NO180442B - Antiretroviral hydrazine derivatives - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R1 and R9, independently of each other, denote hydrogen, acyl or unsubstituted or substituted alkyl; sulpho; or sulphonyl which is substituted by unsubstituted or substituted alkyl, aryl or heterocyclyl, with the proviso that at most one of the radicals R1 and R9 denotes hydrogen; and R2 and R8, in each case independently of each other, denote hydrogen or unsubstituted or substituted alkyl; R3 and R4, independently of each other, denote hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl; R5 denotes acyloxy; R6 denotes hydrogen; and R7 denotes unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or aryl; are described, as are salts of the said compounds, insofar as salt-forming groups are present; these compounds exhibit anti-retroviral activity.

Description

The invention relates to new antiretroviral active compounds, methods for the preparation of these compounds, new intermediate compounds for the preparation of these compounds, especially those with antiretroviral action, pharmaceutical preparations with these compounds, and these compounds for the preparation of pharmaceutical preparations.

A number of diseases are caused by retroviruses.

According to current knowledge, AIDS is a disease caused by the retrovirus HIV ("Human Immunodeficiency Virus"). Millions are already infected today. The disease is constantly spreading and in practice leads to the death of the patient.

Until now, retroviruses HIV-1 and HIV-2 (HIV stands for "Human Immunodeficiency Virus") have been identified as the cause of disease. For therapy, the search for preparations is interesting, which themselves detect the multiplication of viruses, without damaging intact cells and tissues in the patient.

The retroviral proteases are proteolytic enzymes which, due to an aspartate residue present in the active center, are cleaved by aspartate protease. They participate in the multiplication cycle of a number of retroviruses by maturing the infectious virus within infected cells.

HIV-1 and HIV-2 have in their genome e.g. each a region that codes for a "gag protease". These enzymes are required for the correct proteolytic cleavage of the precursor proteins that precede the "Group Specific Antigens" (gag) coding genome segment. With this, the structural proteins of the viral core, English "Core" are released, the "gag protease" itself is a component of the pol genome section of HIV-1 and HIV-2 encoded precursor protein, which also contains sections for "reverse transcriptase" and " integrase" and is presumably autoproteolytically cleaved.

"gag protease" cleaves the main core protein ("Major Core Protein") p24 of HIV-1 and HIV-2 preferably N-terminal to the proline residue, e.g. in the divalent radicals Phe-Pro, Leu-Pro or Tyr-Pro.

Due to the central role of the "gag protease" in processing the aforementioned "core proteins", it is assumed that an effective inhibition of these enzymes in vivo prevents assembly of mature viruses, so that corresponding inhibitors can be used therapeutically .

In general, for combating retroviral diseases such as AIDS, it has been necessary for a long time to provide compounds as inhibitors which are effective against the aforementioned retroviral gag proteases, in particular the gag protease of HIV-1 (HIV-1 protease), but also HIV-2 and additional AIDS viruses.

The main goal so far has been to provide such compounds that exhibit the best possible pharmacokinetic properties.

The prerequisite for therapeutic effect in vivo is the achievement of good bioavailability, e.g. a good resorbability and/or a high blood level, also with enteral or oral administration, in order to reach the infected cells in a sufficiently high concentration.

The task of the present invention is to provide compounds with excellent antiretroviral activity, particularly very good bioavailability.

The compound according to the invention relates to compounds of the formula where Rjl and Rg independently of each other mean lower alkoxylower oxycarbonyl-(1)-valyl or lower alkoxycarbonyl-(1)-valyl;

R 3 means C 3 -C 7 cycloalkyl lower alkyl, or phenyl lower alkyl; R 5 means lower alkanoyloxy, pyridyl lower alkanoyloxy or lower alkyl lower alkanoyloxy;

and R7 independently of R3 has the meaning mentioned there;

as well as salts of the said compounds, as long as salt-forming groups are present.

In the description of the present invention, the definitions of groups or residues, e.g. lower alkyl, lower alkoxy, lower alkanoyl etc, the term "lower" used, that the groups or residues thus defined, if not otherwise expressly defined, contain a maximum of up to and including 7 and preferably up to and including 4 C atoms. In the case of lower alkenyl or lower alkynyl, there are 2 to 7, preferably 3 to 7, especially 3 or 4 carbon atoms.

Those with R3 and R4 respectively. Carbon atoms substituted with R5 and R5 in connection with formula I can, as long as they are asymmetric as well as any further asymmetric carbon atoms present, be in (R), (S) or (R,S) configuration. Thus, the present compounds can also occur as isomeric mixtures or as pure isomers, in particular as diastereomer mixtures, enantiomeric pairs or pure enantiomers. Preferably, the compound of formula I, in which the carbon atoms substituted by R 3 or by R 5 each have the (S) configuration and further asymmetric carbon atoms, if present, may exist independently of each other in (R)-, (S)- or (R, S) configuration.

The general terms and references used in the description of the present invention have the following meaning, unless otherwise stated: In lower alkoxy-lower oxycarbonyl-(1)-valyl or lower alkoxycarbonyl-(1 )-valyl, R 1 or R 2 is the α-amino group in Val N -acylated with lower alkoxycarbonyl, e.g. methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentoxy-, isopentoxy-, neopentoxy-, tert-pentoxy -, n-hexoxy-, isohexoxy- or n-heptoxycarbonyl, or with lower alkoxy lower oxycarbonyl such as 2-methoxyethoxycarbonyl.

In particular, the carboxy function of the carbonyl group is bound acyl group R-L or Rg or substituted amino acid selected from N-(2-methoxy)ethoxycarbonylvaline, N-methoxycarbonylvaline, N-ethoxycarbonylvaline, N-isobutoxycarbonylvaline, or N-tert-butoxycarbonylvaline, where valine occurs in the (L) form.

C3-C7 cycloalkyl lower alkyl, where cycloalkyl has 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, where cycloalkyl is unsubstituted and is bound to lower alkyl, in particular methyl, ethyl, n-propyl, isopropyl, N-butyl, isobutyl or tert-butyl, preferably terminal, e.g. cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl lower alkyl, such as -methyl or -ethyl, particularly preferred cyclohexyl lower alkyl, such as cyclohexylmethyl.

Salts of compounds of formula I are particularly acid addition salts, salts with bases or, where there are several salt-forming groups, possibly also mixed salts or internal salts.

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

Such salts are e.g. those of compounds of formula I with an acidic group, e.g. a carboxy-, sulfo- or formed with one or two hydroxy group-substituted phosphoryl groups and is e.g. derived salts with suitable bases that are non-toxic, of metals from group Ia, Ib, Ila and Ilb in the periodic table of the elements, primarily suitable alkali metals, e.g. lithium, sodium or potassium, or alkaline earth metal salts, e.g. magnesium or calcium salts, further zinc salts or ammonium salts, also such salts which are formed with organic amines such as optionally with hydroxy-substituted mono-, di- or trialkylamines, especially mono-, di- or trilower alkylamines or with quaternary ammonium compounds, e.g. N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris-(2-hydroxylower alkyl)-amines, such as mono-, bis- or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert -butylamine or tris(hydroxymethyl)methylamine, N,N-diloweralkyl-N-(hydroxyloweralkyl)amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amines or tri-(2-hydroxyethyl) -amines, N-methyl-D-glucamine or quaternary ammonium salts, such as tetrabutyl ammonium salts. The compounds of formula I_.with a basic group e.g. an amino group can form acid addition salts, e.g. with inorganic acids, e.g. hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carbonic, sulfonic, sulfo- or phosphoric acids or N-substituted sulfamic acids, such as e.g. Acetic acid, propionic acid, glycolic acid, Bernsteinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucoronic acid, citric acid, benzoic acid, zimtic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid, or isonicotinic acid, further amino acid such as e.g. the a-amino acids mentioned above, especially glutamic acid or aspartic acid, as well as with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates) or with other organic compound acids, such as ascorbic acid. Compounds of formula I with acids and basic groups can also form internal salts.

Pharmaceutically unsuitable salts can also be used for isolation or purification.

The compounds of formula I have valuable pharmacological properties. They are antiretroviral effective, especially against AIDS, e.g. HIV-1 and HIV-2. They serve as metabolic advantages for binding with formula II

where the residues have the meanings mentioned for the compounds of formula I (analogous to compound of formula I, where instead of hydroxy stands for R5), which are suitable as inhibitors of retroviral aspartate proteases, in particular as inhibitors against the gag protease of HIV-1 or HIV-2 (and possibly aspartoproteases of retroviruses, which induce AIDS-analogous symptoms), and thus for the treatment of retroviral diseases, such as AIDS or its benefits. The compounds of formula II (with hydroxy in place of R5 in formula I) are thus released in the body of the treated animal, preferably a warm-blooded animal including man, by compound of formula I.

The compound of formula I exhibits advantageous pharmacodynamic properties compared to the compound of formula II, which e.g. can be coated in the following way: The compounds of formula I or, as a control, the comparison compound of formula II are dissolved in dimethylsulfoxide (DMSO) at a concentration of 240 mg/ml. The resulting solution is diluted with 20% (v/v) hydroxypropyl-3-cyclodextrin (EPeCD), to a test substance concentration of 12 mg/ml. The solution is administered to mice by artificial gavage in a dose of 120 mg/kg. 60, 90 and 120 minutes after administration, the animals are killed and a blood sample is taken. Three to four animals are examined per time point. The blood is heparinized and processed in the following analysis: An internal standard is added to the heparinized blood in a final concentration of 4 µM. The blood is centrifuged. 0.25 ml of plasma is withdrawn and deproteinized with a small volume of acetonitrile. After centrifugation, the supernatant is dried under vacuum and the residue suspended in 20 µl 3M NaCl solution and 100 µl 0.05 M phthalate buffer at a pH of 3.0. The suspension is first extracted with 1 ml, then with 0.2 ml of diisopropyl ether. The diisopropyl ether is evaporated to dryness and the residue is dissolved in 50% (v/v) aqueous acetonitrile. This solution is examined by reverse-phase HPLC.

Analysis with reverse-phase HPLC is carried out with a 125x4.6 mm Nucleosil C^g column (reverse-phase material from the company Macherey-Nagel, Duren, Germany on the basis of hydrocarbon residues with 18 carbon atoms derivatized gel), this is equilibrated with a mobile phase of 50% acetonitrile in water/0.1% trifluoroacetic acid. The flow rate is 1 ml/min. Detection takes place at 215 nm. The standard for the compounds in the blood is worked up analogously to the blood sample and standard curves are used, which are determined due to in-vivo concentration.

When comparing the compound of formula I with those of formula II (active components, where acyloxy R5 is replaced by hydroxy), the following results are obtained: concentration of active components of formula II in the blood of mice can, after oral administration, have a compound of formula I, e.g. a compound of formula I where R 1 means acetyl, at most times, preferably at all of the above times, be significantly higher than when administering the compound of formula II in unesterified form, e.g. more than three times as high, especially more than 10 times as high, primarily approx. 20 to 150 times as high. Alternatively, absorption of the compound of formula I, e.g. those where R 1 means acyl be significantly higher than absorption of the compound of formula II, e.g. more than four times as high. It is also possible to achieve a longer time with a compound of formula I in a higher blood level than with a compound of formula II. Preferably, the achievable blood concentration of the active ingredient of formula II at the mentioned time points is significantly above those measured in cell tests for corresponding compounds of formula II in ED90 (see below).

The compound of formula I and also the compound of formula II can also be used for the comparison of different test systems on different animal species, this provides a further commercial applicability. By comparing the blood levels in different animal species, different animal models can thus be compared.

Those from the compounds of the present invention under physiological conditions releasable or as starting compounds for the preparation of compound of formula I serving compound of formula II, or their salts, exhibit an inhibitory effect on viral aspartate proteases, in particular a gag-protease inhibitory effect. First of all, in the tests described below, in concentrations from 10~<6> to 10~<9> mol/l, they inhibit the action of the gag protease of HIV-1 and HIV-2 and are therefore suitable as a remedy against diseases that are caused by these retroviruses, e.g. against AIDS or its benefits.

The blood level or the compound of formula II can be determined analogously to the methods mentioned for the compound of formula I above.

The ability of the compound of formula II to inhibit the proteolytic activity of e.g. HIV protease, allows e.g. demonstrate according to the method described by von J. Hansen et al., The EMBO Journal 7, 1785-1791 (1988). In this, the inhibition is measured by the effect on gag protease on substrate, which is a fusion protein expressed in E. coli from gag precursor protein and MS-2. The substrate and its cleavage product are separated through polyacrylamine gel electrophoresis and made visible by immunoblotting with monoclonal antibodies against MS-2.

In a further simple processable test, it is possible to determine quantitative calculation and a synthetic peptide is used as substrate for gag protease, which corresponds to the cleavage site of gag precursor protein. This substrate and cleavage product can be measured by high pressure liquid chromatography (HPLC).

For example, it becomes analogous to Richards, A.D., et al., J. Biol. Chem. 265, (14), 7733-7736 (1990) described method as substrate used a recombinant HIV-1 protease (preparation according to Billich, S., et al., J. Biol. Chem. 263(34), 17905-17908 (1990) a synthetic chromophore peptide (e.g. HKARVL[N02]FEANleS (Bachem, Switzerland) or an icosapeptide such as RRSNOVSQNYPIVQNIQGRR (prepared by peptide synthesis according to a known method: J. Schneider, et al., Cell 54, 363-368

(1988)), which corresponds to the cleavage site of gag precursor protein. This substrate and cleavage product can be measured by high pressure liquid chromatography (HPLC). Here, a testing inhibitor of formula II is dissolved in dimethylsulfoxide; the enzyme test is carried out by adding the inhibitor in a suitable dilution in 20 mM g<->morpholinoethanesulfonic acid (MES) buffer pH 6.0 to the assay mix of 67.2 pM of the above-mentioned chromophoric peptide in 0.3 M sodium acetate, 0.1 M NaCl pH 7.4 or 122 µM of the above-mentioned icosapeptide in 20 mM MES buffer pH 6.0. The size of the mixture is 100 µl. The reaction is started by adding in the first row 1 pl, in the next row 10 pl HIV-1 protease and in the first case after 15 minutes by adding 100 pl 0.3 p ECIO4, in the second case after an hour's incubation at 37°C and stopped at 10 µl 0.3 M HCIO 4 . The reaction products are quantified after centrifugation of the sample for 5 minutes at 10,000 x g in 100 µl (mixture with chromofort peptide) or 20 µl (icosapeptide mixture) of the obtained supernatant and after application to a 125 x 4.6 mm Nucleosil C18-5p-HPLC column (Macherey & Nagel, Duren) and elution by measuring peaks for the cleavage product of formula II at 280 nm (mixture with chromophoric peptide) or at 215 nm (mixture with icosapeptide), gradient: 100$ El.1 -+ 509é El. 1/5056 El.2 (El.l: 7556 acetonitrile, 9056 H2 O, 0.156 trifluoroacetic acid (TFA); El.2: 7556 acetonitrile, 2556 H2 O, 0.0856 TFA) during 15 minutes; flow rate 1 ml/min.

Here, preferably ICsg values (IC50 = the concentrations at which the activity of HIV-1 protease in relation to a control without an inhibitor decreases by 5056) from approx. 10"<6> to 10~q M, especially from about 10"<7> to about 10"<8>M.

In a further test, it turns out that in connection with formula I the releasable compounds with formula II cells, which are normally infected by HIV, are protected before such an infection or at least make such an infection slower. Here, human T-cell leukemia cell line MT-2 (Science 229, 563

(1985)), which is extremely sensitive to the cytophagic effect of HIV, incubated with HIV alone or with HIV in the presence of the compounds according to the invention and assessed after a few days of viability of the cells thus treated.

Here, the MT-2 cells are maintained in RPMI 1640 medium (Gibco, Switzerland; RPMI 1640 contained in an amino acid mixture without L-Gln), which is supplemented with 1056 heat-activated fetal calf serum, L-glutamine, Hepes (2-[4 -(2-hydroxyethyl)-l-piperazino]-ethanesulfonic acid) and standard antibiotics, moistened with air at 37° C with 556 CO2 • 50 ul of the relevant test compound in the culture medium and 100 ul of HIV-1 in the culture medium (800 TCID50 /ml)

(TCID50 = Tissue Culture Infectious Doses 50 = dose, which infects the MT-2 cells with 5056) is added to 4xl0<3 >exponentially growing MT-2 cells in 50 µl of culture medium per immersion in 96-well microtiter plates. Parallel mixtures of an additional microtiter plate with cells and test compounds yield 100 µl of virus-free culture medium. After 4 days of incubation, reverse transcriptase (RT) activity is measured in 10 µl of cell supernatant. RT activity is determined in 50 mM Tris (α,α,α-tris(hydroxymethyl)methylamine, Ultra pur, Merck, Germany) pH 7.8; 75 mM KCl, 2 mM dithiothreitol, 5 mM MgCl 2 ; 0.05$ Nonidet P-40 (Detergent: Sigma, Switzerland); 50 pg/ml polyadenylic acid (Pharmacia, Sweden); 1.6 pg/ml dT(12-18) (Sigma, Switzerland). The mixture is filtered off through an acrodisc filter (0.45 p; Gellman Science Incw Ann Arbor) and stored at -20° C. To samples of this solution, 0.156 (v/v) [alpha-<32>P]dTTP to achieve a final radioactivity of 10 pCi/ml. 10 µl of the culture supernatant is applied to a new 96-well microtiter plate and to these 30 µl of said RT cocktail is added. After mixing, the plates are incubated for 1.5 to 3 hours at 37°C. 5 µl of this reaction is transferred onto Whatman DE81 paper (Whatmat). Dried filters are washed 3 times for 5 minutes with 300 mM NaCl/25 mM Tri-sodium citrate and 1 time with 9556 ethanol and air-dried again. The determination takes place in a Matrix Packard 96-well counter (Packard). The ED90 value is calculated and defined as the lowest concentration of the test compound in question, which lowers the RT activity by 9056 compared to the

treated the cell mixtures not treated with test substance. The RT activity is thus a measure of HIV-1 multiplication.

The compound with hydroxy in place of R5 thus shows an ED90 of 10-<5> to 10"<8> M, preferably from about 5 x 10~<7> to 5 x 10"<8> M.

Particularly preferred is a compound of formula I, where R^ and Rg mean N-methoxycarbonylvalyl, R2, R4, R^ and Rg mean hydrogen, R3 means benzyl or further cyclohexylmethyl, R5 means lower alkanoyloxy, especially acetyloxy, or pyridylcarbonyloxy, especially 2- pyridylcarbonyloxy, and R7 means cyclohexylmethyl and further benzyl, as well as pharmaceutically usable salts thereof, in particular an isomer of these compounds, in which R3 and R5 bearing carbon atoms are in (S) configuration.

Particularly preferred is also a compound of formula I, where R1 and Rg independently mean N-lower alkylcarbonylvalyl, R2 means hydrogen, R3 means phenylmethyl or cyclohexylmethyl, R4 means hydrogen, R5 means loweralkylloweralkanoyloxy or pyridylcarbonyloxy, R5 means hydrogen, R7 phenylmethyl or cyclohexylmethyl. and Rg means hydrogen, or a pharmaceutically acceptable salt thereof.

Particularly preferred of these compounds are

1- [2 ( S ) - (2-pyridy 1 -carbonyl )oxy-3( S )-(tert-butoxy-carbonyl )amino-4-phenyl-butyl]-1 - [cyclohexylmethyl] - 2-[ tert-butoxy-carbonyl]hydrazine of formula I, or a pharmaceutically acceptable salt thereof.

Particularly preferred are the compounds mentioned in the examples or their salts.

The compound of formula I and salts of such compounds with at least one salt-forming group are obtained by methods known per se, e.g. in that one

a) acylates a hydroxy compound of formula II,

where the residues have the aforementioned meaning as in connection with formula

I, with a carboxylic acid of formula III,

or a reactive acid derivative thereof, where R5 has the aforementioned meaning as in connection with formula I, where the free functional groups in the starting materials with formulas II and III, which are not to participate in the reaction, are possibly present in protected form, and split off the protective groups present, or

b) condenses an amino compound of formula

where the residues have the aforementioned meaning, with an acid of formula

or a reactive acid derivative thereof, where R9 > has the aforementioned meaning, in which the free functional groups, with the exception of those that participate in the necessary reaction, are in protected form, and cleave off existing protective groups, or

c) condenses an amino compound of formula

where the residues have the above-mentioned meaning, with an acid with

formula

or reactive acid derivative thereof, where » has the aforementioned meaning, in which free functional groups, with the exception of those that participate in the necessary reaction, are present in protected form, and cleave off existing protective groups, or

d) for the preparation of a compound of formula I, where R^ and Rg mean two identical residues and the other residues have the aforementioned

meaning, condenses a diamino compound of formula

where the residues have the meaning mentioned above, with an acid or reactive acid derivatives suitable for the introduction of identical residues R-^ and Rg, where R^ and Rg have the meaning mentioned above, whereby free functional groups with the exception of those which necessarily participate in reaction exists in a protected form, and splits off existing protective groups, or

e) cleaves in a compound of formula I',

where Ryt means hydrogen and the other residues have the aforementioned

meaning, by substitution with a compound of formula

XII,

where X is a cleavable group and R7 has the meaning as in formula I, the residue introduces R7, in which a free functional group is present with the exception of those that participate in the reaction in protected form, and optionally cleaves the protective group present, or

f) in a connection with formula I, where the substituents have the meaning mentioned above with the proviso that the one in question

the compound of formula I is at least protected with a functional group with a protecting group, cleaves off the protecting group and optionally transfers the compounds of formula I obtained according to the above-mentioned process steps a) to f) with at least one salt-forming group to its salt

or an obtainable salt to the free compound or another salt and/or separates the possibly obtained isomer mixtures and/or converts a compound of formula I according to the invention into another compound of formula I according to the invention.

The aforementioned methods are described in more detail below; unless otherwise stated, the residues R , R 3 , R 4 , R 5 , R fc , R 7 and R 9 have the meaning as the aforementioned meanings in the compounds of formula I:

Method a) (Acylation of a hydroxy group) The acylation of the hydroxy group takes place e.g. in a manner known per se using an acid of formula III, where R5 has the aforementioned meaning except for aminocarbonyloxy or a residue of an N-substituted carbamic acid, or a reactive derivative thereof, bound over its aminocarbonyloxy group. As a reactive derivative, it is e.g. optionally with a carboxylic acid of formula IX

where R5" is an acyloxy as defined above, occurring acyl residue and there means a reactively activated hydroxy, (the compounds of formula IX thus contain, instead of a hydroxy functional bound to the carbonyl group, reactively activated hydroxy, preferably as subsequently defined). The free carboxylic acid of formula III can e.g. be prepared with strong acids such as halogenated, sulphurous, sulphonic or carboxylic acids or acid ion exchangers, e.g. by chloric, bromic or iodic acid, sulfuric acid, a possibly e.g. with halogen-substituted alkanecarboxylic acid or with an acid of formula III, preferably with an excess of acid of formula III, necessary during the formation of rising reaction water by water binding agent, during azeotropic distillation of reaction water or during extractive esterification, by

acid anhydrides especially inorganic or above all organic acid anhydrides, e.g. carboxylic anhydride such as lower alkane carboxylic anhydrides (except formic anhydride), e.g. acetic anhydride, or with suitable activation or coupling reagents of the following type, especially also in situ. R5»-Z^ can in particular stand for a carboxylic acid azide (Z^ = azido; obtainable, for example, by reaction of a corresponding acid ester with the corresponding hydrazide and treatment with nitric acid); for a carboxylic acid halide (Z^ = halogen, above all chlorine or bromine), especially an acid chloride or bromide, such as e.g. is formed by reaction with organic acid halides, in particular with oxalyl dihalides such as oxalyl dichloride, with organic acid halides e.g. with acid halides of phosphorus or sulphur, such as phosphorus trichloride, phosphorus bromide, phosphorus pentachloride, phosphorus pentaramide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride or thionyl bromide, or above all under gentle conditions with tetralower alkyl-α-halogenamines, e.g. tetramethyl-a-halogenoenamines, in particular 1-chloro-N,N,2-trimethyl-l-propenamine (preferably by reaction in inert solvents, in particular chlorinated hydrocarbons such as methylene chloride or chloroform or ethers such as diethyl ether, dioxane or tetrahydrofuran, at preferred temperatures between -78 and 50°C, especially at -60 to 30°C, e.g. between -10 and room temperature (cf. Devos, A., et al~-, .J.C.S. Chem. Commun. 1979, 1180-81 and Haveaux, B., et al., Org. Synth. 59,

26 (1980))), where they obtained the acid halides, e.g. acid chloride of formula IX, where Z^ means chlorine, can also be used directly in situ, e.g. by reaction with the compound of formula II in the presence of tertiary nitrogen bases such as pyridine and/or dimethylaminopyridine (DMAP, which is preferably added in catalytic amounts), at preferred temperatures between -20 and 50°C, in particular between 0°C and room temperature); for an activated ester where Z^ means a residue of an alcohol with electron-withdrawing substituents, in particular cyanomethoxy or aryloxy, where aryl preferably means phenyl or naphthyl, which may be substituted with halogen, nitro and/or cyano, one or more times, f .eg nitrophenoxy such as 4-nitrophenoxy or 2,4-dinitrophenoxy, or polyhalophenoxy, such as pentachlorophenoxy; or for a symmetrical or preferably asymmetric acid anhydride, which can for example be formed by the action of a salt, eg a alkali metal salt of an acid of formula III or its reaction partners, preferably a lower alkane carboxylic acid such as acetic acid, as a sodium or potassium salt, on a complementary acid halide, particularly in the case le reaction with a salt of a carboxylic acid of formula III of a carboxylic acid halide, e.g. chloride, as acetyl chloride in the case of reaction of a carboxylic acid halide of formula IX, where Z-^ means halogen, e.g. chlorine or bromine, with a salt of a lower alkane carboxylic acid, especially sodium or potassium acetate. Carbodiimides, e.g. N,N'-di-C1-C4-alkyl- or N,N<»->di-C5-C7-cycloalkyl carbodiimide, such as diisopropylcarbodiimide or N,N<*->dicyclohexyl carbodiimide, advantageously during addition of an activation catalyst such as N-hydroxysuccinimide or optionally, e.g. by halogen, C₁-C₁-alkyl or C₁-C₁-alkyl, substituted N-hydroxy-benzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, C₁-C₄-alkylhaloformate, e.g. . isobutyl chloroformate, suitable carbonyl compounds, e.g. N,N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, suitable acylamino compounds, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or suitable phosphorylcyanamide or -azide, e.g. diethylphosphorylcyanamide or diphenylphosphorylazide, further triphenyl-phosphine-disulfide or 1-C1-C4-alkyl-2-halogen-pyridinium-halide, e.g. 1-methyl-2-chloropyridinium iodide. If in connection with formula III there are two free carboxy groups, e.g. in carboxyl lower alkanoic acids, such as 3-carboxypropanoic acid, an internal anhydride can also be present as an activated acid derivative, e.g. succinic anhydride. ;Z± preferably means halogen, such as chlorine or bromine, as well as acyloxy, e.g. lower alkanoyloxy, such as acetyloxy. The reactions can be carried out under per se known reaction conditions, at normal temperatures in the presence and especially in the case of the use of lower alkanoyloxy hydrides for activation of carboxylic acid with formula III, absence of inert solvents or diluents, e.g. in acid amides, e.g. carboxylic acid amides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPTJ), or amide organic acids, such as hexamethylphosphoric acid triamide, ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons such as haloalkanes, e.g. methylene chloride or chloroform, ketones such as acetone, nitriles such as acetonitrile, acid anhydrides such as acetic anhydride, esters such as acetic acid ethyl ester, bisalkanesulfines such as dimethylsulfoxide, nitrogen heterocycles such as pyridine or mixtures of these solvents, in particular in anhydrous solvents or solvent mixtures, where the relevant suitable solvents can be selected from among the above-mentioned reactions, if it is reasonable and appropriate, using salts of the suitable compounds, in particular of metal salt-used carboxylic acids such as alkali or alkaline earth metal salts, e.g. sodium or potassium salts in the absence or presence of catalysts such as dimethylaminopyridine, condensing agents or neutralizing agents, such as tertiary nitrogen bases, e.g. pyridine, triethylamine, N-methylmorpholine, dimethylaminopyridine or ethyldiisopropylamine, according to reaction type and/or reaction participants under atmospheric pressure or in a closed apparatus, under normal pressure and further under elevated pressure, e.g. by a pressure that occurs in the reaction mixture under the reaction conditions in a closed tube, and/or in an inert atmosphere, e.g. under an argon or nitrogen atmosphere. It is preferred with reaction conditions that are each specifically mentioned or are primarily analogous to the examples mentioned. The course of the reaction is suitably carried out using usual analytical methods, in particular with thin-layer chromatography. From these reaction conditions one can choose from the suitable described reactions in the text, where specific mentioned reaction conditions are particularly preferred. The reaction according to the invention is preferably carried out under mild conditions, particularly in temperatures between -10°C and 60°C, e.g. at 0°C to room temperature, or slightly elevated temperatures at approx. 50°C, e.g. at approx. 0"C to room temperature. Both reaction with a carboxylic acid halide of formula IX, where Z\ means halogen such as chlorine or bromine, and also by reaction with an anhydride, in particular with a symmetrical anhydride (Z^ = 0-^5")» use in particular in relation to the compound of formula I approximately equimolar amounts or an excess of a corresponding compound of formula IX (halide or R 5»-0-R 5»)> for example 0.95- to 10 times the molar amount. ;Preferred compounds of formula II for method a) is the starting compound of formula ;;where the residues have the aforementioned meanings as in connection with formula I, as well as the salts of the aforementioned compounds, provided that salt-forming groups are present. ;Functional groups in the starting materials, their conversion should be avoided , especially carboxy, amino, or hydroxy, and sulfo groups, can be protected with suitable protecting groups (conventional protecting groups), which are used in the usual way in the synthesis of peptide compounds, but also of cephalosporins and penicillins lliners as well as nucleic acid derivatives and sugars. These protective groups can already be present in the first step, and must protect the relevant functional groups against unwanted side reactions such as acylations, etherification, esterification, oxidations, solvolysis, etc. In the specific cases, the protective groups can effect a selective, e.g. stereoselective course of turnover. Characteristic of the protective groups is that they can be split off easily, i.e. without any desired side reactions, e.g. solvolytic, reductive, proteolytic or also enzymatic, e.g. also under physiological conditions and above all that they are no longer present in the final products. Protection of functional groups by such protecting groups, protecting groups themselves, as well as their cleavage reactions are e.g. described in the standard work 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 Chemnie", Houben-Weyl, 4th edition, volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosåuren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Mono-saccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974. ; A carboxy group is e.g. protected as an ester group, which under mild conditions is selectively cleavable. A carboxy group protected in esterified form is primarily esterified with a lower alkyl group, which 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 with suitable substituents. A protected carboxy group which is esterified with a lower alkyl group is e.g. methoxycarbonyl or ethoxycarbonyl. A protected carboxy group which is esterified with a lower alkyl group, which is branched in the 1-position of the lower alkyl group, is e.g. tert-lower oxycarbonyl, e.g. tert-butoxycarbonyl. A protected carboxy group which is esterified with a lower alkyl group, which is in the 1- or 2-position in the lower alkyl group substituted with suitable substituents is e.g. arylmethoxycarbonyl with one or two aryl residues, where aryl is unsubstituted or substituted, e.g. with lower alkyl, e.g. tert-lower alkyl, such as tert-butyl, lower alkoxy, e.g. methoxy, hydroxy, halogen, such as e.g. chlorine and/or nitro mono-, di- or tri-substituted phenyl, e.g. benzyloxycarbonyl, with the aforementioned substituents of substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl or 4-methoxybenzyloxy-carbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted with the aforementioned substituents, e.g. di-(4-methoxyphenyl)-methoxycarbonyl, further also a lower alkyl group esterified carboxy, where the lower alkyl group is substituted in the 1- or 2-position with suitable substituents, such as 1-lower alkyllower alkylcarbonyl, e.g. methoxy-methoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthiolower oxycarbonyl, e.g. 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, where the aroyl group optionally represents e.g. with halogen, such as bromine-substituted benzoyl, e.g. phenacetyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, as well as 2-(trisubstituted silyl)-lower methoxycarbonyl, where the substituents are independent of each other an optionally, e.g. with lower alkyl, lower alkoxy, aryl, halogen, and/or nitro substituted aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon residue, e.g. as above substituted lower alkyl, phenyl lower alkyl, cycloalkyl or phenyl, e.g. 2-trilower alkylsilyl lower oxycarbonyl, such as 2-trilower alkylsilyl ethoxycarbonyl, e.g. 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethylsilyl)ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl. A carboxy group can also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is e.g. a tri-lower alkylsilyloxycarbonyl group, e.g. trimethylsilyloxycarbonyl. The silicon atom in the silyloxycarbonyl group can also be substituted with two lower alkyl groups, e.g. methyl group and the amino group or the carboxy group with an additional molecule of formula I. The connection with such protective groups allows e.g. prepared with dimethylchlorosilane as silylating agent. A protected carboxy group is preferably tert-lower carboxycarbonyl, e.g. tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl. A protected amino group can be protected with an amino protecting group, e.g. in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or present as an azido group. In a corresponding acylamino group, acyl is e.g. the acyl residue of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially one possibly e.g. with halogen or aryl substituted lower alkane carboxylic acid or optionally e.g. with halogen, lower alkoxy or nitro-substituted benzoic acid, or preferably a carboxylic acid half-ester. Such acyl groups are e.g. lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halolower alkanoyl, e.g. 2-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, optionally e.g. with halogen, lower alkoxy or nitro substituted benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably branched in the 1-position of the lower alkyl radical or in the 1- or 2-position of a suitable substituted lower alkoxycarbonyl, e.g. tert-lower aryloxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl with one, two or three aryl residues, which optionally e.g. represents with lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine and/or nitro mono- or polysubstituted phenyl, e.g. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di-(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl, where the aroyl group is preferably represented by halogen, such as bromine, substituted benzoyl, e.g. phenacyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(trisubstituted silyl)-lower oxycarbonyl, e.g. 2-trilower alkylsilyl lower oxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or triarylsilyl lower oxycarbonyl, e.g. 2-triphenylsilylethoxycarbonyl. ;In an arylmethylamino group, such as e.g. a mono-, di- or especially tri-arylmethylamino group, the aryl residue is particularly optionally substituted phenyl residues, such groups are e.g. benzyl-, diphenylmethyl- or especially tritylamino. In an etherified mercaptoamino group, the mercapto group is primarily present as substituted arylthio or aryllower alkylthio, where aryl e.g. exists with lower alkyl such as methyl or tert-butyl, lower alkoxy such as methoxy, halogen such as chlorine and/or nitro-substituted phenyl, e.g. 4-nitrophenylthio. In a 2-acyl-lower alk-1-enyl residue which can be used as an amino protecting group, acyl, e.g. corresponding residue of a lower alkane carboxylic acid, an optional e.g. with lower alkyl such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or nitro substituted benzoic acid or in particular a carboxylic acid half-ester such as a carboxylic acid-lower alkyl half-ester. Corresponding protecting groups are primarily 1-lower alkanoyl-lower alk-1-en-2-yl, e.g. 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, e.g. lower alkoxycarbonyl-prop-1-en-2-yl, such as 1-ethoxycarbonyl-prop-1-en-2-yl. A silylamino group is e.g. a tri-lower alkylsilylamino group, e.g. trimethylsilylamino or tert-butyl-dimethylsilylamino. The silicon atom in the silylamino group can also be substituted with two lower alkyl groups, e.g. methyl groups and the amino group or the carboxyl group of two molecules in formula I. Compounds with such protective groups allow e.g. prepared with corresponding chlorosilanes, such as dimethylchlorosilane as silylating agent. ;An amino group can also be protected by transfer to a protonated form; as corresponding anions, strong inorganic acids, such as sulfuric acid, phosphoric acid or hydrohalic acids, are especially relevant in the first place, e.g. chlorine or bromine anion, or of organic sulphonic acids such as p-toluenesulphonic acid. Preferred amino protecting groups are lower alkoxycarbonyl, phenyl lower oxycarbonyl, fluorenyl lower oxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl or lower alkoxycarbonyl-lower alk-1-en-2-yl. A hydroxy group can e.g. be protected with an acyl group, e.g. with halogen, such as chlorine, substituted lower alkanoyl such as 2,2-dichloroacetyl or in particular with an acyl residue of a carboxylic acid half-ester mentioned for protection of the amino group. A preferred hydroxy protecting group is e.g. 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl. A hydroxy group can further be protected with trilower alkylsilyl, e.g. trimethylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, an easily cleavable etherified group e.g. an alkyl group, such as tert-lower alkyl, e.g. tert-butyl, an oxa- or a thiaaliphatic or cycloaliphatic, especially 2-oxa- or 2-thialiphatic or -cycloaliphatic hydrocarbon residue, e.g. 1-lower oxylower alkyl or 1-lower alkyl-thiolower alkyl, such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl or 2-oxa- or 2-thiacycloalkyl with 5-7 ring atoms, such as 2- tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, as well as with 1-phenyl lower alkyl such as benzyl, diphenylmethyl or trityl, where the phenyl residue e.g. may be substituted with halogen, e.g. chlorine, lower alkoxy, e.g. methoxy and/or nitro. Two in a molecule occurring, in particular adjacent hydroxy groups or a neighboring hydroxy and amino group can e.g. be protected with a divalent protecting group, such as a methylene group preferably substituted by one or two lower alkyl residues or oxo, e.g. with unsubstituted or substituted alkylidene, e.g. lower alkylidene, such as isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzylidene. ;A protection group, e.g. carboxy protecting group, in connection with the present application is also an easily cleavable way with the protective functional group, e.g. carboxy group connected polymer carrier, such as e.g. is suitable for Merrifield synthesis. Such a suitable polymer carrier is e.g. a by copolymerization with divinylbenzene weakly crosslinked polystyrene resin, which for reversible binding carries a suitable bridging link. ;Release of protective groups also takes place according to the methods described under procedure f) (removal of protective groups). ;Method b) (Condensation for the production of an amide bond) ;In the starting materials of formulas IV and V, functional groups, with the exception of groups that participate in the reaction or that do not react under the reaction conditions, are protected independently of each other with a protective group mentioned under method a) . ;The acids of formula V contain a free carboxy group or reactive derivative thereof, so that reactive acid derivatives of compounds of formula V can also be present, e.g. in the derivative activated ester or reactive anhydrides, further reactive cyclic amides. Reactive acid derivatives can also be formed in situ. Activated esters of carboxylic acids of formula V are particularly unsaturated esters at the connecting carbon atom of the esterified residue, e.g. of vinyl ester type such as vinyl esters (obtainable e.g. by transesterification of a corresponding ester with vinyl acetate; the activated vinyl ester method), carbamoyl esters (obtainable e.g. by treatment of the corresponding acid with an isoxazolium reagent; 1,2-oxazolium - or the Woodward method), or 1-lower oxyvinyl ester (obtainable e.g. by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or amidino-type esters, such as N,N'-disubstituted amidino ester (obtainable e.g. by treatment of the corresponding acid with a suitable N,N'-disubstituted carbodiimide, e.g. N,N'-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amidino ester (obtainable e.g. by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters in particular by electron-withdrawing substituent-signed substituted phenyl esters (obtainable e.g. by treatment of the corresponding acid with a suitable substituted phenol, e.g. 4 -nitrophenol, 4-methylsulfony lphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide; the method by activated aryl residues), cyanomethyl ester (obtainable e.g. by treating the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioester, especially optionally e.g. by nitro, substituted phenyl thioester (obtainable e.g. by treating the corresponding acid with possibly e.g. by nitro-substituted thiophenols, including by means of the anhydride or carbodiimide method; method by activated thiol ester), or especially amino or amido ester (obtainable e.g. by treating the corresponding acid with an N-hydroxyamino or N-hydroxyamide compound, e.g. N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3- dicarboxylic acid imide, 1-hydroxybenztriazole or 3-hydroxy-3,4-dihydro-1,2,3-benztriazin-4-one, e.g. by the anhydride or carbodiimide method; the activated N-hydroxyester method). Internal esters can also be used, e.g. -γ-lactones. Anhydrides of carboxylic acids of formula V can be symmetrical or preferably mixed anhydrides of these acids, e.g. anhydrides with inorganic acids.., such as acid halides, especially acid chlorides (obtainable e.g. by treating corresponding acids with thionyl chloride, phosphorus pentachloride, phosgene, l-chloro-N,N,2-trimethyl-l-propenamine (reaction conditions as mentioned under method a)) or oxalyl chloride; acid chloride method; azides (obtainable e.g. from corresponding acid esters and by corresponding hydrazine and its treatment with nitric acid; azide method), anhydrides with hydrocarbon half-esters, e.g. hydrocarbon lower alkyl half esters (obtainable by treatment with the corresponding acid with formic acid lower alkyl esters or with a l-lower alkyl oxycarbonyl-2-lower alkyl oxy-1,2-dihydroquinoline; the method for mixed O-alkyl hydrocarbon acid anhydrides), or anhydrides with dihalogenated, especially dichlorinated phosphoric acid (obtainable f .e.g. by treating the corresponding acid with phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (e.g. such as can be obtained with phenyl-N-phenylphosphoramidochloridate or by reacting alkylphosphoric acid amides in the presence of sulphonic acid anhydrides and/or racemization-reducing additives -tives, such as N-hydroxybenztriazole, or in the presence of cyanophosphonic acid diethyl ester) or with phosphoric acid derivatives, or anhydrides with organic acids such as mixed anhydrides with organic carboxylic acids (obtainable e.g. by treating the corresponding acid with an optionally substituted lower alkane or phenyl lower alkane carboxylic acid halide, eg phenylacetic acid, pivali n acid or trifluoroacetic acid chloride; method for mixed carboxylic acid anhydrides) or with organic sulphonic acids (achievable e.g. by treating a salt such as alkali metal salt, corresponding acid with a suitable organic sulphonic acid halide such as lower alkane or aryl, e.g. methane or p-toluene sulphonic acid chloride; method by mixed sulphonic acid anhydrides) as well as symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of carbodiimides or of 1-diethylaminopropyne; method for symmetrical anhydrides). Suitable cyclic amides of carboxylic acids of formula V are particularly amides with a five-membered diazacyclic aromatic character, such as amides with imidazoles, e.g. imidazole (obtainable e.g. by treating the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, e.g. 3,5-dimethyl-pyrazole (obtainable e.g. via the acid hydrazide by treatment with acetylacetone; pyrazole method). As mentioned, derivatives of carboxylic acids of formula V, which are used as acylating agents, can also be formed in situ. Thus, one can e.g. form N,N'-disubstituted amidino ester in situ, by bringing the mixture of the starting materials of formula IV and the acid used as acylating agent in the presence of a suitable N,N'-disubstituted carbodiimide, e.g. N,N'-cyclohexylcarbodiimide, to reaction. Furthermore, amino or amido esters can be formed which use acid as acylating agent in the presence of the acylation starting material of formula IV, by reacting "the mixture of corresponding acid and amino starting materials in the presence of an N,N'-di-substituted carbodiimide , eg N,N'-dicyclohexylcarbodiimide, and an N-hydroxyamine or N-hydroxy-amide, eg N-hydroxysuccinimide, optionally in the presence of a suitable base eg 4-dimethylamino-pyridine. by reaction with the N,N,N',N'-tetraalkyluronium compound, such as O-benztriazol-lyl-N,N,N',N'-tetra-methyl-uronium-hexafluorophosphate, 0-(1 , 2 -dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate or O-(3,4-dihydro-4-oxo-1,2,3-benz-triazole-3 -yl)-N,N,N'N'-1etramethyluronium tetrafluoroborate, which is activated in situ Finally, phosphoric anhydrides of carboxylic acids of formula V can be prepared in situ, by reacting an alkylphosphoric acid amide as hexamethylphosphoric acid triamide in the presence of a sulfonic anhydride, which 4- toluenesulfonic anhydride with a salt such as tetrafluoroborate, e.g. sodium tetrafluoroborate or with another progeny of hexamethylphosphoric acid triamide such as benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemization-reducing additive such as N-hydroxybenztriazole. ;The amino group in the compound of formula IV which participates in the reaction preferably carries at least one reactive hydrogen atom, particularly when the carboxy or protective groups thus reacting are present in a reactive form; however, they can also be derivatized themselves, e.g. by reaction with a phosphite such as diethylchlorophosphite, 1,2-phenylenechlorophosphite, ethyldichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite. A derivative of such a compound with an amino group is e.g. also a carbamic acid halide or an isocyanate, where the amino groups that participate in the reaction are substituted with halocarbonyl, e.g. chlorocarbonyl or converted as an isocyanate group, where in the latter case only the compound of formula I is available, which carries a hydrogen atom on the nitrogen atom of the amide group formed through the reaction. Condensation for producing an amide bond can be carried out in a manner known per se, such as e.g. described in standard works such as "Eouben-Weyl, Methoden der organischen Chemie", 4th edition, Volume 15/11 (1974), Volume IX (1955) Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" ( E. Gross and J. Meienhofer, Eg.), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer Verlag, Berlin 1984. ;Condensation of a free carboxylic acid of formula V with a corresponding amine of formula IV can in particular be carried out in the presence of a common condensing agent, or using carboxylic acid anhydrides or carboxylic acid halides, such as -chlorides or of activated carboxylic acid esters, such as p-nitrophenyl esters. Common condensation agents are e.g. carbodiimides, e.g. diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, further suitable carbonyl compounds, e.g. N,N'-carbonyldiimidazole, 1,2-oxazolium compounds, e.g. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline, N,N,N',N'-tetraalkyluronium compounds, such as 0-benztriazol-1-yl-N,N,N',N'-tetra- methyluronium hexafluorophosphate, further activated phosphoric acid derivatives, e.g. diphenylphosphorylazide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride or 1-benztriazolyloxy-tris-(dimethylamino)-phosphonium-hexafluoro-phosphate. If it is desired to add an organic base, preferably a tertiary amine, e.g. a trilower alkylamide with bulky residues, such as ethyldiisopropylamine or triethylamine, and/or a heterocyclic base, e.g. 4-dimethylaminopyridine or preferably N-methylmorpholine or pyridine. Condensation of activated ester, reactive anhydride or reactive cyclic amide with corresponding amines is usually carried out in the presence of an organic base, e.g. simple trilower alkylamines, e.g. triethylamine or tributylamine, or one of the aforementioned organic bases. If desired, a condensation agent is additionally used as described for free carboxylic acids. Condensation of acid anhydrides with amines can e.g. take place in the presence of inorganic carbonates, e.g. ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (optionally together with a sulfate). ;Carboxylic acid chlorides e.g. derived chlorocarboxylic acid derivatives of those in the acids of formula V, or sulphonic acid chlorides are condensed with corresponding amines preferably in the presence of an organic amine, e.g. the aforementioned trilower alkylamines or heterocyclic bases, optionally in the presence of a hydrogen sulfate. Condensation is preferably carried out in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, e.g. in a carboxylic acid amide, e.g. formamide or dimethylformamide, a halogenated hydrocarbon e.g. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone e.g. acetone, a cyclic ether e.g. tetrahydrofuran, an ester e.g. acetic acid ethyl ester or a nitrile e.g. acetonitrile or in a mixture thereof, possibly at a lowered or elevated temperature, e.g. in a temperature range from approx. -40°C to approx. +100°C, preferably from approx. -10°C to approx. +50"C, in that case when using arylsulfonyl residues is also at approx. +100 to +200"C, and possibly under inert gas, e.g. nitrogen or argon atmosphere. ;Also aqueous, e.g. alcoholic, e.g. ethanol or aromatic solvents, e.g. benzene or toluene is possible. In the presence of alkali hydroxides as bases, acetone can optionally also be used. Condensation can also take place as a known solid-phase synthesis technique, such as e.g. is described by R. Merrifield and described e.g. in Angew. Chem. 97, 801-812 (1985), Naturwissenschaften 71, 252-258 (1984 ) or in R.A. Houghton, Proe. Nati. Acad. Pollock. USA 82, 5131-5135 (1985). ;Depending on the starting compounds used, the residues R^ and Rg in the obtained compounds of formula I may be identical or different from each other. ;Release of the protecting groups also takes place according to the methods described under method f) (protection group removal). Method c) (Preparation of an amide bond) In the starting materials of formula VI and VII, functional groups, with the exception of groups that will participate in reaction or those that do not react under the reaction conditions, are independently protected with one of those under method a) said protective groups. The method is completely analogous to that mentioned under method b), when instead of the compound of formula IV, those of formula VI are used and instead of the compound of formula V, the compound of formula VII is used. Depending on the starting compounds used, the residues R^ and Rg in the obtained compounds of formula I may be identical or different from each other. ;In the reaction of method b), but also in c) and d), in the individual cases acyl hydrolysis of the acyl residue can also occur in the acyloxy R5 on the nitrogen atom, linked to Rg; Analogous side reactions are possible by method c) or ;d). The release of protective groups takes place according to the methods described in procedure f) (removal of protective groups). ;Procedure d) (Preparation of amide compounds) ;In the starting materials of formula VIII and by introducing identical residues R^ and Rg» suitable acids or their reactive derivatives, functional groups, which do not participate in the reaction or do not react under the reaction conditions, are protected regardless of each other with one of the aforementioned protecting groups under method a). The acids suitable for introducing identical residues R^ and Rg preferably have one of the formulas V or VII, or they exist as reactive derivatives of such an acid as described above. Preferred as optionally protected starting compounds of formula VIII are those described in the transition compounds section as preferred. The conditions for the method are analogous to those mentioned under method b) where, instead of the compound of formula IV, those of formula VIII are used and instead of the compound of formula V, those of formula V or VII are used. ;Release of protective groups takes place according to the described methods under procedure f) (protection group cleavage). ;Procedure e) (Alkylation of a secondary nitrogen atom) ;In the starting materials of formula I' and for introducing the residue R7 suitable compounds of formula XII or their reactive derivatives are functional groups, which do not participate in reaction or which do not react under the reaction conditions, and these are independently protected with the aforementioned protecting groups under method a). A cleavable group X is in particular a nucleofuge cleavable group selected from hydroxy esterified with a strong organic or inorganic acid, which with a mineral acid e.g. halohydrogen acid such as hydrogen chloride, hydrogen bromide or hydrogen iodide or a strong organic sulphonic acid such as a possibly, e.g. with halogen, such as fluorine, substituted lower alkanesulphonic acid or an aromatic sulphonic acid, e.g. an optionally lower alkyl such as methyl, halogen, such as bromine and/or nitro substituted benzenesulfonic acid, e.g. a methanesulfonic, p-bromotoluenesulfonic acid or p-toluenesulfonic acid esterified hydroxy or with nitrogen hydrogen esterified hydroxy. ;Substitution can proceed under conditions with a nucleophilic substituent of first or second order. For example, a compound of formula XII can be used, especially one where X has a leaving group with a higher polarizability in the electron hole, e.g. iodine, in a polar aprotic solvent, e.g. acetone, acetronitrile, nitromethane, dimethylsulfoxide or dimethylformamide. The reaction can also optionally take place as a solvent in an organic solvent, e.g. ethanol, tetrahydrofuran or acetone, where it is mixed in. The substitution reaction is carried out at room temperature or at a lowered or elevated temperature, e.g. in a temperature range from approx.-40°C to approx. 100°C, preferably from approx. -10°C to approx. 50"C, and possibly under an inert gas, e.g. nitrogen or argon atmosphere. ;Release of protected groups takes place possibly according to the described methods under method f) (protection group removal). ;Procedure f) (Protection group removal) ;Removal of protective groups that do not is a constituent of the desired end product with formula I, e.g. carboxy, amino, hydroxy, mercapto and/or sulfo protecting group, takes place in a manner known per se, e.g. by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis or by means of reduction, in particular hydrogenolysis or chemical reduction as well as photolysis, optionally stepwise or simultaneously, where enzymatic methods can also be used. Removal of the protective groups is, for example, described in method a) in the section above of protective groups in mentioned standard works. ;Thus, for example, protected carboxy, e.g. tert-lower carboxycarbonyl, in the 2-position with a trisubstituted silyl group or in the 1- position with lower alkoxy or lower alkylthio-substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl be transferred by treatment with a suitable acid, such as formic acid, hydrogen chloride or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole to free carboxyl. From lower alkoxycarbonyl can also be used with bases such as hydroxide, e.g. alkali metal hydroxides such as NaOH or KOH, release carboxy. Any substituted benzyloxycarbonyl can e.g. be released by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitable substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can, also by reduction, e.g. by treatment with an alkali metal such as sodium dithionite, or with a reducing metal, e.g. zinc or a reducing metal salt, such as chromium II salt, e.g. chromium II chloride, in the usual way in the presence of a hydrogen-releasing agent, which together with the metal can obtain nascent hydrogen, as an acid, primarily a suitable carboxylic acid as a possibly e.g. with hydroxy-substituted lower alkane carboxylic acid, e.g. acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, where water is preferably added to be transferred to free carboxy. By treatment with a metal or metal salt as described above, 2-halogen lavereal oxycarbonyl (possibly after conversion of a 2-bromo lavereal oxycarbonyl group to a corresponding 2-iodo lavereal oxycarbonyl group) or aroylmethoxycarbonyl can also be converted to free carboxyl. Aroylmethoxycarbonyl can likewise be treated with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodate. 2-(Trisubstituted silyl)-lower real oxycarbonyl as 2-trilower alkylsilyl lower real oxycarbonyl can also be transferred by treatment with a fluoride anion-giving salt of hydrofluoric acid such as an alkali metal fluoride e.g. sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether ("Kronen ether"), or with a fluoride of an organic quaternary base such as tetralaverealkyl ammonium fluoride or trilaverealalkylaryllaverealkylammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethylsulfoxide e1Lfix . N,N-dimethylacetamide, to free carboxy. As organic silyloxycarbonyl, as trilower alkylsilyloxycarbonyl, e.g. trimethylsilyloxycarbonyl, protected carboxy can be treated solvolytically in the usual way, e.g. with water, an alcohol or acid or besides fluoride, be released as above described. Esterified carboxy can also be released enzymatically, e.g. by esterases or suitable peptidases, e.g. esterified arginine or lysine, as lysine methyl ester, using trypsin. A protected amino group is released in a manner known per se and depending on the protecting group in different ways, preferably by means of solvolysis or reduction. Lavereal oxycarbonylami.no as tert-butoxycarbonylamino can be used in the presence of acid, e.g. mineral acid, e.g. halogen hydrogen, such as hydrogen chloride or sulfuric or phosphoric acid, preferably of hydrogen chloride, or of strong organic acids such as trihaloacetic acid, e.g. trifluoroacetic acid or formic acid in polar solvents such as water or ethers, preferably cyclic ethers such as dioxane, 2-halo-laverealoxycarbonylamino (optionally after conversion of a 2-bromolaverealoxycarbonylamino group into a 2-iodo-laverealoxycarbonylamino group), or directly dissolved in a liquid organic carboxylic acid such as formic acid, aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino, can e.g. by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid, be split off. Aroylmethoxycarbonylamino can also be used when treated with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate and 4-nitrobenzyloxycarbonylamino also when treated with an alkali metal, e.g. sodium dithionite. Optionally substituted diphenylmethoxycarbonylamino, tert-lower alkylamino or 2-(trisubstituted silyl)-lower alkylamino, such as 2-trilower alkylsilyllower oxycarbonylamino, can be cleaved with a suitable acid, e.g. formic acid or trifluoroacetic acid optionally substituted benzyloxycarbonylamino,. e.g. 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, optionally substituted triaryl-methylamino or formylamino, e.g. by treatment with an acid, such as mineral acid, e.g. hydrogen chloride, or an organic acid, e.g. formic acid, acetic acid or trifluoroacetic acid, possibly in the presence of water, and a silylamino-protected amino group is released, e.g. by means of hydrolysis or alcoholysis. One with 2-haloacetyl, e.g. 2-Chloroacetyl protected amino group can, by treatment with thiourea in the presence of a base or a thiolate salt, such as an alkali metal thiolate of thiourea and subsequent solvolysis such as alcoholysis or hydrolysis be released from the resulting substitution products from trifluoroacetylami.no becomes e.g. treated with bases such as alkali metal hydroxides or carbonates such as Na2C03 or K2CO3 in polar solvents e.g. alcohols such as methanol, at temperatures between 0 and 100°C, in particular at 40 to 80°C. An amino group protected with 2-(trisubstituted silyl)-lower carboxycarbonyl, such as 2-trilower alkylsilyl lower oxycarbonyl, can also be cleaved off by treatment with a fluoride anion-giving salt of hydrogen fluoride which in connection with the release of a corresponding protected carboxy group and transferred to a free amino group. Likewise, nitrogen-bound silyl such as trimethylsilyl can be cleaved directly on the heteroatom with the help of fluoride ions. In the form of an azido group, protected amino is e.g. transferred by reduction to free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel by reduction by means of mercapto compounds such as dithiothreitol or mercaptoethanol, or also by treatment with zinc in the presence of a acid such as acetic acid. Catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. methylene chloride or also in water or a mixture of water or an organic solvent such as an alcohol or dioxane at approx. 20° C ±.il. 25° C, or, also during cooling or heating. ;One with a suitable acyl group, a tri-lower alkylsilyl group or, in the event of a substituted 1-phenyl lower alkyl protected hydroxy group, is released analogously to a corresponding protected amino group. A hydroxy group protected with 2,2-dichloroacetyl is e.g. released with basic hydrolysis, a with tert-lower alkyl or with a 2-oxa- or 2-thia-aliphatic or ;-cycloaliphatic hydrocarbon residue protected hydroxy group with azidolysis, e.g. by treatment with a mineral acid or a strong carboxylic acid, e.g. trifluoroacetic acid. Two hydroxy groups or a neighboring amino and hydroxy group which together with a divalent protecting group, preferably a lower alkyl mono- or disubstituted methylene group, as with the lower alkylidene, e.g. isopropylidene, cycloalkylidene, e.g. cyclohexylidene, or benzylidene, can be liberated by acid solvolysis, especially in the presence of a mineral acid or a strong organic acid. A tri-lower alkylsilyl group is likewise cleaved by azidolysis, e.g. by mineral acid, preferably hydrogen fluoride or a strong carboxylic acid. 2-halogen lower oxycarbonyl becomes with the above-mentioned reducing agents e.g. reducing metal such as zinc, reducing metal salts such as chromium-II salts or in the case of sulfur compounds, e.g. sodium dithionite and preferably sodium sulphite and carbon disulphur. Where there are several protected functional groups, when desired, the protective groups can be selected so that more than one such group can be cleaved at the same time, e.g. acidolytically, as by treatment with trifluoroacetic acid or with hydrogen and a hydrogenation catalyst, such as a palladium-charcoal catalyst. Conversely, the groups can be selected so that not all of them are cleaved at the same time, but in the desired order, where corresponding intermediate products are obtained. ;Further process precautions ;In the further process precautions that can be carried out as desired, functional groups of the starting compounds, which do not participate in reaction, can be present in unprotected or in protected form, e.g. with one or more of the above-mentioned protecting groups under method ;a). The protective groups can be retained in the final products or removed in whole or in part by one of the methods mentioned in procedure f). Salts of compounds of formula I with at least one salt-forming group can be prepared in a manner known per se. Thus, salts of compounds of formula I with acidic groups can be prepared, e.g. by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. sodium salt of 2-ethylhexanoic acid with organic alkali or alkaline earth metal compounds such as corresponding hydroxides, carbonates or hydrogen carbonates such as sodium and potassium hydroxides, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, preferably using stoichiometric amounts and only a small excess of the salt-forming agent. Acid addition salts of compounds of formula I are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I, which contain acidic and basic salt-forming groups, e.g. a free carboxy group and a free amino group can e.g. be formed by neutralization of salts, such as acid addition salts at the isoelectric point, e.g. with weak bases or when treated with ion exchangers. Salts can be transferred in the usual way to free compounds, metal and ammonium salts, e.g. by treatment with suitable acids and acid addition salts, e.g. by treatment with suitable basic agents. ;Stereoisomeric mixtures, mixtures of diastereomers and/or enantiomers, such as e.g. racemic mixtures can also be separated in a manner known per se by suitable separation procedures into the corresponding isomers. Thus, diastereomer mixtures can be separated by fractional crystallization, chromatography, solvent distribution, etc. into the individual diastereomers. The racemates can, after transfer of the optical antipodes to diastereomers, e.g. by reaction with optically active compounds, e.g. optically active acids or bases be separated by chromatography on optically active compounds of coated column materials or by enzymatic methods, e.g. by selective conversion of only one of both enantiomers. This separation can both take place at the stage of one of the starting products and also of the compounds of formula I themselves. ;For certain chirality centers in connection with formula I, the configuration can be chosen inversely. For example, in the configuration of asymmetric carbon atoms that carry nucleophilic substituents such as amino or hydroxy, by nucleophilic substitution of a different order, possibly after transfer of bound nucleophilic substituents, a suitable nucleofuge leaving group can be exchanged and reaction with an original substituent introduced reagent. In a compound of formula I, a phenyl residue present in R7 can be hydrogenated, preferably by catalytic hydrogenation, particularly in the presence of heavy metal oxides such as rhodium/platinum mixed oxides, e.g. with Nishimura catalyst, preferably in polar solvent such as an alcohol, e.g. methanol or ethanol, at temperatures between 0 and 80°C, in particular between 10 and 40°C, and at a hydrogen pressure of from 1 to 10 atm, preferably at normal pressure. ;Starting materials: ;New starting materials and/or intermediate products as well as methods for their production are likewise subject to the present invention. Preferably, such starting compounds are used and reaction conditions are chosen so that the compounds produced are reached. ;It should be noted that in starting compounds with the formulas IV, VI and VIII, migration of the acyl residue from acyloxy R5 can take place to a nitrogen atom - therefore the above-mentioned methods b), c) and d) are considered to be reserved for these. Method a), e) and f) and their starting compounds are preferably particularly method a) and f). In the preparation of all the starting materials, free functional groups, which do not participate in the reaction, can be present in unprotected or protected form, e.g. protected with the aforementioned protecting groups under the above-mentioned method a). These protecting groups can at suitable times be released with the described reactions under method f). Introduction of the protection groups takes place e.g. as stated in the description of method a). The hydroxy compounds of formula II and further starting compounds used as starting materials are obtained analogously to European patent application No. EP 0 521 827 (published 7 January 1993), preferably by using correspondingly substituted compounds, e.g. by adding a hydrazine derivative with the formula ;where the residues have the above-mentioned meaning, to an epoxide with the formula, preferably with the formula ;where each of the residues has the above-mentioned meaning, whereby free functional groups with the exception of those present in protected form, and split off present protection groups. In the event that a compound of formula XIV A is used, the preferred starting materials mentioned in connection with formula II' are used, under method a). The reaction-participating amino groups of the hydrazine derivative of formula XIII preferably have at least one free hydrogen atom according to the meaning of R7; however, they can also be derivatized themselves, in order to increase the reactivity of the hydrazine derivative. Addition of compounds of formula XIII and epoxide (oxirane) of formula XIV takes place preferably under normal conditions by addition of nucleophiles to epoxides. The addition takes place particularly in aqueous solution and/or in the presence of polar solvents such as alcohols, e.g. methanol, ethanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide or phenols such as phenol, also under anhydrous conditions in apolar solvents such as benzene or toluene, or in benzene/water emulsions possibly in the presence of acidic or basic catalysts e.g. lu"L,. as caustic soda or in the presence of hydrazine-doped solid catalysts such as aluminum oxide in ethers, e.g. diethyl ether, generally at temperatures from about 0°C to reflux temperature, preferably between 20°C and 130°C, possibly under reflux -flow under elevated pressure, e.g. in a bomb tube, where the boiling temperature of the reaction mixture may also be exceeded, and/or under inert gas such as nitrogen or argon, where each of the compounds of formula XIII and XIV may be present in excess, e.g. eg in a molar ratio of 1:1 to 1:100, preferably in a molar ratio of 1:1 to 1:10, especially in a ratio of 1:1 to 1:3.;The starting compounds with the formulas XIII and XIV are known and can, if they are new be prepared by methods known per se, for example from hydrazine or suitable derivatives of compound of formula XIII, from suitable amino acids or their analogues, for example with one of the mentioned side chains R3, the compounds of formula XIV. The compounds of formula XIII are available, for example ig from hydrazine or their suitable derivatives of the formula ; where R-Q means hydrogen or an amino protecting group, as described above under method a), in particular tert-lower alkyloxycarbonyl, such as tert-butoxycarbonyl, aryl lower alkyloxycarbonyl, such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, or one of the above-mentioned acyl-amino protecting groups, by introducing this during the introduction of R7 as defined under method e) with a compound of formula XII under conditions described under method e) or a residue R7 by reaction of a suitable carbonyl compound with free amino group of compound of formula XV or its acylated derivatives and subsequent reduction of the obtained hydrazone to form hydraz.inderivatives of formula ;where the residues in all the aforementioned compounds have the above-mentioned meaning and functional groups in the participating reagents which shall not participating in the reaction is possibly protected, and protection group if it ik ke corresponds to a residue Rg in connection with formula I, is cleaved off and then a residue Rg excluding hydrogen is introduced, optionally by condensation, under the above-mentioned conditions in method b) with acids of formula V or by alkylation with a compound of formula Xla, as defined above. ;The carbonyl compounds suitable for the production of a compound of formula XVI used for the introduction of R7 are known, and are produced by methods known per se or are commercially available aldehydes or ketones, their reactive carbonyl groups after reaction with a compound of formula XV and subsequent reduction of the components with one of the aforementioned residues R7, is preferably cyclohexyl lower alkanealdehyde or phenyl lower alkanealdehyde. Reaction of these carbonyl compounds with compound of formula XVI to corresponding hydrazones takes place during reaction of carbonyl compounds with amines under normal conditions, preferably in polar organic solvents, e.g. ethers, such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic acid amides such as dimethylformamide or esters such as acetic acid ethyl ester or in aqueous solutions, preferably in methanol, further in the presence or absence of acid catalysts, e.g. carboxylic acids such as formic acid or acetic acid or sulphonic acids such as p-toluenesulphonic acid at temperatures between 0°C and the reflux temperature in the reaction mixture, preferably at temperatures from 20°C to the reflux temperature in the reaction mixture. ;Reduction of the obtained hydrazones preferably takes place by hydrogenation in the presence of a suitable catalyst. Suitable catalysts for hydrogenation are metals such as nickel, iron and cobalt or ruthenium, or noble metals or their oxides, such as palladium or rhodium, respectively. their oxides, possibly e.g. applied to suitable carrier materials such as barium sulphate, aluminum oxide or activated carbon or as shell catalysts such as Raney nickel. Common solvents for catalytic hydrogenation are e.g. water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, ether, such as dioxane, chlorohydrocarbons, such as dichloromethane, carboxylic acid amides, such as dimethylformamide or carboxylic acids, such as glacial acetic acid, or mixtures of these solvents. The hydrogenation takes place at temperatures of 10 to 250°C, preferably from room temperature to 100°C and at hydrogen pressure from 1 to 200 bar, preferably from 1 to 10 bar, in conventional apparatus. Particularly preferred for the preparation of compounds of formula XV are the reaction conditions, which are analogous to those described in J. Chem. Soc. Perkin I, 1712 (1975). The compounds of formula XIV are e.g. available by reduction of per se known, commercially available or preparable by a per se known method amino acid or analogues of the formula; where Rio means hydrogen or an amino protecting group mentioned under method a) especially tert-lower oxycarbonyl, such as tert-butoxycarbonyl . the radicals have the aforementioned meaning, preferably to aldehydes of formula where the radicals have the aforementioned meaning (obtainable e.g. from compound of formula XVII A), by reaction of these aldehydes with a ylide compound, preferably a sulfur-ylide compound to an epoxide with formula where the residues have the aforementioned meaning, preferably for compounds with formula ; (achievable e.g . from a compound with formula XVIII A), where the residues have the aforementioned meaning, removal of the protecting group Rio» provided that they do not correspond to the residue Rj in a compound of formula I, and (for the introduction of Rj excluding hydrogen) by acylation of the amino group in the resulting compound with a acid of formula VII, where R^» has the mentioned meaning, under the conditions described under method b), where a compound of formula XIV A is obtained preferably from a starting material of formula XIX A. ;Reduction of amino acids of formula XVII or XVII A to corresponding aldehydes XVIII and XVIII A take place e.g. by reduction to corresponding alcohols and subsequent oxidation to said aldehydes. ;Reduction to alcohols takes place e.g. by hydrogenation of amino acid halides or other activated carboxylic acid derivatives (e.g. with activated hydroxy analogous compound to formula IX, as defined under method a)) under for hydrogenation of the compounds of formula XVI the hydrazones obtained under the mentioned conditions or with complex hydrides which sodium borohydride. Subsequent oxidation of the obtained alcohols preferably takes place with oxidizing agents, which makes it possible to obtain selective (ie without further oxidation of the aldehydes to carboxylic acids) aldehydes of formula XVIII or XVIII A, e.g. with potassium ferrate (K2Fe04) in aqueous as well as brown in organic solvents or organic chromic acid derivatives such as pyridinium dichromate or tert-butyl chromate in inert organic solvents, e.g. chlorinated hydrocarbons such as methylene chloride or chloroform in the presence or absence of basic amines, e.g. trilower alkylamines such as triethylamine at temperatures from -50 to 100°C, preferably at -10 to 50°C, e.g. as described in European patent application EP-A-0 236 734, or primarily by oxidation of the hydroxy group with a sulfoxide such as dimethyl sulfoxide in the presence of a hydroxy group-activating reagent, e.g. a carboxylic acid chloride such as oxalyl chloride, in an inert solvent, e.g. a chlorinated hydrocarbon, such as dichloromethane and/or an acyclic or cyclic ether such as tetrahydrofuran at -80 to 0°C, e.g. -78 to -50°C. ;Also the direct reduction of amino acids to aldehydes is possible, e.g. by hydration in the presence of a partially bound palladium catalyst or by reduction of the corresponding amino acid ester, e.g. lower alkyl esters such as ethyl esters with complex hydrides, e.g. borohydrides, such as sodium borohydride or preferably aluminum borohydrides, e.g. lithium aluminum hydride, lithium tri-(tert-butoxy) aluminum hydride or especially diisobutylaluminum hydride, in apolar solvents, e.g. hydrocarbons or aromatic solvents such as toluene at -100 to 0°C, preferably -70 to -30°C and subsequent conversion to corresponding semicarbazones, e.g. with corresponding acid salts of semicarbazones such as semicarbazide hydrochloride in aqueous solvent systems such as alcohol/water, e.g. ethanol/water, at temperatures between -20 and 60°C, preferably 10 to 30°C and reaction of the obtained semicarbazone with a reactive aldehyde e.g. formaldehyde, in an inert solvent, e.g. an inert polar solvent, e.g. a carboxylic acid amide, such as dimethylformamide at temperatures between -30 and 60°C, preferably 0 to 30°C and then an acid, e.g. a strong mineral acid such as hydrohalic acid, in aqueous solution, optionally in the presence of the solvents used above, at temperatures between -40 and 50°C, preferably between -10 and 30°C. Corresponding esters are obtained by reacting amino acids with corresponding alcohols, e.g. ethanol, analogous to the aforementioned conditions for acylation or method ;a), e.g. by reaction with inorganic acid halides, such as thionium chloride in organic solvent mixtures, such as mixtures of aromatic and alcoholic solvents, e.g. toluene and ethanol at temperatures between -50 and 50°C, preferably between -10 and 20°C (necessary when using the protecting group). Preparation of compounds of formula XVIII or XVIII A takes place in a particularly preferred manner under the conditions mentioned as reaction conditions in J. Org. Chem. 47, 3016; (1982) or J. Org. Chem. 43, 3624 (1978). A suitable sulfuric acid ylide for converting compounds of formula XVIII or XVIII A into epoxides of formula XIX or XIX A is, for example, a dialkylsulfonium methylide, e.g. dimethylsulfonium methylide, an alkyl or phenyl-dialkylaminosulfoxonium methylide, e.g. methyl or phenyl-dimethylaminosulfoxonium methylide, or a dialkylsulfoxonium methylide, e.g. dimethyl or diethylsulfoxonium methylide. ;The sulfur-ylide compounds in question are prepared appropriately in situ from corresponding sulfonium or sulfoxonium salt and a base, e.g. sodium hydride, in a dipolar aprotic solvent, e.g. dimethyl sulfoxide, or in an ether, e.g. tetrahydrofuran or 1,2-dimethoxyethane, and then reacted with a compound of formula XVIII or XVIII A. The reaction takes place in the normal way at room temperature, under cooling, e.g. up to -20°C, or under light heating, e.g. to 40°C. The simultaneously formed sulfide, sulfinamide or sulphoxide is then removed by aqueous work-up. Reaction with a sulfur ylide takes place in a particularly preferred manner analogous to the conditions mentioned in J. Org. Chem. 50, 4615 (1985). ;The compound of formula XIX (preferably XIX A) can also be prepared from a compound of formula XVIII (preferably XVIII A), as defined above, by their reaction with a trilower alkyl-silylmethyl-Grignard compound, preferably from the corresponding halogen-methyl- silane, such as chloromethyl-trimethyl-silane, in an inert solvent, e.g. an ether such as dioxane or diethyl ether at temperatures between 0 and 50°C, e.g. between room temperature and about 40°C, subsequent elimination to remove the silyl residue and form a double bond, e.g. by means of a Lewis acid, such as BF3, where preferably also a present amino protecting group R10 is cleaved off, in an inert LM, e.g. an ether, such as diethyl ether or a halohydrocarbon such as dichloromethane or a mixture thereof, at temperatures between -50°C and reflux temperature, in particular between 0 and 30°C, when necessary, renewed acylation by introducing an amino protecting group such as Rio' as defined above and oxidation of the obtained double bond to oxirane, preferably with a percarboxylic acid, e.g. m-chloroperbenzoic acid, in an inert solvent, e.g. halogenated hydrocarbon such as dichloromethane, at temperatures between -20°C and reflux temperature in the mixture, e.g. at 10 to 30°C. The preferred starting material with formula II' in method a) or a salt thereof, is e.g. prepared by adding a hydrazine derivative with the above-defined formula XVI to an epoxide with the above-defined formula XIV A, and optionally transferring a compound with the formula II' obtained according to the above-mentioned methods with at least one salt-forming group to its salt or an obtained salt to free compound or another salt and/or optionally separates the obtained isomer mixtures and/or cleaves the present protecting groups in a compound of formula II and/or converts a compound of formula II according to the invention into another compound of formula II according to the invention. "Preparation and conversion of salts, separation of isomer mixtures, removal of protective groups and conversion of compound of formula II" takes place analogously to the procedure described for the compound of formula I. The starting materials for method b), c) and d) can be produced in ways known per se, e.g. compounds of formula IV can be prepared from hydrazine derivatives of formula XIII, where Ro. means hydrogen and the other residues have the aforementioned meaning as in connection with formula IV and epoxides with formula XIV, where the residues have the aforementioned meaning as in connection with formula IV, and then acylation of the obtained compound with formula IV, "especially formula IV"; where the residues have the aforementioned meaning as in connection with formula I and where instead of a compound of formula IV in the present residue R5 there is a free hydroxy group, react with a carboxylic acid of formula III or an activated carboxylic acid derivative thereof, as described under method a ) (obtains the starting material of formula IV for method b)); compound of formula VI from hydrazine derivatives of formula III, where the residues have the aforementioned meaning as in connection with formula VI, and epoxides of formula XIV, where R^ means hydrogen and the other residues has the aforementioned meaning as in connection with formula VI, and then acylation of the obtained compound with formula VI', especially formula VI"; where the residues have the aforementioned meaning ng which in connection with formula I and instead of in a compound of formula VI with the present residue R5 a free hydroxy group is present, reacts with a carboxylic acid of formula III or an activated carboxylic acid derivative thereof, as described under method a) (obtains starting materials with formula VI for procedure c)); and compound of formula VIII from hydrazine derivatives of formula XIII, where Rg means hydrogen and ;- the other residues have the aforementioned meaning as for compound of formula VIII and epoxides of formula VIV, where R± means hydrogen and the other residues have the mentioned meaning as in ;compounds of formula IX and subsequent acylation of the obtained compounds of formula VIII', especially formula VIII" ;where Rg has the aforementioned meaning as for compounds of formula I and where instead of in a compound of formula IV there is residue R5 a free hydroxy group , with a carboxylic acid of formula III or an activated carboxylic acid derivative thereof, as described under method a) (obtains the starting materials of formula VIII for method d)); analogy to method a), if necessary using and removing protective groups. Preferably present by the mentioned the preparation methods for the preparation of preferred compound of formula IV (via IV"), VI (via VI") and VIII (via VIII"), wherein the carbon atoms carrying R3 or R5 both exist in (S)-configuration, and epoxides of formula XIV A are used. "The compound of formula I', where the substituents have the meaning mentioned above, can be e.g. prepared from a compound of formula XIII', where the residues have the aforementioned meaning as in connection with formula I, by reaction with a compound of formula XIV, especially XIV A (which in the preferred compound of formula I' leads, where the carbon atoms, each R3 and R5 bearer, both present in (S) configuration), as for the reaction of compound of formula XIII with those described by formula XIV or XIV A, and by subsequent acylation of the obtained compound of formula I" especially formula I "', where the residues have the aforementioned meaning as in connection with formula I', with a compound of formula III or an activated carboxylic acid derivative thereof (preparation of the acyloxy R5 residues) under reaction conditions analogous to those described under method a) (instead of the compound with formula II, an analogous compound is used, where R7 is replaced by the residue R7")" in which the present functional groups which are not to participate in the reaction are there in a protected form and can b li released after raction. Of the starting compounds with formula II or II', the formula 1 is preferred. These compounds belong on the one hand to method a) as preferred intermediate compounds, and on the other hand are themselves a preferred compound according to the invention, in that they exhibit a good pharmacological effect, particularly due to an unexpectedly good effect in the cell test described above , which includes a high efficacy in vivo. The following compounds are preferred: 1-[2(S)-hydroxy-3(S)-(N-acetyl-(L)-valyl)amino-4-phenyl-butyl]-1-[4-biphenylylmethyl]-2 -[N-acetyl-(L)-valyl]hydrazine; 1-[2(S )-hydroxy-3(S )-(N-methoxycarbonyl-(L )-valyl)amino-4-phenylbutyl]-1- [4-biphenylylmethyl]-2- [N-methoxycarbonyl- (L )-valyl]hydrazine; or ;1-[2 ( S )-hydroxy-3( S )- (N-ethoxycarbonyl-(L )-valyl)amino-4-;phenylbutyl]-1-[4-bi phenylylmethyl]-2-[N- ethoxycarbonyl-(L)-valyl]hydrazine; or pharmaceutically usable salts thereof. Finally, the following compound of formula II is preferred: 1-[2 ( S )-hydroxy-3 ( S )- (N-ethoxycarbonyl-(L )-valyl)amino-4-phenylbutyl]-1-[cyclohexylmethyl ]-2-[N-ethoxycarbonyl-(L)-valyl]hydrazine; ;1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-cyclohexylbutyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl -(L)-valyl]hydrazine; 1-[2(S)-hydroxy-3(S)-(N-(n-propyloxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[ N-(n-propyl)oxy-carbonyl-(L)-valyl]hydrazine; ;1-[2(R )-hydroxy-3(S)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl] -1 - [cyclohexylmethyl] -2 -[ N-methoxy-carbonyl-(L)-valyl]hydrazine; ;1-[2(R )-hydroxy-3(R)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[ N-methoxy-carbonyl-(L)-valyl]hydrazine; ;1-[2 (S )-hydroxy-3(S)-(N-(methoxy-carbonyl)-(L)-valyl]amino-4-cyclohexylbutyl]-1-[phenylmethyl]-2-[N-methoxy -carbonyl)-(L)-valyl]hydrazine; or a pharmaceutically acceptable salt thereof. ;Preparation of the compounds of formula II', especially preparation of compound of formula II" according to the invention takes place, for example, ;i) analogous to the reaction of the starting materials of formula XIII with those of formula XIV A, such as those described in the preparation of the compounds of formula II, where in the case of the compounds of formula II' the residues in the starting compounds for the compounds of formula I have the aforementioned meaning, while in the case of compounds of formula II" in the starting materials R^ and Rg each mean N- methoxycarbonyl-(L)-valyl, R4 and R5 mean hydrogen, R3 means benzyl and R7 means cyclohexylmethyl, or ;ii) analogous method b), where instead of the starting materials with formula IV, those with formula IV, especially IV, are used" as defined above, whereby in the case of preparation of formula II" the residues have significance as compound of formula IV, while in the case of preparation of compound of formula II" in the starting materials R^ and Rg' are each N-methoxy bonyl-(L)-valyl, R4 and R5 mean hydrogen, R3 means benzyl and R7 means cyclohexylmethyl, or ;iii) analogous method c), where instead of the starting materials of formula VI, those of formula VI', especially VI" are used . stands for N-methoxycarbonyl-(L)-valyl, R4 and R^, means hydrogen, R3 means benzyl and R7 means cyclohexylmethyl, or ;iv) analogous to method d), where instead of the starting materials with formula VIII, formula VIII is used ', especially VIII", as defined above, whereby in the case of the preparation of the compound of formula IX', the residues have the aforementioned meaning as for compounds of formula VIII', while in the case of the preparation of compounds of formula II" in the starting materials R^» and Rg» each for N- methoxycarbonyl-(L)-valyl, R4 and R5 mean hydrogen, R3 means benzyl and R7 means cyclohexylmethyl, or; v) analogous to method e), where instead of the starting materials with formula IV, those with formula IV are used, especially IV" , as defined above, whereby in the case of preparing the compound of formula II' the residues have the aforementioned meaning as for the compound of formula I", while in the case of preparing the compound of formula II" in the starting materials R^ and Rg each N-methoxycarbonyl-(L)-valyl, R 4 and R 4 ) means hydrogen, R 3 means benzyl and R 7 H means cyclohexylmethyl, or; vi) in that case when using protected starting materials, e.g. in one of the methods mentioned above, by splitting off the protecting groups analogous to method ;f). If it is desired, one of the aforementioned methods i) to vi) of the obtained compounds of formula II', especially II" can be transferred to their salts or an obtainable salt to free compounds or to another salt and/or optionally separate the isomer mixture obtained and/or a compound of formula II', especially II" according to the invention, to another compound of formula II', especially II' according to the invention. The conditions thus correspond to those described above for the compound with formula I of the above-mentioned additional method caveats. Preparation of the compounds of formula II according to the invention takes place in a particularly preferred manner from compounds of formula VIII", where R4 and R^ mean hydrogen, R3 means benzyl and R7 means cyclohexylmethyl and from N-methoxycarbonyl-(L)-valine or reactive acid derivatives thereof (corresponding to the compounds of formula V and VII, where Rg» and Rg» mean N-methoxycarbonyl-(L)-valyl), in analogy to method d) as described above. ;The acids of formulas III, V, VII and IX the acid derivatives thereof, e.g. the formulas V, V" or IX' are commercially obtainable, or when they are new, be prepared by methods known per se, e.g. analogous to the aforementioned methods in the examples using suitable starting materials. The same applies to all additional starting materials. In all previously and subsequently mentioned methods the following generally applies: As a result of considerations between the compound of formula I and their salts and starting material (starting substances and intermediates) in free form and in the form of their salts, in the aforementioned and subsequently with free connections or their salts possibly also corresponding salts respectively free connections. All of the above-mentioned method steps can be carried out under specific reaction conditions known per se, in the absence or usually the presence of solvents or diluents, preferably those which are inert in relation to the reagents used and dissolve these in the absence or presence of catalysts , condensation agents or neutralizing agents, e.g. ion exchangers such as cation exchangers, e.g. in H+<-> form, depending on the reaction type and/or reaction participants at a lower, normal or elevated temperature, e.g. in the temperature range from approx.-100°C to approx. 190°C, preferably from approx. -80°C to approx. 150"C, e.g. at -80 to -60"C at room temperature, at -20 to 40°C or at reflux temperature, under atmospheric pressure or in a closed apparatus, optionally under pressure and/or in an inert atmosphere, e.g. under an argon or nitrogen atmosphere. From all the reaction steps occurring isomer mixtures can be separated into simple isomers, e.g. diastereomers or enantiomers or the appropriate mixtures of isomers, e.g. racemates or diastereomer mixtures, e.g. analogous to the methods described under "further procedure-disclaimer". ;In certain cases, e.g. by hydration, it is possible to achieve stereoselective reactions, so that e.g. it is possible with a simplified extraction of certain isomers. For the solvents that are chosen for the relevant reactions, it can e.g. water, ester, such as lower alkyl-lower alkyl anoates are used, e.g. acetic acid ethyl ester, ether such as aliphatic ether, e.g. diethyl ether or cyclic ether, e.g. 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, e.g. pyridine, carboxylic anhydride, such as lower alkanoic anhydrides, e.g. acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the description of the method. Such solvent mixtures can also be used in processing, e.g. by chromatography or distribution. The compounds, including their salts, can also be obtained in the form of hydrates, or their crystals can e.g. the solvents used for crystallization. The invention also relates to such embodiments and variants where compounds are obtained from a process step as an intermediate by starting from the missing process steps that are carried out, or from starting substances that are formed under the reaction conditions or in the form of a derivative, e.g. in protected form or as a salt, or a compound obtained from the process according to the invention under the process conditions and further processed in situ. In the method of the present invention, such starting materials are preferably used which lead to the previously indicated valuable described compounds (formula I or II). In the first place, reaction conditions analogous to those mentioned in the examples are preferred. As far as necessary, protected starting compounds can be used from all process steps and the protecting groups can be removed in suitable reaction steps. ;Protection group, their introduction and their release are described under procedures a) and f). ;Pharmaceutical preparations: ;The compound can be used in pharmaceutical preparations containing the compound of formula I or (especially the aforementioned compounds which are preferred) of formula II. The pharmacologically applicable compounds in the present compound can e.g. be used for the production of pharmaceutical preparations, which contain an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically usable carriers. The invention also includes a pharmaceutical composition (preparation), which is suitable for administration to a warm-blooded person, especially a human, for the treatment or limitation of disease which ensures an inhibition of a retroviral protease, in particular a retroviral aspartate protease such as HIV-1-. or HIV-2 gag protease, e.g. a retroviral disease such as AIDS comprises a retroviral inhibition effective amount of a compound of formula I or II", or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier material. The pharmaceutical preparations according to the invention are such for enteral, such as nasal, rectal or oral or parenteral, such as intramuscular or intravenous administration to warm-blooded animals (humans and animals), containing an effective dose of the pharmacologically active substance alone or together with a significant amount of a pharmaceutically usable carrier material. The dosage of the active substance depends on the warm-blooded species, body weight, age and individual condition, individual pharmacokinetic realities, the disease being treated as well as the method of application. The invention also enables a method for the treatment of viruses, in particular diseases caused by retroviruses, e.g. AIDS, characterized by administering a therapeutic activity m engde of the compound of formula I or II', especially to a warm-blooded, e.g. human being, who due to one of the aforementioned diseases, particularly AIDS, needs such treatment. The dosage amount to be administered to the warm-blooded, e.g. human of approx. 70 kg body weight, lies between approx. 3 mg and approx. 3 g, preferably between 10 mg and approx. 1.5 g, e.g. at approximately 100 mg per 1000 mg per person and day, divided into preferably 1 to 3 single doses, which e.g. can be the same size. Usually, children receive half the dose of an adult. ;The pharmaceutical preparations contain from approx. 156 to approx. 9556, preferably of approx. 2056 to approx. 9056 of the active ingredient. Pharmaceutical preparations can e.g. present in dosage unit forms, such as ampoules, glasses, suppositories, dragees, tablets or capsules. The pharmaceutical preparations are prepared in a manner known per se, e.g. using conventional dissolving, lyophilizing, mixing, granulating or coating methods. Solutions of active substances are preferably used alongside suspensions and particularly in isotonic aqueous solutions or suspensions, where these e.g. can be produced by lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, cross-linking and/or emulsifiers, solubility mediators, salts for regulating osmotic pressure and/or buffer and are produced in a manner known per se, e.g. using conventional dissolution and lyophilization methods. The aforementioned solutions or suspensions may contain viscosity-increasing substances such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatins. ;Suspensions in oils containing as an oily component the usual vegetable, synthetic or semi-synthetic oils for injection purposes. Of these, liquid fatty acid esters should be mentioned in particular, which as acid component contain a long-chain fatty acid with 8-22, especially 12-22 carbon atoms, such as e.g. lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or similar unsaturated acids such as e.g. oleic acid, elaidic acid, erucic acid, brasidic acid, or linoleic acid, optionally with the addition of antioxidants such as e.g. vitamin E, 3-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol components of these fatty acids have a maximum of 6 carbon atoms and are monovalent or polyvalent, e.g. mono-, di- or trivalent alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol or their isomers, above all glycol or glycerin. As fatty acid esters, e.g. mention: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrifil M 2375" (polyoxyethylene glycerintrioleate from the company Gattefossé, Paris), "Miglyol 812" (triglyceride saturated fatty acids with chain length Cg to C-^g from the company Hvils AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and above all peanut oil. ;Manufacture of the injection preparations takes place in the usual way under sterile conditions, likewise filling in ampoules or glasses, as well as closing the container. ;Pharmaceutical preparations for oral use can can be achieved by allowing the active substance to be combined with the carrier substances, mixing an obtained mixture and possibly granulating, when desired or necessary, after adding suitable excipients for tablets, dragon cores or capsules. Thus, active substances can also be incorporated into the plastic carrier that are indicated or which can be diffused. ;Suitable carriers are especially fillers such as sugar, e.g pp. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch glue when using e.g. of corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or when desired, explosives, such as the above-mentioned starches, further carboxymethylstarch, cross-linked polyvinylpyrrolidone, agar, alginic acid and /or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow-regulating lubricants, e.g. silicic acid, talc, stearic acid or a salt thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, the dragon cores are provided with suitable, possibly stomach acid-resistant coatings, whereby one, among other things, uses concentrated sugar solutions that possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solutions in suitable organic solvents and for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Capsules are capsules made of gelatin as well as soft, closed capsules made of gelatins and plasticizers such as glycerin or sorbitol. The capsules can be present in the active substance in the form of a granule, e.g. with fillers such as lactose, binders such as starch and/or lubricants such as talc or magnesium stearate, and optionally with stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycol, whereby stabilizers and/or antibacterial agents can also be added. The tablets or the dragee coatings and the capsule shells can be added with dyes or pigments, e.g. for identification or for further characterization of different active ingredient doses. ;The following examples serve to illustrate the invention, but should in no way limit its scope. ;The temperatures are indicated in degrees Celcius (° C ). If no temperature is specified, the reaction takes place at room temperature. The Rf values, which indicate the ratio between the migration length of the relevant substance and the migration length of the flux front, are measured on silica gel thin-layer plates by thin-layer chromatography (DC) in the following solvent systems; DC flux systems;; The abbreviation <M>Rf(A)" means, for example, that the Rf value has been measured in solvent system A. The quantity ratio of solvents to each other is indicated in volume fractions. + 0.0556 TFA Column (250 x 4.6 mm) packed with "Reversed-Phase" material C^g-Nucleosil (5>m average grain size with the octadecylsilanes covalently derivatized silica gel, Macherey & Nagel, Duren, BRD). Detection by UV absorption at 215 nm. Retention times ("tRet ^ tlir stated in minutes. Flow rate 1 ml/min. ;For designation of the flow systems, the same abbreviations are used for flame chromatography and medium pressure chromatography.;Other short designations and abbreviations used have the following meaning g: abs. absolute (applies that the solvent is anhydrous) atm physical atmosphere (pressure unit) - 1 atm. ;equivalent to 1.013 bar ;Bo tert-butoxycarbonyl ;BOP benzotriazol-l-yl-oxy-tris-(dimethylamino)-phosphonium-hexafluoro-phosphate ;DCC dicyclohexylcarbodiimide ;DMAP dimethylaminopyridine ;DIPE diisopropyl ether ;DMF dimethylformamide ;DMSO dimethylsulfoxide ;EDC N -ethyl-N' - (3-dimeth<y>lamino<p>rop<y>Ll) -carbodiimide-;hydrochloride ;Ether diethyl ether ;ges. saturated ;h hour(s) ;HB TU 0-benztriazol-l-yl-N,N,N',N<*->tetramethyl-uronium-hexafluorophosphate

HOBt 1-hydroxy-benztriol

HV high vacuum

my minute(s)

MS mass spectroscopy

NMM N-methyl-morpholine

Ref.-ex. reference example

RT room temperature

EV rotary evaporator

Sole saturated sodium chloride solution

THF tetrahydrofuran

TFA trifluoroacetic acid

Z benzyloxycarbonyl

Mass spectroscopic measurement values are obtained either by conventional MS or by the "Fast-Atom-Bombardment" (FAB-MS) method. The mass specification refers primarily to the unprotonated molecular ion (M)<+> or the protonated molecular ion

(M+H)<+.>

The value for proton nuclear resonance spectroscopy (<1>H-NMR) is given in ppm (parts per million) with respect to tetramethyl-silane as internal standard, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double-doublet, br <= width.

The value for IR spectra is given in cm~<l>, in round brackets are the relevant solvents. If specified, s means a strong, m a medium and w a weak intensity of the bands in question.

The residue with the designation -[Phe^Phe] means the divalent radical of 3(S)-amino-4-phenyl-1-(N-benzylhydrazino)-butan-2(S)-ol and has the formula

The residue designated -[Phe<NN>Cha] means the divalent radical of 3(S )-amino-4-phenyl-1-(N-cyclohexylmethyl-hydrazino )-butan-2(S)-ol and has the formula The divalent the radical of 1-[2(S)-acetoxy-3(S)-amino-4-phenylbutyl]-[1-cyclohexylmethyl]hydrazine has the formula

For the designation of divalent radicals of natural α-amino acids, the usual abbreviations within peptide chemistry are used. Here, however, there are amino acids which in the compound names are to the right of the radicals -[Phe^NPhe] , or [Phe<NN>Cha], deviating from normal peptide nomenclature, where to the left of the amino and to the right of the carboxy terminal is the binding the carboxy group on the left, which is symbolized by a (♦-), and the reverse bond direction is symbolized (inversion). The configuration of the α-carbon atom, when known, is indicated by prefixes or (L)-or (D)-. Tyrosine radicals etherified to the phenolic hydroxy groups with the residues R are denoted by Tyr(OR). Nie means the radical of norleucine.

Reference Example 1: Boe-[Phe^Phe]-Boe:

A solution of 300 mg (1.14 mmol) (2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane (J. Org. Chem. 50, 4615 (1985 )) and 253 mg ( 1.14 mmol) of tert-butyl-3-benzyl-carbazate (J. Chem. Soc. Perkin I, 1712 (1975)) in 4 ml of methanol is heated during 12 hours under reflux. After cooling the reaction mixture to 0", a large part of the title compound precipitates. The original liquor is evaporated and the remainder dissolved in a little methylene chloride. After adding dropwise hexane, the title compound further precipitates as a white precipitate. FAB-MS: (M+H)<+> = 486, tRet(<I>) <=> 26.8 min, Rf(E) = 0.70.

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

191 mg Z-(L)-valine, 336 mg (0.76 mmol) BOP and 103 mg (0.76 mmol) HOBt are dissolved in 5 ml of a 0.3 M solution of NMM in DMF, added after 10 minutes 100 mg (0.25 mmol) H-[Phe<NN>Phe]-H • 3HC1 and stir for 2 hours at RT under a nitrogen atmosphere. The reaction mixture is evaporated, the residue dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phases are filtered through water, evaporated and the residue purified by means of chromatography on silica gel with methylene chloride/ether (1:1). After lyophilization of the product-containing fraction of dioxane, the title compound is obtained as a white solid. FAB-MS: (M+H)<+> = 752, <t>Ret(I) = 27.8 min, Rf(E) = 0.45.

The starting material is produced in the following way.

a) H-[PheN<N>Phe]-H • 3HC1:

A solution of 280 mg (0.58 mmol) Boe-[Phe<NN>Phe]-Boe from ref. ex. 1 in 10 ml of 4 N hydrogen chloride in dioxane is stirred for 2 hours at RT under a nitrogen atmosphere and then lyophilized. Renewed lyophilization from dioxane/tert-butanol gives the title compound as a flocculated solid. FAB-MS: (M+H)<+> = 286, <t>Ret(II) = 23.1 min, Rf(C) = 0.17.

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

In an analogous way as described in ref.eg. 2 is obtained from 50 mg (0.13 mmol) H-[Phe<NN>Phe]-H ■ 3HC1, 83 mg (0.83 mmol) Boc-(L)-valine, 168 mg (0.38 mmol) BOP, 51 mg (0.38 mmol) HOBt and 2.5 ml 0.3 M NMM in DMF after chromatographic purification on silica gel with chloroform/methanol (95:5) and lyophilization from the dioxane title compound. FAB-MS: (M+H)<+> = 684, t<Ret>(I) = 27.4 min, Rf(E) = 0.38.

Reference Example 4: Boe-[Phe<NN>Cha]-Boe:

Analogous to ref.-ex. 1 is obtained from 231 mg (0.88 mmol)

(2R,3S)-1-[3-Boc-amino-3-phenylethyl]oxiram and 200 mg (0.88 mmol) of tert-butyl-3-cyclohexylmethyl-carbazate gave the title compound as a white precipitate from hexane. FAB-MS: (M+H)<+> = 492, <t>Ret(I) = 30.4 min, Rf(E) = 0.78.

The starting material is produced in the following way:

a) tert-butyl-3-cyclohexylmethylcarbazate:

10.2 g (45.1 mmol) of cyclohexylcarbaldehyde-tert-butoxycarbonylhydrazone, dissolved in 400 ml of methanol, is hydrogenated in the presence of 5.1 g of 556 palladium on charcoal at RT and 4 atm hydrogen pressure. After completion of the reaction, it is filtered from the catalyst and the filtrate evaporated. The residue is dissolved in methylene chloride and washed with water. After evaporation of the organic phase, the title compound is obtained as a colorless resin. <3->H-NMR (200 Mhz, CDC13): 6.1 (s, br, 1H), 3.9 (s, br, 1H), 2.65 (d, 2H), 1.8-0 .75 (m, 11E), 1.45 (s, 9H), <t>Ret(I) = 32.0 min., Rf(E) = 0.75.

b) cyclohexylcarbaldehyde-tert-butoxycarbonylhydrazone:

A solution of 10.8 g (81.2 mmol) of tert-butylcarbazate and

10.1 g (90 mmol) of cyclohexylcarbaldehyde in 400 ml of ethanol was heated during 2 hours under reflux. Half of the solvent is then distilled off and the title compound is precipitated by the addition of water. It is directly used further in a).

Reference Example 5: H-( L)- Val-[ PheNNPhe] «-( ( L)- val )- H - 3HCl: A solution of 40 mg (0.06 mmol) Boc-(L)-Val-[Phe< NN>Phe]-♦-( (L )-Val )-Boc from ref.-ex. 3 in 4 ml of 4 N hydrogen chloride is stirred in dioxane during 1 hour at room temperature. It is then diluted with dioxane and, after lyophilization, the title compound is obtained as hydrochloride. FAB-MS: (M+H)<+> = 484, <t>Ret(II) = 25.8 min, Rf(A) = 0.45.

Reference example 6: Boc-( L)- Val-[ PheNNCha] <-( ( L)- Val )- Boc: This is obtained by starting from 500 mg (1.25 mmol) H-[Phe<NN>Cha]- H 3HC1, 1.08 g (4.98 mmol) Boc-(L)-valine, 1.89 g (4.98 mmol) HBTU and 1.39 ml (9.96 mmol) triethylamine after chromatographic purification on silica gel with methylene chloride/ether (1:1) and dioxane lyophilization of the title compound as a flocculated solid. FAB-MS: (M+H)<+> = 690, tRet(I) = 2973 min, Rf(E) = 0.48.

The starting material is produced in the following way:

a) H-[PheNNCha]-H • 3HCl

1.10 g (2.2 mmol) Boc-[Phe<NN>Cha]-Boe from ref.-ex. 4 will be

dissolved in 20 ml of 4 N hydrogen chloride in dioxane and stirred for 3 hours at RT. After lyophilization of the reaction mixture, the title compound is obtained as hydrochloride. FAB-MS: (M+H)<+> = 292, <t>Ret(II) = 27.3 min.

Reference example 7: H-( L)- Val-[ PheNNChaX ( L)- Val )- H • 3HC1: Analogous to ex. 6 from 632 mg (0.91 mmol) Boc-(L)-Val-[PheNNCha]«-((L)-Val )-Boc from ref.-ex. 6 after lyophilisation the title compound as hydrochloride. FAB-MS: (M+H)<+> = 490, tRet(II) = 29.4 min, Rf(K) = 0.23.

Reference example 8: Z-( D)- Val-[ PheNNPhe] <-( ( D)- Val )- Z: Analogous to ref.-ex. 2 is obtained from 50 mg (0.123 mmol) H-[Phe<NN>Phe]-H • 3 HC1 from ref.-ex. 2a, 95 mg (0.38 mmol) Z-(D)-valine, 168 mg (0.38 mmol) BOP, 51 mg (0.38 mmol) and 2.53 ml 0.3 M NMM in DMF the title compound after lyophilization from

dioxane. FAB-MS (M+E)<+> = 752, tRet(H) = 0.21.

Example 1: 1-r2(S)-acetoxy-3(S)-(N-(2-methoxyethoxycarbonyl)-(D-valyl)-amino-4-phenyl-butyl-1-1-cycloheximimethyl-2-fN-(2 -methoxyethoxycarbonyl)-( L )- valylhydrazine: Under a nitrogen atmosphere, 200 mg (0.29 mmol) N-(2-methoxyethoxycarbonyl) - (L ) - Val - [PheNNCha]«-(N-(2-methoxy-ethoxycarbonyl ) -(L)-Val) alkylated in 4 mL THF and 60 µl (0.43 mmol) triethylamine in the presence of 0.5 mg (0.003 mmol) DMAP with 40 µl (0.43 mmol) acetic anhydride over 3 h at RT. The reaction mixture is partitioned between 3 portions of methylene chloride, water, saturated NaHCO 3 solution and brine. After drying with NaHCO 3 , evaporation and column chromatography (SiO 2 , methylene chloride/methanol 30:1), the title compound is obtained from the organic phases: DC Rf(Z) = 0.17, tRet(I) = 22.5 min, FAB-MS (M+H)<+> = 736.

The starting materials are produced as follows:

a) N-(2-methoxyethoxycarbonyl)-(L)-Val-[PheNNCha]«-(N-(2-methoxyethoxycarbonyl)-(L)-Val): Analogous to ref.-ex. 2) 820 mg (3.74 mmol) of N-(2-methoxyethyloxycarbonyl)-L)-valine is activated with 1.65 g (3.74 mmol)

BOP and 505 mg (3.74 mmol) HOBT in 25 ml of a 0.3 M solution of NMM in DMF and reacted after 10 min with 500 mg (1.25 mmol) H-[Phe<NN>Cha]-H (hydrochloride salt) (cf. ref. ex. 10a) during 18 hours. The reaction mixture is evaporated on a HV, the residue dissolved in CHCl 3 and washed with 10% citric acid solution, saturated NaHCC 3 solution and salt water. The aqueous phase is extracted with 2 portions of CHCl3, the organic phases are dried with Na2S04 and evaporated. Column chromatography (SiO 2 , CHCl 3 /MeOH = 30:1) and precipitation with hexane from a CH 2 Cl 2 solution gives the title compound: D CRf(T) = 0.37, tRet(I) = 21.5 min., FAB-MS (M +H)<+> = 694.

b ) Chlorformic acid-(2-methoxyethyl)-ester:

Under nitrogen atmospheres, 100 ml (202 mmol) of a 20% solution of phosgene in toluene are added dropwise at 0 to 5°C, 13.3 ml (168 mmol) of 2-methoxy-ethanol, stirred for 90 minutes at 0°C and 18 hours . The reaction mixture is extracted with water, the organic phases are filtered through water and evaporated: IR (CH2C12): u.a. 3055w, 2995w, 2935w, 2895w, 2825w, 1775s, 1167s, 1127s; 3 H NMR (200 MHz, CDCl 3 ): 3.38 (s, 3H), 3.64 and 4.44 (2h, J = 5Hz, each 2H).

c) N-(2-Methoxy-ethoxycarbonyl)-(L)-valine:

To 2.59 g (22.1 mmol) of L-valine in 26.4 ml of 2N_-NaOH add

a solution of 3.06 g (22.1 mmol) of chloroformic acid (2-methoxy-ethyl)-ester in 18 ml of dioxane and stirred for 18 hours at room temperature thereafter. The reaction mixture is extracted with chloroform, the inorganic phases are acidified with 4N HCl and extracted again with chloroform. Drying and evaporation of the latter obtained chloroform phase gives the title compound: ^-H-NMR (200 MHz, CDCl3): 0.92 and 0.99 (2d, J = 7Hz, 6H), 2.2 (m, 1H) , 3.38 (s, 3H), 3.59 and 4.24 (2m, each ,2H), 4.3 (m, 1H), 5.4 (d, J = 9Hz, HN), 8.5 (sb, 1H).

Example 2: 1-2(S)-acetoxy-3(S)-(N-methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-fcyclohexylmethyl1-2-fN-(methoxycarbonyl)- ( L )-val<y>llh<y>drazine: Analogous to example 1) 200 mg (0.33 mmol) of N-(methoxycarbonyl )-(L )-Val-[PheNNCha]«-(N-(methoxy -carbonyl )-(L)-Val) reacted in 4 mL THF and 68 µl (0.50 mmol) triethylamine in the presence of 1.2 mg (0.01 mmol) DMAP with 46 µl (0.50 mmol) acetic anhydride. Precipitation with DIPE from a concentrated solution of the crude product in methanol gives a pure title compound: DC Rf(A') = 0.42, <t>Ret(I) =22.6 min., FAB-MS (M+H)< +> = 648.

The starting material is produced as follows:

a) N-(Methoxycarbonyl)-(L)-Val-[PheNNCha]<-(N-(Methoxycarbonyl)-(L)-Val) (= l-[2(S)-hydroxy-3(S) -(N-(methoxycarbonyl)-(L)-valyl)-amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[ N-(methoxycarbonyl)-(L)-valyl] hydrazine: Analogous to ref .-ex.'2) becomes 1.47 g (8.4 mmol) N-(methoxycarbonyl)-(L)-Valine with 3.71 g (8.4 mmol) 'BOP and 1.13 g (8, 4 mmol) HOBT in 54 ml of a 0.3 M solution of NMM activated in DMF and reacted after 15 minutes with 1.2 g (2.8 mmol) H-[Phe<NN>Cha]-H (hydrochloride salt ) (cf. ref. ex. 10a) within 18 hours. The reaction mixture is evaporated at RT at 50° C (-♦ brown residue), the residue is dissolved in methylene chloride and washed 2x with saturated NaHCC^ solution as well as salt water. The aqueous phase is extracted with 2 portions of methylene chloride, the organic phases are dried with NaCl and evaporated. Filtration through silica gel (methylene chloride/methanol 15:1) and precipitation twice with DIPE from a concentrated methylene chloride solution gives the title compound: DC Rf(U) = 0.33; "tRet^1) = 21.5 min., FAB-MS (M+H)<+> = 606.

The starting material is produced as follows:

b) N-(methoxys-carbonyl)-(L)-valine:

To 7.0 g (60 mmol) L-valine in 100 ml 2N NaOH and 30 ml dioxane

5.67 g (60 mmol) of chloroformic acid methyl ester are added (-+ exothermic reaction) and stirred for 18 hours thereafter at RT. The reaction mixture was extracted with methylene chloride, the aqueous phase acidified with 27 ml of 4 N HCl and extracted again with methylene chloride. Drying and evaporation of the latter methylene chloride phase gives the title compound: tRet^) = 7'2 min., <i>H-NMR (200 MHz, CD30D): 0.96 (t, J = 7Hz, 6H), 2.16 (m, 1H), 3.67 (s, 3H), 4.06 (m, 1H), 7.07 (d, J = 8Hz, HN partially yielded).

Example 3: 1-T2(S)-(2-pyridylcarbonyl)oxy-3(S)-(N-(methoxycarbonyl)-(L)valyl)amino-4-phenyl-butyl-1-cyclohexy Ime tyll -2-n-(methoxycarbonyl)-(L)-valylhydrazine

Under a nitrogen atmosphere, 56 µl (0.4 mmol) of l-chloro-N,N,2-trimethyl-l-propenamine (B .Haveaux, D. Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M. Murakami, M. Yoshioka and W. Nagata, Organic Syntheses 59, 26

(1980)). After 45 minutes at RT, 1.3 ml of pyridine, 100 mg (0.165 mmol) N-(methoxycarbonyl)-(L)-Val-[PheNNCha]«-(N-(methoxycarbonyl)-(L) are added -Val) (Example 2a) and a spatula tip DMAP and then stir for 18 hours at RT. The dark reaction mixture is distributed between 3 portions of methylene chloride, 2 portions of saturated NaHCO 3 solution, water and salt water. Column chromatography (SiO 2 , ethyl acetate) of the evaporation residue with Na 2 SO 4 dried methylene chloride phase gives the pure title compound: DC Rf(0) = 0.23; tRet(I) = 22.5 min., FAB-MS (M+H)<+> = 711.

Example 4:

Following one of the aforementioned methods, the following is produced: a) 1-[2(S)-propionyloxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1 -[cyclohexylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]hydrazine; b) 1-[2(S)-butyryloxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N- (methoxycarbonyl)-(L)-valyl]hydrazine; c ) 1-[2(S)-pentanoyloxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N- (methoxycarbonyl)-(L)-valyl]hydrazine; d) 1-[2(S)-(2-pyridylacetyl)oxy-3(S)-(N-methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2 -[N-(methoxycarbonyl)-(L)-valyl]hydrazine; e) 1-[2(S)-(3-(pyridin-2-yl)-propionyl)oxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)-amino-4-phenylbutyl) ]-1-[cyclohexylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]hydrazine.

Example 5:

According to one of the above-mentioned methods, the monoacetylated derivatives are prepared from the title compound in reference examples 1 to L-9, which in the relevant central divalent butan-2(S)-ol derivatized radicals with one of the designations -[PheN<N> Phe] or -[PheN<N>Cha], instead of free 2(S)-hydroxy group contains a 2(S)-acetoxy group.

Example 6: 1- f 2 (S 1 - hydroxy-3 (S) - (N-ethoxycarbonyl-(L)-valyl)amino-4-phenylbutyl-1-rcyclohexylmethyl-2-fN-ethoxycarbonyl-d)-valyl-1hydrazine

Analogously to reference example 2, one obtains from 500 mg (1.25 mmol) H-[Phe<NN>Cha]-H • 3HC1 from reference example 6a, 708 mg (3.74 mmol) N-ethoxycarbonyl-(L)-valine, 1.65 g (3.74 mmol) BOP, 505 mg (3.74 mmol) HOBt and 24.7 ml 0.3 M N-methylmorphol in DMF the title compound after chromatographic purification (SiOg, methylene chloride/diethyl ether (1:1 )) and precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane. FAB-MS (M+H)<+> = 634, <t>Ret(I) = 24.2 min., Rf(H) = 0.3.

The output connection is produced in the following way:

a) N-ethoxycarbonyl-(L)-valine: Analogous to reference example lc is obtained by starting from 10 g (85.3 mmol) (L)-valine and 9.3 g

(85.3 mmol) ethyl chloroformate the title compound as a colorless oil. ^H-NMR (200 MHz, CDCl3): 5.15 (d, broad, 1H), 4.32 (m, 1H), 4.15 (q, J = 7Hz, 2H), 2.25 (m, 1H), 1.25 (t, J = 7Hz, 3H), 0.98 (d, J = 7Hz, 3H), 0.92 (d, J = 7Hz, 3H).

Example 7:

Analogous to the aforementioned and subsequent examples and methods, the following compounds are obtained: A) 1-[2(S)-hydroxy-3(S)-(N-acetyl-(L)-valyl)amino-4-phenylbutyl]- 1-[4-biphenylylmethyl]-2-[N-acetyl-(L)-valyl]hydrazine B) 1-[2(S)-hydroxy-3(S)-(N-methoxycarbonyl-tL)-valyl)amino -4-phenylbutyl] -1-[4-biphenylylmethyl] -2-[N-methoxycarbonyl-(L )-valyl]hydrazine C) 1-[2(S)-hydroxy-3(S)-(N- ethoxycarbonyl-(L)-valyl)amino-4-phenylbutyl]-1-[4-biphenylylmethyl]-2-[N-ethoxycarbonyl-(L )-valyl]hydrazine

Example 8: 1- T2( S )-butyrvlox-3( S )- ( N -( methoxy- carbonyl )-( L )- valvyl )-amino-4-phenyl-butyl-1-cyclohexylmethyl! - 2- rN-methoxycarbonyl-(L)- valvylhydrazine: To an ice-cooled mixture of 200 mg (0.33 mmol) 1-[2(S)-hydroxy-3(S)-(N-(methoxy-carbonyl) )-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]hydrazine (Example 2a) in 2,6 dioxane and 0.4 ml of pyridine, 50 µl (0.495 mmol) of butyric acid chloride and 2 mg (0.017 mmol) of DMP are added. After 18 hours at RT, according to HPLC, the reaction mixture additionally contains 1-[2(S)-hydroxy-3( S )- (N - (methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl]- 1-[Cyclohexylmethyl]-2-[N-methoxy-carbonyl-(L)-valyl]hydrazine, in addition, an additional 0.75 equivalents of butyric acid chloride and some small grains of DMAP are added. After a further 18 hours, a third portion of 1.5 equivalents of butyric acid chloride is added and stirred for a further night at RT (-» HPLC: completely reacted). The reaction mixture is diluted with ethyl acetate, washed with 2 portions of saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with ethyl acetate, the organic phases are dried with NaCl and evaporated. Digestion of the oil residue in an ultrasonic bath from hexane leads to a pure title compound: DC Rf(0) = 0.67, tRet(<y>) = 17»2 min., FAB-MS (M+H)<+> = 676.

Example 9: l-r2(S)-(methoxy-acetoxy)-(N-(methoxy-carbonyl)-(L)-valyl)amino-4-phenyl-butyl1-l-cyclohexylmethyl-2-rN-methoxy-carbonyl -( L )-valyl-hydrazine: 200 mg (0.33 mmol) 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl )-(L )-valyl)amino-4-phenyl-butyl ]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]hydrazine (Example 2a) in 2.6 ml of dioxane and 0.4 ml of pyridine is reacted with 50 µl (0.495 mmol) of methoxyacetic acid chloride and 2 mg (0.017 mmol) DMAP. For complete reaction, 0.5 equivalents of methoxy-acetic acid chloride and a few small grains of DMAP are added and stirred. Extraction and digestion in an ultrasonic bath from DIPE/hexane gives the pure title compound: DC Rf(0) = 0.48; tRet^) = 15.6 min.; FAB-MS (M+H)<+> = 678.

Example 10: Gelatin solution:

A sterile aqueous solution with 20% cyclodextrins as solubilizers of one of the compounds of formula I mentioned above in the examples, as active ingredient while heating with a sterile gelatin solution, which contains phenol as a preservative, is mixed under aseptic conditions, so that 1, 0 mg of the solution has the following composition:

Example 11: Sterile desiccant for in. ieks. ion:

5 mg of one of the compounds mentioned in the previous examples with formula I as active ingredient is dissolved in 1 ml in an aqueous solution with 20 mg of mannitol and 20% cyclodextrins as solvent. The solution is sterile filtered and filled under aseptic conditions into a 2 ml ampoule, deep-cooled and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of water or 1 ml of physiological saline solution. The solution is used intramuscularly or intravenously. These formulations can also be filled into double-chamber syringe ampoules.

Example 12: Nasal sprain:

In a mixture of 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol, 500 mg of finely ground powder (<5.0 pm) of one of the aforementioned compounds of formula I in the examples of formula I is added. The suspension is filled into a container with dosing valves. 5.0 g of Freon 12 are filled under pressure through the valve in a container. When shaken, "Freon" is dissolved in the Myglyol-benzylalcohol mixture. This spray container contains approx. 100 single doses, and the single doses can be applied.

Example 13: Varnish tablets

For the production of 10,000 tablets, each containing 100 mg of active ingredient, the following ingredients are processed:

A mixture of one of the aforementioned compounds in the examples with formula I as active ingredient, 50 g of corn starch and colloidal silicic acid is processed with a starch paste of 250 g of corn starch and 2.2 kg of demineralized water into a moist mass. This is passed through a 3 mm mesh screen and dried at 45°C for 30 minutes in a fluidized bed dryer. The dried granulate is pressed through a 1 mm mesh screen, mixed with a previously screened mixture (1 mm screen) of 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch and pressed into slightly curved tablets.

Claims (8)

1. Compound, characterized by formula where Ri and Rg independently of each other mean lower alkoxylower oxycarbonyl-(1)-valyl or lower alkoxycarbonyl-(1)-valyl; R 3 means C 3 -C 7 cycloalkyl lower alkyl, or phenyl lower alkyl; R 5 means lower alkanoyloxy, pyridyl lower alkanoyloxy or lower alkyl lower alkanoyloxy; and R7 independently of R3 has the meaning mentioned there; as well as salts of the aforementioned compounds, as long as salt-forming groups are present. 2. Compound according to claim 1, characterized in that it is 1-[2(S)-acetoxy-3(S)-(N-(2-methoxyethoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1 -[cyclohexylmethyl]-2-[N-(2-methoxyethoxycarbonyl)-(L)-valyl]hydrazine, or pharmaceutically usable salts thereof. 3. Compound according to claim 1, characterized in that it is l-[2(S)-acetoxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-l-[ cyclohexylmethyl]-2-[N-(methoxycarbonyl)-(L )-valyl]hydrazine, or pharmaceutically usable salts thereof. 4. Compound according to claim 1, characterized in that it is 1- [2 ( S ) - ( 2-pyr idy 1 carbonyl )oxy-3 ( S )-(N-(methoxycarbonyl )-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl ]-2-[N-(methoxycarbonyl)-(L)-valyl]hydrazine, or pharmaceutically acceptable salts thereof. 5. Compound according to claim 1, characterized in that it is selected from 1-[2(S)-butyryloxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)-amino-4-phenyl-butyl] -1-[cyclohexylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]hydrazine; and 1- [2 (S )-(methoxy-acetoxy )-3-(S)-(N-(methoxy-carbonyl )-(L)-valyl )amino-4-phenyl-butyl]-1-[cyclohexylmethyl]- 2-[N-methoxycarbonyl-(L)-valyl]hydrazine, or a pharmaceutically usable salt thereof. 6. Compound, characterized in that it is selected from compounds with the designations 1-[2(S)-hydroxy-3(S)-(N-acetyl-(L)-valyl)amino-4-phenylbutyl]-1-[4- biphenylmethyl]-2[N-acetyl-(L)-valyl]hydrazine, 1-[2(S )-hydroxy-3(S )-(N-methoxycarbonyl-(L)-valyl )amino-4-phenylbutyl]- 1-[4-biphenylmethyl]-2[N-methoxycarbonyl-(L)-valyl]hydrazine; and 1-[2(S )-hydroxy-3(S )-(N-ethoxycarbonyl-(L)-valyl )amino-4-phenylbutyl]-1-[4-biphenylmethyl]-2 [N-ethoxycarbonyl - (L )-valyl]hydrazine, or a pharmaceutically acceptable salt thereof. 7. Pharmaceutical preparation characterized in that it contains a compound according to any one of claims 1-6 or a pharmaceutically usable salt of such a compound with at least one salt-forming group together with a pharmaceutically usable carrier material. 8. Use of one of the compounds mentioned in claims 1-6 or a pharmaceutically usable salt of such a compound with at least one salt-forming group for the production of pharmaceutical preparations for use in the treatment of retroviral diseases.