SK279706B6 - Hydrazine derivatives, pharmaceutical compositions them containing, their use, methods of their preparation, as well as intermediates for their preparation - Google Patents

Abstract

There are described hydrazine derivatives of general formula (I), the residuals whereof have their meanings as described in the Claims, pharmaceutical compositions containing these derivatives and their use. There are further described methods of the general compound (I) preparation, wherein a hydrazine derivative of general formula (III)-in which R7 and R9 have their meanings as stated in the 8th patent claim-adds to epoxide of general formula (IV) wherein R1 and R3 have their meanings as stated in the 8th patent claim. There are also described intermediates of general formula (II), wherein R3 and R7 have their meanings as stated in the 1st patent claim, for the preparation of the general formula (I) compounds. The said compounds of the general formula (I) are useful as inhibitors of HIV protease.

Description

(57) Annotation:

Disclosed are hydrazine derivatives of the general formula (I) in which the radicals have the meanings described in the claims, the pharmaceutical compositions containing the derivatives and their use. Methods for making compounds of formula (I), e.g. such that the hydrazine derivative of formula (III), wherein R ⁷ and R ⁹ are as defined in claim 8, is added to the epoxide of formula (IV), wherein R ¹ and R ³ are as defined in 8. claim. Further described are intermediates of formula (II) wherein R ³ and R ⁷ are as defined in claim 1 for the preparation of compounds of formula (I). The compounds of formula (I) suppress the HIV protease.

(III)

(II) (II)

Technical field

The present invention relates to a new class of hydrolyzable analogues of aspartate cleavable peptides, i.e. hydrazine derivatives, a process for their preparation, pharmaceutical compositions containing these analogues of peptides and their use as medicaments or for the manufacture of pharmaceutical compositions for controlling viral diseases as well as novel intermediates. for the production of these compounds.

BACKGROUND OF THE INVENTION

Immune deficiency AIDS ('acquired immune deficiency syndrome') is a fatal disease. These diseases are spreading on a global scale to an increasing extent mainly within certain risk groups but also outside these risk groups. This disease affects millions of people and its causative suppression is one of the most important goals of modern medicine. Until now, the retroviruses HIV-1 and HIV-2 (HIV is a human immunodeficiency virus) have been able to identify the cause of the disease and be characterized from a molecular biological point of view. For the treatment, it is beyond the existing possibilities to change the symptoms of AIDS, and thus some preventive options are of particular interest, in particular the search for agents that limit the reproduction of viruses without damaging the affected cells and tissues of the patient.

In particular, those compounds that inhibit the process of protein building units of the virus biosynthesized in human cells, infectious virions, and thus the completion of the precise construction of these building units, show the promise of success.

IIIV-1 and HIV-2 always have a region in their genome that encodes for a "gag protease". This "gag protease" is responsible for the precise proteolytic cleavage of the precursor proteins that arise from regions of the genome coding for gag (group specific antigens). In doing so, the structural proteins of the viral core are released. The "gag-Protease" itself is part of the precursor of the protein encoded by the region of the HIV-1 and HIV-2 genome, which also contains a region for "reverse transcriptase" and "integrase" and is believed to cleave autoproteolytically.

The "gag-Protease" cleaves the major core protein of p24 HIV-1 and HIV-2, preferably the nitrogen terminus of the proline residue, for example, in the bivalent radical Phe-Pro, Leu-Pro or Tyr-Pro. It is a protease with a catalytically active aspartate residue, in the active center, the so-called aspartate protease.

If the effect of the "gag protease" could be avoided, the virus would no longer have the proteins necessary to build the viral nucleus. This would lead to the restriction or complete prevention of virus reproduction. Thus, there is a need for a "gag protease" inhibitory agent that can be used as an antiviral agent against AIDS and other retroviral diseases.

In addition, PCT patent application WO 92/08698 and European patent application EP 0 402 646 disclose HIV protease inhibitors which are structurally distinct from the compounds of the invention. FR. U.S. Pat. 1 355 993, DE 12 54 461 and the article in Chem. Ber. 108, 813-819 (1975) relate to hydrazine derivatives which are structurally distinct from the compounds of the present invention and which have no pharmaceutical use. WO 93/18006 discloses hydrazine derivatives as HIV protease inhibitors, but this document has a later priority than that claimed in the patent application which led to this patent.

A number of "gag protease" suppressants have already been synthetically produced, which contain central groups which do not, however, represent proteolytically cleavable peptide isosteres. Until now, however, despite intensive research, it has not yet been possible to prepare a suitable formulation of aspartate protease for use in humans for the control of AIDS with a large extent of infection. In particular, pharmacodynamic problems are critical. In addition, the most commonly known gag-protease inhibiting substances to date have more than two asymmetric carbon atoms in said central building unit, which necessitates a relatively expensive stereospecific synthesis or isomer separation.

It is therefore an object of the present invention to provide a novel class of inhibitory agents for viral aspartate protease with one central building unit. Moreover, the synthesis of the central building unit should simply be spherical. Furthermore, the new central building units have amino groups at both ends, so that, for example, structures analogous to retro-inverso peptides are obtained when selecting suitable substituents.

SUMMARY OF THE INVENTION

The compounds of this invention are compounds of formula (I)

in which

R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted by amino- (lower alkanoyl) - at the amino atom of the amino group, lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl- (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) ), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) ) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted or acylated with one of the remainder of R ¹ or R ⁹ , except that at most one of R ¹ and R ⁹ is hydrogen,

R ³ represents a lower alkyl group, a cyclohexyl- (lower alkyl) group or a phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, and

R ⁷ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy or a cyano group and the term "lower" means that the radical thus defined contains from 1 to a maximum of 7 carbon atoms, including the limits herein, or a salt thereof, if salt-forming groups are present.

As used herein, the term "lower" as used to define groups or moieties, such as lower alkyl, lower alkoxy, lower alkanoyl, and the like, means, unless otherwise noted, that the groups or moieties defined herein contain up to 7 carbon atoms , preferably up to and including 4 carbon atoms.

Unless otherwise stated, the substituents in the radicals R ^{@ 1} , R ^{@ 3} , R ^{@ 7} and / or R ^{@ 9} are present independently of one another or more than once, in particular up to three times.

The carbon atoms in the compounds of formula (I) substituted by R ³ or the central hydroxy group may, if asymmetric, be in the (R), (S) or (R, S) configuration, and may optionally also contain other asymmetric carbon atoms . Thus, the compounds of the invention may be in the form of isomeric mixtures or pure isomers, in particular as diastereomeric mixtures, enantiomeric vapors or pure enantiomers. Preferred compounds of formula (I) wherein the carbon atom substituted with R ³ or hydroxy group, has the configuration (S), and further are optionally provided asymmetric carbon atoms each and independently in the (R), (S) or (R, S ).

The general terms and designations used in the description of the present invention preferably have the meanings given below, wherein individual residues or any combination of said residues may be used in place of the general definition in different planes of the definition.

R ¹ and R ⁹ are lower alkanoyl such as formyl, acetyl, propionyl, butyryl or pivaloyl, phenyl- (lower alkanoyl) such as benzoyl, phenylacetyl and 3-phenylpropionyl, phenyl- (lower alkanoyl) a group wherein the lower alkanoyl residue is substituted with a carbamoyl group such as 2 (R, S) -carbamoyl-3-phenylpropionyl, 3-phenyl-2-carbamoylpropionyl, 3-phenyl-2-tert-butylcarbamoylpropionyl, quinolyl- (lower alkanoyl) a group such as quinolylcarbonyl such as 2-, 3- or 4-quinolylcarbonyl, a morpholinyl- (lower alkanoyl) group such as morpholinylcarbonyl such as morpholinocarbonyl, a thiomorpholinyl- (lower alkanoyl) group such as a thiomorpholinylcarbonyl such as thiomorpholinocarbonyl alkanoyl) such as 3- (tetrazol-1-yl) -propionyl and pyridyl- (lower alkanoyl), for example pyridylacetyl, such as 2-, 3- or 4-pyridylacetyl, especially selected from morpholinocarbonyl, thiomorphol nocarbonyl, pyridylacetyl, quinolin-2-ylacetyl and 2-morpholino-2-isopropylacetyl, and particularly preferably morpholinocarbonyl, thiomorpholinocarbonyl, quinolin-2-ylcarbonyl, 3- (tetrazol-1-yl) propionylcarbonyl or 2- or 3-ethyl-3-carbonyl .

N-morpholino- or N-thiomorpholinocarbonyl substituted on the nitrogen atom with an amino- (lower alkanoyl) group, for example N-morpholino- or N-thiomorpholinocarbonylamino-lower alkanoyl) such as N-morpholino- or N-thiomorpholinocarbonylaminoacetyl, lower-halogen- alkanoyl) which preferably contains up to 3 carbon atoms, for example α-haloacetyl, such as α-fluoro-, α-chloro-, α-bromo-, α-iodo-, α, α, α-trifluoro or α, α , α-tri- chloroacetyl, or halopropionyl, such as β-chloro- or β-bromopropionyl, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), such as 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyryl or 2- [N- (pyridyl- (lower alkyl)] - carbamoyl] - (lower alkanoyl) group such as [2 (R, S) -] N- (2-pyridylmethyl) carbamoyl / -3-methyl] butyryl, (lower alkoxy) -carbonyl, for example methoxy-, ethoxy-, isopropoxy-, isobutoxy- or tert- (lower alkoxy) -carbonyl, such as tert butoxycarbonyl or isobutoxycarbonyl, phenyl- (lower alkoxy) carbonyl, such as benzyloxycarbonyl, which is particularly preferred, 2-tetrahydrofuranyl- (lower alkoxy) -carbonyl, such as 2-tetrahydrofuranylmethoxycarbonyl, N-pyridyl- (lower alkyl) - An N- (lower alkyl) carbamoyl group, such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, an amino acid residue selected from glycine (H-Gly-OH), alanine (H) via a carboxy group -Ala-OH), valine (H-Val-OH), leucine (H-Leu-OH), isoleucine (H-Ile-OH), asparagine (H-Asn-OH), glutamic acid (H-Glu-OH) ), particularly preferably an aliphatic amino acid residue selected from valine, leucine and isoleucine, or an amino acid selected from glycine, glutamic acid and asparagine, wherein each of said amino acids is in the form of D, L or (D, L), preferably (except Val, which may also be in the form of D or (D, L)) may be in the form of L, wherein the α-aminos the upina is unsubstituted or substituted by a lower alkanoyl group such as acetyl, phenyl- (lower alkanoyl) group or carbamoyl and is unbranched or branched, morpholino-, thiomorpholino-, pyridyl-, quinolyl- or tetrazolyl- (lower alkanoyl-) group, pyridylcarbonyl 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, quinolyl-2-ylcarbonyl, pyridyl acetyl such as 2- or 3-pyridylacetyl, morpholinoacetyl, pyridylpropionyl such as 3- (2- or 3-pyridyl) propionyl, 3-morpholinopropionyl or tetrazolyl-propionyl such as 3- (tetrazolyl-1-yl) -propionyl, a halogen- (lower alkanoyl) group containing up to 3 carbon atoms and containing an amino- (lower alkanoyl) group substituted with N-morpholino- or N -thiomorpholinocarbonyl on the nitrogen atom of the amino group, for example α-haloacetyl such as α-fluoro-, α-chloro-, α-bromo-, α-iodo-, α, α, α-trifluoro- or α, α, α-trichloroacetyl or halopropionyl, such as β-chloro- or β-bromopropionyl, substituted with 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) a (lower alkoxy) carbonyl group such as a tert-butoxycarbonyl, 2- (N-morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl) group such as a 2 (R, S) - / N- ( 2-morpholinoethyl) carbamoyl / -3-methylbutyryl, or 2- [N- (pyridyl- (lower alkyl)] - carbamoyl] - (lower alkanoyl group such as [2 (R, S) -) - N- (2 -pyridylmethyl) carbamoyl [-3-methyl] butyryl, (lower alkyl) -sulfonyl group such as methylsulfonyl or ethylsulfonyl, morpholinosulfonyl or thiomorpholinosulfonyl group, (lower alkyl) -sulfonyl group such as methylsulfonyl, ethylsulfonyl or n-propylsulfonyl tert-butylsulfonyl and morpholinosulfonyl or thiomorpholinosulfonyl.

In a particularly preferred embodiment of the invention, no morpholinosulfonyl group or thiomorpholinosulfonyl group is present as a substituent. R ³ and R ⁷ are independently selected from

- a lower alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl,

- a cyclohexyl- (lower alkyl) group such as cyclohexylmethyl and a phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, and

2-phenylethyl, 3-phenylpropyl, 4-fluorobenzyl, 4-cyanobenzyl or 4-methoxybenzyl, particularly preferably from the phenyl- (lower alkyl) group as hereinbefore defined.

Salts of the compounds of formula (I) are, in particular, acid addition salts, salts with bases or, where polyvalent salt groups are present, optionally also mixed or internal salts.

The salts are, in particular, pharmaceutically usable, non-toxic salts of the compounds of formula (I).

Such salts comprise, for example, compounds of formula (I) with an acidic group such as a carboxy group and are, for example, their salts with suitable bases, such as non-toxic salts derived from metals of Ia, Ib, IIa and IIb. salts such as lithium, sodium or potassium salts or alkaline earth salts such as magnesium or calcium salts, zinc salts or ammonium salts, and also those formed with organic amines such as optionally hydroxy substituted mono-, di- or trialkylamines , especially mono-, di- or tri- (lower alkyl) amines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamine, triethylamine, mono- or tris- [2- (hydroxy-) alkyl) - amines such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) amine, N, N, -di- (lower alkyl) - N / hydroxy (lower (alkyl) - amines such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, N-methyl-D-glucamine or quaternary ammonium salts such as tributylammonium salts. Compounds of formula (I) with basic groups, for example amino, may form salts with, for example, inorganic acids such as hydrohalic acids such as hydrochloric, sulfuric or phosphoric acid, or with organic carboxylic acids, sulfonyl acids, sulfo acids or phosphorus-containing acids such as is acetic acid, propionic, glycolic, succinic, maleic, hydroxymalein, methylmaleinic, fumaric, malic, tartaric, gluconic, glucaric, gluconuric, citric, benzoic, cinnamon, almond, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, emmonium, nicotinic or isonicotinic, further with amino acids such as the named α-amino acids, especially glutamic and aspartic acid, as well as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzene zenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, with N-cyclohexylsulfamic acid (to form cyclamate) or other acidic organic compounds such as ascorbic acid. Compounds of formula (I) with acidic or basic groups may also form internal salts.

Pharmacologically unsuitable salts may also find use for isolation or purification.

The compounds of the invention have a viral aspartate protease inhibiting effect, in particular a gag protease inhibiting effect. These compounds inhibit in particular the effect of the gag-HIV-1 and HIV-2 in the tests described in the concentration of from 10 ^-6 to 10''mol / l and are therefore suitable as agents against the diseases caused by these or related retroviruses, such as AIDS.

The ability of the compounds of formula (I) to inhibit the proteolytic activity of, for example, HIV-1 protease, can be demonstrated, for example, by the method of J. Hansen et al. in The EMBO Joumal 7, 1785-1791 (1988). The suppression of the effect of the gag protease on the substrate, which is the fusion protein of Escherichia coli from the precursor of the gag protein and MS-2, is measured. The substrate and its cleavage products are separated by gel electrophoresis into polyamide and rendered visible by immuno-blotting paper (Immunoblotting) with monoclonal antithodies against MS-2.

In an even simpler assay that allows a fairly quantitative expression of the result, a synthetic peptide that corresponds to the gag protein precursor cleavage site is used as the substrate for the gag protease. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

For example, a synthetic chromophoric peptide (e.g., HKARVL (NO. NO.)) May be used as a substrate for recombinant HIV-1 protease (produced according to S. Billich et al. In J. Biol. Chem., 264 (34), 17905-17908 (1990)). ₂ ) FEANleS (Bachem, Switzerland)) or icosapeptide (such as RRSNQVSQNYPIVQNIQGRR (produced by peptide synthesis according to a known method)), which corresponds to the gag protein precursor cleavage site. This substrate and its cleavage products can be measured by high pressure liquid chromatography (HPLC).

To this end, the test compound suppressant of formula (I) is dissolved in dimethylsulfoxide and the enzyme test is carried out, while a suitably diluted suppressor compound in 200 mmol of β-morpholinoethanesulfonic acid (MES buffer) is used. with a pH of 6.0, it is contacted with a test mixture consisting of 67.2 pmol of said chromophore peptide in 0.3 mol of sodium acetate, 0.1 mol of sodium chloride, at a pH of 7.4 or 122 pmol of said icosapeptide in 20 mmol MES buffer with pH 6.0. The handle size is 100 pl. The reaction is started by the addition of HIV-1 protease with a volume of 2 µl in the first case and 10 µl in the second case and stops after 15 minutes of incubation at 37 ° C by the addition of 100 µl of 0.3 molar perchloric acid and One hour of incubation at 37 ° C by the addition of 10 µl of 0.3 molar perchloric acid. The reaction product is quantified by centrifuging the sample for 5 minutes at 10,000 xg in 100 µl (chromophomic peptide feed) or 20 µl (icosapeptide feed) of the supernatant obtained and loaded onto a Nuclosil ^R C18-5p-HPLC column (Macharey & Nagel) , Diiren) and elution based on the peak height of the cleavage product at 280 (chromophomic peptide feed) or 215 (icosapeptide feed) nm, gradient: 100% El.l -> 50% El.1 / 50% E1.2 (E1: 75% acetonitrile, 90% water, 0.1% trifluoroacetic acid, E 1.2: 75% acetonitrile, 25% water, 0.08% trifluoroacetic acid) for 15 minutes, at a flow rate of 1 mL / min.

IC ₅₀ values are preferably determined (IC ₅₀ being the concentration at which the HIV-1 protease activity decreases in comparison with the control in the absence of a 50% suppressant) from about 10 to ⁶ 10 to ⁹ mol, in particular from about 10 to ⁷ mol to about 10 to ⁸ mol.

In another assay, the compounds of the invention may be shown to protect cells that are usually infected with HIV from such an infection or at least to slow such infection. Hereby, human leukemia T cells of the cell line MT-2 (Science 229, 563 (1985)), which are particularly sensitive to the cytopathogenic effect of HIV, are incubated with HIV alone or with HIV in the presence of the compounds of the invention. of treated cells.

For this, MT-2 cells are maintained in RPMI 1640 (Gipco, Switzerland, RPMI 1640 contains a mixture of amino acids without L-Gln), supplemented with 10% heat-inactivated fetal calf serum, L-glutamine, 2- / 4- ( 2-hydroxyethyl) -1-piperazino / ethanesulfonic acid (Hepes) and standard antibiotics, at 37 ° C in humid air containing 5% carbon dioxide. 50 µl of each test compound in culture medium and 100 µl of HIV-1 in culture medium (800 TCID50 / ml) (TCID50 dose infecting cell culture 50, with 50 indicating the dose that infects 50% of MT-2 cells) are added to 4 x 10 ³ exponentially washed MT-2 cells in 50 μΐ culture medium per well on a 96-well microtiter plate. The concurrent batch on another microtiter plate with cells and test compound contains 100 μΐ virus free culture medium. After a 4-day incubation, reverse transcriptase (RT) activity is determined in a 10 μΐ cell supernatant. RT-activity is determined in 50 mmol tris- (α, α, α-hydroxymethyl) methylamine (ultrapure, Merck, Germany) at pH 7.8, 75 mmol potassium chloride, mmol dithiothreitol, 5 mmol magnesium chloride, 0.05 % Nonidet P-40 (Sigma, Switzerland, surfactant), 50 µg / ml polyadrenylic acid (Pharmacia, Switzerland), 1.6 µg / ml dT (12-18) (Sigma, Switzerland). Filter the mixture through a 0.45 μ Acrodisc filter (Gellman Science Inc., Ann Arbor) and store at -20 ° C. To an aliquot of this solution was added 0.1% by volume of [α- ^{32 P} ] dTTP to achieve a final activity of 10 ⁴⁶ with ⁴ µm ⁴ . Transfer 10 μ kult of the culture supernatant to a new 96-well microtiter plate and add 30 μΐ of the RT-cocktail described above, then incubate the plate for 90 minutes to hours at 37 ° C. 5 μΐ of this reaction mixture is transferred to Whatman DE81 filter paper (Whatman). The dried filter is washed three times for 5 minutes each with 300 mmol of sodium chloride in 25 mmol of trisodium citrate and once with 95% ethanol and air-dried again. The evaluation is performed on a Matrix Packard 96well Counter (Packard). ED90 values are obtained and defined as the lowest concentration of test compound that causes a decrease in RT-activity by 90% compared to seed of cells not treated with the test substance. RT-activity is a measure for increasing HIV-1.

The compounds of the present invention have ED90 values of from about 10 ⁵ to 10 ⁸ mol, preferably from 5 x 10 ⁷ to 5 x 10 ⁸ mol.

For the following groups of compounds of formula (I), it is meaningful, for example, to substitute the radicals from the above general definitions or to introduce or exclude the definitions from other groups, for example to replace the generally defined radicals by the radicals of a particular definition.

Preferred is a compound of formula (I) wherein R ¹ is (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, a monovalent aliphatic amino acid residue attached via a carboxy group selected from valine, alanine, leucine and isoleucine, or a radical bonded via a carboxy group to an amino atom of an amino group which is acylated with one of the radicals selected from phenyl- (lower alkanoyl), morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), (lower alkoxy) -carbonyl or phenyl (lower alkoxyj-carbonyl, wherein all of said amino acids are in the D, (D, L) and L, R ³ is phenyl (lower alkyl) group, R ⁷ is lower alkyl, cyclohexyl (lower alkyl or phenyl- (lower alkyl) group and R ⁹ has one of the meanings given for R ¹ , and the asymmetric carbon atoms bearing the radical R ³ and the hydroxy group have S-conf the term "lower" means that the radical thus defined contains from 1 to a maximum of 7 carbon atoms, including the limits herein, or a salt thereof, if salt-forming groups are present.

Particularly preferred are the compounds and salts thereof exemplified.

The compounds of formula (I) and salts of such compounds with at least one salt-forming group are prepared in a manner known per se, for example by: (a) a hydrazine derivative of formula (III)

R

HM .R '(III),

H in which

R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl group), a phenyl- (lower alkanoyl) group wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- ( lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholino-carbonyl substituted with amino- (lower alkanoyl), halogen- (lower alkanoyl) on the nitrogen atom of the amino group, containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), ( lower alkoxy) carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, lower alkyl] sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbam an acyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the previously mentioned residues R ¹ or R ⁹ , a

R ⁷ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl phenyl- (lower alkyl) group which is not substituted or substituted by a halogen atom, a lower alkoxy group or a cyano group is added to the cpoxide of the general formula (IV)

in which

R ¹ is H, lower alkanoyl, phenyl (lower alkanoyl) group, a phenyl (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino (lower alkanoyl), pyridyl (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino atom of the amino group, halogen- (lower alkanoyl) group up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbam an acyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the latter residues R ¹ or R ^9; and

R ³ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl- (lower alkyl) group which is not substituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, the free functional groups, except for those involved in the reaction, being optionally present protected form, and optionally protecting groups present are cleaved, or

(b) for the preparation of compounds of formula (I) wherein R ¹ , R ³ , R ⁷ and R ⁹ have the meanings given for a compound of formula (I) provided that R ^{1 is} not hydrogen, an amino compound of formula (V) ^{rZ h} and in which

R ¹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group wherein the lower alkanoyl radical is substituted with carbamoyl, morpholino-lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- ( lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino atom of the amino group, halogen- (lower alkanoyl) group three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, (lower alkoxy) - carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carb a moyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remainder R ¹ or R ⁹ a

R ³ and R ⁷ are each independently lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, is condensed with an acid of the formula (VI)

R’-OH (VI) in which

R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino atom of the amino group, halogen- (lower alkanoyl) group up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) carbamoy [/ - (lower alkanoyl)], (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carb a moyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L 1, wherein the α-amino group is unsubstituted or acylated by one of the remainder R) ¹ or R ⁹ and or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or cj to produce compounds of formula (I) wherein R ¹ , R ³ , R ⁷ and R ⁹ have the meanings given for a compound of formula (I) with the proviso that R ^{9 is} not a hydrogen atom, an amino compound of formula (VII)

in which

R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino atom of the amino group, halogen- (lower alkanoyl) group up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) carbamoy or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the latter residues R ¹ or R ^9; and

SK 279706-6

R ³ and R ⁷ are each independently lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, is condensed with an acid of formula ( VIII)

R'-OH (VIII) in which

R ¹ represents lower alkanoyl, phenyl- (lower alkanoyl), phenyl- (lower alkanoyl), wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl) ), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino nitrogen of the amino group, halogen- (lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbamoyl gr or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remaining named R residues ¹ or R ⁹ and or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or

d) for the production of a hydrazine derivative of the general formula (I), in which R ¹ and R ⁹ represent two identical radicals as defined in claim 1, except for a hydrogen atom, and the other radicals have the same meanings, a diaminocompound of formula (IX)

(ix) in which

R ³ and R ⁷ independently represent a lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, is condensed with an acid of the formula ( VIII)

THE CORNER (VIII) or formula (VI) R ⁹ OH (VI)

In which

R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted with amino- (lower alkanoyl) at the nitrogen atom of the amino group, (lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - ( lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower) alkyl) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not is substituted or acylated with one of the remainder of R ¹ or R ⁹ mentioned, or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or

(e) for the production of a hydrazine derivative of the general formula (I) in which R ¹ , R ³ , R ⁷ and R ⁹ have the meanings given for the compound of the general formula (I),

in which

R ⁷ represents a hydrogen atom and

R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted by amino- (lower alkanoyl) - at the amino atom of the amino group, lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) l) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not is substituted or acylated with one of the remaining R ¹ or R ⁹ , provided that at most one of R ¹ or R ⁹ is hydrogen, and

R ³ is lower alkyl, cyclohexyl-lower alkyl) or phenyl- (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, introduces the radical R ^{7 by} substitution with a compound of formula (XII)

R ⁷ -X (XII) wherein

X represents a leaving group and

R ⁷ is as defined above, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or

f) a hydrazine derivative of the general formula (I), wherein

R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted by amino- (lower alkanoyl) - at the amino atom of the amino group, lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) ) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted or acylated with one of the remainder of R ¹ or R ⁹ , provided that at most one of R ¹ or R ⁹ is hydrogen, and with the proviso that there is at least one functional group in the compound of formula (I) in question. the protecting groups present are cleaved, and, where appropriate, the hydrazine derivative of formula (I) with at least one salt-forming group obtained by one of methods a) to (i) is converted into its salt or the resulting salt is converted into a free salt. the hydrazine derivative or other salt and / or the optionally obtained isomeric mixture is separated and / or the hydrazine derivative of the general formula (I) according to t The present invention converts to another hydrazine derivative of formula (I) of the invention.

Said methods are described in more detail below.

Method a) (Addition of amine to epoxide)

The amino group of the hydrazine derivative of the general formula (III) involved in the reaction preferably has at least one free hydrogen atom according to the meaning of R ⁷ , but can also be derivatized itself in order to increase the reactivity of the hydrazine derivative.

In particular, the epoxide of formula (IV) has a structure which makes it possible to advantageously carry out the quantitative addition of the hydrazine derivative.

Functional groups in the starting materials to be avoided, in particular carboxy, amino, hydroxy, mercapto and sulfo groups, may be protected by suitable protecting groups which are commonly used in the synthesis of peptide compounds, but also of cephalosporins and nucleicates as well as penicillins. and sugars. These protecting groups may already be present in the substances obtained from the preceding steps and are intended to protect the respective functional groups against unwanted side reactions such as acylation, etherification, esterification, oxidation, solvolysis and the like. In certain cases, the protecting groups may additionally act selectively, for example, to carry out a stereoselective reaction. Characteristic of protecting groups is that they cleave easily, that is, without undesirable side reactions, for example solvolytically, reducing or photolytically, or also enzymatically, for example also under physiological conditions. Residues analogous to protecting groups may also be present in the final materials. Compounds of formula (I) with protected functional groups may have higher metabolic stability or other improved pharmacodynamic properties than the corresponding compounds with free functional groups. In the narrower sense, protecting groups in the foregoing and following description are to be understood as meaning appropriate moieties which are no longer present in the final compounds.

The protection of functional groups with such protecting groups, the protecting groups themselves, as well as the reactions leading to their cleavage, are described in basic works such as in JF McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York (1973), Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York (1981), in "The Peptides," Vol. 3 (E. Gross and J. Meienhofer, Ed.) Academic Press, London and New York (1981), in "Mcthoden der Organischen Chemie", Houben-Weyl, 4th Ed., Vol. 15/1, Georg Thieme Verlag, Stuttgart (1974), in H. - D. Jakubke and H. Jescheit, "Aminosäuren, Peptide, Proteine", Verlag Chemie, Weinhein, Deefieled Beach and Basel (1982) and in Jochen Lehmann, " Chemie der Kohlenhydrate: Monosaccharide and Derivatives', Georg Thieme Verlag, Stuttgart (1974).

For example, the carboxy group is protected as an ester group that is selectively cleaved under mild conditions. The carboxy group protected in esterified form is esterified in particular by a lower alkyl group which is preferably branched at the 1-position of the lower alkyl group or substituted at the 1-position or the 2-position of the lower alkyl group by suitable substituents.

A protected carboxy group which is esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

A protected carboxy group which is esterified with a lower alkyl group which is branched at the 1-position of the lower alkyl group is, for example, a tert- (lower alkoxy) -carbonyl group, for example tert-butoxycarbonyl.

A protected carboxy group which is esterified with a lower alkyl group which is substituted at the 1 or 2 position of the lower alkyl group by a suitable substituent is, for example, arylmethoxycarbonyl with one or two asylum residues, wherein the asyl is phenyl or mono-, di- or trisubstituted, e.g. an alkyl group such as a tertiary (lower alkyl) group such as tert-butyl, a lower alkoxy group such as methoxy, hydroxy, a halogen atom such as chlorine, and / or a nitro group such as benzyloxycarbonyl, benzyloxycarbonyl substituted with said substituents such as for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl optionally substituted by said substituents, for example di- (4-methoxyphenyl) methoxycarbonyl, further lower alkyl substituted carboxy, wherein the lower alkyl group is in the 1 or 2 position with a suitable substituent such as a 1- (lower alkoxy) - (lower alkoxy) carbonyl group, for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1- (lower alkyl) -thio- (lower alkoxy) carbonyl group, for example 1 -methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, wherein the aroyl group is benzoyl optionally substituted, for example, by a halogen atom such as bromine, for example phacyclicloxycarbonyl, 2-halo- (lower alkoxy) -carbonyl, for example 2,2,2-carbonylcarbhoxyethoxycarbonyl or 2-iodoethoxycarbonyl, as well as 2- (trisubstituted silyl) - (lower alkoxy) carbonyl, wherein the substituents independently represent an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical optionally substituted, for example, by a lower alkyl group, a lower alkoxy group, an aryl, or nitro, for example optionally as indicated by su a substituted-alkyl, phenyl- (lower alkyl), cycloalkyl or phenyl group, for example 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl, such as a 2-tri- (lower alkyl) -silylethoxycarbonyl group, for example 2 -trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl or 2-triarylsilylethoxycarbonyl such as triphenylsilylethoxycarbonyl.

The carboxy group may also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a tri- (lower alkyl) -silyloxycarbonyl group such as trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be substituted by two lower alkyl groups, for example methyl groups, and the amino or carboxy group may be substituted by a second molecule of formula (I). Compounds with such protecting groups can be prepared, for example, by reaction with dimethylchlorosilane as a silylating agent.

The protected carboxy group is preferably a tert- (lower alkoxy) carbonyl group, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.

The protected amino group may be protected with an amino protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercapto, 2-acyl- (lower alk-1-enyl) -amino or silylamino group, or as an azido group.

In the corresponding acylamino group, the acyl moiety is, for example, an acyl radical of an organic carboxylic acid, for example up to 18 carbon atoms, particularly optionally substituted, for example with halogen or aryl, or substituted (lower alkane) carboxylic acid or optionally with halogen, lower alkoxy or nitro substituted. benzoic acid, or preferably a semi-ester of carbonic acid. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halogen- (lower alkanoyl), for example 2-haloacetyl, such as 2-chloro, 2-bromo, 2-iodo, 2,2 Benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, (lower alkoxy) -carbonyl, optionally substituted with a halogen atom, a lower alkoxy or a nitro group, a 2-trifluoro- or 2,2,2-trichloroacetyl group, preferably branched at the 1-position of the lower alkyl radical or at the 1 or 2-position an optionally substituted (lower alkoxy) -carbonyl group, for example a tertiary- (lower alkoxy) -carbonyl group such as tert-butoxycarbonyl, arylmethoxycarbonyl with one, two or three aryl radicals, which optionally represent, for example, a lower alkyl group, in particular a tertiary (lower alkyl) group such as tert-butyl, a lower alkoxy group such as a methoxy group, a hydroxy group, a halogen atom such as chlorine and / or nitro optionally mono- or polysubstituted phenyl, e.g. bromo substituted benzoyl, e.g. phenacyloxycarbonyl, 2-halo- (lower alkoxy) carbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, 2- (trisubstituted silyl) - (lower alkoxy) -carbonyl , for example 2-tri- (lower alkyl) -silyl (lower alkoxy) -carbonyl, such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) -carbonyl, or triarylsilyl- (lower alkoxy) -carbonyl, for example 2 -trifenylsilyletoxykarbonyl.

In the arylmethylamino group, which for example represents a mono-, di or especially triarylmethylamino group, the aryl radicals in particular are optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl or, in particular, tritylamino.

In an etherified mercapto group, the mercapto group is in particular as a substituted arylthio or aryl- (lower alkyl) -thio group, the aryl moiety being, for example, optionally as, for example, a lower alkyl group such as methyl or tert-butyl, a lower alkoxy group such as methoxy, a halogen atom such as chlorine and / or nitro substituted phenyl such as 4-nitrophenylthio.

In the 2-acyl- (lower alk-1-enyl) moiety useful as an amino protecting group, the acyl is, for example, the corresponding lower alkanecarboxylic acid, benzoic acid, optionally substituted, for example, by a lower alkyl group such as methyl or tert-butyl, lower alkoxy , such as methoxy, a halogen atom such as chlorine, and / or a nitro group, or in particular a carbonic acid semi-ester such as (lower alkyl) carbonic acid ester. The corresponding groups are especially 1- (lower alkanoyl) - (lower alk-1-ene-2- 1- (lower alkanoyl) -prop-1-en-2-yl, such as 1-acetylprop-1-en-2-yl, or (lower alkoxy) -carbonyl- (lower alk-1-yl); en-2-yl) groups, for example (lower alkoxy) carbonylprop-1-en-2-yl such as 1-ethoxycarbonylprop-1-en-2-yl.

A silylamino group is, for example, a tri- (lower alkyl) -silylamino group, for example a trimethylsilylamino group or a tert-butyldimethylsilylamino group. The silylamino silicon atom may also be substituted with only two lower alkyl groups, for example methyl groups, and the amino or carboxy group may be substituted with the second molecule of formula (I). Compounds with such protecting groups may be prepared, for example, by reaction with the corresponding chlorosilanes, such as dimethylchlorosilane, as a silylating agent.

The amino group may also be protected by conversion to a protonated form, and the corresponding anions are in particular anions of strong inorganic acids such as sulfuric, phosphoric or hydrohalic acids, for example chlorine or bromine, or organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino protecting groups are (lower alkoxy) carbonyl, phenyl- (lower alkoxy) carbonyl, fluorophenyl- (lower alkoxy) carbonyl, 2- (lower alkanoyl) - (lower alk-1-en-2-yl) or a (lower alkoxy) -carbonyl- (lower alk-1-en-2-yl) group.

The hydroxy group may be protected, for example, by an acyl group, for example a halogen atom such as chlorine, substituted by a lower alkanoyl group such as 2,2-dichloroacetyl or, in particular, by the acyl residue of the carbonic acid half ester mentioned for protected amino groups. A preferred hydroxy protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. The hydroxy group may be further protected by a tri- (lower alkyl) -silyl group, for example trimethylsilyl, triisopropylsilyl or tert-butyldimethylsilyl, an easily cleavable ether-forming group, for example an alkyl group such as a tert- (lower alkyl group, for example tert-butyl) , oxa- or thiaaliphatic or -cycloaliphatic, in particular 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radicals, for example 1- (lower alkoxy) - (lower alkyl) or 1- (lower alkyl) -thio- (lower alkyl) groups, such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl 1-methylitoethyl or 1-ethylthioethyl, or 2-oxa or 2-oxa, or 2-thiacycloalkyl of 5 to 7 ring atoms such as 2-tetrahydrofuryl or 2 -tetrahydropyranyl, or the corresponding thiaanalogues, as well as a 1-phenyl- (lower alkyl) group such as benzyl, diphenylmethyl or trityl, wherein the phenyl radical may be substituted, for example, by an atom halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro.

Two hydroxy groups occurring in a single molecule, especially when adjacent, or adjacent hydroxy and amino, may be protected, for example, by bivalent protecting groups, such as preferably methylene substituted by one or two lower alkyl radicals or oxo groups, for example as optionally substituted alkylidene, for example lower alkylidene. , such as isopropylidene, cycloalkylidene, such as cyclohexylidene, carbonyl or benzylidene.

For the purposes of the present invention, as a protecting group, for example a carboxy-protecting group, is also expressly meant to include a polymeric carrier attaching an easily cleavable protecting group, for example a carboxy group, as suitable, for example, for Merrifield synthesis. Such a suitable polymeric carrier is, for example, a polystyrene resin weakly crosslinked by copolymerization with divinylbenzene, which carries a bridging member for reversible bonding.

The addition of the compounds of formula (III) to the epoxides of formula (IV) is preferably carried out under reaction conditions customary for the addition of a nucleophilic agent to the epoxides.

The addition is preferably carried out in aqueous solution and / or in the presence of polar solvents such as alcohols such as methanol, ethanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide or phenols such as phenol, or also under anhydrous conditions in a non-polar solvent such as benzene or toluene, or in an emulsion of benzene and water, optionally in the presence of an acidic or basic catalyst such as a hydroxide solution such as sodium hydroxide or in the presence of a solid phase catalyst providing hydrazine such as alumina in ethers, for example in diethyl ether, generally at temperatures from about 0 ° C to the reflux temperature of the corresponding reaction mixture, preferably from 20 to 130 ° C, optionally under reflux (reflux), at elevated pressure, for example in a pressure tube, the boiling point may also be exceeded and / or under an inert gas such as argon or nitrogen. In this case, one of the two compounds of the formulas (III) and (IV) can always be present in excess, for example in a molar ratio of from 1: 1 to 1: 100, preferably in a molar ratio of from 1: 1 to 1: 10, particularly preferably ratio from 1: 1 to 1: 3.

Deprotection is optionally carried out according to the methods described under method f) (deprotection).

Method b) (Preparation of an amide bond)

In the starting compounds of formulas (V) and (VI), the functional groups, except those to be involved in the reaction or which do not react under the reaction conditions, are independently protected by the protecting groups mentioned under method a).

Compounds of formula (VI) contain a free carboxy group or reactive derivatives of these acids, for example, cleavable activated esters or reactive anhydrides and reactive cyclic amides. Reactive acid derivatives may also be formed in situ.

The activated carboxy-terminal esters of the compounds of formula (VI) are, in particular, unsaturated esters of a bonded carbon atom of an esterifying moiety, for example of the vinyl ester type, such as vinyl ether (which can be produced by reaction of the corresponding ester with vinyl acetate, activated vinyl ester method). can be produced, for example, by treating the corresponding acid with an isoxazolium reagent, 1,2-oxazolium or Woodward method), or a 1- (lower alkoxy) vinyl ester (which can be produced, for example, by treating the corresponding acid with a (lower alkoxy) acetylene, ethoxyacetylene method) or amidine ester such as N, N'-disubstituted amidinoester (which may be obtained by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example Ν, Ν'-dicyclohexylcarbodiimide, carbodiimide method) or Ν, Ν'-disubstituted amidinoester (kt for example, a suitable aryl ester, in particular a phenyl ester substituted with electron-withdrawing substituents (which may be obtained, for example, by treating the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-nitrophenol), -methylsulfonylphenol, 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 active aryl ester method, cyanomethyl ester (which may be obtained, for example, by treating the corresponding acid with acetonitrile in the presence of a base, a cyanomethyl ether method), a thioester, in particular a phenylthioester optionally substituted with, for example, nitro (obtainable for example by treating the corresponding acid with a thiophenol optionally substituted with, for example, nitro) an anhydride or carboxdiimide method, an activated thiolester method) or, in particular, an amino or amido ester (obtainable by treating the corresponding acid with an N-hydroxyamino- or N-hydroxyamido compound, for example N-hydroxysuccininide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxyphthalimide) hydroxy-5-norbomene-2,3-dicarboxylic acid, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benztriazin-4-one, for example the anhydride or carbodiimide method, activated N-hydroxyester method ). Internal esters, for example τ-lactones, can also be used.

The acid anhydrides may be symmetrical or mixed anhydrides of these acids, for example anhydrides with inorganic acids such as acid halides, in particular acid chlorides (which may be obtained, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride, phosgene or oxalyl chloride). which can be obtained, for example, from the corresponding acid ester via the corresponding hydrazide and its treatment with nitric acid, the azide method), anhydrides with semi-esters of carbonic acid, which can be obtained, for example, by treating the corresponding acid with (lower alkyl) chloroformates or 1- (lower alkoxy) -carbonyl-2- (lower alkoxy) -1,2-dihydroquinoline (mixed O-alkylcarbonic anhydride method) or anhydrides with dihalogenated, in particular dichlorophosphoric acid (which can be obtained, for example, by treatment with the corresponding acids with phosphorus oxychloride, phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those that can be prepared with phenyl-N-phenylphosphoramidochloridate or by reaction of alkylphosphoric amides in the presence of sulfonic anhydride and / or additives causing a decrease in racemization such as N -hydroxybenztriazole, or in the presence of diethyl cyanophosphonic acid ester or orthophosphoric acid derivatives or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (which can be obtained, for example, by treating the corresponding acid with an optionally substituted halide (lower alkane) - or phenyl- lower alkane) carboxylic acid, for example with phenylacetic, pivalic or trifluoroacetic acid chloride, mixed carboxylic acid anhydride method) or with organic sulfonic acids (which can be obtained by treatment with salts such as alkali metal salts of the corresponding acid with a suitable organic sulfonic acid halide such as chloride (lower alkane or aryl-, e.g. methane or p-toluenesulfonic acid, mixed sulfonic anhydride method), as well as symmetrical anhydrides (which can be obtained, for example) by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylaminopropin, symmetric anhydride method).

Suitable cyclic amides are in particular amides with five-membered aromatic diazacyclides, such as amides with imidazoles, for example imidazole (which can be obtained, for example, by treatment of the corresponding acid Ν, Ν'-carbonyldiimidazole, imidazole method) or pyrazole, for example 3,5-dimethylpyrazole can be obtained, for example, via an acid hydrazide by treatment with acetylacetone, the pyrazolidide method).

As mentioned above, the carboxylic acid derivatives used as acylating agent can also be formed in situ. For example, Ν, Ν'-disubstituted amidinoesters are formed in situ when a mixture of the starting compound of formula (V) and the acid used as acylating agent is reacted in the presence of a suitable Ν, Ν'-disubstituted carbodiimide such as Ν, Ν'-cyclohexylcarbodiimide. . Furthermore, the amino or amido ester of the acid used as acylating agent may be formed in the presence of a starting compound of formula (V) to be acylated by reacting a mixture of the corresponding acid and amino compound as starting materials in the presence of N, N'-disubstituted carbodiimide. , N'-dicyclohexylcarbodiimide and N-hydroxylamine or N-hydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base, for example 4-dimethylaminopyridine. Further, in situ activation can be achieved by reaction of Ν, Ν, Ν ', Ν'-tetraalkyluronium compound such as O-benztriazole-1-Ν, Ν, Ν', Ν'-tetramethyluronium hexafluorophosphate, O- (1,2-dihydro- 2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or O- (3,4-dihydro-4-oxo-1,2,3-benztriazolin-3-yl) -N, N , N ', N'-tetramethyluronium tetrafluoroborate. Finally, carboxylic anhydrides of formula (VI) or (VII) with phosphoric acid can be prepared in situ by reacting an alkylphosphoric amide such as phosphoric acid hexamethylamide in the presence of sulfonic anhydride such as 4-toluenesulfonic anhydride with a salt such as tetrafluoroborate, for example sodium tetrafluoroborate, or another compound derived from hexamethylaminophosphoric acid such as benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluoride, preferably in the presence of racemization reducing additives such as N-hydroxybenztriazole.

In a similar manner, a variety of reaction types for carboxylic acids of formula (VI), also with compounds of formula (III) having a terminal sulfonyl or phosphoryl group, can be carried out by condensation with a compound of formula (V) to sulfonamides.

Thus, for example, activated sulfonic acid esters, for example the corresponding, especially nitro substituted aryl esters, such as phenyl esters, may be used, and the amine component of formula (V) may also be used as an alkali metal amide, for example an alkali metal arylamide such as sodium aniline or nitric heterocyclic salt. , for example, potassium pyrrolidine.

In addition, reactive anhydrides such as the corresponding symmetric (which can be prepared, for example, by reaction of a silver alkylsulfonic acid salt with an alkylsulfonyl chloride) or preferably asymmetric acid anhydrides, for example anhydrides with inorganic acids such as sulfonyl halides, especially sulfonyl chlorides acids with inorganic acid chlorides such as thionyl chloride or phosphorus pentachloride), organic carboxylic acids (which can be obtained, for example, by treating a sulfonic acid halide with a carboxylic acid salt, such as an alkali metal salt, in a manner similar to the abovementioned mixed sulfonic anhydride method) or azides (which may be obtained from the corresponding sulfonic acid chloride and sodium azide or via the corresponding hydrazide and its treatment with nitric acid, with the azide method).

The amino group of the compound of formula (V) involved in the reaction preferably contains at least one reactive hydrogen atom, especially when a reactive carboxy, sulfonyl or phosphoryl group is available in reactive form. These amino groups may also themselves be derivatized, for example by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene chlorophosphite or tetraethylpyrophosphite. For example, a derivative of such an amino group compound is also a carbamic acid halide or isocyanate, wherein the amino group involved in the reaction is changed as an isocyanate to an optionally substituted halocarbonyl such as chlorocarbonyl, in which case only compounds of formula (I) are available. The nitrogen of the amido group formed by the reaction bears a hydrogen atom.

The condensation to achieve the amide bond can be carried out in a manner known per se, for example as described in the basic literature, such as Houben-Weyl, "Methoden der organischen Chemie", 4th ed. Vol. 15/11. (1974), Vol. IX (1955) and Vol. Ell (1985), Georg Thieme Verlag, Stuttgart, " The Peptides " (E. Gross and J. Meienhofer, Ed.), Vol. 1 and 2, Academic Press, London and New York (1979 and 1980) or M. Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin (1984).

The condensation of the free carboxylic acid with the corresponding amine can advantageously be carried out in the presence of the usual condensing agents or by the use of carboxylic acid anhydrides or halides such as chlorides of these acids or activated carboxylic acid esters such as p-nitrophenyl esters. Conventional condensing agents are, for example, carbodiimides, for example diethyl, dipropyl-, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or, in particular, dicyclohexylcarbodiimide, further suitable carbonyl compounds, for example carbonylimidazole, 1,2-oxazolium compound, for example 2-ethyl -5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, Ν, Ν, Ν ', Ν'-tetraalkyluronium compounds such as O-benzotriazole-1-Ν, Ν, Ν', Ν'-tetramethyluronium hexafluorophosphate, further activated phosphoric acid derivatives, for example, diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylchlorophosphoramide, (2-oxo-3-oxazolidinyl) phosphine or 1-benztriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate.

If desired, an organic base, preferably a tertiary amine, for example tri- (lower alkyl) amine with a bulky residue, for example ethyldiisopropylamine or triethylamine, and / or a heterocyclic base, for example 4-dimethylaminopyridine or preferably 4-methylmorpholine or pyridine, is added.

The condensation of the activated ester, reactive anhydride or reactive cyclic amide with the corresponding amines is usually carried out in the presence of an organic base, for example simple tri- (lower alkyl) amines, for example triethylamine or tributylamine, or said organic bases. If necessary, the condensing agent described above for the free carboxylic acids is additionally used.

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

Carboxylic acid chlorides, for example the chlorofluoric acid derivatives of the acid of formula (VI), or sulfonic acid chlorides, are condensed with the corresponding amines, preferably in the presence of an organic amine, for example the three (lower alkyl) amines or heterocyclic bases; .

The condensation is preferably carried out in an inert, aprotic, preferably anhydrous solvent or solvent mixture, for example a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, ketone, for example acetone, cyclic ether, for example tetrahydrofuran esters, for example ethyl acetate or nitrile, for example acetonitrile, or mixtures thereof, optionally at a reduced or elevated temperature, for example in a temperature range of from about -40 to about +100 ° C, preferably from about -10 to about +50 ° C, at if arylsulfonyl esters are used, also at a temperature in the range of about +100 to +200 ° C and optionally under an atmosphere of an inert gas such as nitrogen or argon.

An aqueous, for example, alcoholic solvent, such as ethanol, or an aromatic solvent, such as benzene or toluene, is also possible. Acetone may also optionally be added in the presence of alkali metal hydroxides as a base.

The condensation may also be carried out by a technical method known as solid phase synthesis as reported by R. Merrifield and described, for example, in Angew. Chem., 97, 801-812 (1985), Naturwissenschanen, 71, 252-258 (1984) or R.A. Houghten, Proc. Natl. Acad. Sci. USA, 82, 5134-5355 (1985).

Depending on the starting compounds used, the radicals R ^{@ 1} and R @ ⁹ in the compounds of the formula I obtained may be identical or different from one another.

The release of the protected groups is optionally carried out under variant f) (cleavage of the protecting groups).

Method c (Preparation of the amide bond)

In the starting compounds of the formulas (VII) and (VIII), the functional groups, with the exception of those which are to be present in the reaction or do not react under the reaction conditions, are protected independently of each other by the protecting groups mentioned under process a).

The process is quite analogous to the process of (b) above, when a compound of formula (VII) is used instead of a compound of formula (V) and a compound of formula (VIII) is used in place of a compound of formula (VI) and R ¹ is formed on acylation. compounds of formula (VII) instead of R ⁹ in compounds of formula (V).

Depending on the starting compounds used, the radicals R ^{@ 1} and R @ ⁹ in the compounds of the formula I obtained may be identical or different from one another.

The release of the protected groups is optionally carried out according to the method described under variant f) (cleavage of the protecting groups).

Method d) (Preparation of an amide bond)

In the starting compounds of the general formula (IX) and the acids or their reactive derivatives suitable for introducing identical radicals R ^{@ 1} and R ^{@ 9} , the functional groups which are not to participate in the reaction or do not react under the reaction conditions are protected independently of each other by the protecting groups mentioned under a) .

Acids suitable for introducing identical residues R ¹ and R ⁹ preferably have the general formula (VI) or the general formula (VIII). Preferred starting compounds of formula (IX), as optionally protected by a protecting group, are compounds of formula (II), which are described in the section on starting compounds.

The process is quite analogous to the process of b), wherein compounds of formula (IX) are used instead of compounds of formula (V) and compounds of formula (VI) or (VIII) are used instead of compounds of formula (VI).

The liberation of the protected groups is optionally carried out as described below for process f) (deprotection).

Method e) (Alkylation of Secondary Nitrogen)

In the starting compounds of formula (I ') and the compound of formula (XII) or their reactive derivatives suitable for introducing the radical R ⁷ , the functional groups which are not to be present in the reaction or which are not reactive under the reaction conditions are independently protected. one of the protecting groups mentioned under method a).

In particular, the leaving group (X) is a nucleofugic leaving group selected from hydroxy groups esterified with a strong inorganic or organic acid, such as a mineral acid such as hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or hydroxy groups esterified with a strong organic sulfonic acid such as (lower). - sulfonic acid or aromatic sulfonic acid, which are optionally substituted, for example, by a halogen atom, such as fluorine, such as optionally lower alkyl, such as methyl, halogen, such as bromine and / or nitro substituted benzenesulfonic acid, such as methanesulfonic acid, p-bromotoluenesulfonic or p-toluenesulfonic or hydroxy groups esterified with hydrochloric acid

The substitution may be carried out under nucleophilic substitution conditions of the first or second order.

Compounds of formula (XII) in which (X) is a leaving group with an electron-coated higher polarity such as iodine can be used, for example, in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide. The reaction may also be carried out in water or in an organic solvent used as a cosolvent such as ethanol, tetrahydrofuran or acetone. The substitution reaction is carried out optionally at a reduced or elevated temperature, for example in a temperature range of from about -40 to about 100 ° C, preferably from about -10 to about 50 ° C and optionally under an atmosphere of an inert gas such as nitrogen or argon.

The release of the protecting groups is carried out optionally according to the methods described under method f) (cleavage of the protecting groups).

Method f) (Cleavage of protecting groups)

The cleavage of protecting groups which are not part of the desired final compound of formula (I), for example protecting groups for carboxy, amino and / or hydroxy, is carried out in a manner known per se, for example by solvolysis, in particular hydrolysis, alcohololysis or acidolysis, or reduction, in particular by hydrogenolysis or by chemical reduction, as well as by photolysis, optionally in steps or simultaneously, and enzymatic methods may also be used. The cleavage of the protecting groups is described, for example, below in the section dealing with the basic work on the cleavage of the protecting groups.

Thus, for example, a protected carboxy group, for example a tertiary- (lower alkoxy) -carbonyl group, in the 2-position with a trisubstituted silyl group or in the 1-position with a lower alkoxy or (lower alkyl) -thio group (lower alkoxy) -carbonyl or optionally substituted diphenylmethoxycarbonyl to the free carboxy group by treatment with a suitable acid, such as formic, hydrochloric or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole The carboxy group may also be liberated from the (lower alkoxy) carbonyl group by treatment with a base such as hydroxide. An optionally substituted benzyloxycarbonyl group can be liberated, for example, by hydrogenolysis, i.e. treatment with hydrogen, in the presence of a metal-based hydrogenation catalyst such as a palladium catalyst. Furthermore, a suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl can also be obtained by reduction, for example by treatment with an alkali metal dithionite such as sodium thionite, with a reducing metal such as zinc or reducing with a metal salt such as a chromium salt, e.g. a hydrogen-providing agent which, together with the metal, can lead to the production of hydrogen at birth, such as an acid, in particular a suitable carboxylic acid, such as (lower alkanes-carboxylic acid optionally substituted, for example, by a hydroxy group such as acetic, formic, glycolic, diphenylglycolic, lactic acid , almond, 4-chloromethyl or tartaric, or an alcohol or thiol, with water preferably being added. The 2-halogen- (lower alkoxy) -carbonyl group (optionally after converting the 2-bromo- (lower alkoxy) -carbonyl group to the corresponding 2-iodo- (lower alkoxy) -carbonyl) may also be treated with the reducing metal or metal salt as described above. The aroylmethoxycarbonyl group may be cleaved optionally by treatment with a nucleophilic reagent, preferably salt-forming, such as sodium thiophenolate or sodium iodide 2- (Trisubstituted silyl) - (lower alkoxy) -carbonyl group (lower alkoxy) -carbonyl group - (lower alkyl) -silyl- (lower alkoxy) -carbonyl group may be treated with a salt providing a fluoride anion from hydrofluoric acid such as an alkali metal fluoride, for example sodium fluoride or potassium fluoride, optionally in the presence of a macrocyclic polyether (crown-ether) or with a quaternary organic base fluoride such as tetra (lower alkyl) ammonium or a tri- (lower alkyl) -aryl- (lower alkyl) ammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic polar solvent such as dimethylsulfoxide or Ν, dim-dimethylacetamide, can be converted to the free carboxy group. A carboxy group protected as an organic silyloxycarbonyl by a tri- (lower alkyl) silyloxycarbonyl group, for example trimethylsilyloxycarbonyl, can be liberated in a conventional manner by solvolytic treatment, for example by treatment with water, an alcohol or an acid other than fluoride, as described. or by suitable peptidases, for example by esterified arginine or lysine such as lysine methyl ester, by trypsin.

The protected amino group is liberated in a manner known per se and depending on the nature of the protecting groups in various ways, preferably by solvolysis or reduction. (Lower alkoxy-carbonylamino, such as tert-butoxycarbonylamino, may be cleaved in the presence of acids, for example mineral acids, for example hydrohalic acids, such as hydrochloric or hydrobromic acid, or sulfuric or phosphoric acids, preferably hydrochloric acid

Or strong organic acids, such as trihaleacetic acid, for example trifluoroacetic acid or formic acid, in polar solvents such as water or ethers, preferably cyclic ethers such as dioxane. 2-Halo- (lower alkoxy) carbonylamino, optionally after converting the 2-bromo- (lower alkoxy) carbonylamino group to 2-iodo (lower alkoxy) carbonylamino or directly dissolved in a liquid organic carboxylic acid such as formic acid, aroylmethoxycarbonylamino or 4- The nitrobenzyloxycarbonylamino group can also be cleaved, for example, by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. optionally substituted by diphenylmethoxycarbonylamino, tert- (lower alkoxy) carbonylamino or 2- (trisubstituted silyl) - (lower alkoxy) carbonylamino such as i. The 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonylamino group may be removed by treatment with a suitable acid, e.g. formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino may be removed, for example, by hydrogenolysis, i.e. treatment with hydrogen in the presence of a suitable hydrogenation catalyst. such as a platinum or palladium catalyst. An optionally substituted triarylmethylamino or formylamino group can be removed, for example, by treatment with an acid such as a mineral acid such as hydrochloric acid or an organic acid such as formic, acetic or trifluoroacetic acid, optionally in the presence of water. The amino group protected as a silylamino group can be released, for example, by hydrolysis or alcoholysis. The amino group protected with 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base or with a thiolate salt such as an alkali metal thiourea thiolate followed by solvolysis such as alcoholysis or hydrolysis of the resulting substitution product. The trifluoroethylamino group can be liberated by the amino group, for example, by hydrogenolysis with a base such as alkali metal hydroxides or carbonates such as sodium or potassium carbonate in polar solvents such as alcohols such as methanol at a temperature of from 0 to 100 ° C, in particular from 40 to 80 C. The amino group protected with 2- (trisubstituted silyl) - (lower alkoxy) -carbonyl, such as 2-tri- (lower alkyl) -silyl- (lower alkoxy) -carbonyl, can be converted to the free amino group by treatment with a salt providing fluoride anions from It is also possible to directly cleave a heteroatom, such as a nitrogen-protected silyl group, such as trimethylsilyl 1, using a fluoride ion.

The azido-protected amino group can be converted to the free amino group by, for example, reduction, such as catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, reduction by mercapto compounds such as dithiothreitol or mercaptoethanol acids such as acetic acid The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon such as methylene chloride, or else in water or a mixture of water and an organic solvent such as alcohol or dioxane at a temperature of about 20 to 25 ° C or cooling or heating.

A hydroxy group protected with a suitable acyl group, a tri- (lower alkyl) -silyl group or an optionally substituted 1-phenyl- (lower alkyl) group is liberated analogously to the corresponding protected amino group. The hydroxy group protected with 2,2-dichloroacetyl is released, for example, by basic hydrolysis, the hydroxy- or mercapto group protected with a t- (lower alkyl) group or a 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon residue is liberated by acidolysis, for example or a strong carboxylic acid, for example trifluoroacetic acid. Two hydroxy or adjacent amino and hydroxy groups which are protected together by a bivalent protecting group, preferably for example lower alkyl, one or two substituted methylene, such as lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene , in particular in the presence of a mineral acid or a strong organic acid. The tri- (lower alkyl) -silyl group is also cleaved by acidolysis, for example by treatment with a mineral acid, preferably hydrofluoric acid or a strong carboxylic acid. The 2-halo- (lower alkoxy) carbonyl group is removed by said reducing agent, for example a reducing metal such as zinc, a reducing metal salt, such as a chromium salt or sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulphide.

If there are multiple protected functional groups, if desired, the protecting groups may be selected by simultaneously cleaving more than one such group, for example acidolytically, such as treatment with hydrofluoric acid, or treatment with hydrogen in the presence of a hydrogenation catalyst such as palladium on carbon . Conversely, the groups may also be selected such that they are not all cleaved simultaneously, but may be cleaved in the desired order to give the corresponding intermediates.

Additional method features

Additional features of the process that are carried out as necessary may protect the functional groups of the starting compounds that are not to be involved in the reaction, or may be in a protected form, for example, as one or more of the protecting groups listed under (a). The protecting groups may be retained in the final compounds or cleaved in whole or in part by the methods described under process f).

Salts of compounds of formula (I) that contain at least one salt-forming group can be prepared by a method known in the art. For example, salts of compounds of formula (I) containing acidic groups may be formed, for example, by treatment with metal compounds, such as salts of suitable organic carboxylic acids with alkali metals, for example sodium 2-ethylhexanoic acid, with organic alkali or alkaline earth metal compounds. , such as corresponding hydroxides, carbonates or bicarbonates, such as sodium or potassium hydroxide, carbonate or bicarbonate, with the corresponding

Calcium compounds or with ammonia or a suitable organic amine, preferably stoichiometric amounts of the compounds or a small excess of salt-forming agent are used. The acid addition salts of the compounds of formula (I) are obtained in the customary manner, for example by treatment with an acid or a suitable anion exchange agent. Internal salts of the compounds of formula (I) which contain acidic or basic salt-forming groups, for example, a free carboxy group and a free amino group. may be formed, for example, by neutralizing salts, such as acid addition salts, to an isoelectric point, for example by treatment with weak bases or with ion exchangers.

Salts can be converted into the free compounds, metal and ammonium salts, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with suitable basic agents.

Stereoisomeric mixtures, such as mixtures of diastereoisomers and / or enantiomers, such as racemic mixtures, can be separated into the corresponding isomers in a manner known per se by appropriate resolution procedures. Thus, diastereomeric mixtures may be separated into their individual diastereoisomers by fractional crystallization, chromatography, treatment with solvents allowing separation and the like. The racemates can be separated from one another by converting the optical antipodes into diastereoisomers, for example by reaction with optically active compounds, such as optically active acids or bases, by column chromatography of the material consisting of optically active compounds or by enzymatic methods, for example by selective reaction with only one of the two enantiomers. This separation can be carried out both in the preparation step of one of the starting compounds and also in the compounds of the general formula (I) themselves.

The opposite configuration can be achieved at the individual chirality centers in the compound of formula. For example, the configuration of asymmetric carbon atoms that contain nucleophilic substituents, such as amino or hydroxy, may be reversed by nucleophilic substitution of the second order, optionally after converting the bound nucleophilic substituent to a suitable nucleophilic group and reacting with the reagent introducing the original substituent. with hydroxy groups such as hydroxy bearing carbon atoms of formula (I) by oxidation and reduction of compounds of formula (I).

Polar protic solvents, such as methanol, ethanol or isopropanol, are suitable for use with tetrabromohydride, and polar aprotic solvents, such as tetrahydrofuran, are suitable for other reducing agents.

In a compound of formula (I) wherein R ¹ and R ⁹ contain no aryl moiety or such residue is not very reactive, the aryl moiety present in R ⁷ and R ³ , especially the phenyl moiety, can be hydrogenated, for example by catalytic hydrogenation, in particular in the presence of heavy metal oxides such as mixed oxide of platinum and platinum, for example by means of a Nishimura catalyst, preferably in a polar solvent such as an alcohol such as methanol or ethanol at temperatures from 0 to 80 ° C, in particular from 10 to 40 ° C and hydrogen pressure from 100 kPa to 1 MPa, preferably at a pressure close to normal pressure.

In the compound of formula (I), the free amino group present may be acylated, for example to introduce one of the radicals described for R ¹ or R ⁹ . The acylation is carried out according to methods b), c) or d) for condensation or methods mentioned for protecting groups, or according to one of the methods described in Organikum, 17th ed., VEB Deutscher Verlag der Wissenschaften, Berlin-East Germany (1988). .

All of the above process steps may be carried out under known, preferably specifically mentioned reaction conditions, in the absence or usually in the presence of a solvent or diluent, preferably those which are inert to and dissolve the reagents used, in the absence or presence of a catalyst, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, for example in the H ⁺ form, depending on the type of reaction and / or the components involved in the reaction at reduced, normal or elevated temperature, for example in the temperature range of about -100 to about 190 ° C preferably from about -80 to about 150 ° C, for example from -80 to -60 ° C, at room temperature, or from -20 to 40 ° C or the boiling point of the solvent used, at atmospheric pressure or in a sealed container, optionally under pressure, and / or under an inert gas atmosphere, for example under an argon or nitrogen atmosphere.

All of the starting compounds and intermediates, if they contain salt-forming groups, may be presented in the form of salts. Salts may also be introduced during the reaction of such compounds, provided that this does not interfere with the reaction.

Isomeric mixtures occurring in all reaction steps may be separated into individual isomers, for example diastereomers or enantiomers, or any mixture of isomers, for example racemates or diastereoisomeric mixtures, for example by analogous methods to those described under "Additional Process Features".

In certain cases, for example hydrogenation, stereoselective reactions can be achieved so that, for example, it is possible to facilitate the recovery of the individual isomers.

Solvents from which solvents suitable for the reaction in question may be selected include, for example, water, esters such as (lower alkyl) - (lower alkanoates), for example diethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, acid amides such as dimethylformamide, bases such as heterocyclic nitrogen bases pyridine, carboxylic acid anhydrides such as lower alkanoic anhydrides, for example acetic anhydride, cyclic, straight or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of these solvents, for example aqueous solutions, unless otherwise specified. Such solvent mixtures also find use in post-work-up, for example chromatography or separation.

The invention also relates to such embodiments of the process starting from compounds obtained at any stage as intermediates and carrying out the remaining steps or interrupting the process at any stage, or starting materials formed under the reaction conditions, or in the form of a reactive derivative or a salt, or the compounds obtained by the process of the invention are formed under the conditions of the processes and further processed in situ. Thereafter, it is preferable to start from such compounds which lead to the compounds which are described as being preferred, particularly as being particularly preferred and / or preferred.

Pharmaceutical compositions

The present invention also relates to pharmaceutical compositions comprising compounds of formula (I).

For example, the pharmacologically useful compounds of the invention can be used to produce pharmaceutical compositions comprising an effective amount of the active compound together or in admixture with a significant amount of an inorganic or organic, solid or liquid, pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition (preparation) which is suitable for administration to warm-blooded individuals, in particular humans, for the treatment or prevention of diseases related to the suppression of retroviral proteases, in particular retroviral aspartate proteases such as HIV-1- or HIV-2. a gag protease, for example a retroviral disease such as AIDS, comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective to inhibit a retroviral protease, together with at least one pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as mtramuscular or intravenous administration to a warm-blooded individual (human or animal) comprising an effective dose of a pharmacologically active compound, alone or together with a significant amount of of a usable carrier. The dose of the active ingredient depends on the species of warm-blooded individual, its body weight, age and individual condition, the individual pharmacokinetic factors critical to the disease being treated, as well as the routes of administration.

usefulness

The invention relates to a method for the treatment of diseases caused by viruses, in particular retroviruses, for example AIDS, comprising administering a therapeutically significant amount of a compound of the formula I according to the invention to a warm-blooded individual, for example a human in need thereof. AIDS. The dosage amount for treating a warm-blooded individual, for example a human having a body weight of about 70 kg, is from about 3 mg to about 3 g, preferably from about 10 mg to about 1.5 g, for example from about 300 to 1000 mg per person per day. preferably divided into 1 to 3 unit doses, which may be, for example, of the same size. Children usually receive half the adult dose.

The pharmaceutical compositions contain from about 1 to about 95%, preferably from about 20 to about 90%, of the active ingredient.

For example, the pharmaceutical compositions of the invention may be in the form of dosage units such as ampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical compositions of the invention may be manufactured in a manner known per se, for example by conventional methods of dissolving, lyophilizing, kneading, granulating or draining.

Solutions and, in addition, suspensions of the active ingredient, in particular isotonic aqueous solutions or suspensions, are preferably used, and these forms can be prepared, for example, from lyophilized preparations which contain the active ingredient alone or together with a suitable carrier, for example mannitol, before use. These pharmaceutical compositions may be sterilized and / or contain adjuvants, for example, preservatives, stabilizers, surface-active and / or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and / or buffers, and may be manufactured in a manner known per se, e.g. by means of dissolution or lyophilization. These solutions or suspensions may contain viscosity enhancers such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain, as the oil component, the customary oils for injection purposes which are of vegetable, synthetic or polysynthetic origin. In particular, liquid esters of fatty acids which, as an acid-derived component, contain a long-chain fatty acid radical having from 8 to 22 carbon atoms, in particular from 12 to 22 carbon atoms, such as those derived from lauric, tridecylic, myristic, pentadecyl, palmitic, margaric, stearic, arachidic, behenic or corresponding unsaturated acids such as oleic, elaidic, erucic, brasidic or linoleic acid, optionally with the addition of antioxidants such as vitamin E, β-carotine or 3,5-diterc .-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters contains at most 6 carbon atoms and is a monovalent or polyvalent radical, for example, a monovalent, divalent or trivalent alcohol, such as methanol, ethanol, propanol, butanol or pentanol, or isomers thereof, in particular glycol and glycerin. Examples of fatty acid esters are ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerine trioleate from Gattenfossé, Paris), "Miglyol 812" (triglyceride of unsaturated fatty acids having a chain length of 8 to 12 carbon atoms AG, Hills) ), in particular vegetable oils such as cottonseed oil, almond, olive, castor, sesame or soybean oil, but in particular sunflower oil.

Injectable preparations are made in a conventional manner under sterile conditions, as well as filling ampoules or vials, as well as dispensing such containers.

Pharmaceutical compositions for oral use can be obtained by mixing the active ingredient with a solid carrier, optionally granulating the resulting mixture, and if desired or necessary adding the appropriate excipients to form tablets, dragee cores or capsules. The active ingredient can also be introduced into plastic carriers which allow the active ingredients to be dosed or diffused.

Suitable carriers are, in particular, fillers, such as sugar, for example sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium phosphate or dibasic calcium phosphate, binders such as starch seedlings obtained, for example, using corn, wheat, rice or potato starch, gelatin , tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrants such as said starches, further carboxymethylated starches, cross-linked polyvinylpyrrolidone, agar, alginic acid or its sodium salt, such as. In particular, the auxiliaries are flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. ladra dragees are provided with a suitable coating which is optionally resistant to gastric juices, including, but not limited to, concentrated sugar solutions which may eventually deplete gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or for coating resistant to gastric juices, solutions of suitable cellulosic agents such as cellulose ethyl phthalate or cellulose hydroxypropyl methyl phthalate. The capsules are gelatin insertable capsules and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable oily excipient such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers and / or antibacterial agents may also be added. Dyestuffs or pigments may be added to the tablets or coated dragees and the capsule shells, for example to distinguish or label different doses of the active ingredient.

Starting compounds

Novel starting materials and / or intermediates, as well as their production process, are also an object of the present invention. Preferably, such starting materials are used and the reaction conditions are selected to provide the compounds which are mentioned as being preferred.

In the production of the starting materials, free functional groups which are not to be involved in the reaction in question may be protected or submitted in protected form, for example protected by the protecting groups mentioned under method a). These protecting groups may be released at the appropriate time by the reactions described under process f).

The starting compounds for process (a) are known compounds or, if new, can be prepared in a manner known per se, for example from hydrazine or its suitable derivatives of a compound of formula (III), and from suitable amino acids or analogs thereof, for example with one R ³ side chain , compounds of formula (IV).

For example, compounds of formula (III) are available from compounds of formula (XV)

H ₂ N-NH-R (XV) in which

R ¹¹ represents a hydrogen atom or an amino protecting group as described under process b), in particular a tertiary (lower alkoxy) carbonyl group such as tert-butoxycarbonyl, aryl- (lower alkoxy) carbonyl group such as benzyloxycarbonyl or 9 -fluorenylmethoxycarbonyl or one of the abovementioned acyl groups as amino protecting group, when the compound of formula (I) for the introduction of R ^{7 is} alkylated with a compound of formula (XII) as described under process e) or used to introduce the residue R ⁷ reacting a suitable carbonyl compound with the free amino group of a compound of formula (VIII) or an acylated derivative thereof, followed by reduction of the obtained hydrazone to give a hydrazine derivative of formula (XVI)

R ⁷ -NH-NH-R (XVI), wherein the radicals in all the above compounds have the indicated meanings and the functional groups in the reagents not to be involved in the reaction are optionally protected or an R ¹¹ protecting group, if not corresponding to R ⁹ in the compound of formula (I) and / or other protecting groups are cleaved.

The carbonyl compounds used to produce compounds of formula (XVI) suitable for the introduction of R ⁷ are aldehydes or ketones whose reactive carbonyl group, after reaction with a compound of formula (XV) and subsequent reduction, is part of one of said R ⁷ radicals, preferably aldehydes which are suitable for introducing a lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group.

The reaction of the carbonyl compounds with compounds of formula (XVI) to the corresponding hydrazones is carried out under conditions customary for the reaction of carbonyl compounds with amines, preferably in polar organic solvents, for example ethers such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic amides as dimethyl formamide or esters such as ethyl acetate or in aqueous solutions, preferably in methanol, further in the presence or absence of acid catalysts such as carboxylic acids such as formic or acetic acid, or sulfonic acids such as ptoluenesulfonic acid, at temperatures from 0 ° C to the reflux temperature of the reaction mixture, preferably at a temperature of from 20 ° C to the reflux temperature of the reaction mixture.

The reduction of the hydrazones obtained is preferably carried out by hydrogenation in the presence of a suitable catalyst. Suitable catalysts for hydrogenation are metals such as nickel, iron, cobalt or ruthenium, or noble metals or their oxides, such as palladium or rhodium, or their oxides, optionally deposited, for example, on a suitable carrier, such as barium sulphate, alumina or active coal, or as skeletal catalysts, such as Raney nickel. Solvents useful for catalytic hydrogenation are, for example, water, alcohols such as methanol or ethanol, esters such as ethyl acetate, ethers such as dioxane, chlorinated hydrocarbons such as dichloromethane, carboxylic acid amides such as dimethylformamide, or carboxylic acids such as acetic acid or mixtures of these solvents. The hydrogenation is carried out at temperatures of from 10 to 250 ° C, preferably from room temperature to 100 ° C, at a hydrogen pressure of from 100 kPa to 20 MPa, preferably from 100 kPa to 1 MPa, in conventional equipment.

Particularly preferred reaction conditions for the preparation of compounds of formula (XV) are analogous to those described in J. Chem. Soc. Perkin I, 1712 (1975).

The compounds of formula (IV) are available, for example, by reducing amino acids of formula (XVIII) R ^'-Nl I.Co ° H (XVIII), wherein

R ¹⁰ represents a hydrogen atom or an amino protecting group mentioned in process a), in particular a tert- (lower alkoxy) carbonyl group such as tert-butoxycarbonyl, aryl- (lower alkoxy) carbonyl group such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl or one of said acyl amino protecting groups; and

R ³ has the meanings given for compounds of formula (I), preferably amino acids of formula (XVIII A)

K - NK COOH (XVIII A), f?

in which the radicals have the indicated meanings, to the aldehydes of the general formula (XIX) _{R -} NH4 CHOphi (XIX), in which the radicals have the mentioned meanings, preferably to the aldehydes of the general formula (XIX A) R * - NH4 - CHO

S ¹ (XIX a), wherein the radicals are as defined above, (which can be obtained for example from a compound of formula (XVIII A)), by reacting the aldehydes with a ylide compound, preferably with ylide compounds of sulfur, and the epoxide of formula (XX)

wherein the radicals are as defined above, preferably to compounds of formula (XX A)

H

B = -O ^R - ^NH x Xj: (XX A), wherein the radicals have the meanings indicated (which can be obtained, for example, from the compounds of the general formula (XIX A)), optionally by cleavage of the R ¹¹ protecting group, ⁹ in a compound of formula (1), and acylating the amino group of the resultant compound with acids of formula (VIII) wherein the radicals have the meanings given under the conditions described for process b) and / or alkylating the amino group of the resulting compound with a reagent with nucleofusic leaving groups. of formula (X) or (XI), in which the radicals have the meanings indicated, under the conditions described under the additional features of the process.

The reduction of the amino acids of formula (XVIII) or (XVIII A) to the corresponding aldehydes of formula (XIX) or (XIX A) is carried out, for example, by reduction to the corresponding alcohols and by the associated oxidation to said aldehydes.

The reduction to alcohols is effected, for example, by hydrogenation of acid halides or other carboxylic acid derivatives activated as described under process b), under conditions indicated for the hydrogenation of hydrazones obtained from compounds of formula (XVI), or complex hydrides such as sodium borohydride. The subsequent oxidation of the alcohols obtained is, for example, possible by oxidation of the hydroxy group with a sulfoxide such as dimethylsulfoxide in the presence of a hydroxy-activating reagent such as a carboxylic acid chloride such as oxalyl chloride in an inert solvent such as a halogenated hydrocarbon such as dichloromethane and / or acyclic or cyclic ethers is tetrahydrofuran, at a temperature of from -80 to 0 ° C, for example from -78 to -50 ° C.

Also, direct reduction of amino acids to aldehydes is possible, for example, by hydrogenation in the presence of a partially poisoned palladium catalyst, or by reduction of the corresponding amino acid esters, for example a (lower alkyl) ester such as ethyl ester, by treatment with complex hydrides such as borohydrides such as sodium borohydride or preferably aluminum hydrides e.g. lithium aluminum hydride, lithium (tert-butoxy) aluminum hydride or, in particular, diisobutylaluminum hydride in non-polar solvents, for example in hydrocarbons or aromatic solvents such as toluene, at a temperature of -100 to 0 ° C, preferably -70 to -30 ° C, and coupled reaction to the corresponding semicarbazones, for example the corresponding semicarbazone salts with acids such as semicarbazide hydrochloride, in aqueous solvent systems such as alcohols with water, e.g. aqueous ethanol, at temperatures from -20 to 60 ° C, preferably from 10 to 30 ° C , and rea reacting the obtained semicarbazones with a reactive aldehyde, for example formaldehyde, in an inert solvent, for example a polar organic solvent, for example a carboxylic acid amide, such as dimethylformamide, at temperatures from -30 to 60 ° C, preferably 0 to 30 ° C, and then acid, for example, a strong mineral acid, such as hydrohalic acid, in aqueous solution, optionally in the presence of a solvent used hitherto, at temperatures from -40 to 50 ° C, preferably from -10 to 30 ° C. The corresponding esters are obtained by reacting amino acids with the corresponding carboxylic acids, for example ethanol, analogously to the condensation used for process b), for example by reaction with inorganic acid halides such as thionyl chloride, in organic solvent mixtures such as aromatic and alcoholic solvent mixtures such as toluene and ethanol, at temperatures from -50 to 50 ° C, preferably from -10 to 20 ° C.

The preparation of the compounds of formula (XIX) and (XIX A) is carried out in a particularly advantageous manner under conditions analogous to those described in J. Org. Chem. 47, 3016 (1982) or J. Org. Chem. 43, 3624 (1978).

The sulfur-containing ylide suitable for the reaction of compounds of formula (XIX) or (XIX A) to epoxides of formula (XX) or (XX A) is, for example, dialkylsulfonium methylide, for example dimethylsulfonium methylide, alkyl- or phenyldialkylaminosulfoniummethylide, for example methyl or phenyldimethyl or a dialkylsulfoxonium methylide, for example dimethyl or diethylsulfoxonium methylide.

The corresponding sulfur-containing ylide compound is conveniently prepared in situ from the corresponding sulfonium or sulfoxonium salt and base, for example sodium hydride, in a dipolar aprotic solvent, for example dimethylsulfoxide, or in an ether, for example tetrahydrofuran or 1,2-dimethoxyethane, coupled with compounds of formula ( XIX) or (XIX A). The reaction is usually carried out at room temperature, with cooling down to, for example, -20 ° C or with slight heating, for example up to 40 ° C. The resulting sulfide, sulfinamide or sulfoxide is finally removed by treatment in the presence of water.

The reaction with the sulfur-containing ylide compound is particularly preferably carried out under analogous conditions to those described in J. Org. Chem. 50, 4615 (1985).

A compound of formula (XX) (preferably of formula (XX A)) may also be prepared from a compound of formula (XIX) (preferably of formula (XIX A)) as defined by reacting it with a tri (lower alkyl) silylmethyl Grignard compound , for example, from a corresponding halomethylsilane, such as chloromethyltrimethylsilane, in an inert solvent, for example an ether, such as dioxane or diethyl ether, at temperatures from 0 to 50 ° C, for example room temperature to about 40 ° C, followed by elimination with removal of the silyl residue to with a Lewis acid such as boron trifluoride, preferably also cleaving the present amino protecting group R ¹⁰ in an inert solvent such as an ether such as diethyl ether or a halogenated hydrocarbon such as dichloromethane or mixtures thereof at temperatures ranging from -50 to reflux, in particular from 0 to 30 ° C this requires re-acylation of the amino protecting group as defined by R ¹⁰ and oxidation of the resulting double bond to the oxirane, preferably by treatment with peroxycarboxylic acid, for example m-chloroperbenzoic acid, in an inert solvent such as a chlorinated hydrocarbon such as dichloromethane temperatures from -20 ° C to the reflux temperature of the reaction mixture, for example at 10 to 30 ° C.

The starting compounds for processes b), c) and d) are known or, if new, can be prepared by conventional methods. For example, a compound of formula (V) can be prepared from a suitable hydrazine derivative of formula (III) wherein R ⁹ is hydrogen and the remaining residues have the meanings given for compounds of formula (V) and suitable epoxides of formula (IV), wherein the radicals have the meanings given for compounds of formula (V), method b). The compound of formula (VII) is prepared from a suitable hydrazine derivative of formula (III) wherein the radicals have the meanings given for compounds of formula (VII) and suitable epoxides of formula (IV) wherein R ¹ is hydrogen and the remaining the radicals have the meanings given for the compounds of the general formula (VII), method c). The compound of formula (IX) is prepared from suitable hydrazine derivatives of formula (III) wherein R ⁹ is hydrogen and the remaining residues have the meanings given for compounds of formula (IX), method d) and suitable epoxides of formula (IV) wherein R ¹ represents a hydrogen atom and the remaining radicals have the meanings given for the compound of formula (IX), method d), analogously to method a), optionally in the use and cleavage of protecting groups.

Compounds of formula (I ') in which the substituents have the meanings indicated can be prepared, for example, from compounds of formula (II')

H

HN p *

X (III '), H in which the radicals have the meanings given for compounds of formula (1) as described in process b), by reaction with a compound of formula (IV), wherein the functional groups present are to be absent as in protected form, and may be removed after reaction.

Preferred for process d) are the starting compounds of formula (II)

H OH R *

L ¹

R 'h (II)>

in which

R ³ and R ⁷ have the meanings given for the compound of formula (I) as well as the salts of these compounds when they contain salt-forming groups which are intermediates according to the invention.

In particular, these compounds may be protected on one or both amino groups, and if there are a pair of amino protecting groups, these may be identical or different from each other.

Suitable amino protecting groups are, for example, those mentioned under process a). The radicals R ³ and R ⁷ given for the compounds of the general formula (II) have the meanings defined for the compounds of the general formula (I) in the definition of the radicals R ³ and R '.

Highly preferred are compounds of formula (II) wherein R ³ is cyclohexyl (lower alkyl), phenyl (lower alkyl) or p-fluorophenyl (lower alkyl) and R ⁷ is lower alkyl, cyclohexyl (lower alkyl) , phenyl- (lower alkyl), p-cyanophenyl- (lower alkyl) or p-fluorophenyl- (lower alkyl) groups, as well as salts of said compounds, if they contain such salt-forming groups.

Particularly preferred are compounds of formula (II) wherein R ³ is phenyl (lower alkyl) and R ⁷ is lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) as well as salts of these compounds if they contain salt-forming groups.

Particularly preferred are compounds of formula (II) wherein R ³ is cyclohexylmethyl, benzyl or p-fluorobenzyl and R ⁷ is n-butyl, isobutyl, cyclohexylmethyl, benzyl, p-fluorobenzyl or p-cyanobenzyl, as well as salts of such compounds, if they contain salt-forming groups.

Particularly preferred are compounds of formula (II) wherein R ³ is benzyl and R ⁷ is isobutyl, cyclohexylmethyl or benzyl, as well as salts of such compounds if they contain salt-forming groups.

Particularly preferred are the compounds of formula (II) listed in the Examples.

Compounds of formula (II) in which the substituents have the meanings indicated, or salts thereof, if they contain salt-forming groups, are prepared, for example, by the hydrazine derivative of formula (XVI)

R 1 -NH-NH-R ¹¹ (XVI) wherein

R ¹¹ is an amino protecting group, adds to the epoxide of formula (XX A)

H ^r - ^nh ^ Aj XX (XX A) in which

R ¹⁰ is an amino protecting group and, if desired, the compound of formula (II) obtained according to the preceding process a) with at least one salt-forming group, is converted to its salt or the obtained salt is converted to a free compound or another salt; optionally, the resulting isomeric mixture is separated and / or the protecting groups present in the compound of formula (II) are cleaved and / or the compound of formula (II) of the invention is converted to another compound of formula (II) of the invention.

The production and formation of salts, the separation of isomeric mixtures, the cleavage of the protecting groups and the conversion of the compounds of the general formula (II) are carried out analogously to the process for the preparation of the compounds of the general formula (I).

Particularly preferred is the preparation of the starting compounds of formula (II) in which the substituents are as defined by cleavage of the protecting groups from a compound of formula (II) in which one or both of the amino groups is protected with amino protecting groups, particularly under conditions described for the hydrolysis of the compounds of formula (I) as indicated in the additional features of the method.

Processes for the addition of compounds of formula (XVI) to compounds of formula (XX A) are described in process a) for the preparation of a compound of formula (I).

The production of protected compounds of formula (I) is carried out, for example, according to methods known hitherto, in particular from compounds of formula (III) and (IV), the functional groups in these compounds being optionally protected by protecting groups as described under process a).

The acids of formula (VI), (VIII), (XVII) and (XXI), as well as the compounds with nucleofugic groups of formula (XII), are known substances or, if new, can be prepared according to methods known per se .

DETAILED DESCRIPTION OF THE INVENTION

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

As is customary, temperatures are given in degrees Celsius (° C). If no temperature data is given, the reaction is carried out at room temperature. _Rf values which indicate the ratio of retardation of each compound to that of the solvent, to thin out the gel plates by thin layer chromatography, using the following solvent systems:

A Chloroform, methanol, water and acetic acid 75: 27: 5: 0.5 B Chloroform, methanol, water and acetic acid 90: 10: 1: 0.5 C Chloroform, methanol, water and acetic acid 85: 13: 1.5: 0.5 D Chloroform and methanol 8: 1 E Chloroform and methanol 95: 5 F Hexane and ethyl acetate 2 - 1 G Methylene chloride, diethyl ether and methanol 20: 20: 1 H Methylene chloride and diethyl ether 1 - 1 1 Toluene and ethyl acetate 2 - 1 The Chloroform and methanol 5: 1 J Methylene chloride and diethyl ether 5: 1 L Hexane and ethyl acetate That made the score 4 - 1 M Hexane and ethyl acetate 5: 1 N Hexane and ethyl acetate 1 - 1 ABOUT ethyl acetate - P Methylene chloride, ethanol and ammonia (3 equivalents) 90: 10: 1 Q Methylene chloride and diethyl ether 10: 1 R Hexane and ethyl acetate 3 - 1 WITH Methylene chloride and diethyl ether 20: 1 T Chloroform and methanol 30: 1

For Chloroform and methanol15: 1

In methylene chloride, diethyl ether and 1: 1: 3 hexane

W Methylene chloride and diethyl ether 20: 1

X 40: 1 methylene chloride and methanol

Y Toluene and ethyl acetate 4: 1

For example, the abbreviation "Rf (A)" means that the R _f value is determined in the solvent system A. The proportions of the relative amounts of the solvents are always given in parts by volume,

Gradient High Performance Liquid Chromatography (HPLC):

I: 20% -> 100% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid over 35 minutes,

II: 0% -> 40% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid over 30 minutes,

III: 20% -> 60% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid over 60 minutes,

IV: 10% -> 50% acetonitrile, 0.05% trifluoroacetic acid in water, 0.05% trifluoroacetic acid over 60 minutes.

The column (250 x 4.6 mm) is filled with the "reverse phase" of C ₁₈ -Nucleosil ^R (medium grain size 5 µm, with covalently denatized octadecylsilane silica gel, Macherey & Nagel, Diiren, Germany). Detection is based on absorption in ultraviolet radiation at a wavelength of 215 nm. The retention time (t _Ra ) is given in minutes. The liquid flow rate is 1 ml / min.

The same abbreviations are used to designate solvent systems for flash chromatography and medium pressure chromatography.

The following abbreviations have the following meanings:

Boe tert-butoxycarbonyl ether diethyl ether h hour (s) min. minute (s)

MS mass spectroscopy

Z - benzyloxycarbonyl.

Mass spectroscopy values are obtained either by conventional mass spectroscopy (MS) or by "fast atom bombardment" (FAB-MS). Mass data refers primarily to the non-protonated ion of the molecule (M) ⁺ or to the protonated ion of the molecule (M + H) ⁺ .

Proton nuclear resonance spectroscopy (1 H-NMR) values are reported in ppm (parts per million), based on tetramethylsilane as an internal standard. The abbreviations have the following meanings: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet.

Values for infrared spectroscopy (IR) are given in cm ^-1 , with solvent in round brackets. When the intensity of the bands is given, s denotes strong, m moderate and w weak intensity.

The residue labeled - [Phc ^NN Phe] - represents the bivalent radical 3 (S) -amino-4-phenyl-1- (N-benzylhydrazino) butan-2 (S) -ol and has the formula

The residue labeled - [Phe ^NN Cha] - represents the bivalent radical 3 (S) -amino-4-phenyl-1- (N-cyclohexylmethylhydrazino) butan-2 (S) -ol and has the formula

The radical labeled - [Phe ^ Leu] - represents the bivalent radical 3 (S) -amino-4-phenyl-1- (N-isobutylhydrazino) butan-2 (S) -ol and has the formula

The radical marked - | Phe ^NN Nle] - represents the 3 (S) -amino-4-phenyl-1- (Nn-butylhydrazino) butan-2 (S) -ol radical and has the formula

The residue - [Phc ^NN (pF) Phc] - represents the 3 (S) -amino-4-phenyl-1- [N- (p-fluorophenylmethyl) hydrazino] butan-2 (S) -ol divalent radical and has formula

The residue - - (pF) Phe ^NN (pF) Phe] - represents the divalent radical 3 (S) -amino-4- (p-fluorophenyl) -1- [N- (p-fluorophenylmethyl) -hydrazino] butane-2 (S) -ol and has the formula

The residue labeled - [Phe ^NN (p-CN) PheJ- represents the bivalent radical 3 (S) -amino-4-phenyl-1- [N- (p-cyanophenylmethyl) hydrazino / butan-2 (S) -ol] and has the formula

The residue - [Ch _and NNLeu] - represents the divalent radical 3 (S) -amino-4-cyclohexyl-1- (N-isobutylhydrazino) butan-2 (S) -ol and has the formula

Abbreviations commonly used in peptide chemistry are used to denote the naturally occurring α-amino acid bivalent radicals. However, they have amino acids that are to the right of the radicals - [Phe ^NN Phe] -, - [Phe ^ Cha) -, - [Phe ^ Leu) -, - [Phe ^ Nle] -, - [Phe ^NN ( pF) Phe] -, - [(p-FjPhe ^ p-FjPhe] -, - [Phe ^ p-CNjPhe) - or - [ChaNNLeu] -, different from the conventional peptide nomenclature where the left amino terminal is on the left and the carboxy terminal on the right , the carboxy-binding group on the left, indicated by an arrow (<-), which in turn symbolizes the direction of binding. The configuration at the carbon atom at position a, as is known, is indicated in front by the symbol (L) - or (D) -. Tyrosine radicals etherified with a phenolic hydroxy group with the radical R are designated Tyr (OR). No is a norluecin radical.

Example 1

Boc- [Phe ^w Phe] -Boc

A solution of 300 mg (1.14 mmol) of (2R) - 1 '(S) -Boc-amino-2'-phenylethyl / oxirane (J. Org. Chem. 50, 4615 (1985)) and 253 mg (1.14 mmol) mmol) of tert-butyl 3-benzylcarbazate (J. Org. Soc., Perkin I, 1712 (1975)) in 4 ml of methanol is refluxed for 12 hours. After cooling the reaction mixture to 0 ° C, much of the title compound precipitated. The mother liquors were evaporated and the residue was dissolved in a small amount of methylene chloride. After hexane was added dropwise, a further portion of the title compound precipitated as a white precipitate. FAB-MS: (M + H) &lt; ^{+ &gt}; = 486, t _Ret (I) = 26.8 min. Rf (E) = 0.70.

Example 2

Z- (L) -Val [Phe Phe ™] '- / (L) -Val-Z /

191 mg (0.76 mmol) of Z- (L) -valine, 336 mg (0.76 mmol) of benztriazol-1-yloxy-tris (dimethylamino) are dissolved in 5 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide. of phosphonium hexafluorophosphate and 103 mg (0.76 mmol) of 1'-hydroxybenztriazole, after 10 minutes, 100 mg (0.25 mmol) of H- [Phe ^NS Phe] -II trihydrochloride are added and stirred for 2 hours at room temperature. under a nitrogen atmosphere. The reaction mixture was evaporated, the residue was dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and the residue purified by chromatography on silica gel using methylene chloride / ether (1: 1). After freeze drying of the fractions containing the product from dioxane, the title compound is obtained as a white solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = 725, WI) = 27.8 min. Rf (E) = 0.45.

The starting material is produced as follows:

a) H-tPhe-Phel-HJHCl

A solution of 280 mg (0.58 mmol) of Boc [Phe ^NN Phe] -Boc from Example 1 in 10 ml of 4N hydrogen chloride in dioxane was stirred for 2 hours at room temperature under a nitrogen atmosphere and then lyophilized. Re-lyophilization from a mixture of dioxane and tert-butanol gives the title compound as a flocculent solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = 286, t _RCl (I) = 23.1 min. RKE = 0.17.

Example 3

Boc- (L) -Val- [Phc ^NN Phc] <- / (L) -Val-Boc /

In an analogous manner to that described in Example 2, from 50 mg (0.13 mmol) of H- [Phe ^NN Phe] -H trihydrochloride was obtained, 83 mg (0.83 mmol) of Boc- (L) -valine, 168 mg (0). , 38 mmol) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg (0.38 mmol) of 1'-hydroxybenzotriazole and 2.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide after chromatographic purification on silica gel using chloroform mixture and methanol in a ratio of 95: 5 and freeze-drying from dioxane the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 684, t _R t (I) = 27.4 min. Rf (E) = 0.38.

Example 4

Boc - [Phc ^NN Cha] - Boc

In a similar manner to Example 1, 231 mg (0.88 mmol) of (2R, 3S) -1- (3-Boc-amino-2-phenylethyl) oxirane and 200 mg (0.88 mmol) of tert-butyl are obtained. Of 3-cyclohexylmethylcarbazate, the title compound which, upon treatment with hexane, formed a white precipitate. FAB-MS: (M + H) &lt; ^{+ &gt}; = 492, t _Ret (I) = 30.4 min. Rf (E) = 0.78.

The starting compound is prepared as follows:

a) tert-Butyl 1-3-cyclohexylmethylcarbazate

10.2 g (45.1 mmol) of cyclohexylcarbaldehyde tert-butoxycarbonylhydrazone, dissolved in 400 ml of methanol, are hydrogenated in the presence of 5.1 g of 5% platinum on carbon at room temperature under a hydrogen pressure of 400 kPa. After completion of the reaction, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in methylene chloride and washed with water. Evaporation of the organic phase yields the title compound which is a colorless resin. 1 H-NMR (200 MHz, CDCl ₃ ): 6.1 (broad singlet, 1H), 3.9 (broad singlet, 1H), 2.65 (d, 2H), 1.8 - 0.75 (m 1 H, 1.54 (s, 9H) ppm, t _Ret (1) = 32.0 min. Rf (E) = 0.75.

b) tert-Butoxycarbonylhydrazone cyclohexylcarbaldehyde

A solution of tert-butylcarbazate (10.8 g, 81.2 mmol) and cyclohexylcarbaldehyde (10.1 g, 90 mmol) in ethanol (400 mL) was refluxed for 2 hours. Finally, half the solvent was distilled off and the title compound was precipitated by the addition of water. The obtained substance is further used directly in step a).

Example 5 H- (L) -Val- [Phe ^NN Phe] - / (L) -Val / -H 3 HCl

A solution of 40 mg (0.06 mmol) of Boc- (L) -Val- [Phe ^NN Phe] < - &gt; / (L) -Vac-Boc from Example 3 in 4 ml of 4N hydrogen chloride in dioxane is stirred at room temperature for 1 hour. The reaction mixture was then diluted with dioxane and lyophilized to afford the title compound as the hydrochloride. FAB-MS: (M + H) &lt; ^{+ &gt}; = 484, t _R t (I) = 25.8 min. Rf (E) = 0.45.

Example 6 N-Thiomorpholinocarbonyl- (L) -Val- [Phe ^NN Phe] - (N-Thiomorpholinocarbonyl- (L) -Val)

A solution of 20 mg (0.03 mmol) of H- (L) -Val- [Phc ^NN Phc] <- / (L) -Val / -H trihydrochloride from Example 5 in 0.5 ml of dimethylformamide was gradually added to room temperature at room temperature. contact with 35 μΐ (0.25 mmol) of triethylamine and 16 mg (0.1 mmol) of (4-thiomorpholinylcarbonyl) chloride and stir at room temperature for 1 hour. The reaction mixture was diluted with chloroform and then washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and the residue chromatographed on silica gel using a mixture of chloroform and methanol with a variable ratio of from 15: 1 to 8: 1.

Product containing fractions were evaporated and precipitated with a mixture of methylene chloride and diisopropyl ether. After lyophilization from dioxane, the title compound is obtained as a flocculent solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = 742, t _Ret (I) = 21.6 min. Rf (E) = 0.54.

The starting material is produced as follows:

a) (4-Thiomorpholinylcarbonyl) chloride

To a solution of 85 ml (165 mmol) of 20% phosgene in toluene at 0 ° C was added dropwise a solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene, and the white suspension was stirred for 1 hour at room temperature. Excess phosgene is removed by introducing nitrogen, the suspension is filtered and the filtrate is evaporated. The title compound is obtained as a yellow oil. IC (CH 2 Cl 2): 1735, 1450, 1440, 1405, 1370, 1290, 1180 cm ^-1 .

EXAMPLE 7 N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Phe] - [N-thiomorpholinocarbonyl- (L) -Val]

A solution of 100 mg (0.25 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, 163 mg (0.76 mmol) of N-morpholinocarbonyl- (L) -tartrate and 288 mg (0.76 mmol) ) O-Benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium fluorophosphate in 2 ml of dimethylformamide was contacted with 210 μΙ (1.52 mmol) of triethylamine and stirred at room temperature for 16 hours under a nitrogen atmosphere. .

The reaction mixture was completely evaporated, the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool, evaporated and chromatographed on silica gel using methylene chloride / methanol (15: 1). The title compound is precipitated with a mixture of methylene chloride and hexane and is freeze-dried from dioxane / tert-butanol to give a flocculent solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = 710, t _Ret (I) = 16.3 min. Rf (E) = 0.16.

The starting compound is prepared as follows:

a) N-Morpholinocarbonyl- (L) -valine

2.7 g (8.4 mmol) of N-morpholmocarbonyl- (L) -valine benzyl ester are dissolved in 75 ml of ethyl acetate and hydrogenated in the presence of 500 mg of 10% palladium on carbon at 100 kPa hydrogen at room temperature for 3 hours. The catalyst was filtered off and the solvent was evaporated to give the title compound as a colorless oil. 1 H-NMR (300 MHz, CD ₃ OD): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H), 0 95 (2d, 6H) ppm.

b) N-Morpholinocarbonyl- (L) -valine benzyl ester

A solution of 4 g (10.5 mmol) of (L) -valine benzyl ester 4-toluenesulfonate in 56 ml of methylene chloride was treated with 0.8 ml (8.1 mmol) of (morpholinocarbonyl) chloride (see J. Med. Chem. 31, 2277 (1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated. Chromatography on silica gel with ethyl acetate as eluent gave N-morpholinocarbonyl- (L) -valine benzyl ester as a colorless oil. The ester is used immediately in step a).

Example 8

Phenylacetyl- (L) -Val- [Phe ^NN Phe] - (N-phenylacetyl- (L) -Val)

In analogy to Example 7, from 100 mg (0.25 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, 143 mg (0.61 mmol) of phenylacetyl- (L) -valine are obtained. Tokyo Univ. Agric., 20, 51 (1978)), 230 mg (0.61 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 200 µl (1.42 mmol) triethylamine after chromatographic purification using methylene chloride / ether / methanol (20: 20: 1) and lyophilization from dioxane / tert-butanol as the title compound. FAB-MS: (M + H) ⁺ = 720, t _Rct (I) = = _23> 7min., R _f (C) -0.21.

Example 9 N- (3-Pyridylacetyl) - (L) -Val- [Phe ^NN Phe] - (N- (3-pyridylacetyl) - (L) -Val)

Analogously to Example 7, from 100 mg (0.25 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, 567 mg (1.52 mmol) of O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) -valine and 316 µL (2.3 mmol) of triethylamine after chromatographic purification using chloroform / methanol 5 : 1a by freeze drying from a mixture of dioxane and tert-butanol the title compound as a white solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = = 720, t _Ret (1H) = 27.9 min. Rf (A) = 0.71.

The starting compound is prepared as follows:

a) N- (3-Pyridylacetyl) - (L) -valine

3.4 g of N- (3-pyridylacetyl) - (L) -valine tert-butyl ester are dissolved in 20 ml of a 1: 1 mixture of trifluoroacetic acid and methylene chloride and stirred at room temperature for 16 hours. The reaction solution was completely evaporated and the residue digested with diisopropyl ether. The title compound is obtained as a white amorphous solid.

1 H-NMR (200 MHz, CD ₃ OD): 8.9-8.6 (broad multiplet, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m 1 H, 3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6H) ppm.

b) N- (3-Pyridylacetyl) - (L) -valine tert-butyl ester

To a solution of 3.36 g (16 mmol) of (L) -valine tert-butyl ester hydrochloride, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml. 4.2 ml of triethylamine are added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 48 hours and then diluted with methylene chloride and washed with citric acid as well as saturated sodium bicarbonate solution. The organic phase is filtered through cotton wool and after evaporation of the solvent, N- (3-pyridylacetyl- (L) -valine tert-butyl ester is used immediately in step a).

Example 10 Boc- (L) -Val- [Phe ^NN Cha] - - ((L) -Val) -Boc In a similar manner to Example 7, starting from 500 mg (1.25 mmol) of H- trihydrochloride, [Phe ^NN Cha] -H, 1.08 g (4.98 mmol) of Boc- (L) -valine, 1.89 g (4.98 mmol) of O-benztriazol-1-yl-N, N, N ' , N'-tetramethyluronium hexafluorophosphate and 1.39 mL (9.96 mmol) of triethylamine, after chromatography on silica gel using methylene chloride / ether (1: 1) and lyophilization from dioxane, the title compound consisting of a flaky solid. FAB-MS: (M + H) &lt; ^{+ &gt}; = 690, t _Ret (I) = 29.3 min. Rf (H) = 0.48.

The starting compound is prepared as follows:

a) H- [Phe ^NN Cha] -H 3 HCl

1.10 g (2.2 mmol) of Boc- [Phe ' ^N Cha] -Boc from Example 4 were dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 3 hours. After lyophilization of the reaction mixture, the title compound is obtained as the hydrochloride. FAB-MS: (M &lt; + &gt; + H) &lt; ^{+ &gt}; = 292, t _R &lt; 1 &^gt;

Example 11

Z- (L) -Val- [Phe ^NN Cha] - (L) -Val / -Z

Analogously to Example 2, from 50 mg (0.12 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a, 94 mg (0.37 mmol) of Z- (L) -valine, 165 mg (0) was obtained. , 37 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg (0.37 mmol) of O-benzthiatriazole-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 2.5 ml of 0.3 molar N -methylmorpholine in dimethylformamide, after chromatography on silica gel using a 1: 1 mixture of methylene chloride and ether, lyophilization from dioxane, the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 758.1 [delta] (1) = 29.1 min. Rf (H) = 0.55.

Example 12

Boc-F-Phe-Boc ^ Leuj

Similar to Example 1, starting from 1.0 g (3.8 mmol) of (2R) - (1 '(S) -Boc-amino-2'-phenylethoxy) oxirane and 7.15 mg (3 (8 mmol) of tert-butyl 3-isobutylcarbazate (for preparation see J. Chem. Soc., Perkin I, 1712 (1975)), the title compound which, after treatment with hexane, is a precipitate. FAB-MS: (M + H) &lt; ^{+ &gt}; = 452, t _Ret (I) = 27.2 min. Rf (I) = 0.55.

Example 13 Z- (L) -Val- [Phe ^NN Leu] <- / (L) -Val / -Z

As in Example 2, starting from 60 mg (0.17 mmol) of H-lPhc-Leuj-H trihydrochloride, 125 mg (0.50 mmol of Z- (L) -valine), 221 mg (0.50 mmol) was obtained. mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 67 mg (0.50 mmol) of 1'-hydroxybenzotriazole and 3.3 ml of 0.3 molar N-methylmorpholine in dimethylformamide, after chromatography on silica gel using a mixture of: methylene chloride / ether (1: 1) and freeze-dried from dioxane, title compound FAB-MS: (M + H) ⁺ = 718, [α] D (1) = 26.8 min, RJ) = 0.38.

The starting compound is prepared as follows:

a) H- [Phe ^NN Leu] -H 3 HCl

Similar to example 10a, starting with 1.21 g (2.48 mmol) of Boc- [Phe ^{r 'r'} Leu] -Boc from Example 12, the title compound, which is as a lyophilisate. FAB-MS: (M + H) &lt; ^{+ &gt}; = 252, t _Ret (H) = 20.9 min. Rf (K) = 0.23.

Example 14 H- (L) -Val- [Phe ^NN Cha] - (L) -Val / -H 3 HCl

Analogously to Example 10a, the title compound is obtained from 632 mg (0.91 mmol) of Boc- (L) -Val- [Phe ^NN Cha] - [(L) -Val] -Boc from Example 10 after lyophilization, which is in the form of the hydrochloride. FAB-MS: (M + + H) < ^{+ &gt}; = 490, t _Ret (II) = 29.4 min. Rf (K) = 0.23.

Example 15 N- (3-Pyridylacetyl) - (L) -Val- [Phe ^NN Leu] - N- (3-pyridylacetyl) - (Ly-Val)

Similar to Example 9, from 90 mg (0.25 mmol) of H- [Phe ^NN Leu] -H trihydrochloride from Example 13a was obtained, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) - valine, 576 mg (1.52 mmol) of O-benzotriazole-11 N, N, N ', N'-tetramethyluronium hexafluorophosphate and 316 µl (2.5 mmol) of triethylamine after chromatographic purification using methylene chloride / methanol (15: 1) by lyophilization from a mixture of dioxane, tert-butanol and water, the title compound. FAB-MS: (M + H) = 688, t _Ret (TV) = 15.5 min. Rf (D) = 0.37.

Example 16

N-Trifluoroacetyl- [Phc ^NN (pF) Phe] -Boc

A solution of 4.0 g (15.4 mmol) of 2 (R) - 1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane and 3.89 g (16.2 mmol) of tert-butyl-3- of (p-fluorophenylmethyl) carbazate in 35 ml of methanol is heated at 80 ° C for about 20 hours in a pressure tube. Evaporate the reaction, dissolve the residue in dichloromethane and precipitate the title compound from the solution by treatment with hexane (in a refrigerator). Further product was obtained by column chromatography (silica gel, methylene chloride / ether 95: 7). DC: R f (J) = 0.57, t _Ret (I) = 24.3 min. FAB-MS: (M + H) &lt; ^{+ &gt}; = 500.

The starting compound is prepared as follows:

a) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane

Under a nitrogen atmosphere, 24.7 g (1.02 mol) of magnesium are introduced into 100 ml of absolute ether and a small amount of iodine is added over 35 minutes while 132.5 ml (0.95 mol) of chloromethyltrimethylsilane and 300 ml of ether are added at a temperature is maintained at 38 ° C with an ice bath. The resulting reaction mixture is then stirred at room temperature for 90 minutes. After cooling to -60 ° C, a suspension of 48.6 g (0.195 mol) of N-Boc-phenylalaninal (manufactured by DJ Kempf, J. Org. Chem. 51, 3921 (1986)) in 1100 ml is added over 40 minutes. ether. The reaction mixture is heated at room temperature for 90 minutes and further stirred at this temperature for a further 90 minutes. The reaction mixture was then poured into 2 L and 1.5 L of 10% aqueous citric acid. The separated aqueous phase is extracted twice with 500 ml of ether each time. The two ether extracts were washed with 500 ml of 10% citric acid and twice with saturated sodium chloride solution. After drying over sodium sulfate, evaporation under reduced pressure is carried out and the title compound obtained is used without further purification. DC: Rf (L) = 0.6; FAB-MS: (M + H) &lt; ^{+ &gt}; = 338.

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

A solution of 18.8 g (0.055 mol) of 3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilylbutane in 420 ml of methylene chloride at 5 ° C for 10 minutes contact with 35.6 ml (0.28 mol) of an approximately 48% solution of boron trifluoride in ether. The reaction mixture is then stirred for 16 hours at room temperature, cooled to 10 ° C and treated with 276 ml of 4 N sodium hydroxide solution over 20 minutes. The aqueous phase is separated and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The title compound was used without further purification. DC: Rf (C) = 0.15; IR (methylene chloride): 3370, 3020, 2920, 1640, 1605 cm @ ^-1 .

c) N-Trifluoro-1-phenyl-3-butene-2 (S) -amine

11.9 g (81 mmol) of 1-phenyl-1-3-buten-2 (S) -amine are dissolved in 210 ml of methylene chloride and 70 ml of pyridine and treated dropwise at 0 ° C with 17.0 ml ( 121 mmol) of trifluoroacetic anhydride. After stirring at 0 ° C for 30 min, the reaction mixture was extracted twice with dilute hydrochloric acid, water, and brine. The aqueous phase was washed twice more with methylene chloride, dried over sodium sulfate and evaporated. DC: Rf (M) = 0.4.

d) 2 (R) - 1 '(S) - (Trifluoroacetylamino) -2'-phenylethyl / oxirane

A solution of 14.5 g (60 mmol) of N-trifluoroacetyl-1-phenyl-3-buten-2 (S) -amine in 600 ml of chloroform was added to 54.28 g (314 mmol) of m-chloroperbenzoic acid and stirred at room temperature for 24 hours. The reaction mixture was washed twice with 10% sodium sulfite solution, twice with saturated sodium carbonate solution, water and saturated sodium chloride solution. The aqueous phase is extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated. This gave the title compound, which was used without further purification in the next step. DC: R ((N) = 0.6).

e) tert-Butoxycarbonylhydrazone of p-fluorophenylcarbaldehyde

As in Example 4b, 32 g (242 mmol) of tert-butylcarbazate and 30 g (242 mmol) of p-fluorobenzaldehyde in 300 mL of ethanol at 80 ° C are reacted for 3 hours to give the title compound which, upon cooling and Dilution of the reaction mixture with water crystallizes. TLC: R _t (N) = 0.48; t _Ret (I) = 19.4 min. t-Butyl 3- (p-fluorophenylmethyl) carbazate

Analogously to Example 4a, 55 g (231 mmol) of t-butoxycarbonylhydrazone of p-fluorophenylcarbaldehyde in 500 ml of tetrahydrofuran in the presence of 5.5 g of 5% palladium on carbon are hydrogenated to give the title compound. 1 H-NMR (200 MHz, CD ₃ OD): 7.35 (dd, 8 and 6 Hz, 2H), 7.05 (t, 8 Hz, 2H), 3.9 (s, 2H), 1, 45 (s, 9H) ppm.

Example 17 N-Morpholinocarbonyl- (L) -Val [Phe ^NN (pF) Phe] -Boc

A mixture of 185 mg (0.80 mmol) of N-morpholinocarbonyl- (L) -valine (for preparation see Example 7a), 270 mg (0.67 mmol) of H- [Phe ^{>, with} (pF) Phe] -Boc, 311 mg (0.70 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 95 mg (0.70 mol) of 1'-hydroxybenztriazole are dissolved in 6.8 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide at room temperature. and stirred at room temperature for 5 hours. The reaction mixture was evaporated under high vacuum and the residue was partitioned between 4 parts of methylene chloride, 2 parts of 1M sodium carbonate solution, water and saturated sodium chloride solution. The combined organic phases dried over sodium sulfate were evaporated and purified by column chromatography (silica gel, ethyl acetate as eluent). DC: R / O) = 0.38, t _Hc , (I) = 21.8 min. FAB-MS: (M + H) &lt; ^{+ &gt}; = 616.

The starting compound is prepared as follows:

a) H- [Phe ^NV (pF) Phc] -Boc

At 70 ° C, to a solution of 0.3 g (0.6 mmol) of N-trifluoroacetyl- [Phe ^NN (pF) Phe] -Boc (see Example 16) in 50 ml of methanol is added dropwise under nitrogen atmosphere 15 ml of 1- % potassium carbonate solution and stirred for 25 hours at this temperature. The reaction mixture was evaporated under high vacuum, the residue was mixed with methylene chloride and washed twice with water and saturated sodium chloride solution. The aqueous phase is extracted twice with methylene chloride, the organic phases are dried over sodium sulphate and evaporated. The crude material was used in the next step without further purification. t _R t (I) = 16.2 min.

Example 18 N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -Z

A solution of 86 mg (0.34 mmol) of Z- (L) -Val and 160 mg (0.31 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] -H in 2.7 ml A 0.25 molar solution of N-methylmorpholine in acetonitrile (0.25 mol of N-methylmorpholine in acetonitrile) was contacted with 129 mg (0.34 mmol) of O-benztriazol-1-yl-Ν, Ν, Ν ', Ν'hexafluorophosphate. The reaction mixture was allowed to stand at room temperature for 4 hours and the residue was partitioned between 3 parts of methylene chloride, 2 parts of saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate and evaporation affords the title compound which is obtained pure after digestion from a 1: 1 mixture of methylene chloride and ether. DC: Rf (P) = 0.4, t _Ret (I) = 22.4 min. FAB-MS: (M + H) &lt; ^{+ &gt}; = 749.

The starting compound is prepared as follows:

a) N-Morpholino-carbonyl- (L) -Val- [Phe ^NN tp-F] Phe] -H

210 mg (0.34 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^KV - (pF) - Phe] -Boc (Example 17) was dissolved in 105 ml formic acid and stirred at room temperature for 4 hours . The solvent is then evaporated, the residue is taken up in methylene chloride and the solution is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. Extraction of the aqueous phases with 2 parts of methylene chloride, drying of the organic phases with sodium sulfate and evaporation affords the title compound which is used without further purification in the next step. t _Ret (I) = 12.9 mins.

Example 19 N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -H

160 mg (0.21 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - [(L) -Val] -Z (Example 18) in 6 ml of ethanol are hydrogenated at normal pressure. in the presence of 40 mg of 10% palladium on carbon. Filtration through Celite ^R (kieselguhr, filter aid from Fluka, Buchs, Switzerland), evaporation and freeze-drying from dioxane gave the title compound. t _Rel (hydrochloride, I) = 13.4 min. FAB-MS: (M + H) < ^{+ &gt}; = 615.

Example 20 N-Morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - [(L) -Val] - (N-morpholinocarbonyl-Gly)

A solution of 26.9 mg (0.143 mmol) of N-morpholinocarbonylglycine and 80 mg (0.130 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN (pF) -Phe] - / (L) -Val / -H in 1.1 ml of 0.25-molar N-methylmorpholine in acetonitrile was contacted with 54 mg (0.143 mmol) of O-benztriazol-1-yl-Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate and stirred for 16 hours at room temperature. The reaction mixture was evaporated and the residue partitioned between 3 parts ethyl acetate, water, 2 parts saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Drying of the organic phase with sodium sulfate and evaporation affords the title compound which, upon dissolution in a small amount of dimethylformamide, precipitates with diisopropyl ether as a pure substance. Thin Layer Chromatography: t _Ret (I) = 15.1 min. FAB-MS: (M + H) &lt; ^{+ &gt}; = 785.

The starting compound is prepared as follows:

(a) N-morpholinocarbonylglycine benzyl ester

Similar to Example 7b, 7.69 g (22.8 mmol) of glycine benzyl ester 4-toluenesulfonate are reacted and

2.8 g (19 mmol) of (morpholinocarbonyl) chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiisopropylamine for 18 hours. Extraction with methylene chloride and digestion with hexane gave the title compound as a pure precipitate. t _Ret (I) = 11.6 min.

b) N-Morpholinocarbonylglycine

Analogously to Example 7a, 4.8 g (18.3 mmol) of N-morpholinocarbonylglycine benzyl ester in 100 ml of ethyl acetate in the presence of 1 g of 10% palladium on carbon was hydrogenated to give the title compound. 1 H-NMR (300 MHz, CDCl ₃ ): 3.88 (s, 2H), 3.64 (s, 4H), 3.50 (s, 2H), 3.35 (s, 4H) ppm.

Example 21

Z- (L) -Val- [Phe ' ^{, JN} (' pF) Phe] -Boc

A solution of 335 mg (1.33 mmol) of Z- (L) -Val and 448 mg (1.11 mmol) of H- [Phe ^NN (pF) Phe] -Boc (for preparation see Example 17a) in 9.4 ml of 25- of molar N-methylmorpholine in acetonitrile (0.25 mol of N-methylmorpholine in acetonitrile) was treated with 463 mg (1.22 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate. After stirring at room temperature for 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated to give the title compound which was purified by column chromatography (silica gel, hexane / ethyl acetate varying from 4: 1 to 1: 1). t _Ret (I) = 26.6 min. FAB-MS: (M + H) &lt; ^{+ &gt}; = 637.

Example 22

Z- (L) -Val- [Phe ^NN (pF) Phe] <- / (L) -Val / -Boc

Similar to Example 18, 165 g (0.76 mmol) of Boc- (L) -Val and 371 mg (0.69 mmol) of Z- (L) -Val- [Phe ^NN- β-F) Phe] were reacted. -H in 6 ml of 0.25-molar N-methylmorpholine in acetonitrile with 289 mg (0.76 mmol) of O-benztriazol-1-yl-N, N'-tetramethyluronium hexafluorophosphate, to a compound which crystallizes directly from the reaction mixture and can be filtered. t _Ret (I) = 27.2 min, FAB-MS: (M + H) &lt; ^{+ &gt}; = 736.

The starting compound is prepared as follows:

a) Z- (L) -Val- [Phe ^w (pF) Phe] -H

As in Example 18a, the protecting group was removed from 440 mg (0.69 mmol) of Z-β-Val-β-β-β-Phe-Boc by treatment with 212 mL of formic acid to give the title compound. t _Ret (I) = 17.8 min.

Example 23

Z- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -H

Similar to Example 18a, the protecting group was removed from 250 mg (0.34 mmol) of Z- (L) -Val- [Phe ^NN - (pF) Phe] - / (L) -Val / -Boc (Example 22). with 50 mL formic acid to give the title compound. t _Ret (I) = 18.0 min, FAB-MS: (M + H) < ^{+ &gt}; = 636.

Example 24 Z- (L) -Val- [Phe ^NN (pF) Phe] <- ((L) -Val) <- (N-morpholinocarbonyl-Gly)

Analogously to Example 20, 32 mg (0.17 mmol) of N-morpholinocarbonylglycine (Example 20b) and 99 mg (0.16 mmol) of Z- (L) -Val- [Phe ^NN (pF) Phe] <- / ( L) -Val / -H in 1.3 ml of 0.25-molar N-methylmorpholine in acetonitrile was treated with 65 mg (0.17 mmol) of O-benztriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate to give the title compound, which crystallizes directly from the reaction solution. .Delta. (1) = 21.1 min., FAB-MS: (M + H) + = 806.

Example 25

Z- (L) -Asn- [Phe ^NN IP-F) Phe] -Boc

To a solution of 2.09 g (5.2 mmol) of H- [Phe ^NN (pF) Phe] -Boc (for preparation see Example 17a) in 68 ml of dimethylformamide and 2.7 ml (16 mmol) of N-ethyldiisopropylamine was added 3.times. 0 g (7.8 mmol) of Z- (L) -asparagine p-nitrophenyl ester (Bachcm, Bubendorf, Switzerland). The reaction mixture is stirred for 16 hours at room temperature, then evaporated under high vacuum, the residue is shaken with a large amount of methylene chloride (because it is poorly soluble) and washed with 2 portions of 5% potassium carbonate solution. The aqueous phases are extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulphate and evaporated. Then, the crude product was dissolved in a small amount of methanol and precipitated by the addition of toluene at -20 ° C to give the title compound. t _Ra (I) = 21.2 min.

Example 26

H- (L) -Asn- [Phe ^NX (pF) Phc] -Boc

As in Example 19, 0.40 g (0.61 mmol) of Z- (L) -Asn- [Phc ^NN (pF) Phe] -Boc in 20 mL of methanol was hydrogenated to give the title compound. t R e (D = 14.9 min.

Example 27 Quinoline-2-carbonyl- (L) -Asn- [Phe ^NN (pF) Phe] -Boc

Analogously to Example 17, 134 mg (0.78 mmol) of quinoline-2-carboxylic acid (Fluka, Buchs, Switzerland) were reacted in 4 ml of 0.3 molar N-methylmorpholine in dimethylformamide with 344 mg (0.78 mmol). ) benztriazol-1-yloxy-tns (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.78 mmol) of 1'-hydroxybenztriazole and 268 mg (0.52 mmol) of H- (L) -Asn- [Phe ^NN (pF) Phe] - Boc. Since H- (L) -Asn- [Phe ^NN (pF) Phe] -Boc is still present after stirring at room temperature for 16 hours according to gas chromatography, 299 mg of benztriazol-1-yioxytris (dimethylamino) phosphonium hexafluorophosphate are added once more, 70 mg of β-hydroxybenzotriazole, 89 mg of quinaldinic acid and 113 μΐ of N-methylmorpholine. After an additional 16 hours, the reaction mixture was evaporated and the residue was partitioned between 3 parts methylene chloride, 2 parts saturated sodium bicarbonate solution and saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate and evaporated. The crude material was dissolved in a small amount of dimethylformamide, precipitated with diisopropyl ether, and cooled to 20 ° C to give the title compound. t _Ret (I) = 22.8 min, FAB-MS: (M + H) &lt; ^{+ &gt}; = 673.

EXAMPLE 28 Z- (L) -Asn- [Phe ^NN (pF) Phe] < - &gt; / (L) -Val / -Z mg (0.35 mmol) of Z- (L) -Val in 3.8 ml. Of 3-normal N-methylmorpholine in dimethylformamide was activated with 153 mg (0.35 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 47 mg (0.35 mmol) of 1'-hydroxybenzotriazole and after 15 minutes was reacted with 144 mg (0.23 mmol) of Z- (L) -Asn- [Phe ^NN IP-F) Phe] -H. The reaction mixture is stirred for 14 hours at room temperature, then evaporated, the residue is dissolved in 2 ml of methanol and partitioned between 3 parts of methylene chloride and 2 parts of sodium bicarbonate solution, the organic phase is dried over sodium sulphate and evaporated. Repeated dissolution of the crude material in a small amount of dimethylformamide and precipitation with diisopropyl ether gave the title compound. t _Ret (I) = 22.2 min, FAB-MS: (M + H) &lt; ^{+ &gt}; = 785.

The starting compound is prepared as follows:

a) Z- (L) -Asn- [Phe ^NN (pF) Phe] -H.2HC1

A solution of 150 mg (0.23 mmol) of Z- (L) -AMPhe ^NN (pF) Phe] -Boc (Example 25) in 1 mL of dioxane was treated with 2 mL of 4N hydrogen chloride in dioxane (Fluka, Buchs, Switzerland). After 90 minutes at room temperature, the reaction mixture is lyophilized and the lyophilisate is immediately reacted.

Example 29 Trifluoroacetyl- [Phe ^NN (pF) Phe] - / (L) -Val / -Z

In analogy to Example 17, 239 mg (0.95 mmol) of Z- (L) -Val were reacted in 10.5 ml of 0.3 molar.

Of N-methylmorpholine in dimethylformamide with 421 mg (0.95 mmol) of benztriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 129 mg (0.95 mmol) of 1-hydroxybenzotriazole and 0.3 g (0.3 mmol) of N-trifluoroacetyl- [Phe ^M '(pF) Phe-H for 15 hours. Column chromatography (silica gel, methylene chloride / ether 10: 1), and precipitation from dimethylformamide solution by treatment with diisopropyl ether gave the title compound. R f (Q) = 0.15, t _Ret (I) = 25.9 min, FAB-MS: (M + H) ⁺ = 633.

The starting compound is prepared as follows: a) N-Trifluoroacetyl- [Phe ^NN (pF) Phe] -H

At 0 ° C, 0.20 g (0.40 mmol) of N-trifluoroacetyl- [Phe ^NN (pF) Phe] -Boc (production see Example 16) was contacted in 5 mL of methylene chloride with 5 mL of trifluoroacetic acid. The reaction mixture was stirred for 4 hours at 0 ° C and 2 hours at room temperature, then the reaction mixture was evaporated. Lyophilization of the residue from dioxane gave the title compound which was reacted further without further purification. t _Ra (I) = 14.7 min.

EXAMPLE 30 Z-Ij-Ans-Phe-Ph-Phe-Boc

Analogously to Example 25, 167 mg (0.34 mmol) of H- [Phe ^NN Phe] -Boc in 3.6 ml of dimethylformamide and 0.18 ml (1 mmol) of N-ethyldiisopropylamine were reacted with 0.20 g (0) of the product. , 52 mmol) of Z- (L) -asparagine p-nitrophenyl ester to the title compound, which was purified after column chromatography (silica gel, ethyl acetate). DC R 1 (O) = 0.19, t _Ret (I) = 20.9 min.

The starting compound is prepared as follows:

a) N-Trifluoroacetyl [Phe ^NN Phe] -Boc

Similar to Example 16, 1.82 g (7.0 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2'-phenylethyl / oxirane (Example 16d) and 1.58 g (7 mmol) were reacted. Tert-butyl 3-benzylcarbazate (J. Chem. Soc., Perkin I, 1712 (1975)) in 15 mL of methanol in a pressure tube to give the title compound, which was isolated by column chromatography (silica gel, mixture). methylene chloride / ether (50: 1). DC Rf = 0.38, t _Ret (I) = 24.5 min.

b) H- [Phc ^NN Phe] -Boc

Analogously to Example 17a, 258 mg (0.53 mmol) of N-trifluoroacetyl- [Phe ^NN Phe] -Boc in 60 mL of methanol was reacted with 10.7 mL of 1M potassium carbonate solution to give the title compound.

Example 31

Z-Val-iLJ KP-FjPhe ^ iP-Boc FjPheJ

Analogously to Example 21, 18 mg (0.070 mmol) of Z- (L) -Val and 27 mg (0.064 mmol) of H - [(pF) Phe ^KN - (pF) Phe] -Boc in 0.6 ml of 0 were reacted. Of 25-molar N-methylmorpholine in acetonitrile with 26.6 mg (0.070 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate to give the title compound which is purified by dissolving in a small amount methylene chloride and precipitation with diisopropyl ether. FAB-MS: (M @ + + H @ + = 655).

The starting compound is prepared as follows:

a) N-Boc- (p-fluorophenylalanine)

20 g (109 mmol) of p-fluorophenylalanine (Fluka, Buchs, Switzerland) are reacted in 400 ml of a 1: 1 mixture of dioxane and water with 35.5 g (163 mmol) of Boc-anhydride and 150 g (1.09) mol) of potassium carbonate. After 4 hours, the reaction mixture was acidified with citric acid solution and extracted with 3 portions of ethyl acetate. The organic phases are washed with 10% citric acid, water and saturated sodium chloride solution and evaporated. Dissolution of the residue in a small amount of methylene chloride and crystallization with the addition of hexane gave the title compound. t _R t (I) = 16.9.

b) N-Boc- (p-fluorophenylalaninol)

A solution of 17.9 g (63 mmol) of N-Boc- (p-fluorophenylalanine) in 73 ml of absolute tetrahydrofuran with 9.66 ml (69 mmol) of triethylamine is contacted at -5 to -10 ° C and the solution is added dropwise. 9.05 ml (69 mmol) of isobutyl chloroformate in 44 ml of absolute tetrahydrofuran. Stir for 30 minutes at room temperature and then collect the precipitate on a frit. The filtrate was added dropwise with cooling to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. The reaction mixture was stirred at room temperature for 4 hours, then acidified with 10% citric acid, the tetrahydrofuran was partially evaporated on a rotary evaporator and the residue was partitioned between 3 parts ethyl acetate, 2 parts 2 N sodium hydroxide, water, saturated sodium bicarbonate solution. and saturated sodium chloride solution. The organic phase, after drying over sodium sulfate and evaporation, is dissolved in a small amount of methylene chloride and crystallized with the addition of hexane. There was thus obtained the title compound. DC: R f (N) = 0.36, t _Ret (I) = 16.8 min, 1 H-NMR (200 MHz, CD ₃ OD): 7.24 (dd, 8 and 5 Hz, 2H), 6.98 (t, 8 Hz, 2H), 3.73 (m, 1H), 3.47 (d, 5 Hz, 2H), 2.88 (dd, 13 and 6 Hz, 1H), 2.62 (dd, 13 and 8 Hz, 1H), 1.36 (s, 9H) ppm.

c) N-Boc- (p-fluorophenylalaninal)

Under a nitrogen atmosphere, a solution of 4.0 mL (46.8 mmol) of oxalyl chloride in 44 mL of methylene chloride cooled to -60 ° C was added dropwise with 4.44 mL (62.4 mmol) of dimethyl sulfoxide dissolved in 76 mL of methylene chloride. After stirring for 15 minutes, 8.4 g (31.2 mmol) of N-Boc- (p-fluorophenylalaninol) as a solution in 185 ml of methylene chloride and tetrahydrofuran (1: 1) were added to the clear reaction solution to precipitate a solid. , and stirring is continued for 25 minutes. 17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride are then added. After stirring for 30 minutes, a solution of 278 ml of 20% potassium hydrogen sulphate solution was added dropwise followed by 220 ml of hexane. The reaction mixture is allowed to warm to room temperature, the aqueous phase is separated and extracted with 2 parts of ether. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the title compound which was used in the next step without further purification.

1 H-NMR (200 MHz, CDCl 3): 9.63 (s, 1H), 6.9-7.2 (m, 4H), 5.04 (m, 1H), 4.42 (m, 1H) 3.10 (m, 2H); 1.43 (s, 9H) ppm.

d) N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4- (p-fluorophenyl) -1-trimethylsilylbutane

Analogously to Example 16a, 1.63 g (67 mmol) of magnesium in 33 ml of absolute ether is reacted with 8.3 ml (60 mmol) of chloromethyltrimethylsilane to form a Grignard compound which is treated with 13 mmol of N-Boc- (p- extracts and subjected to column chromatography (silica gel, hexane / ethyl acetate with a variable ratio of from 5: 1 to 4: 1). A diastereomeric mixture of the title compound is obtained. DC: RXL) = 0.32, t _Re , (I) = 24.9 min. (22%) / 25.5 min. (78%), FAB-MS: (M + H) &lt; ^{+ &gt}; = 356.

e) 1- (p-Fluorophenyl) -3-butan-2 (S) -amine

Analogously to Example 16b, 1.1 g (3.1 mmol) of N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4- (p) was reacted.

-fluorophenyl) -1-trimethylsilylbutane in 22 mL of methylene chloride with 1.9 mL (15.5 mmol) of an approximately 48% solution of boron trifluoride in ether to give the title compound.

1 H-NMR (300 MHz, CDCl 3): 7.2-7.10 and 7.05-6.9 (2m, 2H each), 5.9-5.8 (m, 1H), 5.2- 5.0 (m, 2H), 3.57 (m, 1H), 2.79 (dd, 12 and 6 Hz, 1H), 2.62 (dd, 12 and 8 Hz, IH),

1.7 (broad singlet, 2H) ppm.

f) N-Trifluoroacetyl-1- (p-fluorophenyl) -3-butene-2 (S) -amine

Similar to 16c, 364 mg (2.2 mmol) of 1- (p-fluorophenyl) -3-butene-2 (S) -amine are reacted in

1.8 ml methylene chloride and 5.4 ml pyridine with 460 µl (3.3 mmol) trifluoroacetic anhydride. The title compound is obtained, which precipitates in the pure state by digestion with hexane. DC: R f (F) = 0.58, MS: (M) ⁺ = 261.

g) 2 (R) - [1 '(S) - (Trifluoroacetyl) -2' - (p-fluorophenyl) ethyl / oxirane

Analogously to Example 16d, 359 mL (1.37 mmol) of N-trifluoroacetyl-1- (p-fluorophenyl-3-buten-2 (S) -amine) was oxidized in 9 mL of chloroform by treatment with 1.18 g (6.87 mmol) m-chloroperbenzoic acid to give the title compound DC: Rf (R) = 0.45.

h) -Trifluoroacetyl - [(pF) Phe ' ^N (pF) Phe] -Boc

Analogously to Example 16, 415 mg (1.49 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2' - (p-fluorophenyl) ethyl] oxirane and 377 mg (1.57 mmol) were reacted. of tert-butyl 3- (p-fluorophenylmethyl) carbazate in 9 mL of methanol to give the title compound. TLC: R _f (S) = 0.53; FAB-MS (M + H) ⁺ = 518th

1 H-NMR (300 MHz, CD 3 OD): 7.4-7.3 and 7.3-7.2 (2m, 2H each), 7.05-6.9 (m, 4H), 4.23 ( m, 1H), 3.90-3.65 (m, 3H), 3.03-2.78 and 2.74-2.60 (2m, 2H each), 1.30 (s, 9H) ppm.

i) H-Kp-FlPhc-1β-FjPhej-Boc

In analogy to Example 17a, 285 mg (0.55 mmol) of N-trifluoroacetyl - [(pF) Phe ^NN (pF) Phe] -Boc in 45 ml of methanol was reacted with 14 ml of 1-molar potassium carbonate solution to give the title compound. title. t _R t (I) = 16.4.

Example 32

Z- (L) -Val - [(pF) Phe ^{N N} (pF) Phe] -H

Analogously to Example 18a, the protecting group was removed from 215 mg (0.33 mmol) of Z-fLj-Val-Kp-FjPhe-β-FjPhej-Boc by treatment with 100 ml of formic acid. There was thus obtained the title compound. FAB-MS (M + H) &lt; ^{+ &gt}; = 555.

Example 33 Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - [N- (N-2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -Val] -

Analogously to Example 18, 23.6 g (0.089 mmol) of N- [N- (2-pyridylmethyl) -N-methylaminocarbonyl] - (L) -valine are reacted (for preparation see European Patent No. 402 646A1, dated 19 December 1990) and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] -H

33.8 mg (0.089 mmol) of O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate in 0.76 ml of 0.25 molar N-methylmorpholine in acetonitrile to give the title compound which is recrystallized a mixture of dimethylformamide and diisopropyl ether. DC: Rf (O) = 0.39; FAB-MS (M + H) &lt; ^{+ &gt}; = 802.

Example 34

Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] - [N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -Val]

Analogously to Example 18, 26.0 mL (0.089 mmol) of N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -valine was reacted (see Synth., Struct., Funct. Proc. Am. Pept. Symp., 7th, 85 (1981)) and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe ^NN (pF) Phe] -H with 33.8 mg ( 0.089 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate in 0.76 ml of 0.25 molar N-methylmorpholine in acetonitrile to give the title compound, which is recrystallized from a mixture of dimethylformamide and isopropyl ether. DC: Rf (P) = 0.64; FAB-MS (M + H) &lt; ^{+ &gt}; = 829.

Example 35 Acetyl-Val- [Phe ^NN Phe] - (N-acetyl-Val)

Similar to Example 7, from 100 mg (0.25 mmol) of H- [Phe ^KN Phe] -H trihydrochloride from Example 2a, 121 mg (0.76 mmol) of N-acetyl- (L) -valine, 288 mg were obtained. (0.76 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 0.211 mL (1.52 mmol) of triethylamine in dimethylformamide of the title compound after lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 568, t _Rct (I) = 15.0 min, Rf (B) = 0.64.

Example 36

Z- (D) -Val- [Phe ^NN Phe] <- / (D) -Val / -Z

As in Example 2, from 50 mg (0.123 mmol) of H- [Phe ^NN Phe] -H trihydrochloride from Example 2a, 95 mg (0.38 mmol) of Z- (D) -valine, 168 mg (0.38 mmol) was obtained. mmol) of benztriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, 51 mg (0.38 mmol) of 1'-hydroxybenzotriazole and 2.53 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, after lyophilization from dioxane. FAB-MS: (M + H) ⁺ = 752, t _Ret (I) = 26.4 min., R _f (H) - 0, 21.

Example 37 Quinoline-2-carbonyl-Val- [Phe ^NN Phe] - (N-quinoline-2-carbonyl-Val)

145 mg (0.53 mmol) of N- (quinoline-2-carbonyl) - (L) -valine, 235 mg (0.53 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate and 72 mg (0.53) mmol) of 1'-hydroxybenzotriazole was dissolved in 3.5 L of a 0.3 molar solution of N-methylmorpholine in dimethylformamide and after 10 minutes 70 mg (0.18 mmol) of H- [Phe ^NN Phe] -H trihydrochloride (Example 2a) was added. ) and stirred for 5 hours at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated, the residue was dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution, once with 10% citric acid and again once with saturated sodium bicarbonate solution. The organic phases are filtered through cotton wool, evaporated and the residue is precipitated twice from a mixture of methylene chloride and methanol with the addition of diisopropyl ether. After freeze-drying from dioxane, the title compound is obtained as a white solid (mixture of two diastereoisomers which can be distinguished by high performance liquid chromatography). FAB-MS: (M + H) &lt; ^{+ &gt}; = 794, t _Rct (I) = 29.1 and 29.3 min, Rf (B) = 0.81.

The starting compound is prepared as follows:

a) N- (quinoline-2-carbonyl) - (L) -valine

A solution of 2.5 g (14.5 mmol) of (L) -valyl-tert-butyl ester and 2.5 g (14.5 mmol) of quinoline-2-carboxylic acid in 100 ml of a 10: 1 mixture of methylene chloride and tetrahydrofuran This was treated with 3.28 g (15.9 mmol) of Ν, cyk-cyclohexylcarbodiimide and 2.0 ml (14.5 mmol) of triethylamine and stirred at room temperature for 18 hours. The reaction mixture was cooled to -18 ° C and urea was filtered off. The filtrate was evaporated, the residue was dissolved in methylene chloride and washed once with sodium bicarbonate solution and water. The organic phases are filtered through cotton wool, evaporated and chromatographed on silica gel using hexane / ethyl acetate (2: 1) to give N- (quinoline-2-carbonyl) - (L) -valyl-tert-butyl ester. 2.59 g (12.2 mmol) of this compound are left at room temperature for 4.5 hours in a 1: 1 mixture of methylene chloride and trifluoroacetic acid. After evaporation, the residue is purified by chromatography on silica gel using hexane / ethyl acetate (1: 1). 2: 1. The fractions containing the prepared compound were evaporated, redissolved in methylene chloride, and washed with water, 1N sodium hydroxide solution and 1N hydrochloric acid to give the title compound.

1 H-NMR (200 MHz, CD ₃ OD): 1.05 and 1.07 (2d, J = 6 Hz, 6H), 2.40 (m, 1H), 4.65 (m, 1H), 7 70 (m, 1H), 7.875 (m, 1H), 8.00 (dd, 1H), 8.20 (m, 1H), 8.48 (d, 1H) ppm.

Example 38 Acetyl- (L) -Val- [Phe ^NN Cha] - (N-acetyl- (L) -Val)

In a similar manner to Example 37, N-acetyl- (L) -valine trihydrochloride (160 mg, 0.40 mmol) from Example 10a (190 mg, 1.19 mmol) was obtained, 525 mg ( 1.19 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 160 mg (1.19 mmol) of 1'-hydroxybenzotriazole and 7.9 ml of a 0.3 molar solution of N-methylmorpholine in dimethylformamide of the title compound, after precipitation from a mixture of chloroform and methanol with diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 574, t _Ret (I) = 18.1 min, R ((B) = 0.30).

Example 39 N- (3-Pyridylacetyl) - (1) -Val- [Phe ^NN Cha] - (N-pyridylacetyl) - (L) -Val] .3HCl

Analogously to Example 7, from 100 ml (0.25 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) - was obtained. valine of Example 9a, 576 mg (1.52 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 0.316 mL (2.28 mmol) of triethylamine in dimethylformamide the title compound, after Purification by chromatography on silica gel using a 15: 1 mixture of methylene chloride and methanol by lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 728, t _Ret (I) = 11.3 min, R _t (U) = 0.21.

Example 40

Acetyl-lle- [Phe ^NN Cha] - <- (N-acetyl-lle)

Similar to Example 37, from 160 mg (0.40 mmol) of H- [Phe ^NN Cha] -H trihydrochloride from Example 10a, 206 mg (1.19 mmol) of N-acetyl- (L) -isoleucine was obtained, 525 mg. (1.19 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 160 mg (1.19 mmol) of 1'-hydroxybenzotriazole and 7.9 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, after precipitation from a mixture of methylene chloride and methanol with the addition of diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. (This is a mixture of 2 diastereoisomers that can be distinguished by high performance liquid chromatography.)

FAB-MS: (M + H) &lt; ^{+ &gt}; = 602, t _Ret (I) = 20.4 and 20.7 min, R / D) = 0.33.

Example 41 Thiomorpholinocarbonyl- (L) -Val- [Phe ^NN Cha] - (N-thiomorpholinocarbonyl- (L) -Val)

Starting from 70 mg (0.12 mmol) of H- (L) -Val- [Phe ^NN Cha] <- [N- (L) -Val] -H trihydrochloride from Example 14, 58 mg (0.35 mmol). Of (6-thiomorpholinylcarbonyl) chloride of Example 6a and 0.127 ml of triethylamine in 2 ml of DMF, after chromatography on silica gel using methylene chloride / methanol (95: 5) and lyophilization of the fractions containing the product from dioxane, gave the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 748, t _Ret (I) = 24.0 min, Rf (B) = 0.70.

Example 42 Z- (L) -Glu- [Phe ^NN (pF) Phe] - - (L) -Glu / -Z

A solution of 130 mg (0.14 mmol) of Z- (L) -Glu (O-tert-butyl) - [Phe ^NN (pF) Phe] - (L) -Glu (O-tert-butyl) / -Z (where Glu (O-tert-butyl) herein refers to a glutamic acid residue esterified with a tert-butyl group on the carboxy group at position r) in 8 ml of a 1: 1 mixture of methylene chloride and trifluoroacetic acid is stirred for 3 hours at room temperature temperature. The solvent was evaporated under reduced pressure and the residue was precipitated from methylene chloride with the addition of diisopropyl ether. The title compound is obtained, after lyophilization from a mixture of dioxane and tert-butanol. FAB-MS: (M + H) < ^{+ &gt}; = 830 t _Ret (I) = 19.6 min, R &lt; 1 &^gt; (B) = 0.32.

The starting compounds are prepared as follows:

a) Z- (L) -Glu (O-tert-butyl) - [Phe ^NN (pF) Phe] <- / (L) -Glu (O-tert-butyl) / - Z

Analogously to Example 37, Z- (L) -glutamic acid tert-butyl ester was obtained from 100 mg (0.24 mmol) of H- [Phe ^NN (pF) Phe] -H trihydrochloride. , 321 mg (0.73 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 98 mg (0.73 mmol) of 1'-hydroxybenztriazole and 4.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide compound named in Purification by chromatography on silica gel using methylene chloride / ether (1: 1). _Rct t (I) = 30.2 min., R f (H) = 0.17.

b) H- [Phe ^NN (pF) Phe] -H 3 HCl

Starting from 1.77 g (3.51 mmol) of Boc- [Phe ^NN (pF) Phe] -Boc, analogously to Example 2a, the title compound is obtained after lyophilization. FAB-MS: (M + H) &lt; ^{+ &gt}; = 304 Rf (K) = 0.19.

c) Boc-tPhe-p-FjPhej-Boc

Starting from 2.0 g (7.60 mmol) of (2R) - 1 '- (S) -Boc-amino-2'-phenylethyl / oxirane and 2.17 g (9.04 mmol) of tert-butyl Of 3- (4-fluorophenylmethyl) carbazate from Example 16f, analogously to Example 1, gives the title compound after chromatographic purification on silica gel using hexane / ethyl acetate 2: 1. FAB-MS: (M + H) &lt; ^{+ &gt}; = 504, t _Ret (I) = 26.2 min, Rf (K) = 0.26.

Example 43 N- (2-Pyridylmethyl) -N-methylaminocarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -V al /

As in Example 37, N- (N-) 2- (2- (2- (2-methyl-ethyl) -phenyl) -H) - (Phe- ^N -Ph) -H-trihydrochloride from Example 42b was obtained from 70 mg (0.17 mmol). pyridylmethyl) -N-methylaminocarbonyl / - (L) -valine (described in European Patent No. 0 402 646 A1 of 19 December 1990), 225 mg (0.51 mmol) benztriazol-1-yloxy-tris ( dimethylamino) phosphonium hexafluorophosphate, 69 mg (0.51 mmol) 1'-hydroxybenzotriazole and 3.4 mL of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after chromatography on silica gel using methylene chloride / methanol 15: 1 and lyophilizing the fractions containing the product from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 798, t _Ret (IV) = 35 min, Rf (U) = 0.21.

Example 44

N- [3- (Tetrazol-1-yl) -propionyl] -N- (Phe ^NN (pF) Phe) - [N- (3- (tetrazol-1-yl) -propionyl) -Val]

Analogous to Example 37, from 100 mg (0.24 mmol) of H- [Phe ^NN (pF) Phe] -H trihydrochloride from Example 42b, 146 mg (0.61 mmol) of N- [3- (tetrazol-1)] was obtained. -yl) -propionyl- (L) -valine, 268 mg (0.61 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 82 mg (0.61 mmol) of 1'-hydroxybenzotriazole and 4 ml of 0.3 of the title compound after precipitation from methylene chloride with addition of diisopropyl ether and lyophilization from dioxane. (According to high performance liquid chromatography, 4 diastereoisomers can be distinguished.) FAB-MS: (M + H) ⁺ = 750, t _Ret (III) = 30.8, 31.4, 32.4 and 32.8 min, Rf ( K = 0.5.

Example 44a

N- / 3- (tetrazol-l-yl) -propionyl / - (L) -valine

In analogy to Example 9b, starting from 4 g (16.4 mmol) of (L) -valine benzyl ester hydrochloride, 2.1 g (14.9 mmol) of 3- (tetrazol-1-yl) propionic acid (2.1 g, 14.9 mmol) is obtained. for manufacture (see U.S. Patent No. 4,794,109 of December 27, 1988), 2.4 mL of cyanophosphonic acid dimethyl ester and 4.4 mL of triethylamine in dimethylformamide, after chromatography on silica gel using a 30: 1 mixture of methylene chloride and methanol. N- [3- (Tetrazol-1-yl) propionyl] - (L) -valine benzyl ester. 2.66 g (8.03 mmol) of this compound is hydrogenated in 9: 1 methanol: water in the presence of 530 g of 10% palladium on carbon at 100 kPa of hydrogen to precipitate from methanol and diisopropyl ether to give the title compound. .

1 H-NMR (200 MHz, CD ₃ OD): 0.9 (d, J = 7 Hz, 6H), 2.1 (m, 1H), 2.95 (m, 2H), 4.29 (d J = 6 Hz, 1H), 4.78 (m, 2H), 9.15 (s, 1H) ppm.

Example 45 Z- (L) -Val- [Phe ^NN (pF) Phe] - / (L) -Val / -Z

Analogously to Example 37, from 100 mg (0.24 mmol) of H-fhe-p-F-Phej-H trihydrochloride from Example 42b, 182 mg (0.38 mmol) of Z- (L) -valine, 321 mg (0) were obtained. , 73 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 98 mg (0.73 mmol) of 1'-hydroxybenzotriazole and 4.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, after precipitation from methylene chloride with addition of diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 770, [delta] _RM (I) = 26.3 min, R f (OH) = 0.25.

Example 46 Acetyl-Val- [Phe ^NN (pF) Phe] - (N-acetyl-Val)

Analogously to Example 37, from 80 (0.19 mmol) of H- [Phe ^SN (pF) Phc] -H trihydrochloride from Example 42b, 124 mg (0.78 mmol) of N-acetyl- (L) -valine was obtained. 344 mg (0.78 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.76 mmol) of 1'-hydroxybenzotriazole and 4.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound After precipitating twice from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. FAB-MS: (M + H) &lt; ^{+ &gt}; = 586, t _Ret (I) = 15.8 min, Rf (E) = 0.32.

Example 47 Acetyl-Val- [Phc ^N 4 (p-CN) Ph] - (N -acetyl-Val) Analogous to Example 37, 80- (0.19 mmol) of H- [Phe ^NIS (p- CN) Phe] -H, 124 mg (0.78 mmol) of N-acetyl- (L) -valine, 344 mg (0.78 mmol) of benztriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 105 mg (0.76) mmol) of 1'-hydroxybenzotriazole and 4.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from dioxane, as a mixture of two diastereoisomers capable of being distinguished by HPLC. FAB-MS: (M + H) &lt; ^{+ &gt}; = 593, t _Ret (I) = 14.4 min, Rf (D) = 0.39.

The starting compounds are prepared as follows:

a) H-tPhe-p-CNjPhe-HAHCl

Analogously to Example 2a), the title compound is obtained after lyophilization starting from 2.69 g (5.27 mmol) of Boc- [Phe ^NN (p-CN) Phe] -Boc. FAB-MS; (M + H) ⁺ = 311, Rf (K) = 0.16.

b) Boc - [Phe ^NN (p - CN) Phe] - Boc

As in Example 1, starting from 2.0 g (7.60 mmol) of (2R) - 1 '- (S) -Boc-amino-2'-phenylethyl] oxirane and 1.87 mmol of tert. -butyl-3- (4-cyanophenylmethyl) carbazate, the title compound, after crystallization from a mixture of methanol and diisopropyl ether. FAB-MS. (M + H) ⁺ = 511, t _R (I) = 25 min, R f (Y) = 0.19.

c) tert-Butyl 3- (4-cyanophenylmethyl) carbazate

Analogously to Example 4b, 10 g (76.3 mmol) of 4-cyanobenzaldehyde and 10 g (76.3 mmol) of tert-butylcarbazate in ethanol are reacted to tert-butoxycarbonylhydrazone of 4-cyanophenylcarbaldehyde. 11.1 g of this compound are hydrogenated in 150 ml of tetrahydrofuran in the presence of 2 g of 10% palladium on carbon at 200 kPa of hydrogen. There was thus obtained the title compound. 1 H-NMR (200 MHz, CDCl ₃ ): 7.65 (d, J = 8Hz, 2H), 7.45 (d, J = 8Hz, 2H), 6.08 (broad singlet, 1H), 4.3 (broad singlet, 1H), 4.02 (s, 2H), 1.45 (s, 9H) ppm.

Example 48 Z- (L) -Val- [Phe ^NN (p-CN) Phe] - / (L) -Val / -Z

Analogously to Example 37, from 70 mg (0.17 mmol) of H-fPhe-fp-CN-Phe-H trihydrochloride (from Example 47a), 125 mg (0.5 mmol) of Z- (L) -valine, 221 mg, were obtained. (0.5 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 68 mg (0.5 mmol) of 1'-hydroxybenzotriazole and 3.33 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, after precipitation from methylene chloride with addition of hexane and freeze-drying from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 777. t _Ret (I) = 25.3 min, Rf (D) = 0.69.

Example 49

Z- (L) -Ile- [Phe ^NN Leu] <- / (L) -Ile / -Z

Analogous to Example 37, from 70 mg (0.19 mmol) of H-fhe-Leuj-H trihydrochloride (from Example 13a), 154 mg (0.58 mmol) of Z- (L) -isoleucine, 257 mg ( 0.58 mmol) of benztriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 79 mg (0.58 mmol) of 1'-hydroxybenzotriazole and 3.88 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound after chromatography Silica gel with 3: 1 methylene chloride / ether, precipitation of product containing fractions from methylene chloride / diisopropyl ether and freeze drying from dioxane. FAB-MS: (M + H) + = 746, t _RH (1) = 28.2 min, Rf (H) = 0.39.

Example 50

Isobutoxycarbonyl- (L) -Val- [Phe ^NN Leu] <- (N-isobutoxycarbonyl- (L) -Val)

Analogously to Example 37, © 70 mg (0.19 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 130 mg (0.58 mmol) of N- (isobutylcarbonyl) - (L) was obtained. -valine, 256 mg (0.58 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 78 mg (0.58 mmol) of 1'-hydroxybenztriazole and 3.9 ml of 0.3 molar N-metymorpholine in dimethylformamide title compound, after chromatography on silica gel with methylene chloride / ether (1: 1) by lyophilization of the fractions containing the product from dioxane FAB-MS: (M + H) ⁺ = 650, t _Ret (I) = 26.4 min Rf (H) = 0.38.

The starting compound is prepared as follows:

a) N- (Isobutoxycarbonyl) - (L) -valine

A solution of 10 g (85.3 mmol) of (L) -valine in 100 ml of 2 N sodium hydroxide solution was contacted with 11.2 ml (85.3 mmol) of isobutyl chloroformate and stirred at room temperature for 18 hours. The reaction solution was washed with methylene chloride and acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic extracts were washed with saturated sodium chloride solution, filtered through cotton wool and evaporated to give the title compound as a colorless resin.

1 H-NMR (200 MHz, CD, OD): 0.95 (m, 12H), 1.9 (m, 1H), 2.15 (m, 1H), 3.85 (d, J = 7 Hz) , 2H), 4.05 (broad doublet, 1H) ppm.

Example 51 N- [3- (Tetrazol-1-yl) propionyl] - (L) -Val- [Phe ^NN Leu] - N - [(3- (tetrazol-1-yl) propionyl) - (L)-Val] /

Analogously to Example 37, from 150 mg (0.42 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 251 mg (1.04 mmol) of N- [3- (tetrazol-1-)] was obtained. yl) propionyl N- (L) -valine from Example 44a, 460 mg (1.04 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 140 mg (1.04 mmol) 1'-hydroxybenztriazole and 6.9 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from a mixture of dioxane, tert-butanol and water. FAB-MS: (M + H + = 689, t _{R a} (I) = 14.7 min, R f (K) = 0.36).

Example 52

Acetyl-Val- [Phe ^NN Leu] - (N-acetyl-Val)

Analogously to Example 37, from 70 mg (0.19 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 184 mg (1.16 mmol) of N-acetyl- (L) -valine are obtained. 512 mg (1.16 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 156 mg (1.16 mmol) of 1'-hydroxybenzotriazole and 7.8 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound After precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether and lyophilization from a mixture of dioxane, tert-butanol and water. (According to high performance liquid chromatography, two diastereoisomers can be distinguished.) FAB-MS: (M + H) ⁺ = 534, t _Ret (I) = 14.7 and 15.1 min, R _f (D) = 0.35 .

Example 53 Boc- (L) -Val- [Phe ^NN Leu] < - &gt; / (L) -Val / -Boc

As in Example 7, from 300 mg (0.83 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 722 mg (3.33 mmol) of Boc- (L) -valine, 1.262 mg were obtained. (3.33 mmol) of O-benztriazol-1-ylo-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 0.927 mg (6.66 mmol) of triethylamine in dimethylformamide of the title compound, after chromatography on silica gel using a mixture methylene chloride / ether 1: 1, precipitating the product containing fractions and lyophilizing from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 650, t _Ret (I) = 26.3 min, R f (OH) = 0.64.

Example 54 H- (L) -Val- [Phe ^NN Leu] - [(L) -Val] -H 3 HCl

Analogously to Example 5, from 536 mg (0.61 mmol) of Boc- (L) - [Phe ' ^N Leu] - (L) -Val] -Boc from Example 53 and 10 ml of 4-normal hydrogen chloride in dioxane, after lyophilization of the reaction solution, the title compound FAB-MS: (M + H) ⁺ = 450, t _R t (II) = 24.1 min, Rt (K) - 0.25.

Example 55 N-Thiomorpholinocarbonyl- (L) -Val- [Phe ^NN Leu] - (N-thiomorpholinocarbonyl- (L) -Val)

Starting from 100 mg (1.16 mmol) of H- (L) -Val- [Phe ™ Leu] <- / (L) -Val-H trihydrochloride, 78.5 mg (0.47 mmol) (4- of the thiomorpholinylcarbonyl) chloride of Example 6a and 0.172 ml of triethylamine in dimethylformamide, analogously to Example 3, after chromatographic purification on silica gel using methylene chloride / methanol (95: 5), precipitation of product containing fractions from methylene chloride / hexane and freeze-drying from dioxane, gives the title compound which is an amorphous solid. FAB-MS: (M &lt; + &gt; H) &lt; + &gt; = 708, _Rt (I) = 21.4 min, Rf (E) = 0.45.

Example 56

2 (R, S) -Tetrahydrofuylmethoxycarbonyl- (L) -Val- [Cha ^NN Leu] </ N-2 (R, S) -tetrahydrofurylmethoxycarbonyl- (L) -Val]

Analogously to Example 37, N- (2 (R, S) -tetrahydrofurylmethoxycarbonyl) - was obtained from 80 mg (0.22 mmol) of H- [Cha ^N 'Lcu] -H trihydrochloride, 160 mg (0.65 mmol). (L) -valine, 289 mg (0.65 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 88 mg (0.65 mmol) of 1-hydroxybenztriazole and 4.34 ml of 3-molar N-methylmorpholine in dimethylformamide The title compound after chromatographic purification on silica gel with ethyl acetate as eluent and lyophilization of the fractions containing the product from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 712, t _Ret (I) = 22.4 min, Rf (E) = 0.21.

The starting compounds are prepared as follows:

a) H- [Cha ^NN Leu] -H 3 HCl

As in Example 5, 100 mg of the title compound was obtained from 150 mg (0.33 mmol) of Boc-fCha-Leuj-Boc and 10 mL of 4N HCl in dioxane after lyophilization of the reaction solution. Yield: 83%. Rf (K) = 0.26.

b) Boc - [Cha ^NS Leu] - Boc

A solution of 200 mg (0.24 mmol) of Boc- [Phe ^NN Leu] -Boc (Example 12) in 15 mL of methanol is hydrogenated in the presence of 10 mg of Nishimura catalyst (D2 O2, Degussa monohydrate) at 100 psi H 2 pressure 4 hours. The catalyst was filtered off, the solvent was evaporated completely and crystallized from methylene chloride / hexane to give the title compound. t _Ret (I) = 26.7 min, Rf (V) = 0.21.

c) N- (2 (R, S) -Tetrahydrofurylmethoxycarbonyl) - (L) -valine

Similar to Example 50a, from 7 g (60 mmol) of (L) -valine and 9.8 g (60 mmol) of 2 (R, S) -tetrahydrofurylmethyl chloroformate (Hrocrocycles 27, 1155 (1988)) are obtained in 100 ml of 2- normal sodium hydroxide solution and 30 ml dioxane of the title compound as a mixture of 2 diastereoisomers. t _Ret (I) = 23.5 and 23.8 min.

Example 57

Z-Val- [Phe ^NN Leu] <- [N- (3- (tetrazol-1-yl) propionyl) -Val]

Analogously to Example 37, N- [3- (tetrazol-1-yl)] was obtained from 100 mg (0.21 mmol) of Z-Val- [Phe & apos ^{;; K} Leu] -H, 75 mg (0.31 mmol). - (L) -valine / from Example 44a, 137 mg (0.31 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 42 mg (0.31 mmol) of 1'-hydroxybenzotriazole and 2 ml of 0.3- mole of N-methylmorpholine in dimethylformamide, the title compound, after precipitation from a mixture of methylene chloride and hexane and lyophilization from a mixture of dioxane and tert-butanol. (Two diastereoisomers are recognizable by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 708, t _Ret (I) = 21.1 and 21.1 min, R f (D) = 0.45.

The starting compounds are prepared as follows:

a) Z- (L) -Val- [Phe ^NN Leu] -H

A solution of 250 mg (0.43 mmol) of Z- (L) -Val- [Phc ^NN Leu] -Boc in 5 ml of formic acid was stirred at room temperature for 7.5 hours. After this time no starting compound can be determined by high performance liquid chromatography (t _Rct (I) = 27.5) and the reaction solution is evaporated. The residue was dissolved in chloroform and washed with saturated sodium bicarbonate solution. The chloroform phase is filtered through cotton wool to give the crude title compound after evaporation of the solvent. t _Ret (I) = 16.7 min, R f (K) = 0.21.

b) Z- (L) -Val- [Phc ^NN Lcu] -Boc

Similar to Example 37, from 230 mg (0.653 mmol) of H- [Phe ^NN Leu] -Boc, 247 mg (0.98 mmol) of Z- (L) -valine, 434 mg (0.98 mmol) of benztriazole- 1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 133 mg (0.98 mmol) of 1'-hydroxybenzotriazole and 6.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and methanol by addition of diisopropyl ether . FAB-MS: (M + H) &lt; ^{+ &gt}; = 585, t _Ret (I) = 27.5 min, Rf (C) = 0.71.

c) H- [Phe ^VN Lcu] -Boc

Analogous to Example 17a, starting from 1.72 g (2.84 mmol) of N-trifluoroacetyl- [Phe ^NN Leu] -Boc and 24 ml of 1-aqueous sodium carbonate solution in 90 ml of methanol, the title compound is obtained. of the title precipitated from methylene chloride by addition of diisopropyl ether. t _Rel (I) = 14.9 min, Rf (K) = 0.38.

d) -Trifluoroacetyl- [Phe ^NS 1.eLi] -Boc

As in Example 16, starting from 3 g (11.57 mmol) of 2 (R) - / 1 '- (S) - (trifluoroacetyl) -2'-phenylethyl] -oxirane from Example I and 2, 3 g (12.15 mmol) of tert-butyl 3-isobutylcarbazate (for preparation see J. Chem. Soc., Perkin I, 1712 (1975)), the title compound, after chromatography on silica gel using a mixture of methylene chloride and ether (20: 1). t _Ret (I) = 24.7 mm., Rf (W) = 0.36.

Example 58 Acetyl-Val- [Phe ^NN Leu] -N- (2- (R, S) -carbamoyl-3-phenylpropionyl) -Val

Analogous to Example 37, 140 mg (0.3 mmol) of acetyl-1H-Val-Phe-Leu] -H dihydrochloride were obtained, 132 mg (0.45 mmol) of N- / 2- (R, S) -carbamoyl- 3-phenylpropionyl- (L) -valine (for preparation see Synth., Struct., Funct., Proc. Am. Pept. Symp., 7th, 85 (1981)), 199 mg (0.45 mmol) of benztriazole-1- yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 61 mg (0.45 mmol) of 1'-hydroxybenzotriazole and 3.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane . (Two diastereoisomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 667, = 17.9 and 18.4 min, Rf (D) = 0.33.

The starting compounds are prepared as follows:

a) Acetyl-Val- [Phe ^NN Lcu] -H 2 HCl

Starting from 230 mg (0.46 mmol) of acetyl- (L) -Val- [Phe ^NN Leu] -Boc, analogously to Example 2a the title compound is obtained after lyophilization. _Rct t (I) = 10.5 min., R f (D) = 0.38.

b) Acetyl-Val- [Phe ^NN Leu] -Boc

Analogously to Example 37, from 250 mg (0.71 mmol) of H-Phe 2 O-Leuj-Boc from Example 57c), 170 mg (1.07 mmol) of N-acetyl- (L) -valine was obtained, 471 mg ( 1.07 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 144 mg (1.07 mmol) of 1'-hydroxybenzotriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide title compound, after precipitation from methylene chloride by addition of diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 493, t _Rel (1) = 20.5 min, Rf (D) = 0.59.

EXAMPLE 59 N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] - [N- (3- (tetrazolyl-1-yl) propionyl) -Val]

Analogous to Example 37, N- (3-) tetrazole (67 mg, 0.38 mmol) was obtained from 100 mg (0.19 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -H dihydrochloride. -yl) propionyl N- (L) -valine of Example 44a, 124 mg (0.28 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 38 mg (0.28 mmol) of 1'-hydroxybenztriazole and 2, 1 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from methylene chloride by addition of diisopropyl ether and lyophilization from dioxane. (Two diastereoisomers are recognizable by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 687, t _Rc , (I) = 15.2 and 15.4 min, R f (D) = 0.25.

The starting compounds are prepared as follows:

(a) N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -H.2HCl

As in Example 2a, starting from 279 mg (0.49 mmol) of N-morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -Boc, the title compound is obtained after lyophilization. FAB-MS: (M + H) &lt; ^{+ &gt}; = 464, t _Ret (II) = 30.3 min, Rf (D) = 0.46.

b) N-Morpholinocarbonyl- (L) -Val- [Phe ^NN Leu] -Boc

In analogy to Example 37, starting from 250 mg (0.71 mmol) of H-Phe-Leu-Bole from Example 57c), 265 mg (1.07 mmol) of N-morpholinocarbonyl- (L) -valine from of Example 7a, 471 mg (1.07 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 144 mg (1.07 mmol) of 1-hydroxybenztriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide compound The title compound, after precipitation from a mixture of methylene chloride and hexane and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 56493, t _RI (I) = 21.5 min, R / K) = 0.69.

Example 60

N-Trifluoroacetyl- [Phe ^NN Leu] <- [N- (2 (R, S) -carbamoyl-3-phenylpropionyl) - (L) -Val]

Analogous to Example 37, N-trifluoroacetyl- [Phe ^NN Leu] -H dihydrochloride (136 mg, 0.32 mmol) was obtained, 142 mg (0.49 mmol) of N- / 2 (R, S) -carbamoyl-3. -phenylpropionyl- (L) -valine (see Synth, Struct, Funct, Proc. Am. Pept. Symp, 7th, 85 (1981)), 115 mg (0.49 mmol) of benzotriazol-1-yloxy-tris (dimethylamino) ) phosphonium hexafluorophosphate, 66 mg (0.49 mmol) of 1'-hydroxybenzotriazole and 3.5 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound after chromatographic purification on silica gel using chloroform / methanol 15: 1 , precipitating the product-containing fractions from a mixture of methylene chloride and diisopropyl ether and lyophilizing from a mixture of dioxane and tert-butanol. (According to high performance liquid chromatography, 2 diastereoisomers can be recognized.) FAB-MS: (M + H) ⁺ = 622, t _Rn (I) = 21.6 and 22.0 min, R / K) = 0.26.

The starting compound is prepared as follows: a) N-Trifluoroacetyl- [Phe ^NN Leu] -H.2HCl

Analogously to Example 2a, the title compound is obtained starting from 300 mg (0.67 mmol) of N-trifluoroacetyl-Phe2-Leuj-Boc from Example 57d and finally lyophilized. Rf (W) < 0.1.

Example 61

N- (2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl) - (L) -Val- [Phe ^NN Nlc] < - &gt;

Analogous to Example 37, 69 mg (0.27 mmol) of 2 (R, S) - was obtained from 100 mg (0.17 mmol) of Z- (L) -Val- [Phe ^NN Nle] -H dihydrochloride. N- (2-morpholinoethyl) carbamoyl-3-methylbutyric acid (N- (2-morpholinoethyl) phenylpropylmalonic acid monoamide) 119 mg (0.27 mmol) benztriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, 36 mg (0, 27 mmol) of 1-hydroxybenzotriazole and 2.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide of the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. (According to high performance liquid chromatography, two diastereoisomers can be distinguished.) FAB-MS: (M + H) ⁺ = 725, t _Ret (I) = 17.2 and 17.6 min, RXD) = 0.56.

The starting compounds are prepared as follows:

a) Z- (L) -Val- [Phe ^NN Nle] -H, 2HCl

Starting from 310 mg (0.53 mmol) of Z- (L) -Val- [Phe ^NN Nle] -Boc, in a manner analogous to Example 2a, the title compound is obtained after lyophilization. t _Ret (I) = 16.4 min, Rf (U) = 0.25.

b) Z- (L) -Val- [Phc ^NN Nle] -Boc

Analogous to Example 37, from 250 mg (0.71 mmol) of H- [Phe ^NN Nlc] -Boc, 268 mg (1.07 mmol) of Z- (L) -valine, 472 mg (1.07 mmol) was obtained. benzothiazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 144 mg (1.07 mmol) of 1'-hydroxybenzotriazole and 7.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide title compound, after chromatographic purification on silica gel using a 40: 1 mixture of methylene chloride and methanol; and precipitation of product containing fractions from a mixture of methylene chloride and diisopropyl ether. t _Ret (I) = 25.6 min, RKX = 0.17.

c) H-Phe-Nle-Boc

Starting from 830 mg (1.85 mmol) of N-trifluoroacetyl- [Phe ^NN No] -Boc in a manner analogous to Example 17a, the title compound is obtained after precipitation from a mixture of methylene chloride and diisopropyl ether. t _Ret (I) = 15.4 min, Rf (K) = 0.54.

d) N-Trifluoroacetyl- [Phe ^NN Nle] -Boc

Analogous to Example 16, starting from 1 g (3.86 mmol) of 2 (R) - [1 '- (S) - (trifluoroacetylamino) -2-phenyl-ethyl) -oxirane from Example l and 720 g. (3.86 mmol) of tert-butyl 3-butylcarbazate, the title compound, after chromatographic purification on silica gel using methylene chloride / ether (20: 1). T _Ret (I) = 25.3 min, R f Q) = 0.43.

e) tert-Butyl 3-butylcarbazate

Similar to Example 4b, the corresponding t-butoxycarbonylhydrazone of 25 g (yield 99% of theory) was obtained from 18.0 g (136.2 mmol) of t-butylcarbazate and 12.3 ml (136.2 mmol) of n-butanal. ) as a crude material which is hydrogenated as described in Example 4a in the presence of 10 g of 5% platinum on carbon at a hydrogen pressure of 400 kPa. Chromatographic purification of the crude material on silica gel using 1: 1 hexane / ethyl acetate affords the title compound. R f (N) = 0.44, 1 H-NMR (200 MHz, CD ₃ OD): 0.92 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 1.30-1 50 (m, 4H); 2.75 (t, J = 7Hz, 2H) ppm.

f) 2 (R, S) - [N- (2-Morpholinoethyl) carbamoyl] -3-methylbutyric acid

In analogy to Example 9b, from 7 g (43.7 mmol) of racemic isopropylbutyric acid monomethyl ester (Chem. Ber. 119, 1196 (1986)), 6.3 ml (48.1 mmol) of aminoethylmorpholine, 6.6 ml ( 43.7 mmol) of cyanophosphonic acid diethyl ester and 12.8 ml (91.8 mmol) of triethylamine in dimethylformamide methyl ester of 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyric acid (N-morpholinoethylamide methyl ester) isopropylmalonic acid). This material is stirred for 5 hours in a mixture of 28 ml of 2 N sodium hydroxide solution and 28 ml dioxane at room temperature, acidified with 2 N hydrochloric acid and evaporated completely. The residue was digested with ethanol, filtered and evaporated to give the title compound. R f (N) = 0.44, 1 H-NMR (200 MHz, CD ₃ OD): 0.95 and 1.00 (2d, J = 7 Hz, 6H), 2.25 (m, 4H), 2 7 (m, 6H), 2.75 (d, J = 8Hz, 1H), 3.45 (m, 2H), 3.75 (m, 4H) ppm.

Example 62

Z-Val-LLJ jPhe # Nle] · * - / N- (3- (tetrazol-l-yl) -propionyl) -Val /

Similar to Example 37, from 100 mg (0.18 mmol) of Z- (L) -Val- [Phe ^N Nle] -H (from Example 61a), 65 mg (0.27 mmol) of N- (L) -Val- 3- (Tetrazol-1-yl) propionyl) - (L) -valine from Example 44a, 119 mg (0.27 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 36 mg (0.27 mmol) 1'-hydroxybenzotriazole and 2.1 ml of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from a mixture of dioxane and tert-butanol. (Two diastereoisomers can be identified by high performance liquid chromatography.) FAB-MS: (M + H) ⁺ = 708, t _R t, (I) = 20.3 and 20.6 min, R [(D) = 0 , 43rd

Example 63

N- (2 (R, S) - (N- (2-Pyridylmethyl) carbamoyl) -3-methyl) butyryl Z- (L) -Val- [Phe ^NN Nle] (dibenzenesulfonate)

Similar to Example 37, from 95 mg (0.17 mmol) of Z- (L) -Val- [Phe ^NN Nle] -H dihydrochloride (from Example 61a), 60 mg (0.26 mmol) of N- (2) was obtained. (R, S) -isopropylmalonic acid monoamide, 113 mg (0.26 mmol) benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 35 mg (0.26 mmol) 1'-hydroxybenztriazole and 2.0 mL 0 3-molar N-methylmorpholine in dimethylformamide the title compound, after chromatographic purification on silica gel using methylene chloride / methanol (15: 1). The resulting compound is a free amine which is dissolved in methylene chloride and treated with 2 equivalents of acid. benzenesulfone and precipitated by the addition of diisopropyl ether. Lyophilization from tert-butanol affords dibenzenesulfonate. (According to high performance liquid chromatography, 2 diastereoisomers can be recognized.) FAB-MS: (M + + H) ⁺ = 703, t _Ret (I) = 17.7 and 18.0 min, Rf (D) = 0.54 .

The starting compound is prepared as follows:

(a) Isopropyl malonic acid N- (2-picolyl) monoamide

A solution of 15 g (93.6 mmol) of isopropylmalonic acid monomethyl ester (for preparation see Chem. Ber. 119, 1196 (1986)) in 150 ml of tetrahydrofuran was contacted with 10.6 ml (103 mmol) of N-methylmorpholine and then added dropwise. 13.5 ml (103 mmol) of isobutyl chloroformate. The reaction mixture is stirred for 30 minutes, then 15.3 ml (150 mmol) of 2-picolylamine are added and the resulting suspension is stirred for 2 hours. The reaction mixture is diluted with methylene chloride, washed with 1N sodium hydroxide solution and water, the organic phase is filtered through cotton wool and evaporated. Crystallization of the residue gave N- (2-picolylamide) methyl isopropyl malonic acid ester, which was hydrolyzed as described in Example 61f by treatment of the title compound with 2 N sodium hydroxide and dioxane. t _Ret (II) = 16.0 min.

Example 64 Z- (L) -Val- [Phe ^NN (pF) Phe] - N - (3- (tetrazol-1-yl) propionyl) - (L) -Val (benzenesulfonate)

Analogously to Example 37, from Example 22a, 59 mg (0.25 mmol) of N- (3) was obtained from 100 mg (0.16 mmol) of Z- (L) -Val- [Phe ^NN (pF) Phe] -H. - (tetrazol-1-yl) propionyl / - (L) -valine of Example 44a, 109 mg (0.25 mmol) benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 33 mg (0.25 mmol) 1 '- hydroxybenztriazole and 1.19 mL of 0.3 molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether. This compound is formed by the free amine, which is dissolved in a mixture of methylene chloride and methanol, treated with 1 equivalent of benzenesulfonic acid, and precipitated by addition of hexane. Lyophilization from tert-butanol affords the title compound as dibenzenesulfonate. FAB-MS: (M + H) &lt; ^{+ &gt}; = 760, t _Rn (I) = 21.6 min, Rf (B) = 0.49.

Example 65 Methylsulfonyl- [Phe ^NN Phe] - (N-phenylacetyl- (L) -Val)

132 mg (0.28 mmol) of methylsulfonyl- [Phc ^NN Phc] -II dihydrochloride were reacted analogously to Example 7 with 197 mg (0.84 mmol) of N-phenylcetyl- (L) -valine (for preparation see Mem. Tokyo) Univ. Agric. 20, 51 (1978)), 317 mg (0.84 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate and 0.23 mL (1.67 mmol) triethylamine in dimethylaformamide and precipitated from methanol by the addition of ether gave the title compound. FAB-MS: (M + H) &lt; ^{+ &gt}; = 581, t _Rel (I) = 20.2 min, RfB = 0.64.

The starting compounds are prepared as follows:

a) Methylsulfonyl- [Phe ^NK Phc] -H, 2HCl

Analogously to Example 2a, starting from 130 mg (0.28 mmol) of methylsulfonyl- [Phe ^NN Phe] -Boc, the title compound is obtained after lyophilization. FAB-MS: (M + H) ⁺ = 364 t _Rct (II) - 28.5 min., R f (C) = 0.56.

b) Methylsulfonyl- [Phc ^NN Phe] -Boc

Similar to Example 16a, starting from 1.1 g (4.56 mmol) of 2 (R) - [1 ') - (S) - (methylsulfonylamino) -2'-phenylethyl / oxirane and 1.11 g (5%) of the title compound. Tert-butyl 3-benzylcarbazate (for preparation see J. Chem. Soc., Perkin I, 1712 (1975)), the title compound which forms a 4: 1 diastereoisomeric mixture. Crystallization from methylene chloride / hexane improves the ratio in favor of the 2S-diastreoisomers to 10: 1. FAB-MS: (M + H) ⁺ = 464, t _R t (I) = 21.3 min, R f (N) = 0.26.

c) 2 (R) - / 1 '(S) - (Methylsulfonylamino) -2'-phenylethyl / oxirane

A solution of 1 g (6.8 mmol) of 1-phenyl-3-buten-2 (S) -amine from Example 16b in 10 ml of methylene chloride was treated with 2.36 g (13.6 mmol) at 0 ° C. methanesulfonic anhydride and 1.88 ml (13.6 mmol) triethylamine and stirred for 1 hour. The reaction mixture is washed with water and saturated sodium bicarbonate solution, the organic phase is filtered through cotton wool and evaporated to give 2 (S) -methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of this crude material is dissolved in 30 ml of methylene chloride, treated at room temperature with 3.5 g (17.7 mmol) of 4-chloroperbenzoic acid and stirred for 18 hours. The reaction solution was washed five times with 10% aqueous sodium sulfite solution, filtered through cotton wool and evaporated to dryness. According to 1 H-MNR analysis, the crude product contains both (2R) and (2S) epimers in a 4: 1 ratio.

1 H-NMR (200 MHz, CD ₃ OD): 2.30 and 2.52 (2s, together 3H), 2.6-3.2 (m, 5H), 3.55 (m, 1H), 7 32 (m, 5H) ppm.

Example 66 Methoxycarbonyl- (L) -Val- [Phe ^NN Leu] - (N-methoxycarbonyl- (L) -Val)

Analogously to Example 37, from 200 mg (0.55 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 13a), 291 mg (1.66 mmol) of N-methoxycarbonyl- (L) -valine ( for production see Chem. Lett. 705 (1980)), 735 mg (1.66 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 225 mg (1.66 mmol) of 1'-hydroxybenzotriazole and 11 ml of 0.3 N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 566, t _Kn (I) = 18.6 min, Rf (U) = 0.33.

Example 67 Methylcarbonyl- (L) -Val- [Phe ^NN (pF) Phe] - (N-methoxycarbonyl- (L) -Val)

Analogously to Example 37, from 200 mg (0.48 mmol) of H- [Phe ^NN Leu] -H trihydrochloride (from Example 42b), 255 mg (1.45 mmol) of N-methoxycarbonyl- (L) -valine ( for production see Chem. Lett. 705 (1980)), 643 mg (1.45 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 196 mg (1.45 mmol) of 1'-hydroxybenztriazole and 9.7 ml 0.3-molar N-methylmorpholine in dimethylformamide the title compound, after precipitation from a mixture of methylene chloride and diisopropyl ether and lyophilization from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 618, [M] @ ⁺ = 19.5 min, Rf (U) = 0.22.

Example 68 Methylcarbonyl- (L) -Val- [Phe ^NN (p-CN) Phe] - (N-methoxycarbonyl- (L) -Val)

Similar to Example 37, from 200 mg (0.48 mmol) of H- [Phe ^NN (p-CN) Phe] -H trihydrochloride (from Example 47a), 250 mg (1.43 mmol) of N-methoxycarbonyl- ( L) -valine (see Chem. Lett. 705 (1980)), 631 mg (1.43 mmol) of benztriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 193 mg (1.43 mmol) of 1'-hydroxybenzotriazole and 9.5 ml of 0.3-molar N-methylmorpholine in dimethylformamide the title compound after chromatographic purification on silica gel using methylene chloride / methanol (15: 1) and lyophilization of product containing fractions from dioxane. FAB-MS: (M + H) &lt; ^{+ &gt}; = 625, t _Ret (1) = 18 min, Rf (U) = 0.31.

Example 69

Z- (L) -Val- [Phe ^NN (pF) Phe] - (N- (2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methyl) butyryl)

Analogously to Example 18, 23.0 mg (0.089 mmol) of 2 (R, S) - [N- (2-morpholinoethyl) carbamoyl] -3-methylbutyric acid (Example 61 f) and 45 mg (0.081 mmol) were left. Z-III-Val-Kp-FjPhe-p-FjPheJ-H (Example 32) with 33.8 mg (0.089 mmol) of O-benztriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate at 0, 76 ml of 0.25-molar N-methylmorpholine in acetonitrile to the title compound, which precipitated from a mixture of dimethylformamide and diisopropyl ether. DC. Rf (P) = 0.42; FAB-MS: (M + H) &lt; ^{+ &gt}; = 795.

Example 70 Z- (L) -Val - [(pF) Phe ^Nls (pF) Phe] - N - (2 (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl) butyryl /

Similar to Example 18, 21.0 mg (0.089 mmol) of racemic isopropylmalonic acid N- (2-picolyl) amide (Example 63a) and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) were reacted. Phe ^NN (pF) Phe] -H (Example 32) with 33.8 mg (0.089 mmol) O-benztriazol-1-yl--, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate in 0.76 mL 0.25 of N-methylmorpholine in acetonitrile to give the title compound and this precipitates from a mixture of dimethylformamide with diisopropyl ether. DC: Rf (P) = 0.52; FAB-MS: (M + H) &lt; ^{+ &gt}; = 773.

Example 71

As with any of the above processes, the following compounds can also be prepared:

a) Z- (L) -Val - [(pF) Phe ^NN (pF) Phc] <- / (L) -Val] - N - N-

morpholinocarbonyl-Gly /.

(b) N-morpholinocarbonyl- (L) -Val - [(pF) Phe ^NN (pF) Phe] - / (L) -Val (N-morpholinocarbonyl-Gly),

c) N- (quinoline-2-carbonyl) - (L) -Asn- [Phe ^NN (pF) Phe] - [(L) -Val] -Z; and

d) N- (morpholinosulfonyl) - (L) -Val- [Phe ^NN Leu] - (N- (morpholinosulfonyl) - (L) - Val).

Example 72

Gelatin solution

A sterile aqueous solution of 20% cyclodextrin as a co-solvent and one of the compounds of formula (I) mentioned in the previous examples as active ingredient is mixed with a sterile gelatin solution containing phenol as a preservative under heating, under aseptic conditions by heating. obtained

1.0 ml of a solution of the following composition:

active substance 3 mg gelatin 150.0 mg phenol 4.7 mg distilled water with 20% cyclodextrin as a co-solvent 1.0 ml

Example 73

The sterile dry substance for injection of mg of one of the compounds of formula (I) mentioned in the previous examples as active ingredient is dissolved in 1 ml of an aqueous solution with 20 mg of mannitol and 20% cyclodextriene as a co-solvent. The solution is filtered under sterile conditions, filled in aseptic conditions into 2 ml ampoules, cooled to low temperature and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. The solution is used intramuscularly or intravenously. This device can also be filled into double chamber spray ampoules.

Example 74

Nasal spray

A mixture of 3.5 ml of Myglyol 812 ^R and 0.08 mg of benzyl alcohol is suspended in 500 mg of finely divided powder (particle size less than 5.0 μm) of the compound of formula (I) given in any of the preceding examples as the active ingredient. This suspension is filled into containers equipped with a metering valve. Introduce 5.0 g of Freon 12 ^R into the reservoir under pressure using a valve located on the reservoir. By shaking, "Freon" is dissolved in a mixture of Myglyol and benzyl alcohol. This spray container contains approximately 100 dosage units that can be administered individually.

Example 75

Lacquered tablets

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

Active ingredient 1000g Corn starch 680g Colloidal silicic acid 200g Magnesium stearate 20g Stearic acid 50g Sodium carboxymethyl starch 250g Water as needed

A mixture of one of the compounds of formula (I) mentioned in one of the preceding examples as active ingredient, 50 mg of corn starch and silicic acid is treated with a starch wax prepared from 250 mg of corn starch and 2.2 kg of demineralized water to a wet mass. This mass is passed through a 3 mm mesh screen and dried in a fluid bed dryer at 45 ° C for 30 minutes. The dried granulate is passed through a 1 mm mesh screen, mixed with a previously sieved mixture (mesh size 1 mm) of 330 mg corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch, and compressed into a slightly domed tablet.

Efficacy Test for Compounds of the Invention

In an analogous manner to that described by A. D. Richards et al. in J. Biol. Chem., 265 (14), 7733-7736, determined the ability of the following compounds of the examples to inhibit HIV-1 protease (produced according to the data of S. Billich et al. In J. Biol. Chem., 264 (34), 17905-). 17908 (1990)) in the presence of the icosapeptide-substrate analog RRSNQVSQNYPIVQNIQGRR (HIV1-1 protease substrate, produced by peptide synthesis according to the known method described by J. Schneider et al. In Cell 54, 363-368 (1988)), corresponding to the gag-protein precursor cleavage site. This substrate analog and its cleavage intermediates can be quantitatively analyzed by high pressure liquid chromatography (HPLC).

Each test substance is dissolved in dimethylsulfoxide. Testing of the enzyme is carried out after addition of a suitably diluted test substance in 20 mmol of β-morpholinoethanesulfonic acid (MES buffer) at pH 6.0, to a test mixture containing, in 20 mmol of MES buffer at pH 6.0 122 pmol of said icosapeptide. The test volume of each batch is 100 μΐ. The reaction is initiated by the addition of 10 μΐ of HIV-1-protease solution and after incubation for 1 hour at 37 ° C, the reaction is stopped by adding 10 μΐ of 0.3 molar perchloric acid. After centrifugation of the test sample at 5,000 xg for 5 minutes each, 20 μΐ of the supernatant obtained is applied to a 125 x 4.6 mm high pressure liquid chromatography column packed with Nucleosil ^R C18-5 μ (Macherey & Nagel, Diiren, Germany). The cleaved icosapeptide as well as the cleavage product are eluted from the column by gradient: 100% eluate 1-50% eluate 1 + 50% eluate 2 (eluate 1: 10% acetonitrile, 90% water and 0.1% trifluoroacetic acid, eluate 2 (2.75% acetonitrile, 25% water and 0.08% trifluoroacetic acid) over 15 minutes at a flow rate of 1 ml per minute. After elution, the reaction products are quantified using the peak height of the cleavage product at 215 nm.

The measurement results contained in the table are obtained.

table

Suppression value (IC ₅₀ ) for test compounds

Example compound IC _{5 (} , (pmol)) 2 0,033 8 0.36 9 0.5 11 0,095 13 0.01 15 0,015 18 0.35 20 0.3 21 0.85 24 0,014 27 0.14 28 0,028 30 0.95 31 0,085 33 0,025 34 0,033 35 0.03 37 0,065 38 0.0085 40 0.13 41 0.65 43 0.18 44 0.13 45 0,022 46 0,028 47 0.05 48 0,024 49 0.25 50 0.37 51 0,032 52 0,045 55 0,032 56 0,112 57 0,026 58 0,023 59 0.1 61 0.07 62 0.08 63 0.38 64 0.38 66 0,053 67 0,049 68 0,088 69 0.3 70 0.14

IC ₅₀ indicates the concentration of test compound at which the compound exhibits maximal inhibitory effect.

Claims (9)

A hydrazine derivative of the general formula (I) in which R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted by amino- (lower alkanoyl) - at the amino atom of the amino group, lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl- (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) ) a group, (lower alkoxy) carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted; is acylated with one of the remainder of R ¹ or R ⁹ , provided that at most one of R ¹ and R ⁹ is hydrogen, R ³ represents a lower alkyl group, a cyclohexyl- (lower alkyl) group or a phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group, R ⁷ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy or a cyano group and the term "lower" means that the residue so defined contains from 1 up to a maximum of 7 carbon atoms, including the limits herein, or a salt thereof, if salt-forming groups are present. A hydrazine derivative of general formula (I) according to claim 1, wherein R ¹ represents a lower alkanoyl group, a phenyl- (lower alkoxy) carbonyl group, a phenyl- (lower alkoxy) carbonyl group, a monovalent aliphatic amino acid residue attached via a carboxy group selected from valine, alanine, leucine and isoleucine, or a residue linked via a carboxy group an amino nitrogen atom which is acylated by one of the radicals selected from phenyl (lower alkanoyl), morpholino (lower alkanoyl), thiomorpholino (lower alkanoyl), pyridyl-lower alkanoyl), (lower alkoxy) carbonyl or phenyl (lower alkoxy) -carbonyl, all of which are in the form of D, (D, L) or L, R ³ represents a phenyl- (lower alkyl) group, R ⁷ represents a lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group, and R ⁹ has one of the meanings given for R ¹ , and the asymmetric carbon atoms bearing the radical R ³ and the hydroxy group have an S-configuration, the term lower means that the radical thus defined contains from 1 to a maximum of 7 carbon atoms , or a salt thereof, if salt-forming groups are present. A hydrazine derivative of general formula (I) according to claim 1, wherein R ¹ and R ⁹ denote a monovalent radical of the amino acid (L) -valkylated by benzyloxycarbonyl at the amino nitrogen atom, in each case bonded via a carboxy group, R ³ represents benzyl and R ⁷ is benzyl, and the asymmetric carbon atoms bearing the R ³ radicals and the hydroxy group are in the S-configuration as well as pharmaceutically usable salts of the hydrazine derivative. A hydrazine derivative of formula (I) according to claim 1, wherein R ¹ and R ⁹ represent a monovalent radical of the amino acid (L) -valine, acylated with 4-thiomorpholinocarbonyl at the amino atom of the amino group, in each case bonded via a carboxy group, R ³ represents benzyl and R ⁷ is isopropyl and asymmetric carbon atoms bearing R ³ and hydroxy groups are in the S-configuration as well as pharmaceutically usable salts of the hydrazine derivative. Use of a hydrazine derivative of the general formula (I) according to claims 1, 2, 3 or 4 for the manufacture of pharmaceutical compositions for use in a method of therapeutic treatment of the human or animal body. A pharmaceutical composition comprising a hydrazine derivative of formula (I) according to claims 1, 2, 3 or 4, or a pharmaceutically acceptable salt of such a hydrazine derivative with at least one salt-forming group, together with at least one pharmaceutically acceptable carrier. . Use of a hydrazine derivative of the general formula (I) according to claims 1, 2, 3 or 4, or a pharmaceutically acceptable salt of such a hydrazine derivative with at least one salt-forming group, for the manufacture of pharmaceutical compositions for use in inhibiting the HIV-gag protease enzyme. A process for the preparation of a hydrazine derivative of the general formula (I) according to claim 1, wherein the substituents have the meanings given in claim 1, and salts thereof, characterized in that (a) a hydrazine derivative of the general formula (III) I H in which R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholino-carbonyl substituted by amino- (lower alkanoyl), halogen- (lower alkanoyl) on the nitrogen atom of the amino group containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) carb an amoyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remaining residues R ¹ or R ⁹ , and R ⁷ represents a lower alkyl, cyclohexyl- (lower alkyl) or phenyl- (lower alkyl) group which is unsubstituted or substituted by a halogen atom, a lower alkoxy group or a cyano group is added to an epoxide of the formula (IV) in which: R ¹ is H, lower alkanoyl, phenyl (lower alkanoyl) group, a phenyl (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino (lower alkanoyl), pyridyl (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino nitrogen, halogen- (lower alkanoyl), contains up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, (lower) alkoxy-carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carb a moyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remainder R ¹ or R ⁹ a R ³ is lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group which is unsubstituted or substituted by halogen, lower alkoxy or cyano, in which free functional groups with the exception of the groups participating in the reaction, optionally in protected form, and optionally protecting groups present are cleaved, or (b) to produce a hydrazine derivative of formula (I) wherein R ¹ , R ³ , R ⁷ and R ⁹ are as defined for a compound of formula (I) with the proviso that R ^{1 is} not a hydrogen atom, an amino compound of formula (V) wherein R ¹ is H, lower alkanoyl, phenyl (lower alkanoyl) group, a phenyl (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino (lower alkanoyl), pyridyl (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino nitrogen, halogen- (lower alkanoyl), contains up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) group, (lower) alkoxy-carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carb an amoyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remainder R ¹ or R ⁹ a R ³ and R ⁷ are each independently lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, is condensed with an acid of formula ( VI) R ⁹ -OH (VI) wherein R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group, wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino nitrogen, halogen- (lower alkanoyl), contains up to three halogen atoms, 2- (N-morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbam an aryl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remainder R ¹ or R ⁹ and or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or (c) for the preparation of compounds of formula (I) wherein R ¹ , R ³ , R ⁷ and R ⁹ have the meanings given for a compound of formula (I) with the proviso that R ^{9 is} not a hydrogen atom, an amino compound of formula (VII) in which R ⁹ represents a hydrogen atom, a lower alkanoyl group, a phenyl- (lower alkanoyl) group, a phenyl- (lower alkanoyl) group wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino-lower alkanoyl), pyridyl - (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted with amino- (lower alkanoyl), halogen- (lower alkanoyl) on the amino nitrogen atom, containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) carbamoyl) - (lower alkanoyl), (lower) alkoxy) -carbonyl, phenyl- (lower alkoxy) carbonyl, tetrahydrofuranyl- (lower alkoxy) carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbonyl a bamoyl group or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remainder R ¹ or R ⁹ a R ³ and R ⁷ are each independently lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, is condensed with an acid of formula ( VIII) R'-OH (VIII) in which R ¹ represents lower alkanoyl, phenyl- (lower alkanoyl), phenyl- (lower alkanoyl), wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl) ), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino or N-thiomorpholinocarbonyl substituted amino- (lower alkanoyl) on the amino nitrogen atom, halogen- (lower alkanoyl) group containing up to three atoms halogen, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl , phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbamoyl groups or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is unsubstituted or acylated by one of the remaining named R residues ¹ or R ⁹ and or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or d) for the production of a hydrazine derivative of the general formula (I) in which R ¹ and R ⁹ represent two identical radicals as defined in claim 1, except for a hydrogen atom, and the other radicals are as defined, a diamino compound of the general formula (IX) R ³ and R ⁷ are each independently lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl), which is unsubstituted or substituted by halogen, lower alkoxy or cyano, is condensed with an acid of formula ( VIII) R'-OH (VIII) or formula (VI) R’-OH (VI) in which R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl-lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted with amino- (lower alkanoyl) - at the amino atom of the amino group, alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl) ), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuran- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) ) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not substituted or acylated with one of the remainder of R ¹ or R ⁹ and or a reactive derivative thereof, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or (e) for the production of a hydrazine derivative of the general formula (I) in which R ¹ , R ³ , R ⁷ and R ⁹ have the meanings given for a compound of the general formula (I), R ⁷ represents a hydrogen atom and R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl (lower alkanoyl), phenyl (lower alkanoyl) wherein the lower alkanoyl radical is substituted by carbamoyl, morpholino (lower alkanoyl), thiomorpholino- ( lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbonyl substituted by amino- (lower alkanoyl) - at the amino atom of the amino group, lower alkanoyl) containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) -carbamoyl) - (lower alkanoyl), 2- (N-pyridyl- (lower alkyl) -carbamoyl) - (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) l) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or (D, L), wherein the α-amino group is not is substituted or acylated with one of the remaining R ¹ or R ⁹ , provided that at most one of R ¹ or R ⁹ is hydrogen, and R ³ is lower alkyl, cyclohexyl (lower alkyl) or phenyl (lower alkyl) group which is unsubstituted or substituted by halogen, lower alkoxy or cyano, the radical R ⁷ is introduced by substitution of a compound of formula (XII) R ⁷ -X (XII) wherein X represents a leaving group and R ⁷ is as defined above, wherein the free functional groups, except for those involved in the reaction, are optionally in protected form, and optionally protecting groups present are cleaved, or f) in a hydrazine derivative of the formula I wherein R ¹ and R ⁹ are each independently hydrogen, lower alkanoyl, phenyl- (lower alkanoyl), phenyl- (lower alkanoyl), wherein the lower alkanoyl radical is substituted carbamoyl, morpholino- (lower alkanoyl), thiomorpholino- (lower alkanoyl), pyridyl- (lower alkanoyl), quinolyl- (lower alkanoyl), tetrazolyl- (lower alkanoyl), N-morpholino- or N-thiomorpholinocarbones substituted amino- (lower alkanoyl) group, halogen- (lower alkanoyl) group containing up to three halogen atoms, 2- (N-morpholino- (lower alkyl) carbamoyl) - (lower alkanoyl) group, 2- / N- pyridyl- (lower alkyl) -carbamoyl- (lower alkanoyl), (lower alkoxy) -carbonyl, phenyl- (lower alkoxy) -carbonyl, tetrahydrofuranyl- (lower alkoxy) -carbonyl, (lower alkyl) -sulfonyl, morphol inosulfonyl, thiomorpholinosulfonyl, N-pyridyl- (lower alkyl) -N- (lower alkyl) -carbamoyl or an acyl residue of an amino acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic acid and asparagine in the form of D, L or ( D, L), wherein the α-amino group is unsubstituted or is acylated by one of the remainder of R ¹ or R ⁹ , provided that at most one of R ¹ or R ⁹ is hydrogen, and with the further condition that in the respective the compound of formula (I) is at least one protecting group protected, the protecting groups present are cleaved, and, where appropriate, the hydrazine derivative of formula (I) with at least one salt-forming group obtained by one of methods a) to f), converted to its salt, or the obtained salt is converted to the free hydrazine derivative or other salt, and / or the isomeric mixture obtained, if any, is separated and / or For example, the hydrazine derivative of formula (I) of the present invention is converted to another hydrazine derivative of formula (I) of the present invention. An intermediate of formula (II) wherein: R ³ and R ⁷ have the meanings given in claim 1, or salts thereof, if they contain salt-forming groups, for the production of the hydrazine compounds of formula (I) according to claim 1.