compounds of formula I, is condensed with an
 acid of formula
 ##STR10##
 or with a reactive acid derivative thereof, wherein R.sub.1, R.sub.2,
 R.sub.3 and R.sub.4 are as defined for compounds of formula I, free
 functional groups with the exception of those participating in the
 reaction being, if necessary, in protected form, and any protecting groups
 are removed, or
 d) for the preparation of compounds of formula I wherein the substituent
 pairs R.sub.9 and R.sub.10, R.sub.2 and R.sub.7, R.sub.3 and R.sub.8 and
 R.sub.4 and R.sub.9 each represent two identical radicals, as defined for
 compounds of formula I, but none of the radicals R.sub.2, R.sub.3,
 R.sub.4, R.sub.7, R.sub.8 and R.sub.9 is hydrogen, and R.sub.5 and R.sub.6
 are as defined for compounds of formula I, a diamino compound of formula
 ##STR11##
 wherein the radicals are as defined immediately above, is condensed with an
 acid of formula
 ##STR12##
 or with a reactive acid derivative thereof, wherein R.sub.1 ', R.sub.2 ',
 R.sub.3 ' and R.sub.4 ' are as defined for R.sub.1 and R.sub.10, R.sub.2
 and R.sub.7, R.sub.3 and R.sub.8, and R.sub.4 and R.sub.9 in formula I,
 the pairs R.sub.1 and R.sub.10 , R.sub.2 and R.sub.7, R.sub.3 and R.sub.8
 and R.sub.4 and R.sub.9 each representing two identical radicals and none
 of the radicals R.sub.2, R.sub.3, R.sub.4, R.sub.7, R.sub.8 and R.sub.9
 being hydrogen, and free functional groups with the exception of those
 participating in the reaction being, if necessary, in protected form, and
 any protecting groups are removed, or
 e) an imino compound of formula I'
 ##STR13##
 wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7,
 R.sub.8, R.sub.9 and R.sub.10 are as defined for compounds of formula I,
 is reacted with a compound of formula X
 ##STR14##
 wherein X is a leaving group and R.sub.6 is as defined for compounds of
 formula I, free functional groups with the exception of those
 participating in the reaction being, if necessary, in protected form, and
 any protecting groups are removed, or
 f) an imino compound of formula I'
 ##STR15##
 wherein the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.7,
 R.sub.8, R.sub.9 and R.sub.10 are as defined for compounds of formula I,
 is reacted, with reductive alkylation, with an aldehyde of formula X*
 ##STR16##
 wherein R.sub.6 is as defined for compounds of formula I, or a reactive
 derivative thereof, free functional groups with the exception of those
 participating in the reaction being, if necessary, in protected form, and
 any protecting groups are removed,
 and, if desired, a compound of formula I having at least one salt-forming
 group obtainable in accordance with any one of processes a) to f) above is
 converted into a salt or an obtainable salt is converted into the free
 compound or into a different salt and/or isomeric mixtures which may be
 obtainable are separated and/or a compound of formula I according to the
 invention is converted into a different compound of formula I according to
 the invention.
 The above processes are described in more detail below with reference to
 preferred embodiments.
 In the following description of the individual processes and the
 preparation of the starting materials, unless otherwise indicated the
 radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
 R.sub.8, R.sub.9 and R.sub.10 are as defined for compounds of formula I.
 Process a) (Addition of an amine to an epoxide):
 In the hydrazine derivatives of formula III, the amino group participating
 in the reaction preferably has a free hydrogen atom; it may, however,
 itself have been derivatised in order to increase the reactivity of the
 hydrazine derivative.
 The epoxide of formula IV enables the terminal addition of the hydrazine
 derivative to proceed in the preferred manner.
 In starting materials, functional groups the reaction of which is to be
 avoided, especially carboxy, amino and hydroxy groups, can be protected by
 suitable protecting groups (conventional protecting groups) which are
 customarily used in the synthesis of peptide compounds, and also in the
 synthesis of cephalosporins and penicillins as well as nucleic acid
 derivatives and sugars. Those protecting groups may already be present in
 the precursors and are intended to protect the functional groups in
 question against undesired secondary reactions, such as acylation,
 etherification, esterification, oxidation, solvolysis and the like. In
 certain cases the protecting groups can additionally cause reactions to
 proceed selectively, for example stereoselectively. It is characteristic
 of protecting groups that they can be removed easily, i.e. without
 undesired secondary reactions taking place, for example by solvolysis,
 reduction, photolysis, and also enzymatically, for example also under
 physiological conditions. Radicals analogous to protecting groups may also
 be present in the end products, however. Compounds of formula I having
 protected functional groups may have greater metabolic stability or
 pharmacodynamic properties that are better in some other way than the
 corresponding compounds having free functional groups. Hereinabove and
 hereinbelow, protecting groups are referred to in their true sense when
 the radicals in question are not present in the end products.
 The protection of functional groups by such protecting groups, the
 protecting groups themselves and the reactions for their removal are
 described, for example, in standard works such as J. F. W. McOmie,
 "Protective Groups in Organic Chemistry", Plenum Press, London and New
 York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis",
 Wiley, New York 1981, in "The Peptides", Volume 3 (E. Gross and J.
 Meienhofer, eds.), Academic Press, London and New York 1981, in "Methoden
 der organischen Chemie" ("Methods of Organic Chemistry"), Houben-Weyl, 4th
 edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.
 Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" ("Amino acids,
 peptides, proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basle
 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und
 Derivate" ("The Chemistry of Carbohydrates: monosaccharides and
 derivatives"), Georg Thieme Verlag, Stuttgart 1974.
 A carboxy group is protected, for example, in the form of an ester group
 which can be cleaved selectively under mild conditions. A carboxy group
 protected in esterified form is esterified especially by a lower alkyl
 group that is preferably branched in the 1-position of the lower alkyl
 group or substituted in the 1- or 2-position of the lower alkyl group by
 suitable substituents.
 A protected carboxy group esterified by a lower alkyl group is, for
 example, methoxycarbonyl or ethoxycarbonyl.
 A protected carboxy group esterified by a lower alkyl group that is
 branched in the 1-position of the lower alkyl group is, for example,
 tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl.
 A protected carboxy group esterified by a lower alkyl group that is
 substituted in the 1- or 2-position of the lower alkyl group by suitable
 substituents is, for example, arylmethoxycarbonyl having one or two aryl
 radicals, wherein aryl is phenyl that is unsubstituted or mono-, di- or
 tri-substituted, for example, by lower alkyl, for example tert-lower
 alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxy,
 halogen, for example chlorine, and/or by nitro, for example
 benzyloxycarbonyl, benzyloxycarbonyl substituted by the mentioned
 substituents, for example 4-nitrobenzyloxycarbonyl or
 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or
 diphenylmethoxycarbonyl substituted by the mentioned substituents, for
 example di(4-methoxyphenyl)methoxycarbonyl, and also carboxy esterified by
 a lower alkyl group, the lower alkyl group being substituted in the 1- or
 2-position by suitable substituents, such as 1-lower alkoxy-lower
 alkoxycarbonyl, for example methoxymethoxycarbonyl,
 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthio-lower
 alkoxycarbonyl, for example 1-methylthiomethoxycarbonyl or
 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is
 benzoyl that is unsubstituted or substituted, for example, by halogen,
 such as bromine, for example phenacyloxycarbonyl, 2-halo-lower
 alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl,
 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, as well as
 2-(tri-substituted silyl)-lower alkoxycarbonyl wherein the substituents
 are each independently of the others an aliphatic, araliphatic,
 cycloaliphatic or aromatic hydrocarbon radical that is unsubstituted or
 substituted, for example, by lower alkyl, lower alkoxy, aryl, halogen
 and/or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkyl
 or phenyl each of which is unsubstituted or substituted as above, for
 example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-tri-lower
 alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or
 2-(di-n-butyl-methyl-silyl)ethoxycarbonyl, or
 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.
 A carboxy group may also be protected in the form of an organic
 silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example,
 a tri-lower alkylsilyloxycarbonyl group, for example
 trimethylsilyloxycarbonyl.
 A protected carboxy group is preferably tert-lower alkoxycarbonyl, for
 example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.
 A protected amino group may be protected by an amino-protecting group, for
 example in the form of an acylamino, arylmethylamino, etherified
 mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or in the
 form of an azido group.
 In a corresponding acylamino group, acyl is, for example, the acyl radical
 of an organic carboxylic acid having, for example, up to 18 carbon atoms,
 especially an unsubstituted or substituted, for example halo- or
 aryl-substituted, lower alkanecarboxylic acid or an unsubstituted or
 substituted, for example halo-, lower alkoxy- or nitro-substituted,
 benzoic acid, or, preferably, of a carbonic acid semiester. Such acyl
 groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl
 or pivaloyl, halo-lower alkanoyl, for example 2-haloacetyl, such as
 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl,
 unsubstituted or substituted, for example halo-, lower alkoxy or
 nitro-substituted, benzoyl, such as benzoyl, 4-chlorobenzoyl,
 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably lower
 alkoxycarbonyl that is branched in the 1-position of the lower alkyl
 radical or suitably substituted in the 1- or 2-position, for example
 tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl,
 arylmethoxycarbonyl having one, two or three aryl radicals which are
 phenyl that is unsubstituted or mono- or poly-substituted, for example, by
 lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower
 alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by
 nitro, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
 diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or
 di(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl
 group is preferably benzoyl that is unsubstituted or substituted, for
 example, by halogen, such as bromine, for example phenacyloxycarbonyl,
 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl,
 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(tri-substituted
 silyl)-lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower
 alkoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or
 2-(di-n-butylmethyl-silyl)-ethoxycarbonyl, or triarylsilyl-lower
 alkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.
 In an arylmethylamino group, for example a mono-, di- or especially
 tri-arylmethylamino group, the aryl radicals are especially unsubstituted
 or substituted phenyl radicals. Such groups are, for example, benzyl-,
 diphenylmethyl- or especially trityl-amino.
 In an etherified mercaptoamino group the mercapto group is especially in
 the form of substituted arylthio or aryl-lower alkylthio wherein aryl is,
 for example, phenyl that is unsubstituted or substituted, for example, by
 lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy,
 halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio.
 In a 2-acyl-lower alk-1-enyl radical that can be used as an
 amino-protecting group, acyl is, for example, the corresponding radical of
 a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or
 substituted, for example, by lower alkyl, such as methyl or tert-butyl,
 lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro,
 or especially of a carbonic acid semiester, such as a carbonic acid lower
 alkyl semiester. Corresponding protecting groups are especially 1-lower
 alkanoyl-lower alk-1-en-2-yl, for example 1-lower alkanoyl-prop-1-en-2-yl,
 such as 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-lower
 alk-1-en-2-yl, for example lower alkoxycarbonyl-prop-1-en-2-yl, such as
 1-ethoxycarbonyl-prop-1-en-2-yl.
 A silylamino group is, for example, a tri-lower alkylsilylamino group, for
 example trimethylsilylamino or tert-butyl-dimethylsilylamino. The silicon
 atom of the silylamino group can also be substituted by only two lower
 alkyl groups, for example methyl groups, and by the amino group or carboxy
 group of a second molecule of formula I. Compounds having such protecting
 groups can be prepared, for example, using the corresponding
 chlorosilanes, such as dimethylchlorosilane, as silylating agents.
 An amino group can also be protected by conversion into the protonated
 form; suitable corresponding anions are especially those of strong
 inorganic acids, such as sulfuric acid, phosphoric acid or hydrohalic
 acids, for example the chlorine or bromine anion, or of 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 and lower alkoxycarbonyl-lower alk-1-en-2-yl.
 A hydroxy group can be protected, for example, by an acyl group, for
 example lower alkanoyl that is substituted by halogen, such as chlorine,
 such as 2,2-dichloroacetyl, or especially by an acyl radical of a carbonic
 acid semiester mentioned for protected amino groups. A preferred
 hydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl,
 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A hydroxy
 group can also be protected by tri-lower alkylsilyl, for example
 trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, a readily
 removable etherifying group, for example an alkyl group, such as
 tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic or
 cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic,
 hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower
 alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl,
 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or
 2-oxa- or 2-thiacycloalkyl having from 5 to 7 ring atoms, such as
 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia
 analogue, and also by 1-phenyl-lower alkyl, such as benzyl, diphenylmethyl
 or trityl, wherein the phenyl radicals can be substituted, for example, by
 halogen, for example chlorine, lower alkoxy, for example methoxy, and/or
 by nitro.
 A hydroxy group and an amino group that are adjacent to one another in a
 molecule can be protected, for example, by bivalent protecting groups,
 such as a methylene group that is preferably substituted, for example by
 one or two lower alkyl radicals or by oxo, for example unsubstituted or
 substituted alkylidene, for example lower alkylidene, such as
 isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group
 or benzylidene.
 In the context of this disclosure, a protecting group, for example a
 carboxy-protecting group, is to be understood as being expressly also a
 polymeric carrier that is bonded in a readily removable manner to the
 functional group, for example the carboxy group, to be protected, for
 example a carrier suitable for the Merrifield synthesis. Such a suitable
 polymeric carrier is, for example, a polystyrene resin weakly cross-linked
 by copolymerisation with divinylbenzene and carrying bridge members
 suitable for reversible bonding.
 The addition of the compounds of formula III to the epoxides of formula IV
 is carried out preferably under the reaction conditions customarily used
 for the addition of nucleophiles to epoxides.
 The addition is carried out especially in aqueous solution and/or in the
 presence of polar solvents, such as alcohols, for example methanol,
 ethanol, isopropanol or ethylene glycol, ethers, such as dioxane, amides,
 such as dimethylformamide, or phenols, such as phenol, and also under
 anhydrous conditions, in nonpolar solvents, such as benzene or toluene, or
 in benzene/water emulsions, optionally in the presence of acidic or basic
 catalysts, for example alkali hydroxide solutions, such as sodium
 hydroxide solution, or in the presence of solid phase catalysts doped with
 the hydrazine, such as aluminium oxide, in ethers, for example diethyl
 ether, generally at temperatures of from approximately 0.degree. C. to the
 boiling temperature of the reaction mixture in question, preferably from
 20.degree. C. to reflux temperature, optionally under elevated pressure,
 for example in a bomb tube, in which case it is also possible to exceed
 the boiling temperature, and/or under an inert gas, such as nitrogen or
 argon, it being possible for each of the two compounds of formulae III and
 IV to be present in excess, for example in a molar ratio of from 1:1 to
 1:100, preferably in a molar ratio of from 1:1 to 1:10, more especially in
 a ratio of from 1:1 to 1:3.
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups".
 Process b) (Formation of an amide bond)
 In starting materials of formulae V and VI, functional groups, with the
 exception of groups that are to participate in the reaction or that do not
 react under the reaction conditions, are protected independently of one
 another by one of the protecting groups mentioned under Process a).
 The compounds of formula VI either contain a free carboxy group or are in
 the form of a reactive acid derivative thereof, for example in the form of
 a derived activated ester or reactive anhydride, or in the form of a
 reactive cyclic amide. The reactive acid derivatives may also be formed in
 situ.
 Activated esters of compounds of formula VI having a terminal carboxy group
 are especially esters unsaturated at the carbon atom linking the radical
 to be esterified, for example esters of the vinyl ester type, such as
 vinyl esters (obtainable, for example, by transesterification of a
 corresponding ester with vinyl acetate; activated vinyl ester method),
 carbamoyl esters (obtainable, for example, by treatment of the
 corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward
 method), or 1-lower alkoxyvinyl esters (obtainable, for example, by
 treatment of the corresponding acid with a lower alkoxyacetylene;
 ethoxyacetylene method), or esters of the amidino type, such as
 N,N'-disubstituted amidino esters (obtainable, for example, by treatment
 of the corresponding acid with a suitable N,N'-di-substituted
 carbodiimide, for example N,N'-dicyclohexylcarbodiimide or especially
 N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; carbodiimide method), or
 N,N-disubstituted amidino esters (obtainable, for example, by treatment of
 the corresponding acid with an N,N-disubstituted cyanamide; cyanamide
 method), suitable aryl esters, especially phenyl esters suitably
 substituted by electron-attracting substituents (obtainable, for example,
 by treatment of the corresponding acid with a suitably substituted phenol,
 for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol,
 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a
 condensation agent, such as N,N'-dicyclohexylcarbodiimide; activated aryl
 esters method), cyanomethyl esters (obtainable, for example, by treatment
 of the corresponding acid with chloroacetonitrile in the presence of a
 base; cyanomethyl esters method), thio esters, especially unsubstituted or
 substituted, for example nitro-substituted, phenylthio esters (obtainable,
 for example, by treatment of the corresponding acid with unsubstituted or
 substituted, for example nitro-substituted, thiophenols, inter alia by the
 anhydride or carbodiimide method; activated thiol esters method), or
 especially amino or amido esters (obtainable, for example, by treatment of
 the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound,
 for example N-hydroxysuccinimide, N-hydroxypiperidine,
 N-hydroxyphthalimide, N-hydroxy-5-norbornene 2,3-dicarboxylic acid imide,
 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benzo triazin-4-one,
 for example by the anhydride or carbodiimide method; activated N-hydroxy
 esters method). Internal esters, for example .gamma.-lactones, can also be
 used.
 Anhydrides of acids may be symmetric or preferably mixed anhydrides of
 those acids, for example anhydrides with inorganic acids, such as acid
 halides, especially acid chlorides (obtainable, for example, by treatment
 of the corresponding acid with thionyl chloride, phosphorus pentachloride,
 phosgene or oxalyl chloride; acid chloride method), azides (obtainable,
 for example, from a corresponding acid ester via the corresponding
 hydrazide and treatment thereof with nitrous acid; azide method),
 anhydrides with carbonic acid semiesters, for example carbonic acid lower
 alkyl semiesters (especially chloroformic acid methyl esters) (obtainable,
 for example, by treatment of the corresponding acid with chloroformic acid
 lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lower
 alkoxy-1,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides
 method), or anhydrides with dihalogenated, especially dichlorinated,
 phosphoric acid (obtainable, for example, by treatment of the
 corresponding acid with phosphorus oxychloride; phosphorus oxychloride
 method), anhydrides with other phosphoric acid derivatives (for example
 those obtainable with phenyl-N-phenylphosphoramidochloridate or by
 reaction of alkylphosphoric acid amides in the presence of sulfonic acid
 anhydrides and/or racemisation-reducing additives, such as
 N-hydroxybenzotriazole, or in the presence of cyanophosphonic acid diethyl
 ester) or with phosphorous acid derivatives, or anhydrides with organic
 acids, such as mixed anhydrides with organic carboxylic acids (obtainable,
 for example, by treatment of the corresponding acid with an unsubstituted
 or substituted lower alkane- or phenyl-lower alkane-carboxylic acid
 halide, for example phenylacetic acid chloride, pivalic acid chloride or
 trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or
 with organic sulfonic acids (obtainable, for example, by treatment of a
 salt, such as an alkali metal salt, of the corresponding acid with a
 suitable organic sulfonic acid halide, such as a lower alkane- or aryl-,
 for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic
 acid anhydrides method) and symmetric anhydrides (obtainable, for example,
 by condensation of the corresponding acid in the presence of a
 carbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).
 Suitable cyclic amides are especially amides with five-membered diazacycles
 of aromatic character, such as amides with imidazoles, for example
 imidazole (obtainable, for example, by treatment of the corresponding acid
 with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, for example
 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by
 treatment with acetylacetone; pyrazolide method).
 As mentioned, derivatives of carboxylic acids used as acylating agents may
 also be formed in situ. For example, N,N'-disubstituted amidino esters may
 be formed in situ by reacting a mixture of the starting material of
 formula V and the acid used as acylating agent in the presence of a
 suitable N,N'-disubstituted carbodiimide, for example
 N,N'-cyclohexylcarbodiimide or especially
 N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide. In addition, amino or
 amido esters of the acids used as acylating agents may be formed in the
 presence of the starting material of formula V to be acylated, by reacting
 a mixture of the corresponding acid and amino starting materials in the
 presence of an N,N'-disubstituted carbodiimide, for example
 N,N'-dicyclohexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide,
 for example N-hydroxysuccinimide, where appropriate in the presence of a
 suitable base, for example 4-dimethylamino-pyridine. Furthermore,
 activation in situ can be achieved by reaction with
 N,N,N',N'-tetraalkyluronium compounds, such as
 O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate,
 O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium
 tetrafluoroborate or
 O-(3,4-dihydro-4-oxo-1,2,3-benzotriazolin-3-yl)-N,N,N',N'-tetramethyluroni
 um tetrafluoroborate. Finally, phosphoric acid anhydrides of the carboxylic
 acids of formula VI can be prepared in situ by reacting an alkylphosphoric
 acid amide, such as hexamethylphosphoric acid triamide, in the presence of
 a sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with
 a salt, such as a tetrafluoroborate, for example sodium tetrafluoroborate,
 or with another derivative of hexamethylphosphoric acid triamide, such as
 benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluoride,
 preferably in the presence of a racemisation-reducing additive, such as
 N-hydroxybenzotriazole.
 The amino group of compounds of formula V that participates in the reaction
 preferably carries at least one reactive hydrogen atom, especially when
 the carboxy, sulfonyl or phosphoryl group reacting therewith is present in
 reactive form; it may, however, itself have been derivatised, for example
 by reaction with a phosphite, such as diethylchlorophosphite,
 1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene
 chlorophosphite or tetraethylpyrophosphite. A derivative of such a
 compound having an amino group is, for example, also a carbamic acid
 halide or an isocyanate, the amino group that participates in the reaction
 being substituted by halocarbonyl, for example chlorocarbonyl, or modified
 in the form of an isocyanate group, respectively.
 Condensation to form an amide bond can be carried out in a manner known per
 se, for example as described in standard works, such as Houben-Weyl,
 "Methoden der organischen Chemie", 4th edition, Volume 15/II (1974),
 Volume IX (1955), Volume E11 (1985), Georg Thieme Verlag, Stuttgart, "The
 Peptides" (E. Gross and J. Meienhofer, eds.), Volumes 1 and 2, Academic
 Press, London and New York, 1979/1980, or M. Bodansky, "Principles of
 Peptide Synthesis", Springer-Verlag, Berlin 1984.
 The condensation of a free carboxylic acid with the appropriate amine can
 be carried out preferably in the presence of one of the customary
 condensation agents, or using carboxylic acid anhydrides or carboxylic
 acid halides, such as chlorides, or activated carboxylic acid esters, such
 as p-nitrophenyl esters. Customary condensation agents are, for example,
 carbodiimides, for example diethyl-, dipropyl-, or
 dicyclohexyl-carbodiimide or especially
 N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, also suitable carbonyl
 compounds, for example carbonylimidazole, 1,2-oxazolium compounds, for
 example 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and
 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino
 compound, for example 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
 especially O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium
 tetrafluoroborate, also activated phosphoric acid derivatives, for example
 diphenylphosphorylazide, diethylphosphorylcyanide,
 phenyl-N-phenylphosphoroamidochloridate,
 bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride or
 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate.
 If desired, an organic base may be added, preferably a tertiary amine, for
 example a tri-lower alkylamine, especially ethyldiisopropylamine or more
 especially triethylamine, and/or a heterocyclic base, for example
 4-dimethylaminopyridine or preferably N-methylmorpholine or pyridine.
 The condensation of activated esters, reactive anhydrides or reactive
 cyclic amides with the corresponding amines is customarily carried out in
 the presence of an organic base, for example simple tri-lower alkylamines,
 for example triethylamine or tributylamine, or one of the above-mentioned
 organic bases. If desired, a condensation agent is additionally used, for
 example as described for free carboxylic acids.
 The condensation of acid anhydrides with amines can be effected, for
 example, in the presence of inorganic carbonates, for example ammonium or
 alkali metal carbonates or hydrogen carbonates, such as sodium or
 potassium carbonate or hydrogen carbonate (if desired together with a
 sulfate).
 Carboxylic acid chlorides, for example the chlorocarbonic acid derivatives
 derived from the acid of formula VI, are condensed with the corresponding
 amines preferably in the presence of an organic amine, for example the
 above-mentioned tri-lower alkylamines or heterocyclic bases, where
 appropriate in the presence of a hydrogen sulfate or a hydroxide,
 preferably an alkali metal hydroxide, such as sodium hydroxide.
 The condensation is preferably carried out in an inert, aprotic, preferably
 anhydrous, solvent or solvent mixture, for example in a carboxylic acid
 amide, for example formamide or dimethylformamide, a halogenated
 hydrocarbon, for example methylene chloride, carbon tetrachloride or
 chlorobenzene, a ketone, for example acetone, a cyclic ether, for example
 tetrahydrofuran or dioxane, an ester, for example ethyl acetate, or a
 nitrile, for example acetonitrile, or in a mixture thereof, as appropriate
 at reduced or elevated temperature, for example in a temperature range of
 from approximately -40.degree. to approximately +100.degree. C, preferably
 from approximately -10.degree. to approximately +70.degree. C., and when
 arylsulfonyl esters are used also at approximately from +100.degree. to
 +200.degree. C., and if necessary under an inert gas atmosphere, for
 example a nitrogen or argon atmosphere.
 Aqueous, for example alcoholic, solvents, for example ethanol, or aromatic
 solvents, for example benzene or toluene, may also be used. When alkali
 metal hydroxides are present as bases, acetone may also be added where
 appropriate.
 The condensation can also be carried out in accordance with the technique
 known as solid-phase synthesis which originates from R. Merrifield and is
 described, for example, in Angew. Chem. 97, 801-812 (1985),
 Naturwissenschaften 71, 252-258 (1984) or in R. A Houghten, Proc. Natl.
 Acad. Sci. USA 82, 5131-5135 (1985).
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups."
 Process c) (Formation of an amide bond)
 In starting materials of formulae VII and VIII, functional groups, with the
 exception of groups that are to participate in the reaction or that do not
 react under the reaction conditions, are protected independently of one
 another by one of the protecting groups mentioned under Process a).
 The process is entirely analogous to that given under Process b) but
 compounds of formula VII are used instead of those of formula V and
 compounds of formula VIII are used instead of those of formula VI.
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups".
 Process d) (Formation of an amide bond)
 In starting materials of formula IX and in the acid of formula VIIIa
 suitable for the introduction of the identical acyl radicals, or in
 reactive derivatives thereof, functional groups, with the exception of
 groups that are to participate in the reaction or that do not react under
 the reaction conditions, are protected independently of one another by one
 of the protecting groups mentioned under Process a).
 Preferred starting compounds of formula IX, which may be protected by
 protecting groups, are those described below in the section relating to
 starting compounds.
 The process is entirely analogous to that given under Process b) but
 compounds of formula IX are used instead of those of formula V and
 compounds of formula VIIIa are used instead of those of formula VI.
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups".
 Process e) (Alkylation of a secondary nitrogen atom)
 In starting materials of formula I' and formula X or in reactive
 derivatives thereof, functional groups, with the exception of groups that
 are to participate in the reaction or that do not react under the reaction
 conditions, are protected independently of one another by one of the
 protecting groups mentioned under Process a).
 A leaving group X is especially a nucleofugal leaving group selected from
 hydroxy esterified by a strong inorganic or organic acid, such as hydroxy
 esterified by a mineral acid, for example a hydrohalic acid, such as
 hydrochloric, hydrobromic or hydriodic acid, hydroxy esterified by a
 strong organic sulfonic acid, such as a lower alkanesulfonic acid that is
 unsubstituted or substituted, for example, by halogen, such as fluorine,
 or by an aromatic sulfonic acid, for example benzenesulfonic acid that is
 unsubstituted or substituted by lower alkyl, such as methyl, halogen, such
 as bromine, and/or by nitro, for example a methanesulfonic,
 p-bromotoluenesulfonic or p-toluenesulfonic acid, and hydroxy esterified
 by hydrazoic acid.
 The substitution can take place under the conditions of a first or second
 order nucleophilic substitution.
 For example, one of the compounds of formula X wherein X is a leaving group
 having high polarisability of the electron shell, for example iodine, can
 be used in a polar aprotic solvent, for example acetone, acetonitrile,
 nitromethane, dimethyl sulfoxide or dimethylformamide. The reaction can
 also be carried out in water, optionally in admixture with an organic
 solvent, for example ethanol, tetrahydrofuran or acetone, as solubiliser.
 The substitution reaction is carried out, as appropriate, at reduced or
 elevated temperature, for example in a temperature range of from
 approximately -40.degree. to approximately 100.degree. C., preferably from
 approximately -10.degree. to approximately 50.degree. C., and optionally
 under an inert gas, for example under a nitrogen or argon atmosphere.
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups".
 Process f) (Reductive alkylation of a secondary amino group)
 In starting materials of formula I' and formula X* or in reactive
 derivatives thereof, functional groups, with the exception of groups that
 are to participate in the reaction or that do not react under the reaction
 conditions, are protected independently of one another by one of the
 protecting groups mentioned under Process a).
 Reactive derivatives of the compounds of formula I are, for example,
 corresponding bisulfite adducts or especially semiacetals or ketals of
 compounds of formula X* with alcohols, for example lower alkanols; or
 thioacetals of compounds of formula X* with mercaptans, for example lower
 alkanesulfides. The free aldehydes of formula X* are preferred.
 The reductive alkylation is preferably carried out with hydrogenation in
 the presence of a catalyst, especially a noble metal catalyst, such as
 platinum or especially palladium, which is preferably bonded to a carrier
 material, such as carbon, or a heavy metal catalyst, such as Raney nickel,
 at normal pressure or at pressures of from 0.1 to 10 MegaPascal (MPa), or
 with reduction by means of complex hydrides, such as borohydrides,
 especially alkali metal cyanoborohydrides, for example sodium
 cyanoborohydride, in the presence of a suitable acid, preferably
 relatively weak acids, such as lower alkanecarboxylic acids or especially
 a sulfonic acid, such as p-toluenesulfonic acid; in customary solvents,
 for example alcohols, such as methanol or ethanol, in the presence or
 absence of water.
 The freeing of protected groups may be effected in accordance with the
 methods described under the heading "Removal of protecting groups".
 Removal of protecting groups
 The removal of protecting groups that are not constituents of the desired
 end product of formula I, for example carboxy-, amino- and
 hydroxy-protecting groups, is effected in a manner known per se, for
 example by means of solvolysis, especially hydrolysis, alcoholysis or
 acidolysis, or by means of reduction, especially hydrogenolysis or
 chemical reduction, and also photolysis, stepwise or simultaneously as
 appropriate, it being possible also to use enzymatic methods. The removal
 of the protecting groups is described, for example, in the standard works
 mentioned hereinabove in the section relating to protecting groups.
 For example, protected carboxy, for example tert-lower alkoxycarbonyl,
 lower alkoxycarbonyl substituted in the 2-position by a trisubstituted
 silyl group or in the 1-position by lower alkoxy or by lower alkylthio, or
 unsubstituted or substituted diphenylmethoxycarbonyl can be converted into
 free carboxy by treatment with a suitable acid, such as formic acid,
 hydrogen chloride or trifluoroacetic acid, where appropriate with the
 addition of a nucleophilic compound, such as phenol or anisole. Carboxy
 can be freed from lower alkoxycarbonyl also by bases, such as hydroxides,
 for example alkali metal hydroxides, such as NaOH or KOH. Unsubstituted or
 substituted benzyloxycarbonyl can be cleaved, for example, by means of
 hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal
 hydrogenation catalyst, such as a palladium catalyst. In addition,
 suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl,
 can be converted into free carboxy also by reduction, for example by
 treatment with an alkali metal dithionite, such as sodium dithionite, or
 with a reducing metal, for example zinc, or a reducing metal salt, such as
 a chromium(II) salt, for example chromium(II) chloride, customarily in the
 presence of a hydrogen-yielding agent that, together with the metal, is
 capable of producing nascent hydrogen, such as an acid, especially a
 suitable carboxylic acid, such as an unsubstituted or substituted, for
 example hydroxy-substituted, lower alkanecarboxylic acid, 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, water preferably being added. By
 treatment with a reducing metal or metal salt, as described above,
 2-halo-lower alkoxycarbonyl (where appropriate after conversion of a
 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower
 alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into
 free carboxy. Aroylmethoxycarbonyl can be cleaved also by treatment with a
 nucleophilic, preferably salt-forming, reagent, such as sodium
 thiophenolate or sodium iodide. 2-(Tri-substituted silyl)-lower
 alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can
 also be converted into free carboxy by treatment with a salt of
 hydrofluoric acid that yields the fluoride anion, such as an alkali metal
 fluoride, for example sodium or potassium fluoride, where appropriate in
 the presence of a macrocyclic polyether ("crown ether"), or with a
 fluoride of an organic quaternary base, such as tetra-lower alkylammonium
 fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example
 tetraethylammonium fluoride or tetrabutylammonium fluoride, in the
 presence of an aprotic, polar solvent, such as dimethyl sulfoxide or
 N,N-dimethylacetamide. Carboxy protected in the form of organic
 silyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for example
 trimethylsilyloxycarbonyl, can be freed in customary manner by solvolysis,
 for example by treatment with water, an alcohol or an acid, or,
 furthermore, a fluoride, as described above. Esterified carboxy can also
 be freed enzymatically, for example by means of esterases or suitable
 peptidases, for example using trypsin.
 A protected amino group is freed in a manner known per se and, according to
 the nature of the protecting groups, in various ways, preferably by
 solvolysis or reduction. Lower alkoxycarbonylamino, such as
 tert-butoxycarbonylamino, can be cleaved in the presence of acids, for
 example mineral acids, for example a hydrogen halide, such as hydrogen
 chloride or hydrogen bromide, or sulfuric or phosphoric acid, but
 preferably hydrogen chloride, or in the presence of strong organic acids,
 such as a trihaloacetic acid, for example trifluoroacetic acid, or formic
 acid, in polar solvents, such as water, or ethers, preferably cyclic
 ethers, such as dioxane; 2-halo-lower alkoxycarbonylamino (where
 appropriate after conversion of a 2-bromo-lower alkoxycarbonylamino group
 into a 2-iodo-lower alkoxycarbonylamino group), or, dissolved directly in
 a liquid organic carboxylic acid, such as formic acid,
 aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved,
 for example, by treatment with a suitable reducing agent, such as zinc in
 the presence of a suitable carboxylic acid, such as aqueous acetic acid.
 Aroylmethoxycarbonylamino can be cleaved also by treatment with a
 nucleophilic, preferably salt-forming, reagent, such as sodium
 thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an
 alkali metal dithionite, for example sodium dithionite. Unsubstituted or
 substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino
 or 2-(tri-substituted silyl)-lower alkoxycarbonylamino, such as
 2-tri-lower alkylsilyl-lower alkoxycarbonylamino, can be cleaved by
 treatment with a suitable acid, for example formic acid or trifluoroacetic
 acid; unsubstituted or substituted benzyloxycarbonylamino can be cleaved,
 for example, by means of hydrogenolysis, i.e. by treatment with hydrogen
 in the presence of a suitable hydrogenation catalyst, such as a platinum
 or palladium catalyst, unsubstituted or substituted triarylmethylamino or
 formylamino can be cleaved, for example, by treatment with an acid, such
 as a mineral acid, for example hydrochloric acid, or an organic acid, for
 example formic, acetic or trifluoroacetic acid, where appropriate in the
 presence of water, and an amino group protected in the form of silylamino
 can be freed, for example, by means of hydrolysis or alcoholysis. An amino
 group protected by 2-haloacetyl, for example 2-chloroacetyl, can be freed
 by treatment with thiourea in the presence of a base, or with a thiolate
 salt, such as an alkali metal thiolate of thiourea, and subsequent
 solvolysis, such as alcoholysis or hydrolysis, of the resulting
 substitution product, and amino is freed from trifluoroacetylamino, for
 example, by hydrogenolysis with bases, such as alkali metal hydroxides or
 carbonates, such as Na.sub.2 CO.sub.3 or K.sub.2 CO.sub.3, in polar
 solvents, for example alcohols, such as methanol, in the presence or
 absence of water, at temperatures of from 0.degree. to 100.degree. C.,
 especially at reflux temperature. An amino group protected by
 2-(tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower
 alkylsilyl-lower alkoxycarbonyl, can be converted into the free amino
 group also by treatment with a salt of hydrofluoric acid that yields
 fluoride anions, as indicated above in connection with the freeing of a
 correspondingly protected carboxy group. Likewise, silyl, such as
 trimethylsilyl, bonded directly to a hetero atom, such as nitrogen, can be
 removed using fluoride ions.
 Amino protected in the form of an azido group is converted into free amino,
 for example, by reduction, for example by catalytic hydrogenation with
 hydrogen in the presence of a hydrogenation catalyst, such as platinum
 oxide, palladium or Raney nickel, by reduction using mercapto compounds,
 such as dithiothreitol or mercaptoethanol, or by treatment with zinc in
 the presence of an acid, such as acetic acid. The catalytic hydrogenation
 is preferably carried out in an inert solvent, such as a halogenated
 hydrocarbon, for example methylene chloride, or in water or in a mixture
 of water and an organic solvent, such as an alcohol or dioxane, at
 approximately from 20.degree. C. to 25.degree. C., or with cooling or
 heating.
 A hydroxy group protected by a suitable acyl group, by a tri-lower
 alkylsilyl group or by unsubstituted or substituted 1-phenyl-lower alkyl
 is freed analogously to a correspondingly protected amino group. A hydroxy
 group protected by 2,2-dichloroacetyl is freed, for example, by basic
 hydrolysis, and a hydroxy group protected by tert-lower alkyl or by a
 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed
 by acidolysis, for example by treatment with a mineral acid or a strong
 carboxylic acid, for example trifluoroacetic acid. Adjacent hydroxy and
 amino groups that are protected together by a bivalent protecting group,
 preferably, for example, by a methylene group mono- or di-substituted by
 lower alkyl, such as by lower alkylidene, for example isopropylidene,
 cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed
 by acid solvolysis, especially in the presence of a mineral acid or a
 strong organic acid. A tri-lower alkylsilyl group is likewise removed by
 acidolysis, for example by a mineral acid, preferably hydrofluoric acid,
 or a strong carboxylic acid. 2-Halo-lower alkoxycarbonyl is removed using
 the above-mentioned reducing agents, for example a reducing metal, such as
 zinc, reducing metal salts, such as chromium(II) salts, or using sulfur
 compounds, for example sodium dithionite or preferably sodium sulfide and
 carbon disulfide.
 When several protected functional groups are present, if desired the
 protecting groups can be so selected that more than one such group can be
 removed simultaneously, for example by acidolysis, such as by treatment
 with trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst,
 such as a palladium-on-carbon catalyst. Conversely, the groups can also be
 so selected that they cannot all be removed simultaneously, but rather in
 a desired sequence, the corresponding intermediates being obtained.
 Additional Process Steps
 In the additional process steps, which are optional, functional groups of
 the starting compounds that are not intended to take part in the reaction
 may be unprotected or may be in protected form, for example they may be
 protected by one or more of the protecting groups mentioned above under
 Process a). The protecting groups may be retained in the end products or
 some or all of them may be removed in accordance with one of the methods
 mentioned under the heading "Removal of protecting groups".
 Salts of compounds of formula I having a salt-forming group can be prepared
 in a manner known per se. For example, acid addition salts of compounds of
 formula I are obtained, for example, by treatment with an acid or a
 suitable anion exchange reagent
 Salts can be converted into the free compounds in customary manner; for
 example by treatment with a suitable basic agent.
 Stereoisomeric mixtures, for example mixtures of diastereoisomers, can be
 separated into the corresponding isomers in a manner known per se by
 suitable separating procedures. For example, mixtures of diastereoisomers
 can be separated into the individual diastereoisomers by fractional
 crystallisation, chromatography, solvent partitioning and the like. Such
 separation can be carried out either at the stage of one of the starting
 materials or with the compounds of formula I themselves.
 In a compound of formula I wherein R.sub.5 is phenyl, that phenyl radical
 can be hydrogenated, for example by catalytic hydrogenation, especially in
 the presence of heavy metal oxides, such as rhodium/platinum mixed oxides,
 for example with the Nishimura catalyst, preferably in a polar solvent,
 such as an alcohol, for example methanol or ethanol, at temperatures of
 from 0.degree. to 80.degree. C., especially from 10.degree. to 40.degree.
 C., and at a preferred hydrogen pressure of from 1 to 10 atm, preferably
 at about normal pressure.
 General process conditions
 All the process steps given in this text can be carried out under reaction
 conditions known per se, but preferably under those specifically
 mentioned, in the absence or usually in the presence of solvents or
 diluents, preferably those solvents or diluents that are inert towards the
 reagents used and are solvents therefor, in the absence or presence of
 catalysts, condensation agents or neutralising agents, for example ion
 exchangers, such as cation exchangers, for example in the H.sup.+ form,
 depending upon the nature of the reaction and/or the reactants at reduced,
 normal or elevated temperature, for example in a temperature range of from
 approximately -100.degree. to approximately 190.degree. C., preferably
 from approximately -80.degree. to approximately 150.degree. C., for
 example from -80.degree. to -60.degree. C., at room temperature, at from
 -20.degree. to 40.degree. C. or at the boiling point of the solvent used,
 under atmospheric pressure or in a closed vessel, optionally under
 pressure, and/or in an inert atmosphere, for example under an argon or
 nitrogen atmosphere.
 In the case of all starting materials and intermediates, salts may be
 present when salt-forming groups are present. Salts may also be present
 during the reaction of such compounds, provided that the reaction will not
 be affected.
 In all reaction steps, any isomeric mixtures that are formed can be
 separated into the individual isomers, for example diastereoisomers or
 enantiomers, or into any desired mixtures of isomers, for example
 racemates or diastereoisomeric mixtures, for example analogously to the
 methods described under the heading "Additional process steps".
 In certain cases, for example in the case of hydrogenation, it is possible
 to carry out stereoselective reactions so that, for example, individual
 isomers may be obtained more easily.
 The solvents from which those suitable for a particular reaction can be
 selected include, for example, water, esters, such as lower alkyl lower
 alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers,
 for example diethyl ether, or cyclic ethers, for example tetrahydrofuran,
 liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such
 as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile,
 halogenated hydrocarbons, such as methylene chloride, acid amides, such as
 dimethylformamide, bases, such as heterocyclic nitrogen bases, for example
 pyridine, carboxylic acid anhydrides, such as lower alkanoic acid
 anhydrides, for example acetic anhydride, cyclic, linear or branched
 hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of
 those solvents, for example aqueous solutions, unless the description of
 the processes indicates otherwise. Such solvent mixtures can also be used
 in working-up, for example by chromatography or partition.
 The invention relates also to those forms of the process in which a
 compound obtainable as intermediate at any stage is used as starting
 material and the remaining steps are carried out or the process is
 interrupted at any stage or a starting material is formed under the
 reaction conditions or is used in the form of a reactive derivative or
 salt, or a compound obtainable in accordance with the process of the
 invention is produced under the process conditions and further processed
 in situ, it being preferable to use those starting materials which result
 in the compounds described above as being preferred, especially those
 described as being especially preferred, more especially preferred and/or
 very especially preferred.
 The preparation of compounds of formula I is preferably carried out
 analogously to the processes and process steps given in the Examples.
 The compounds of formula I, including their salts, may also be obtained in
 the form of hydrates, or their crystals may include, for example, the
 solvent used for crystallisation.
 Pharmaceutical compositions:
 The invention relates also to pharmaceutical compositions comprising
 compounds of formula I, and especially of formula Ia.
 The pharmacologically acceptable compounds of the present invention may be
 used, for example, in the preparation of pharmaceutical compositions that
 comprise an effective amount of the active ingredient together or in
 admixture with a significant amount of inorganic or organic, solid or
 liquid, pharmaceutically acceptable carriers.
 The invention relates also to a pharmaceutical composition suitable for
 administration to a warm-blooded animal, especially a human being, for the
 treatment or prevention of a disease that is responsive to inhibition of a
 retroviral protease, especially a retroviral aspartate protease, such as
 HIV-1 or HIV-II gag protease, for example a retroviral disease, such as
 AIDS or its preliminary stages, comprising a compound of formula I, or a
 pharmaceutically acceptable salt thereof, in an amount effective in the
 inhibition of the retroviral protease, together with at least one
 pharmaceutically acceptable carrier.
 The pharmaceutical compositions according to the invention are compositions
 for enteral, such as nasal, rectal or oral, or parenteral, such as
 intramuscular or intravenous, administration to warm-blooded animals
 (human beings and animals) that comprise an effective dose of the
 pharmacological active ingredient alone or together with a significant
 amount of a pharmaceutically acceptable carrier. The dose of the active
 ingredient depends on the species of warm-blooded animal, body weight, age
 and individual condition, individual pharmacokinetic data, the disease to
 be treated and the mode of administration.
 The invention relates also to a method of treating diseases caused by
 viruses, especially by retroviruses, especially AIDS or its preliminary
 stages, wherein a therapeutically effective amount of a compound of
 formula I according to the invention, or a pharmaceutically acceptable
 salt thereof, is administered especially to a warm-blooded animal, for
 example a human being, who on account of one of the mentioned diseases,
 especially AIDS or its preliminary stages, requires such treatment.
 The-dose to be administered to warm-blooded animals, for example human
 beings of approximately 70 kg body weight, is from approximately 3 mg to
 approximately 3 g, preferably from approximately 10 mg to approximately
 1.5 g, for example approximately from 50 mg to 1000 mg per person per day,
 divided preferably into 1 to 3 single doses which may, for example, be of
 the same size. Usually, children receive half of the adult dose.
 The pharmaceutical compositions comprise from approximately 1% to
 approximately 95%, preferably from approximately 20% to approximately 90%,
 active ingredient Pharmaceutical compositions according to the invention
 may be, for example, in unit dose form, such as in the form of ampoules,
 vials, suppositories, dragees, tablets or capsules.
 The pharmaceutical compositions of the present invention are prepared in a
 manner known per se, for example by means of conventional dissolving,
 lyophilising, mixing, granulating or confectioning processes.
 Solutions of the active ingredient, and also suspensions, and especially
 isotonic aqueous solutions or suspensions, are preferably used, it being
 possible, for example in the case of lyophilised compositions that
 comprise the active ingredient alone or together with a carrier, for
 example mannitol, for such solutions or suspensions to be made up prior to
 use. The pharmaceutical compositions may be sterilised and/or may comprise
 excipients, for example preservatives, stabilisers, wetting agents and/or
 emulsifiers, solubilisers, salts for regulating the osmotic pressure
 and/or buffers, and are prepared in a manner known per se, for example by
 means of conventional dissolving or lyophilising processes. The said
 solutions or suspensions may comprise viscosity-increasing substances,
 such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran,
 polyvinylpyrrolidone or gelatin.
 Suspensions in oil comprise as the oil component the vegetable, synthetic
 or semi-synthetic oils customary for injection purposes. There may be
 mentioned as such especially liquid fatty acid esters that contain as acid
 component a long-chained fatty acid having from 8 to 22, especially from
 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic
 acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid,
 arachidic acid, behenic acid, or corresponding unsaturated acids, for
 example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic
 acid, if desired with the addition of antioxidants, for-example vitamin E,
 .beta.-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcohol component
 of those fatty acid esters has a maximum of 6 carbon atoms and is a mono-
 or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for
 example methanol, ethanol, propanol, butanol or pentanol or the isomers
 thereof, but especially glycol and glycerol. The following examples of
 fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl
 myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene
 glycerol trioleate, Gattefosse, Paris), "Miglyol 812" (triglyceride of
 saturated fatty acids with a chain length of C.sub.8 to C.sub.12, Huls AG,
 Germany), but especially vegetable oils, such as cottonseed oil, almond
 oil, olive oil, castor oil, soybean oil and more especially groundnut oil
 and sesame oil.
 The injection compositions are prepared in customary manner under sterile
 conditions; the same applies also to introducing the compositions into
 ampoules or vials and sealing the containers.
 Pharmaceutical compositions for oral administration can be obtained by
 combining the active ingredient with solid carriers, if desired
 granulating a resulting mixture, and processing the mixture, if desired or
 necessary, after the addition of appropriate excipients, into tablets,
 dragee cores or capsules. It is also possible for the active ingredients
 to be incorporated into plastics carriers that allow the active
 ingredients to diffuse or be released in measured amounts.
 Suitable carriers are especially fillers, such as sugars, for example
 lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or
 calcium phosphates, for example tri-calcium phosphate or calcium hydrogen
 phosphate, and also binders, such as starch pastes using, for example,
 corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose,
 hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or
 polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the
 above-mentioned starches, also carboxymethyl starch, crosslinked
 polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium
 alginate. Excipients are especially flow conditioners and lubricants, for
 example silicic acid, talc, stearic acid or salts thereof, such as
 magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores
 are provided with suitable, optionally enteric, coatings, there being used
 inter alia concentrated sugar solutions which may comprise gum arabic,
 talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,
 or coating solutions in suitable organic solvents, or, for the preparation
 of enteric coatings, solutions of suitable cellulose preparations, such as
 ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
 Capsules are hard gelatin capsules made of gelatin and also soft, sealed
 capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
 The hard gelatin capsules may comprise the active ingredient in the form
 of granules, for example with fillers, such as lactose, binders, such as
 starches, and/or glidants, such as talc or magnesium stearate, and if
 desired with stabilisers. In capsules the active ingredient is preferably
 dissolved or suspended in suitable oily excipients, such as fatty oils,
 paraffin oil or liquid polyethylene glycols, it likewise being possible
 for stabilisers and/or antibacterial agents to be added.
 There may be mentioned as such oils especially liquid fatty acid esters
 that contain as acid component a long-chained fatty acid, for example
 having from 8 to 22, especially from 12 to 22, carbon atoms, for example
 lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic
 acid, margaric acid, stearic acid, arachidic acid, behenic acid, or
 corresponding unsaturated acids, for example oleic acid, elaidic acid,
 erucic acid, brassidic acid or linoleic acid, if desired with the addition
 of antioxidants, for example vitamin E, .beta.-carotene or
 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty
 acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric,
 for example a mono-, di- or tri-hydric, alcohol, for example methanol,
 ethanol, propanol, butanol or pentanol or the isomers thereof, but
 especially ethylene or propylene glycol and glycerol. The following
 examples of fatty acid esters are therefore to be mentioned: ethyl oleate,
 isopropyl myristate, isopropyl palmitate, "Labrafil M 2375"
 (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812"
 (triglyceride of saturated fatty acids with a chain length of C.sub.8 to
 C.sub.12, Huls AG, Germany), but especially vegetable oils, such as
 cottonseed oil, almond oil, olive oil, castor oil, groundnut oil, soybean
 oil and more especially sesame oil. Paraffin oil is also possible.
 Stabilisers, such as emulsifiers, wetting agents or surfactants, binders,
 such as starch pastes using, for example, corn, wheat, rice or potato
 starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose
 (preferred), sodium carboxymethylcellulose, cyclodextrin(s) and/or
 polyvinylpyrrolidone, and/or antibacterial agents may be added. Suitable
 emulsifiers are especially oleic acid, non-ionic surfactants of the fatty
 acid polyhydroxy alcohol ester type, such as sorbitan monolaurate,
 monooleate, monostearate or monopalmitate, sorbitan tristearate or
 trioleate, polyoxyethylene adducts of fatty acid-polyhydroxy alcohol
 esters, such as polyoxyethylene sorbitan monolaurate, monooleate,
 monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol
 fatty acid esters, such as polyoxyethyl stearate, polyoxyethylene glycol
 (300 or 400) stearate, polyethylene glycol 2000 stearate, especially
 ethylene oxide/propylene oxide block polymers of the .RTM.Pluronic type
 (Wyandotte Chem. Corp.; trade mark of BASF, FRG) or .RTM.Synperonic type
 (ICI). For example, if the active ingredient is not soluble in the
 mentioned oils it is present in the form of a suspension, for example
 having a particle size of approximately from 1 to 100 mm.
 Colourings or pigments may be added to the tablets or dragee coatings or to
 capsule walls, for example for identification purposes or to indicate
 different doses of active ingredient
 Starting materials:
 The present invention relates also to novel starting materials and/or
 intermediates and to processes for their preparation. The starting
 materials used and the reaction conditions selected are preferably those
 which result in the compounds described as being preferred.
 In the preparation of all starting materials, free functional groups that
 are not intended to participate in the reaction in question may be
 unprotected or may be in protected form, for example they may be protected
 by the protecting groups mentioned above under Process a). Those
 protecting groups can be removed at suitable times by the reactions
 described under the heading "Removal of protecting groups".
 The starting materials of Process a) are known or, if novel, can be
 prepared in accordance with processes known per se; for example the
 compounds of formula III can be prepared from hydrazine or suitable
 derivatives thereof, and the compounds of formula IV can be prepared from
 suitable amino acids or analogues thereof, for example having one of the
 mentioned side chains R.sub.5.
 The compounds of formula III can be obtained, for example, from compounds
 of formula
EQU H.sub.2 N--NH--R.sub.11 (XI),
 which are known per se or can be prepared from hydrazine by the
 introduction of protecting groups as described under Process a) and in
 which R.sub.11 is hydrogen or an amino-protecting group as described above
 under Process b), especially tert-lower alkoxycarbonyl, such as
 tert-butoxycarbonyl, aryl-lower alkoxycarbonyl, such as benzyloxycarbonyl
 or 9-fluorenylmethoxycarbonyl, or one of the abovementioned acyl
 amino-protecting groups, especially trifluoroacetyl, by alkylation with a
 compound of formula X as described above under Process e), or by reaction
 of the radical of sub-formula
 ##STR17##
 wherein R.sub.6 is as defined for compounds of formula I, by reaction of a
 suitable carbonyl compound of formula X*, or a reactive derivative
 thereof, both as defined under Process f), with the free amino group of
 the compound of formula XI or an acylated derivative thereof and
 subsequent reduction of the resulting hydrazone to form a hydrazine
 derivative of formula
 ##STR18##
 the radicals in all the mentioned compounds being as defined above and
 functional groups in the reagents in question that are not to participate
 in the reaction being protected as necessary, and removal of the
 protecting group R.sub.11 and by condensation under the conditions
 mentioned above under Process b) with an acid of formula VI, or an acid
 derivative thereof mentioned under Process b).
 The carbonyl compounds of compounds X*, or reactive derivatives thereof,
 suitable for the introduction of the radical of sub-formula A that are
 used for the preparation of the compounds of formula XII, as defined above
 under Process f), are aldehydes or reactive derivatives thereof, the
 reactive carbonyl group of which, after the reaction with compounds of
 formula XI and the subsequent reduction, is a constituent of one of the
 mentioned radicals of sub-formula A, for example preferably
 4-phenylbenzaldehyde or 4(2-cyanophenyl)benzaldehyde.
 The reaction of the carbonyl compounds with the compounds of formula XI to
 form the corresponding hydrazones is carried out under conditions
 customarily used for the reaction of carbonyl compounds with amines,
 preferably in polar 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, such as
 ethyl acetate, or in aqueous solution, preferably in methanol, and also in
 the presence or absence of acid catalysts, for example carboxylic acids,
 such as formic acid or acetic acid, or sulfonic acids, such as
 p-toluenesulfonic acid, at temperatures of from 0.degree. C. to the reflux
 temperature of the reaction mixture, preferably at temperatures of from
 20.degree. C. to the reflux temperature of the reaction mixture.
 Compounds of formula
 ##STR19##
 wherein R.sub.6 and R.sub.11 are as defined for compounds of formula XII
 are obtained.
 The reduction of the resulting hydrazones of formula XII* is preferably
 carried out by hydrogenation in the presence of a suitable catalyst or
 with complex hydrides in the presence of acids. As catalysts suitable for
 hydrogenation there are used metals, such as nickel, iron, cobalt or
 ruthenium, or noble metals or oxides thereof, such as palladium or rhodium
 or oxides thereof, optionally, for example, applied to a suitable carrier,
 such as barium sulfate, aluminium oxide or carbon (active carbon) or in
 the form of skeleton catalysts, such as Raney nickel. Solvents customarily
 used for the 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, carboxylic
 acid amides, such as dimethylformamide, or carboxylic acids, such as
 glacial acetic acid, or mixtures of those solvents. The hydrogenation is
 carried out preferably at temperatures of from 10.degree. to 250.degree.
 C., especially from room temperature to 100.degree. C., and preferably at
 hydrogen pressures of from 1 to 200 bar, especially from 1 to 10 bar, in
 the customary apparatus. For the reduction with complex hydrides,
 especially borohydrides, such as alkali metal cyanoborohydrides, for
 example sodium cyanoborohydride, it is preferable to use weak acids, such
 as sulfonic acids, for example p-toluenesulfonic acid, or carboxylic
 acids, such as acetic acid, preferably in alcohols, such as methanol or
 ethanol, or mixtures thereof with water (see, for example, Tetrahedron 49,
 8605-8628 (1993)).
 It is also possible for compounds of formula XI to be alkylated by
 reduction directly with compounds of formula X*, or reactive derivatives
 thereof, as defined under Process f), analogously to the conditions
 mentioned in Process f).
 Also especially preferred for the preparation of compounds of formula XI
 are reaction conditions analogous to those described in J. Chem. Soc.
 Perkin 1, 1712 (1975).
 Compounds of formula III can also be obtained, for example, by reacting a
 compound of formula XII*, as defined above, wherein R.sub.11 is hydrogen
 (obtainable, for example, by the removal of protecting groups when
 R.sub.11 is a protecting group), directly, with condensation under the
 conditions mentioned under Process b) above with acids of formula VI, or
 the acid derivatives thereof mentioned under Process b), to form compounds
 of formula
 ##STR20##
 wherein the radicals are as defined for compounds of formula I, which are
 then converted into compounds of formula III by reduction under conditions
 analogous to the conditions mentioned for the reduction of hydrazones of
 formula XII*.
 Compounds of formula III* can also be obtained from the corresponding
 compounds of formula III', which are defined as described below, by
 reacting the latter With compounds of formula X*, as defined above, to
 form the hydrazones of formula III* under conditions analogous to those
 described above for the reaction of carbonyl compounds of formula X* with
 hydrazines of formula XI.
 A compound of formula IV can be obtained, for example, by reduction of an
 amino acid of formula
 ##STR21##
 wherein R.sub.12 is hydrogen or one of the amino-protecting groups
 mentioned under Process a), especially tert-lower alkoxycarbonyl, such as
 tert-butoxycarbonyl, aryl-lower alkoxycarbonyl, such as benzyloxycarbonyl
 or 9-fluorenylmethoxycarbonyl, or one of the acyl amino-protecting groups
 mentioned under Process a), especially trifluoroacetyl, and R.sub.5 is as
 defined for compounds of formula I, to form an aldehyde of formula
 ##STR22##
 wherein the radicals are as last defined, subsequent reaction of that
 aldehyde with a ylide compound, preferably a sulfur ylide compound, to
 form an epoxide of formula
 ##STR23##
 wherein the radicals are as last defined, removal of the protecting group
 R.sub.12 (the resulting free amino compound wherein R.sub.12 =hydrogen is
 stable, for example, in the form of an acid addition salt) and finally
 acylation of the amino group of the resulting compound with an acid of
 formula VIII wherein the radicals are as defined for formula VIII, under
 suitable conditions analogous to the conditions described for Process b).
 The reduction of amino acids of formula XIII to the corresponding aldehydes
 of formula XIV is carried out, for example, by reduction to the
 corresponding alcohols and subsequent oxidation to the mentioned
 aldehydes.
 The reduction to the alcohols (a free compound or (if necessary after the
 introduction of protecting groups, as described under Process a)) a
 compound N-protected by R.sub.12, having the formula
 ##STR24##
 wherein the radicals are as defined for compounds of formula XIII) is
 carried out, for example, by hydrogenation of the acid halides or other
 activated carboxylic acid derivatives mentioned under Process b) under the
 conditions mentioned for the hydrogenation of hydrazones obtained from
 compounds of formula XII or with complex hydrides, such as sodium
 borohydride. The subsequent oxidation of the resulting alcohols is
 possible, for example, by oxidation of the hydroxy group with a sulfoxide,
 such as dimethyl sulfoxide, in the presence of a reagent that activates
 the hydroxy group, such as a carboxylic acid chloride, for example oxalyl
 chloride, in inert solvents, for example a halogenated hydrocarbon, such
 as dichloromethane, and/or an acyclic or cyclic ether, such as
 tetrahydrofuran, at from -80.degree. to 0.degree. C., for example from
 -78.degree. to -50.degree. C., or by oxidation, for example, with chromic
 acid or a derivative thereof, such as pyridinium chromate or tert-butyl
 chromate, dichromate/sulfuric acid, sulfur trioxide in the presence of
 heterocyclic bases, such as pyridine/SO.sub.3, and also nitric acid,
 pyrolusite or selenium dioxide, in water, organic solvents, such as
 halogenated solvents, for example methylene chloride, carboxylic acid
 amides, such as dimethylformamide, or di-lower alkylsulfoxides, such as
 dimethyl sulfoxide, in the presence or absence of basic amines, for
 example tri-lower alkylamines, such as triethylamine, at temperatures of
 from -50.degree. to 100.degree. C., preferably at from -10.degree. to
 50.degree. C., or by catalytic dehydrogenation, for example in the
 presence of metallic silver, copper, copper chromium oxide or zinc oxide
 at approximately from 200.degree. to 400.degree. C. (in the contact tube)
 with subsequent rapid cooling.
 The direct reduction of the amino acids to the aldehydes is also possible,
 for example by hydrogenation in the presence of a partially poisoned
 palladium catalyst or by reduction of the corresponding amino acid esters,
 for example the lower alkyl esters, such as the ethyl ester, with complex
 hydrides, for example borohydrides, such as sodium borohydride, or
 preferably aluminium hydrides, for example lithium aluminium hydride,
 lithium tri(tert-butoxy)aluminium hydride or especially
 diisobutylaluminium hydride, in nonpolar solvents, for example in
 hydrocarbons or aromatic solvents, such as toluene, at from -100.degree.
 to 0.degree. C., preferably from -70.degree. to -30.degree. C., and
 subsequent reaction to form the corresponding semicarbazones, for example
 with the corresponding acid salts of semicarbazones, such as semicarbazide
 hydrochloride, in aqueous solvent systems, such as alcohol/water, for
 example ethanol/water, at temperatures of from -20.degree. to 60.degree.
 C., preferably from 10 to 30.degree. C., and reaction of the resulting
 semicarbazone with a reactive aldehyde, for example formaldehyde, in an
 inert solvent, for example a polar organic solvent, for example a
 carboxylic acid amide, such as dimethylformamide, at temperatures of from
 -30.degree. to 60.degree. C., preferably from 0.degree. to 30.degree. C.,
 and then with an acid, for example a strong mineral acid, such as a
 hydrogen halide, in aqueous solution, optionally in the presence of the
 solvent used previously, at temperatures of from -40.degree. to 50.degree.
 C., preferably from -10.degree. to 30.degree. C. The corresponding esters
 are obtained by reaction of the amino acids with a corresponding alcohol,
 for example ethanol, analogously to the conditions employed in the
 condensation under Process b), for example by reaction with inorganic acid
 halides, such as thionyl chloride, in organic solvent mixtures, such as
 mixtures of aromatic and alcoholic solvents, for example toluene and
 ethanol, at temperatures of from -50.degree. to 50.degree. C., preferably
 from -10.degree. to 20.degree. C.
 The preparation of the compounds of formula XIV is carried out in an
 especially preferred manner under conditions analogous to the reaction
 conditions mentioned in J. Org. Chem. 47, 3016 (1982) or J. Org. Chem. 43,
 3624 (1978).
 A sulfur ylide suitable for the conversion of compounds of formula XIV into
 the epoxides of formula XV is, for example, a dialkylsulfonium methylide,
 for example dimethylsulfonium methylide, an alkyl- or
 phenyl-dialkylaminosulfoxonium methylide, for example methyl- or
 phenyl-dimethylaminosulfoxonium methylide, or a dialkylsulfoxonium
 methylide, for example dimethyl- or diethyl-sulfoxonium methylide.
 The sulfur ylide compound in question is advantageously prepared in situ
 from the corresponding sulfonium or sulfoxonium salt and a base, for
 example sodium hydride, in a dipolar aprotic solvent, for example dimethyl
 sulfoxide, or an ether, for example tetrahydrofuran or
 1,2-dimethoxyethane, and is then reacted with the compound of formula XIV.
 The reaction is normally carried out at room temperature, with cooling,
 for example down to -20.degree. C., or with gentle heating, for example up
 to 40.degree. C. The sulfide, sulfinamide or sulfoxide formed at the same
 time is removed in the subsequent aqueous working-up.
 The reaction with a sulfur ylide is effected in an especially preferred
 manner analogously to the conditions mentioned in J. Org. Chem. 50, 4615
 (1985).
 A compound of formula XV can also be obtained from a compound of formula
 XIV, as defined above, by reaction thereof with a tri-lower alkylsilyl
 methyl Grignard compound, for example prepared from the corresponding
 halomethylsilane, such as chloromethyl-trimethylsilane, in an inert
 solvent, for example an ether, such as dioxane or diethyl ether, at
 temperatures of from 0.degree. to 50.degree. C., for example from room
 temperature to approximately 40.degree. C., subsequent elimination with
 removal of the silyl radical and formation of a double bond, for example
 by means of a Lewis acid, such as BF.sub.3, any amino-protecting group
 R.sub.12 preferably also being removed, in an inert solvent, for example
 an ether, such as diethyl ether, or a halogenated hydrocarbon, such as
 dichloromethane, or a mixture thereof, at temperatures of from -50.degree.
 C. to the reflux temperature, especially from 0.degree. to 30.degree. C.,
 if necessary acylation again with the introduction of an amino-protecting
 group R.sub.12, as defined above, and oxidation of the resulting double
 bond to form the oxirane, preferably with a percarboxylic acid, for
 example m-chloroperbenzoic acid or monoperphthalic acid (for example in
 magnesium salt form), in an inert solvent, for example a halogenated
 hydrocarbon; such as dichloromethane, or alcohols, such as methanol, lower
 alkanoylnitriles, such as acetonitrile water or mixtures thereof, at
 temperatures of from -20.degree. C. to the reflux temperature of the
 mixture, for example at from 10.degree. to 50.degree. C.
 Compounds of formula IV are preferably prepared by starting directly with
 an alcohol of formula XIII*, as defined above, which is also commercially
 available, reacting that alcohol with an acid of formula VIII, or with a
 reactive derivative thereof, as defined for Process c), under the
 conditions mentioned therein, with, if necessary, protecting groups being
 introduced, as described under Process a), and removed at suitable times,
 as described under the heading "Removal of protecting groups", there being
 obtained a compound analogous to the compound of formula XIII* wherein the
 place of R.sub.12 is taken by the corresponding acyl radical from the acid
 of formula VIII; the resulting compound is oxidised under conditions
 analogous to those mentioned for the oxidation of alcohols of formula
 XIII* to form the corresponding aldehyde of formula
 ##STR25##
 wherein the radicals are as defined, and that aldehyde is then converted,
 for example with an ylide compound, as described for the conversion of
 compounds of formula XIV into compounds of formula XV, into the compound
 of formula IV.
 The starting materials of Processes b), c) and d) are known or, if novel,
 can be prepared in accordance with processes known per se: for example a
 compound of formula V can be prepared from a suitable hydrazine derivative
 of formula XII wherein R.sub.11 is a protecting group and the remaining
 radicals are as defined for compounds of formula V and a suitable epoxide
 of formula IV wherein the radicals are as defined for compounds of formula
 I (Process b); a compound of formula VII can be prepared from a suitable
 hydrazine derivative of formula III wherein the radicals are as defined
 for compounds of formula I and a suitable epoxide of formula XV wherein
 R.sub.12 is a protecting group and the remaining radicals are as defined
 for compounds of formula I (Process c); and the compound of formula IX can
 be prepared from a suitable hydrazine derivative of formula XII wherein
 R.sub.11 is hydrogen and the remaining radicals are as defined for
 compounds of formula I and a suitable epoxide of formula XV wherein
 R.sub.12 is a protecting group and the remaining radicals are as defined
 for compounds of formula I (Process d), analogously to Process a),
 optionally using and removing protecting groups, as described under
 Process a) and under the heading "Removal of protecting groups", the
 protecting groups R.sub.11 and R.sub.12 preferably being as defined above
 in the definition of compounds of formula XI and XIII, respectively.
 Compounds of formula I' wherein the substituents are as defined above can
 be prepared, for example, from compounds of formula III'
 ##STR26##
 wherein the radicals are as defined for compounds of formula I, in a manner
 analogous to that described for Process b), by reaction with a compound of
 formula IV, wherein any functional groups present that are not to
 participate in the reaction may be protected as described in Process b)
 and freed again after the reaction.
 Compounds of formula III' can be obtained from compounds of formula XI, as
 defined above, by reaction of an acid of formula VI, or a reactive acid
 derivative thereof, wherein the radicals are as defined above, in a manner
 analogous to that described for the reaction of compounds of formula XII
 with an acid of formula VI, and subsequent removal of the protecting group
 R.sub.11 in accordance with one of the methods described under the heading
 "Removal of protecting groups".
 Intermediates to which the invention relates are especially
 (a) compounds of formula IX wherein R.sub.5 is cyclohexyl or especially
 phenyl and R.sub.6 is cyanophenyl or phenyl, preferably 2-cyanophenyl or
 especially phenyl;
 (b) compounds of formula III wherein R.sub.6 is cyanophenyl or phenyl,
 preferably 2-cyanophenyl or especially phenyl, R.sub.7, R.sub.8 and
 R.sub.9 are each lower alkyl, especially methyl, and R.sub.10 is lower
 alkoxycarbonyl, especially methoxycarbonyl;
 (c) compounds of formula IV wherein R.sub.1 is lower alkoxycarbonyl,
 especially methoxycarbonyl, R.sub.2, R.sub.3 and R.sub.4 are each lower
 alkyl, especially methyl, and R.sub.5 is cyclohexyl or especially phenyl;
 (d) compounds of formula V wherein R.sub.1 is lower alkoxycarbonyl,
 especially methoxycarbonyl, R.sub.2, R.sub.3 and R.sub.4 are each lower
 alkyl, especially methyl, R.sub.5 is cyclohexyl or especially phenyl and
 R.sub.6 is cyanophenyl or phenyl, preferably 2-cyanophenyl or especially
 phenyl; and/or
 (e) compounds of formula VII wherein R.sub.5 is cyclohexyl or especially
 phenyl, R.sub.6 is cyano phenyl or phenyl, preferably 2-cyanophenyl or
 especially phenyl, R.sub.7, R.sub.8 and R.sub.9 are each lower alkyl,
 especially methyl, and R.sub.10 is lower alkoxycarbonyl, especially
 methoxycarbonyl,
 or in each case a pharmaceutically acceptable salt thereof where at least
 one salt-forming group is present or (except in the case of compounds of
 formula IV) derivatives thereof having amino-protecting groups.
 Where two amino-protecting groups are present they may be identical or
 different
 The amino-protecting groups used are, for example, the amino-protecting
 groups mentioned above under Process a). Preference is given to the
 corresponding compounds wherein the protecting groups are selected from
 those described as being preferred for R.sub.11 and R.sub.12 in compounds
 of formulae XI and XIII, respectively.
 The preparation of the protected compounds of formula I is carried out, for
 example, in accordance with any one of the processes mentioned
 hereinbefore, especially from compounds of formulae III and IV wherein
 functional groups may be protected by protecting groups, as described
 under Process a).
 The acids of formulae VI, VIII and VIIIa and the compounds of formula X,
 and the aldehydes suitable for the introduction of the radical of
 sub-formula A that are used for the preparation of the compounds of
 formula XII are known or, if novel, can be prepared in accordance with
 processes known per se.
 The preparation of the acids of formula VI is effected by reaction of
 derivatives of lower alkoxycarboxylic acids suitable for the introduction
 of lower alkoxycarbonyl radicals, for example by reaction with the
 corresponding pyrocarbonic acid di-lower alkyl esters (especially
 pyrocarbonic acid dimethyl ester; Aldrich, Buchs, Switzerland) or
 preferably haloformic acid lower alkyl esters, such as chloroformic acid
 lower alkyl esters (especially chloroformic acid methyl ester, Fluka,
 Buchs, Switzerland), with amino acids of the formula
 ##STR27##
 wherein the radicals R.sub.7, R.sub.8 and R.sub.9 are as defined for
 compounds of formula VI, and are especially each methyl (or one is
 hydrogen and two are methyl), under conditions analogous to those
 described for acylation under Process b), especially in an aqueous alkali
 metal hydroxide solution, for example aqueous sodium hydroxide solution,
 in the presence of dioxane at temperatures of from 20 to 100.degree. C.,
 especially from 50 to 70.degree. C.
 Correspondingly, the compounds of formula VIII can be obtained from amino
 acids of formula
 ##STR28##
 wherein R.sub.2, R.sub.3 and R.sub.4 are as defined for compounds of
 formula I and especially one is hydrogen and two are methyl (or all three
 are methyl), and the compounds of formula VIIIa can be obtained from amino
 acids of formula
 ##STR29##
 wherein the radicals R.sub.2 ', R.sub.3 ' and R.sub.4 ' are each as defined
 for compounds of formula VIII'(lower alkyl, not hydrogen), by reaction
 with derivatives of the lower alkoxycarboxylic acid suitable for the
 introduction of lower alkoxycarbonyl radicals.
 The amino acids of formulae XVI, XVII and XVIII are known or can be
 prepared in accordance with processes known per se. They are preferably in
 the (S)-form (in respect of the .alpha.-carbon atom).
 Compounds of formula X can be prepared, for example, as follows:
 The starting materials are compounds of formula
 ##STR30##
 wherein R.sub.6 is as defined for formula I. Those compounds can be
 obtained, for example, by the Ullmann biaryl synthesis method (see Chem.
 Rev. 38, 139 (1946) and 64, 613 (1964)) by copper-catalysed reaction of
 components of the compound of formula XIX each having a phenyl ring and
 having a halogen atom at the linkage site for the two phenyl rings,
 especially chlorine or bromine in one of the components to be coupled and
 iodine in the other; by way of the corresponding biphenylyloxazolines (see
 J. Am. Chem. Soc. 97, 7383 (1975) and cleavage thereof, for example by
 means of phosphorus oxychloride, to form the corresponding compounds
 wherein R.sub.6 is cyanophenyl (especially 2-cyanophenyl) (see Tetrahedron
 Lett. (1983), 1437) or via Ni(O)-catalysed diaryl coupling (see J. Org.
 Chem. 42, 1821 (1977); see also J. Med. Chem. 34(8), 2525-2547 (1991))
 (see especially the preparation of the compound having 3-cyanophenyl
 R.sub.6 in accordance with J. Med. Chem. 34(8), 2525-2547 (1991) and with
 4-cyanophenyl R.sub.6 via p-bromobenzonitrile and p-CH.sub.3 -phenyl-ZnCl
 analogously to J. Org. Chem. 42(10), 1821 (1977)).
 The methyl group can then be converted by free radical halogenation, for
 example with chlorine or bromine, especially by means of N-chloro- or
 N-bromo-amines, such as N-bromosuccinimide, preferably in a chlorinated
 hydrocarbon, such as methylene chloride or chloroform, optionally in the
 presence of catalytic amounts of an initiator for free radical reactions,
 for example a peroxide, such as dibenzoyl peroxide (e.g. 0.1-0.01, such as
 0.07, equivalents) or of an azo compound, such as azobisisobutyronitrile,
 into the corresponding compound of formula X wherein X is halogen,
 especially chlorine or bromine. That compound can then
 (i) be converted by hydrolysis (for example in the presence of alkali
 hydroxide solutions, such as NaOH, often with phase transfer catalysis)
 into an alcohol of formula
 ##STR31##
 wherein R.sub.6 is as defined for compounds of formula I, into which it is
 then possible to introduce other halogen radicals X by reaction with
 inorganic acid halides, such as thionyl or phosphoryl halides (for example
 the chlorides, bromides or iodides); or which can be converted by reaction
 with appropriate other organic or inorganic acids, such as strong organic
 sulfonic acids (for example used in the form of acid chlorides) into the
 other compounds of formula X; or they can
 (ii) be converted directly into other compounds of formula X by
 nucleophilic substitution in accordance with customary procedures with
 introduction of a different radical X.
 The aldehydes of formula X* suitable for the introduction of the radical of
 sub-formula A that are used for the preparation of the compounds of
 formula XII can be obtained, for example, from the compounds of formula
 Xa, as defined above, by oxidation, for example with chromic acid or a
 derivative thereof, such as pyridinium chromate or tert-butyl chromate,
 dichromate/sulfuric acid, sulfur trioxide in the presence of heterocyclic
 bases, such as pyridine/SO.sub.3, also nitric acid, pyrolusite or selenium
 dioxide, in water, organic solvents, such as halogenated solvents, for
 example methylene chloride, carboxylic acid amides, such as
 dimethylformamide, or di-lower alkyl sulfoxides, such as dimethyl
 sulfoxide, in the presence or absence of basic amines, for example
 tri-lower alkylamines, such as triethylamine, at temperatures of from
 -50.degree. to 100.degree. C., preferably at from -10.degree. to
 50.degree. C.; by oxidation of the hydroxy group with a sulfoxide, such as
 dimethyl sulfoxide, in the presence of a reagent that activates the
 hydroxy group, such as oxalyl chloride, in inert solvents, for example a
 halogenated hydrocarbon, such as dichloromethane, and/or an acyclic or
 cyclic ether, such as tetrahydrofuran, at from -80.degree. to -50.degree.
 C.; or by catalytic dehydrogenation, for example in the presence of
 metallic silver, copper, copper chromium oxide or zinc oxide at
 approximately from 200.degree. to 400.degree. C. (in the contact tube)
 with subsequent rapid cooling; or they are commercially available or can
 be prepared in accordance with processes known per se, for example
 4-phenylbenzaldehyde (Fluka, Buchs, Switzerland) or
 4-(2-cyanophenyl)benzaldehyde (see Biomed. Chem. Lett. 3, 2667-2670 (1993)
 and J. Med. Chem. 34, 2525 (1991) cited therein). The corresponding
 reactive derivatives are prepared therefrom in accordance with procedures
 known per se (bisulfite addition compounds, for example, by reaction in
 aqueous concentrated sodium hydrogen sulfite solution; semi-acetals or
 acetals by reaction with the relevant alcohols, in the absence
 (semi-acetals) or presence of acids, such as ammonium chloride or hydrogen
 chloride (acetals); and thioacetals by reaction with corresponding
 mercaptans, also without acids).
 Starting compounds of formula IX wherein the radicals R.sub.5 and R.sub.6
 are as defined for compounds of formula I, or the precursors thereof
 protected at both nitrogen atoms which can be converted into the free
 compounds of formula IX by the removal of protecting groups in accordance
 with the methods described above under the heading "Removal of protecting
 groups", or salts of compounds of formula IX can be prepared also by
 reduction of an oxo compound of formula XX
 ##STR32##
 wherein R.sub.P1 and R.sub.P2 are each an amino-protecting group or
 hydrogen and the other radicals are as defined for compounds of formula I;
 that compound is in turn prepared by hydrogenation with a suitable complex
 hydride or with hydrogen in the presence of a suitable catalyst and acyl
 migration starting from a hydrazone of formula XXI
 ##STR33##
 wherein the radicals are as defined for compounds of formula XX,
 which is in turn obtained preferably from a nitrile of formula XXII
 ##STR34##
 wherein R.sub.P1 ' is an amino-protecting group and R.sub.5 and R.sub.6 are
 as defined for compounds of formula I, by selective catalytic
 hydrogenation ((preferably) via an imino compound of formula XXIII
 ##STR35##
 wherein the radicals are as defined for compounds of formula XXII)
 and reaction with a hydrazine derivative of formula XXIV
 ##STR36##
 wherein R.sub.P2 is as defined for a compound of formula XX, and wherein
 further suitable protecting groups for functional groups may be present;
 the hydrazine derivative being added during the selective catalytic
 hydrogenation (or (further) being reacted with the resulting imino
 compound of formula XXIII only when the catalytic hydrogenation is
 complete),
 the compound of formula XXII being prepared preferably from an aldehyde of
 formula XXV
 ##STR37##
 wherein R.sub.P1 ' is an amino-protecting group and R.sub.5 has one of the
 meanings defined for compounds of formula I,
 by reaction with a reactive derivative of a carboxylic acid of formula XXVI
 ##STR38##
 wherein R.sub.6 is as defined for compounds of formula I, in the presence
 of a cyanide salt;
 the compounds of formulae XX to XXVI being in free form or, where
 salt-forming groups are present and the reaction conditions allow it,
 being used in the form of their salts.
 A suitable amino-protecting group is especially an amino-protecting group
 that is not removed in any of the reductions and/or hydrogenations to be
 carried out in the reactions described hereinabove and hereinbelow. Also
 permissible, however, are protecting groups that are removable by those
 reductions, it being possible, if necessary, for fresh protecting groups
 to be introduced by conventional methods at each reaction step.
 Corresponding amino-protecting groups are defined under Process a) and are
 familiar to the person skilled in the art.
 The reduction of an oxo compound of formula XX is preferably carried out
 using complex hydrides, such as borohydrides or metal hydrides, especially
 with borane/tetrahydrofuran (BH.sub.3 /THF) (especially preferred),
 borane/dimethyl sulfide (BH.sub.3 /(CH.sub.3).sub.2 S),
 tetra(n-butyl)ammonium borohydride ((CH.sub.3 --CH.sub.2 --CH.sub.2
 --CH.sub.2 --)NBH.sub.4), trialkoxyborohydrides, such as tri-lower
 alkoxyborohydrides, alkali metal borohydrides, such as lithium, sodium or
 potassium borohydride, lithium triethylborohydride (Super-Hydride.RTM.),
 potassium tri(sec-butyl)borohydride (K-Selectride.RTM.), potassium
 tri(siamyl)borohydride (KS-Selectride.RTM.), lithium
 tri(sec-butyl)borohydride (L-Selectride.RTM.), lithium
 tri(siamyl)borohydride (LS-Selectride.RTM.), sodium
 tri(sec-butyl)borohydride (N-Selectride.RTM.), alkali metal
 aminoborohydrides or alkali metal (mono- or di-substituted
 amino)borohydrides, such as lithium aminoborohydride, sodium
 dimethylaminoborohydride, lithium diethylaminoborohydride, lithium
 di-n-propyl-amino borohydride, lithium diisopropylaminoborohydride,
 lithium-1-azaheptano-borohydride, lithium pyrrolidino-borohydride, lithium
 morpholino-borohydride, lithium piperidino-borohydride, lithium
 (N-ethyl-N-phenyl-amino)borohydride, sodium bis(2-methoxyethoxy)aluminium
 hydride (Vitride.RTM.), lithium aluminium hydride, lithium
 tri(methoxy)aluminium hydride, diisobutylaluminium hydride (Dibal) or
 lithium tri(tert-butoxy)aluminium hydride, in suitable solvents or solvent
 mixtures, especially ethers, such as tetrahydrofuran (especially
 preferred), di-lower alkyl ethers, such as diethyl ether or dioxane, or
 halogenated hydrocarbons, such as dichloromethane or chloroform, at
 preferred temperatures of from -10.degree. to 80.degree. C., especially
 from 0.degree. to 60.degree. C., for example from 0.degree. C. to room
 temperature (for reagents and reaction conditions see also Heterocycles
 14, 1437 (1980); Tetrahedron Lett. 33(32), 4533 (1992); U.S. Pat. No.
 4,895,943; Synthet. Commun. 21, 1579 (1991); J. Chem. Soc. Perkin I, 1011
 (1986); J. Org. Chem. 45, 1 (1980); or Bioorganic & Medicinal Chemistry
 Letters 4(16), 2055 (1994)).
 When hydrogenation is carried out with a suitable complex hydride or with
 hydrogen in the presence of a suitable catalyst and acyl migration
 starting from a hydrazone of formula XXI, the procedure is preferably as
 follows:
 First the hydrogenation is carried out.
 As the complex hydride suitable for the hydrogenation there is used
 especially an alkali metal borohydride, such as an alkali metal
 cyanoborohydride, especially sodium cyanoborohydride (NaBH.sub.3 CN) in
 the presence of an acid, preferably a relatively strong acid, such as a
 mineral acid, for example sulfuric acid, phosphoric acid, hydrochloric
 acid, bromic acid or hydrofluoric acid, or especially an organic sulfonic
 acid, for example an alkanesulfonic acid, such as methanesulfonic acid, or
 an aromatic sulfonic acid, especially 4-toluenesulfonic acid, the reaction
 being carried out in suitable solvents, especially ethers, such as
 tetrahydrofuran or also dioxane, (see also Tetrahedron Lett. 49, 8605
 (1993)), in the presence of water or in the absence thereof, at preferred
 temperatures of from 0.degree. to 80.degree. C., especially from
 10.degree. to 60.degree. C., for example approximately at room
 temperature.
 The hydrogenation with hydrogen in the presence of a suitable catalyst,
 especially nickel, rhodium, ruthenium, palladium and platinum catalysts,
 more especially Raney nickel or palladium or platinum catalysts,
 optionally on carriers, such as active carbon, aluminium oxide or barium
 sulfate, is preferably carried out at a hydrogen pressure of from 0.1 to
 200 bar, preferably from 1 to 100 bar, and at preferred temperatures of
 from 20.degree. to 120.degree. C., especially from 40.degree. to
 100.degree. C., preferably in the presence of organic solvents, such as
 alkanols, such as methanol, ethanol, isopropanol, sec-butanol or
 tert-butanol, ethers, such as diethyl ether, tetrahydrofuran or dioxane,
 amides, such as N,N-dimethylformamide or N,N-diethylformamide, aromatic
 hydrocarbons, such as toluene or xylene, aliphatic monocarboxylic acids,
 such as lower alkanoic acids, for example formic acid, acetic acid,
 propionic acid, butyric acid, isobutyric acid, iso- and n-valeric acid, or
 esters, such as alkyl esters of aliphatic monocarboxylic acids, for
 example formic acid methyl or ethyl ester, acetic acid methyl, ethyl,
 n-butyl or isobutyl ester, esters of carbonic acid, such as dimethyl or
 diethyl carbonate, or mixtures of the mentioned solvents, with special
 preference being given to acetic acid, methanol, ethanol, isopropanol,
 sec-butanol, tert-butanol or mixtures of those alcohols with ethyl
 acetate.
 Hydrogenation with complex hydrides is preferred over hydrogenation with
 hydrogen in the presence of a suitable catalyst.
 A borate complex is obtained which is either worked up and isolated, for
 example by partition, for example between an aqueous phase and an organic
 phase containing an ester, such as ethyl acetate, as solvent and
 (optionally after drying, for example over sodium sulfate) concentration
 by evaporation of the phase containing the borate complex, or is used
 directly in situ.
 The subsequent acyl migration of the radical p-(R.sub.6)--C.sub.6 H.sub.5
 --C(.dbd.O)-- from the oxygen atom in formula XXI to the hydrazine
 nitrogen atom in formula XX is preferably effected under basic reaction
 conditions, especially in the presence of an aqueous base, especially an
 aqueous alkali metal hydroxide, such as potassium or sodium hydroxide, in
 the absence or presence of further solvents, such as ethers, preferably
 dioxane or di-lower alkoxy-lower alkanes, such as 1,2-dimethoxyethane, at
 preferred temperatures of from -10.degree. to 60.degree. C., especially
 from 0.degree. to 30.degree. C., and results in a corresponding compound
 of formula XX.
 The selective catalytic hydrogenation of the nitrile group in a compound of
 formula XXII is preferably carried out directly in the presence of the
 hydrazine derivative of formula XXIV and without isolation of the imino
 compound of formula XXI using types of catalyst known per se, especially
 cobalt, nickel and noble metal catalysts, such as platinum, rhodium,
 palladium and ruthenium catalysts, which are used in free form or bonded
 to carriers, such as active carbon, aluminium oxide or barium sulfate,
 with special preference being given to rhodium on carriers, such as active
 carbon or aluminium oxide, or especially Raney nickel; in the presence of
 hydrogen, preferably molecular hydrogen; an acid, it being possible to use
 an inorganic or organic acid, especially an inorganic protonic acid, such
 as a hydrohalic acid, for example HCl, HBr and HF, phosphoric acid or
 sulfuric acid, or an organic protonic acid, for example a sulfinic acid,
 such as benzenesulfinic acid, an aliphatic and unsubstituted or
 substituted aromatic sulfonic acid, such as methanesulfonic acid,
 benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or
 naphthalenedisulfonic acid, an aliphatic monocarboxylic acid having
 preferably from 1 to 18 carbon atoms, such as formic acid, acetic acid,
 propionic acid, butyric acid, lauric acid, palmitic acid, stearic acid, a
 halogenated aliphatic monocarboxylic acid, such as chloroacetic acid,
 dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid, an
 aliphatic dicarboxylic acid having preferably from 2 to 12 carbon atoms,
 such as oxalic acid, malonic acid, succinic acid, adipic acid or sebacic
 acid, an unsubstituted or substituted aromatic mono- or di-carboxylic
 acid, such as benzoic acid, toluic acid, naphthoic acid, phthalic acid or
 terephthalic acid; preferably a weak acid, such as aliphatic
 monocarboxylic acids having from 1 to 4 carbon atoms, such as formic acid,
 propionic acid, butyric acid or especially acetic acid; the acid and the
 hydrazine derivative of formula XXIV advantageously being used in an at
 least equimolar amount, based on the compound of formula XXII, and the
 hydrazine derivative preferably being used in an equimolar to twice the
 molar amount and the acid in equimolar to four times the molar amount, and
 it being possible, where appropriate, for excess acid to be used directly
 as solvent; in the presence or absence of an organic or aqueous organic
 solvent or solvent mixture, especially in the presence of alcohols, for
 example lower alkanols, such as methanol, ethanol, n-propanol,
 isopropanol, butanol or pentanol, or aliphatic or cyclic ethers, such as
 diethyl ether, di-n-propyl ether, diisopropyl ether, tetrahydropyran,
 tetrahydrofuran or dioxane; or cyclic or aliphatic amides, such as
 N-methyl-2-pyrrolidone, N-acetyl-2-pyrrolidone, formamide,
 N,N-dialkylamides of aliphatic monocarboxylic acids having from 1 to 3
 carbon atoms in the acid moiety, such as N,N-dimethylformamide,
 N,N-dimethylacetamide and N,N-diethylacetamide, and/or mixtures of the
 mentioned solvents with water, with special preference being given to
 reaction in a C.sub.1 -C.sub.4 alkanol, especially methanol or ethanol, or
 in mixtures thereof with water; at preferred temperatures of from
 0.degree. to 150.degree. C., especially from 20.degree. to 60.degree. C.;
 under normal pressure or under elevated pressure, preferably from normal
 pressure to a pressure of up to 10 bar, preferably up to 4 bar.
 Alternatively it is also possible first to carry out the hydrogenation to
 an imino compound of formula XXIII which, without being isolated or after
 being fully or partially isolated, is then reacted with the hydrazine
 derivative of formula XXIV, the reaction conditions preferably
 corresponding to those last mentioned.
 For the reaction with a reactive derivative of a carboxylic acid of formula
 XXVI there is used as reactive derivative especially a compound of formula
 XXVII
 ##STR39##
 wherein R.sub.6 is as defined for compounds of formula I and wherein X is
 halogen, especially chlorine, or a radical of an acid bonded via an oxygen
 atom, especially a corresponding carboxylic acid, for example an acyloxy
 radical of the carboxylic acid of formula IX itself [radical
 p-(R.sub.6)--C.sub.6 H.sub.5 --C(.dbd.O)--O-- (symmetric anhydride)] or
 especially lower alkanoyloxy, such as acetyloxy, or lower
 alkoxycarbonyloxy, such as isobutyloxycarbonyloxy; as cyanide salt there
 is preferably used an alkali metal cyanide, especially potassium or sodium
 cyanide; the reaction is preferably carried out under phase transfer
 conditions in the presence of a quaternary ammonium salt, especially
 tricaprylmethylammonium halide, such as tricaprylmethylammonium chloride
 (Aliquat), tetraalkylammonium halide, such as tetrabutylammonium chloride,
 trialkyl-aryl-lower alkylammonium halide, such as triethylbenzylammonium
 chloride, benzylcinchoninium halide, such as benzylcinchoninium chloride,
 benzylcinchonidinium halide, such as benzylcinchonidinium chloride, or
 benzylquininium halide, such as benzylquhininium chloride, in a suitable
 aqueous solvent mixture, such as a mixture of halogenated hydrocarbons
 with water, especially methylene chloride/water, 1,1-dichloroethane/water
 or chloroform/water, or mixtures of aliphatic ethers with water, such as
 dialkyl ether/water, for example diethyl ether/water, or cyclic
 ether/water, such as tetrahydrofuran/water or dioxane/water (phase
 separation especially in the case of a high salt concentration). The
 reaction takes place at preferred temperatures of from -20.degree. to
 50.degree. C., especially from approximately 0.degree. C. to room
 temperature.
 The reaction to form a compound of formula XXII starting from a reactive
 acid derivative of a compound of formula XXVI and an aldehyde of formula
 XXV is preferably carried out stereoselectively, so that the molar ratio
 of the resulting compound of formula XXII wherein the asymmetric carbon
 atom carrying the cyano group is in the (R)-configuration to that wherein
 the asymmetric carbon atom carrying the cyano group is in the
 (S)-configuration is greater than approximately 3:1 and is especially from
 4:1 to 10:1.
 Alternatively it is also possible for the reaction of an aldehyde of
 formula XXV with hydrocyanic acid in the presence of the enzyme
 (S)-oxynitrilase, which can be obtained from almonds, either in the
 presence of almonds or almond extracts or of the purified (S)-oxynitrilase
 itself, or preferably in the presence of the enzyme (R)-oxynitrilase from
 Sorghum bicolor; which can be used in the form of cells, cell extracts or
 in purified form, in organic solvents, to be carried out
 stereoselectively, followed by acylation with an acid of formula XXVI or a
 reactive acid derivative thereof, as described above (see Tetrahedron
 Asymmetry 7(3), 663-666 (1996)).
 Starting materials can also be prepared by the processes mentioned in EP 0
 521 827 or obtained from the sources mentioned therein.
 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.

EXAMPLES
 The following Examples serve to illustrate the invention but do not limit
 the scope thereof
 Temperatures are given in degrees Celsius (.degree. C.). Where no
 temperature is specified, the reactions that follow are carried out at
 room temperature. The R.sub.f values, which indicate the ratio of the
 seepage propagation of the substance in question to the seepage
 propagation of the eluant front, are determined on thin-layer silica gel
 plates (Merck, Darmstadt, Germany) by thin-layer chromatography (TLC)
 using the solvent systems indicated.
 The quantitative ratio of solvents to one another is always given in parts
 by volume (v/v). The quantitative ratios given in the definition of the
 eluant systems for column chromatography are also in parts by volume.
 The names customarily used in peptide chemistry are used to denote bivalent
 radicals of natural .alpha.-amino acids. The radical "tert-leucyl" is the
 radical of tert-leucine (.alpha.-tert-butylglycine). The configuration at
 the .alpha.-carbon atom, where known, is indicated by the prefix (L)- or
 (D)-.
 Other abbreviations used:

active ingredient 3 mg
 gelatin 150 mg
 phenol 4.7 mg
 dist. water containing 20% cyclodextrins 1.0 ml
 as solubiliser
 Example 7
 Sterile Dry Substance for Injection
 5 mg of one of the compounds of formula I mentioned in the preceding
 Examples (for example the title compound from Example 1) as active
 ingredient are dissolved in 1 ml of an aqueous solution containing 20 mg
 of mannitol and 20% cyclodextrins as solubiliser. The solution is
 sterile-filtered and, under aseptic conditions, introduced into a 2 ml
 ampoule, deep-frozen and lyophilised. Before use, the lyophilisate is
 dissolved in 1 ml of distilled water or 1 ml of physiological saline. The
 solution is administered intramuscularly or intravenously. The formulation
 can also be introduced into double-chamber disposable syringes.
 Example 8
 Nasal Spray
 500 mg of finely ground (&lt;5.0 mm) powder of one of the compounds of formula
 I mentioned in the preceding Examples (for example the compound from
 Example 1) are suspended as active ingredient in a mixture of 3.5 ml of
 Myglyol 812.RTM. and 0.08 g of benzyl alcohol. The suspension is
 introduced into a container having a metering valve. 5.0 g of Freon
 12.RTM. (dichlorodifluoromethane; trade mark of DuPont) are introduced
 under pressure through the valve into the container. The "Freon" is
 dissolved in the Myglyol/benzyl alcohol mixture by shaking. The spray
 container contains approximately 100 single doses which can be
 administered individually.
 Example 9
 Film-Coated Tablets
 The following constituents are processed for the preparation of 10,000
 tablets each comprising 100 mg of active ingredient:

active ingredient 1000 g
 corn starch 680 g
 colloidal silicic acid 200 g
 magnesium stearate 20 g
 stearic acid 50 g
 sodium carboxymethyl starch 250 g
 water quantum satis
 A mixture of one of the compounds of formula I mentioned in the preceding
 Examples (for example the compound from Example 1) as active ingredient,
 50 g of corn starch and the colloidal silicic acid is processed with a
 starch paste made from 250 g of corn starch and 2.2 kg of demineralised
 water to form a moist mass. That mass is forced through a sieve of 3 mm
 mesh size and dried in a fluidised bed drier at 45.degree. for 30 minutes.
 The dried granules are pressed through a sieve of 1 mm mesh size, mixed
 with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the
 magnesium stearate, the stearic acid and the sodium carboxymethyl starch
 and compressed to form slightly convex tablets.
 Example 10
 Capsules (I)
 Crystalline
 1-(4-biphenylyl)-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)-amino-4(S)-hydrox
 y-5(S)-N-(N-methoxycarbonyl-(L)-valyl)-amino-6-phenyl-2-azahexane (active
 ingredient) is micronised using a customary knife mixer (e.g. Turmix)
 (particle size about 1 to 100 .mu.m). .RTM.Pluronic F 68 (block polymer of
 polyethylene and polypropylene glycol; Wyandotte Chem. Corp., Michigan,
 USA; also obtainable from Emkalyx, France; trade mark of BASF) is likewise
 micronised using a customary mixer and the fines content is removed using
 a sieve (0.5 mm) and used further as below. 16.00 g of sesame oil are
 placed in a glass beaker and 1.20 g of the micronised active ingredient,
 1.20 g of the fines content of .RTM.Pluronic F 68 and 1.20 g of
 hydroxypropylmethylcellulose (Cellulose HP-M-603 from Shin-Etsu Chemicals
 Ltd., Tokyo, JP) are added with stirring using a stirring device
 (IKA-Werk, FRG) combined with a toothed stirrer (diameter 46 mm) (stirring
 speed: 2000 rev/min). Twenty minutes' stirring at the speed indicated
 produces a suspension of pasty consistency which is introduced into hard
 gelatin capsules (20.times.40 mm; R. P. Scherer AG, Eberbach, FRG).
 Example 11
 Capsules (II)
 For the preparation of 10,000 capsules comprising 100 mg of active
 ingredient
 1-(4-biphenylyl)-2-N-(N-methoxycarbonyl-(L)-tert-leucyl)-amino-4(S)-hydrox
 y-5(S)-N-(N-methoxycarbonyl-(L)-valyl)-amino-phenyl-2-azahexane per
 capsule, the following constituents are processed as follows:

active ingredient 1000 g
 .RTM. Pluronic F 68 1000 g
 hydroxypropylmethylcellulose 1000 g
 sesame oil 1000 g
 (for origin of constituents see Example 10)
 The sesame oil is placed in a heatable vessel (Fryma) and the .RTM.Pluronic
 F 68 is scattered in. The vessel is heated to 60.degree. C. and the
 .RTM.Pluronic F 68 is distributed with stirring (duration about 2 hours).
 With stirring and homogenisation, the mixture is cooled to about
 30.degree. C. The hydroxypropylmethylcellulose and the active ingredient
 are scattered in and, with stirring and homogenisation (about 1 hour),
 distributed in the oil mass. The suspension of pasty consistency is
 introduced into hard gelatin capsules (size 0; obtainable, for example,
 from Elanco or Parke-Davies (Caprogel)) or soft gelatin capsules (20 mm
 oblong; R. P. Scherer AG, Eberbach, FRG) using customary apparatus.
 Example 12
 IC.sub.50 Values in Respect of HIV-1-Protease
 In the test system described above (with RRSNQVSQNYPIVQNIQGRR), SEQ ID NO:1
 the following IC.sub.50 values are obtained for Examples 1 to 5:

Example ED.sub.90 (.mu.M)
 1 3
 2 3
 3 10
 4 3
 5 3
 Example 14
 Blood Levels in Mice after Oral Administration
 In the test system described above (with BALB/c mice after peroral
 administration of 120 mg of active ingredient/kg) the following plasma
 levels are obtained: