WO1997030076A1 - Pseudopeptides with an anti-viral action and containing a mercaptal or thioether group - Google Patents

Abstract

The invention concerns pseudopeptides with an anti-viral action, the pseudopeptides containing a mercaptal or thioether group and having general formula (I) in which the substituents are as defined in the description. The invention also concerns methods of preparing such pseudopeptides and their use as antiviral agents, in particular against cytomegaloviruses.

Description

New antiviral pseudopeptides with mercaptal or thioether function

The present invention relates to new antiviral pseudopeptides

Mercaptal or thioether function, process for their preparation and their use as antiviral agents, in particular against cytomegaloviruses.

From the publications J. Antibiot. 44, 1019 (1991), FEBS Letters 3, 253 (1993) and in patent application WO 92/22570, peptide aldehydes are described as inhibitors of the HIV protease or of picornavirus proteases. Furthermore, peptide aldehydes have been described as inhibitors of serine proteases

[US 5,153,176; EP 516 877]

Various nucleoside and nucleotide analogs, anthraquinone derivatives, phosphoric acid salts, cobalt complexes, macrolides and acyl peptides [EP 488041] are known as classes of compounds with anti-cytomegaly activity.

The present invention now relates to new antiviral pseudopeptides with mercaptal or thioether function of the general formula (I)

in which

R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁶ -CH ₂ -O-CO- or R ⁷ -CO-,

wherein R and R are the same or different and are phenyl or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle with up to 4 heteroatoms from the series S, N and / or O, the ring systems optionally up to 3 times are identical or different and are substituted by halogen or by straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,

R »2 represents hydrogen or methyl,

R represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms,

R ^{4 represents} straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl,

R ^{5 represents} a radical of the formula -OCO-R ⁸ ,

wherein

R ^{8 is} straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms,

or

R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical

Formula ^ ( ^{CR R} ). form,

- p

wherein

R ⁹ and R ^{10 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, a represents a number 1, 2 or 3,

and their salts.

The compounds of the general formula (I) according to the invention can also be present in the form of their salts. In general, salts with organic and inorganic bases or acids may be mentioned here.

The acids that can be added preferably include hydrohalic acids, e.g. hydrofluoric acid, hydrochloric acid and hydrobromic acid, especially hydrofluoric acid and hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid as well as sulfonic acids such as e.g. p-toluenesulfonic acid, 1,5-naphthalenedisulfonic acid or camphorsulfonic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. For example, particular preference is given to Sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

Heterocycle generally represents a 5- to 7-membered, preferably 5- to 6-membered, aromatic, optionally benzo-fused ring which can contain up to 4 oxygen, sulfur and / or nitrogen atoms as heteroatoms. 5- and 6-membered rings with one oxygen, sulfur and / or up to 4 nitrogen atoms are preferred. The following are particularly preferred:

Pyrrolyl, quinoxalinyl, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl or tetrazolyl.

zeigt, bis zu 4 asymmetrische Kohlenstoffatome (*). Sie können unabhängig voneinander in der D- oder L-Form, bzw. R- oder S-Konfiguration vorliegen. Die Erfindung umfaßt sowohl die reinen Diastereomeren, Gemische mehrerer Diastereomerer und Racemate.The compounds of the general formula (I) according to the invention, like the rest of the general formula (II)

shows up to 4 asymmetric carbon atoms (*). They can exist independently of one another in the D or L form, or R or S configuration. The invention includes both the pure diastereomers, mixtures of several diastereomers and racemates.

The stereoisomer mixtures and racemates can be separated into the pure stereoisomers by known methods. Mixtures of stereoisomers can be separated either by chromatography or by fractional crystallization. Racemates can be separated, for example, by chromatography on chiral phases.

Preferred compounds of the general formula (I) according to the invention are

in which

R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁶ -CH ₂ -O-CO- or R ⁷ -CO-,

wherein

R ⁶ and R ^{7 are the} same or different and are phenyl, pyridyl, quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which are optionally up to 2 times the same or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or Acyl are each substituted with up to 5 carbon atoms, R ^{2 represents} hydrogen or methyl,

R ^{3 represents} straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

R ^{4 represents} straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl,

R ^{5 represents} a radical of the formula -OCO-R ⁸ ,

wherein

R ^{8 is} straight-chain or branched alkyl having up to 4 carbon atoms, benzyl, phenyl or naphthyl,

or

R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical

Form ^ ( ^{CR R} ) • form,

wherein

R ⁹ and R are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

a represents a number 1, 2 or 3,

and their salts.

Compounds of the general invention are particularly preferred

Formula (I),

in which R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁶ -CH ₂ -O-CO- or R ⁷ -CO-,

woπn

R and R are the same or different and are phenyl, pyridyl, quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which are optionally up to 2 times identical or different by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl up to 4 carbon atoms are substituted,

R »2 represents hydrogen or methyl,

R represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

R ^{4 represents} straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl,

R ^{5 represents} a radical of the formula -OCO-R ⁸ ,

wherein

R ^{8 is} straight-chain or branched alkyl having up to 3 carbon atoms,

or

R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical

Form the formula ^ ( ^{CR R} ) ■

wherein R ⁹ and R ^{10 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

a represents a number 1, 2 or 3,

and their salts.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention have been found, characterized in that aldehydes of the general formula (IH)

in which

1 0 3

R, R and R have the meaning given above,

depending on the meanings of R and R given above with mercaptans of the general formula (IV) or (IVa)

HS-R ⁴ (IV) or HS- (CR ⁹ R ¹⁰ ) _a -SH (τ _Va )

in which

R> 4, R _D 9, r R> 10 and a have the meaning given above,

in inert solvents and in the presence of a base, if appropriate under a protective gas atmosphere, and in the case of the compounds of the general formula R ⁵ -O-CO-R ^8, an acylation is carried out by customary methods.

The process according to the invention can be illustrated by the following formula scheme:

T C

TC

In general, inert organic solvents such as ethers, e.g. Diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p-cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylidium phosphorus, phosphorus methyl amide, Triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Methylene chloride, tetrahydrofuran and dioxane are particularly preferred.

Suitable bases are organic amines, trialkyl (C ₁ -C ₆ ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or

N-methylmorpholine. Triethylamine and N-methylmorpholine are preferred.

The bases are generally used in an amount of 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (IV) or (IVa). The compounds of the general formulas (IV) and (IVa) are known per se or can be prepared by customary methods.

The compounds of the general formula (ED) are new as species and can be prepared by

[A] compounds of the general formula (V)

in welcher

in which

R> 2 has the meaning given above,

D represents an amino protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl or FMOC,

and

E represents benzyl or C _r C ₄ alkyl,

first converted into the free carboxylic acids, then with compounds of the general formula (VI)

in welcher R die oben angegebene Bedeutung hat,

in which R has the meaning given above,

convicted,

after removal of the protective group D in a last step with compounds of the general formula (VII)

R ^] -L (vπ)

in which

R ^{1 has} the meaning given above

and

L represents hydroxy, C 1 -C ₄ -alkoxy, nitro-substituted phenoxy or a typical carboxylic acid-activating radical such as chlorine,

in inert solvents and optionally in the presence of a base and / or auxiliary,

or

[B] Compounds of the general formula (VIII)

in which R ¹ and R ^{2 have} the meaning given above

and

E ^{1 has} the meaning of E given above and is the same or different with it,

first splits off the protective group E 'as described under [A], and then reacts with compounds of the general formula (V) in inert solvents, if appropriate in the presence of a base and / or an auxiliary,

and in both cases [A] and [B] there is oxidation of the hydroxymethyl function

Suitable solvents for all processes are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, p- Cresol, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the named sols, if appropriate to be used with water. Methylene chloride, tetrahydrofuran, dioxane and dioxane / water are particularly preferred

Suitable bases are organic amines, Tπalkyl (C _] -C ₆ ) amme such as

Tπethylamine or heterocycles such as Pyπdin, Methylpipeπdin, Pipendm or N-methylmorpholine are preferred Tπethylamin and N-methylmorpholine

The bases are generally used in an amount of 0.1 mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (V) and (VIII)

The reactions can be carried out at atmospheric pressure, but also at elevated or reduced pressure (for example 0.5 to 3 bar). In general, atmospheric pressure is used The reactions are carried out in a temperature range from 0 ° C. to 100 ° C., preferably at 0 ° C. to 30 ° C. and under normal pressure.

The oxidation of alcohol groups to the corresponding aldehydes is generally carried out in one of the solvents listed above in the presence of one of the bases listed above with oxidizing agents, such as, for example, potassium permanganate, bromine, Jones reagent, pyridine dichromate, pyridinium chlorochromate, pyridine -Sulfur trioxide complex or with chlorine solution and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) [Org. Synth. 69, 212 (1990)] or oxalyl chloride [Swern oxidation (C1COCOC1 / DMSO / CH ₂ C1 ₂ / NEt ₃ ), for example according to RE Ireland et al., J. Org. Chem. 50, 2199 (1985)]. Oxidation is preferably carried out using pyridine

Sulfur trioxide complex in dimethyl sulfoxide in the presence of triethylamine [J.R. Parikh and W. v. Doering, J. Am. Chem. Soc. 89, 1967, 5505-7].

The Oxidaüon is generally carried out in a temperature range from 0 C to +50 C, preferably at room temperature and normal pressure.

The amino protective groups are split off in a manner known per se.

Condensation agents, which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxy group is activated as the anhydride. The usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, NN ¹ -diisopropyl, N, N * -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-, are preferred here. ethyl carbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxytri (dimethylamino) phosphonium hexafluorophosphobot, or 1-hydroxy benzotriazole and as bases alkali metal carbonates, for example sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, for example triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine. Dicyclohexylcarbodiimide is particularly preferred,

N-methylmorpholine and 1-hydroxybenzotriazole. The saponification of the carboxylic acid esters is carried out by customary methods by treating the esters with customary bases in inert solvents, it being possible for the salts initially formed to be converted into the free carboxylic acids by treatment with acid.

Suitable bases for the saponification are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or lithium hydroxide are particularly preferably used

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used.

It is also possible to use mixtures of the solvents mentioned. Water / tetrahydrofuran is preferred

The saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 40 ° C.

In general, the saponification is carried out at normal pressure. However, it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar)

When the saponification is carried out, the base or the acid is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the ester. Molar amounts of the reactants are particularly preferably used

When the reaction is carried out, the salts of the compounds according to the invention are formed in the first step as intermediates which can be isolated. The acids according to the invention are obtained by treating the salts with customary inorganic acids. These preferably include mineral acids, for example

Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid or Phosphoric acid. In the production of the carboxylic acids, it has proven advantageous to acidify the basic reaction mixture of the saponification in a second step without isolating the salts. The acids can then be isolated in the usual way.

The compounds of the general formula (VI) and (VD) are known per se or can be prepared by customary methods.

Some of the compounds of the general formula (V) and (VEI) are known or new and can be prepared by customary methods, for example by reacting compounds of the general formula (IX)

in which

R has the meaning given above

and

T includes the scope of E and E 'listed above,

with amino acid derivatives of the general formula (X)

in which X includes the scope of D and R ¹ listed above,

in one of the abovementioned solvents, preferably methylene chloride, in the presence of an auxiliary and / or base, preferably HOBT and dicyclohexylcarbodiimide

and then, likewise by customary methods, the amino protecting group is split off, preferably Boc with hydrochloric acid in dioxane, Fmoc with piperidine and Z with HBr / HOAc or by hydrogenolysis.

All process steps take place at normal pressure and in a temperature range from 0 ° C to room temperature, preferably at room temperature.

Some of the compounds of the general formulas (IX) and (X) are known or new and can be prepared by customary methods.

The compounds show an antiviral effect against representatives of the Herpetoviridae group, especially against the human cytomegalovirus (HCMV).

The anti-HCMV activity was tested in a screening test system in 96-well

Microtiter plates determined with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures. The influence of the substances on the spread of the cytopathogenic effect was determined in comparison to the reference substance ganciclovir (Cymevene® sodium), a clinically approved anti-HCMV chemotherapeutic agent.

The substances (100 or 50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtiter plates (96-well) in final concentrations of 1000-0.00048 μM (micromolar) in duplicate determinations (4 substances / plate). Toxic and cytostatic effects are also included. After the corresponding substance dilutions (1: 2) on the microtiter plate, a

Suspension of 50-100 HCMV-infected HELF cells and 3 x IO ⁴ non-infected HELF cells in Eagle's MEM (Minimal Essential Medium) with 10% fetal calf serum was added to each well, and the plates at 37 ° C in a CO ₂ Incubator incubated for 6 days. After this time, the cell lawn is in the substance-free virus controls, starting from 50 - 100 infectious centers, completely destroyed by the cytopathogenic effect (CPE) of the HCMV (100% CPE). After staining with neutral red and fixation with formalin / methanol, the plates are evaluated using a projection microscope (plaque viewer). The results for some compounds are summarized in the following table:

Table: Anti-HCM (Davis) activity and anticellular activity

1) CIC50 = highest concentration that shows no obvious anti-cellular effects.

2) IC50 = concentration of the compound according to the invention which effects a 50% inhibition of the CPE.

cιc ₅₀ 3) SI = = selectivity index

IC 50

contains D-arginine (R) It has now been found that the compounds according to the invention inhibit the multiplication of HCMV in HELF cells in concentrations which are in some cases 10-70 times lower than Cymevene® sodium and are in some cases more selective.

The compounds according to the invention are therefore valuable active ingredients for the treatment and prophylaxis of diseases caused by the human cytomegalovirus.

1) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who often develop life-threatening diseases of HCMV pneumomtis and encephalitis, as well as gastrointestinal and systemic HCMV infections.

2) Treatment and prophylaxis of HCMV infections in ATDS patients (retinitis, pneumonitis, gastrointestinal infections)

3) Treatment and prophylaxis of HCMV infections in pregnant women, newborns and young children.

The new active ingredient can be converted in a known manner into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, where, for example, if water is used as a diluent, organic solvents can optionally be used as auxiliary solvents

The application is carried out in the usual way, preferably orally, parenterally or topically, in particular perlingually or intravenously In the case of parenteral use, solutions of the active ingredient can be used using suitable liquid carrier materials.

In general, it has proven advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.01 to 5 mg / kg body weight, for intravenous administration to achieve effective results, and the dosage is approximately 0 for oral administration , 01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication

Type of formulation and the time or interval at which the administration takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

Output connections

Example I

L-leucinol

14 g (0.166 mol) of sodium borohydride are placed in 400 ml of THF and mixed with

20 g (0.152 mol) of L-leucine are added. While stirring, the mixture is cooled to 0 ° C. and 38.6 g (0.152) iodine, dissolved in 100 ml THF, are added dropwise. The mixture is then heated to boiling overnight. After cooling, methanol is added until a clear solution is obtained. After evaporating off the solvents in vacuo (Rotavapor), the mixture is taken up in 300 ml of 20% potassium hydroxide solution. The mixture is stirred for 3 hours at room temperature, extracted 3 times with 100 ml of dichloromethane, the combined dichloromethane solution is shaken out twice with 50 ml of saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness. Yield: 15.6 g (87.5% of theory) of colorless oil, n ²⁰ _D = 1.451

Example U

N ^ tert-butyloxycarbonyl-N ^ tosyl-S-arginyl-S-valine benzyl ester

75 g (0,175 mol) N^tert.Butyloxycarbonyl-N^tosyl-S-arginin werden in 900 ml Dichlormethan gelöst und bei 0°C unter Rühren mit 47,3 g (0,35 mol) N-Hydroxy- benztriazol (HOBT) versetzt. Man läßt 30 min. nachrühren und gibt dann (0°C) 39,8 g (0,193 mol) Dicyclohexylcarbodiimid (DCC) zu. Nach weiteren 15 min Rühren bei 0°C tropft man bei 0°C eine Lösung aus 42,65 g (0,175 mol) S-Valin- benzylester-hydrochlorid, 30,5 ml (0,175 mol) Diisopropylethylamin und 300 ml Dichormethan zu. Man läßt das Reaktionsgemisch über Nacht rühren, wobei die Temperatur auf Raumtemperatur ansteigt. Nach Abfiltrieren des farblosen Nieder¬ schlags wäscht man das Filtrat mit 5 %-Zitronensäurelösung, mit Wasser, mit ge- sättigter Natriumhydrogencarbonat-Lösung und wieder mit Wasser. Nach dem ^X A γ

75 g (0.175 mol) of N ^ tert-butyloxycarbonyl-N ^ tosyl-S-arginine are dissolved in 900 ml of dichloromethane and at 0 ° C with stirring with 47.3 g (0.35 mol) of N-hydroxybenztriazole (HOBT ) offset. It is left for 30 min. stir and then add (0 ° C) 39.8 g (0.193 mol) of dicyclohexylcarbodiimide (DCC). After stirring for a further 15 min at 0 ° C., a solution of 42.65 g (0.175 mol) of S-valine benzyl ester hydrochloride, 30.5 ml (0.175 mol) of diisopropylethylamine and 300 ml of dichormethane is added dropwise at 0 ° C. The reaction mixture is allowed to stir overnight, the temperature rising to room temperature. After the colorless precipitate has been filtered off, the filtrate is washed with 5% citric acid solution, with water, with saturated sodium bicarbonate solution and again with water. After this

Drying the organic phase with sodium sulfate is concentrated and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5 - 9/1). Yield: 91.5 g (84.6% of theory) of colorless crystals R _f = 0.48 (dichloromethane / methanol = 95/5)

Example UI

N ^ tert-butyloxycarbonyl-N ^ -tosyl-S-arginyl-S-valine

91.48 g (0.148 mol) of the substance from Example II are dissolved in 800 ml of ethanol, 9.34 g of Pd / C are added under an argon atmosphere and the mixture is hydrogenated at room temperature overnight (6.5 l added). The catalyst is filtered off and the filtrate is evaporated to dryness. Yield: 78 g (quantitative) colorless crystals R ^ - = 0.75 (dichloromethane / methanol = 9/1) Example IV

N _α- tert-butyloxycarbonyl-N ° -tosyl-S-arginyl-S-valyl-S-leucinol

9.6 g (18.22 mmol) of the substance from Example III, 2.7 g (20 mmol) of HOBT and 3.83 g (20 mmol) of N-cyclohexyl-N '- (2-morphlinolethyl) carbodiimide metho- p-toluenesulfonate (Morpho-CDI) are combined at 0 ° C. and stirred at this temperature for 20 min. A solution of 2.13 g (18.22 mmol) of the substance from Example I and 2.59 g of A 3.5 ml (20 mmol) diisopropylethylamine in 100 ml of dichloromethane is then added dropwise at 0.degree. The mixture is stirred overnight, the temperature rising to room temperature. After washing with saturated

Sodium bicarbonate solution, water and saturated saline are dried with sodium sulfate, filtered and evaporated to dryness in vacuo. Yield: 10.6 g (93.0% of theory) of colorless crystals R _f = 0.74 (dichormethane / methanol = 9/1)

Example V

N ^ Tosyl-S-arginyl-S-valyl-S-leucinol

10,5 g (16,77 mmol) der Verbindung aus Beispiel IV werden über Nacht bei Raumtemperatur mit 200 ml mit chlorwasserstoffgesättigtem Dioxan gerührt. Anschließend dampft man i.V. das Lösemittel ab, nimmt den Rückstand in 200 ml Essigester auf und rührt das anfangs heterogene Gemisch 1 Stunde mit gesättigter Natriumhydrogencarbonatlösung. Man trennt die organische Phase ab, extrahiert die wäßrige Phase noch 2 mal mit 50 ml Essigester, schüttelt die vereinigten Essigesterphasen 2 mal mit gesättigter Kochsalzlösung aus, trocknet mit Natrium¬ sulfat und dampft i.V. zur Trockene ein. Ausbeute: 8,5 g (96,3% d.Th.) farblose Kristalle R_f = 0,23 (Dichlormethan / Methanol = 9/1)

10.5 g (16.77 mmol) of the compound from Example IV are stirred overnight at room temperature with 200 ml of dioxane saturated with hydrogen chloride. The solvent is then evaporated off in vacuo, the residue is taken up in 200 ml of ethyl acetate and the initially heterogeneous mixture is stirred for 1 hour with saturated sodium bicarbonate solution. The organic phase is separated off, the aqueous phase is extracted twice with 50 ml of ethyl acetate, the combined ethyl acetate phases are shaken out twice with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness in vacuo. Yield: 8.5 g (96.3% of theory) of colorless crystals R _f = 0.23 (dichloromethane / methanol = 9/1)

Example VI

2 ', 5'-dimethylbenzyl-4-nitrophenyl carbonate

Analogous to Daniel F. Veber, J. Org. Chem. 42, 20, 1977 p. 3286-8 becomes the title compound from 20 g (0.065 mol) of di- (4-nitrophenyl carbonate) and 9.05 g

(0.065 mol) of 2,5-dimethylbenzyl alcohol. Yield: 16.5 g (83.4% of theory) of colorless product R _f = 0.55 (petroleum ether / ethyl acetate = 5/1)

Example VII

N _α -2,5-dimethylbenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-leucinol

3,85 g (7,32 mmol) der Substanz aus Beispiel V und 3,3 g (10,98 mmol) der Sub¬ stanz aus Beispiel VI werden in 20 ml Dioxan gelöst, mit 20 ml Wasser versetzt und 48 Stunden bei Raumtemperatur gerührt. Die Lösemittel werden i.V. abge¬ dampft und der Rückstand säulenchromatographisch getrennt (Kieselgel 60, Lauf¬ mittel: Dichlormethan / Methanol = 95/5 bis 9/1). Ausbeute: 3,9 g (77,4% d.Th.) farblose Kristalle R_f = 0,63 (Dichlormetan / Methanol = 9: 1)

3.85 g (7.32 mmol) of the substance from Example V and 3.3 g (10.98 mmol) of the substance from Example VI are dissolved in 20 ml of dioxane, mixed with 20 ml of water and at room temperature for 48 hours touched. The solvents are evaporated off in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5 to 9/1). Yield: 3.9 g (77.4% of theory) of colorless crystals R _f = 0.63 (dichlorometane / methanol = 9: 1)

Example Vm

N _α -Benzyloxy carbonyl-N ^ tosyl-S-arginyl-S-valine methyl ester

25 g (54 mmol) of N ^ benzyloxycarbonyl-N ^ -tosyl-S-arginine are dissolved in 150 ml of dichloromethane, cooled to 0 ° C. and 14.8 g (108 mmol) of HOBT are added with stirring. After stirring for 15 minutes at 0 ° C., 12.4 g (59.4 mmol) of dicyclohexylcarbodiimide (DCC) are added, and after a further 15 minutes a solution of 9.05 g (54 mmol) of S-valine methyl ester hydrochloride and 9.2 ml (54 mmol) diisopropylethylamine in 100 ml dichloromethane. The reaction mixture is allowed to stir overnight, the temperature rising to room temperature. The precipitate obtained is separated off, the filtrate is washed with 5% citric acid solution, with water, saturated NaHCO3 solution and again with water. After drying the solution with Na2SO4, evaporate in vacuo to a small volume and separate the substances by column chromatography (silica gel 60, mobile phase. Dichloromethane / methanol = 9/1). Yield: 21.6 g (69.4% of theory) colorless crystals R _f = 0.6 (dichloromethane / methanol = 9/1) Example IX

N ^ benzyloxycarbonyl-N ^ tosyl-S-arginyl-S-valine

7.7 g (13.4 mmol) of the compound from Example VIII are dissolved in 50 ml of ethanol, 47 ml of 1N sodium hydroxide solution are added and the mixture is stirred at room temperature for 3 h. The ethanol is evaporated off in vacuo and the remaining solution is acidified to pH = 6 with 1N hydrochloric acid. After extraction three times with ethyl acetate, the combined ethyl acetate phases are washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness in vacuo. Yield: 6.6 g (87.8% of theory) of colorless crystals R _f = 0.6 (dichloromethane / methanol = 95/5)

Example X

N _α -Benzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-leucinol

^\

1 g (1.78 mmol) of the compound from Example IX is dissolved in 20 ml of dichloromethane, the solution is cooled to 0 ° C. and stirred with 0.26 g (1.96 mmol) HOBT and 0.38 g (1.96 mmol) of morpho-CDI were added. A solution of 0.21 g (1.78 mmol) of the compound from Example I and 0.35 ml (196 mmol) of diisopropylethylamine in 10 ml of dichloromethane is then added dropwise at 0.degree. The mixture is left to stir overnight, the temperature rising to room temperature. The mixture is then diluted with 50 ml of dichloromethane and the solution is shaken out successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying with Na ₂ SO _{4, the} mixture is concentrated to a small volume in vacuo and the residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1). Yield: 0.9 g (85% of theory) colorless Crystals R _f = 0.77 (dichloromethane / methanol = 9/1)

Example XI

N _α -3-pyridylmethyloxycarbonyl-N ^< ^ tosyl-S-arginyl-S-valyl-S-leucinol

The title compound is prepared in analogy to the procedure of Example VII from 0.5 g

(0.95 mmol) of the substance from Example V and 0.52 g (1.9 mmol) of 3-pyridylmethyl-4-nitrophenyl carbonate (shown analogously to Example VI). Yield: 0.49 g (78.0% of theory) of colorless crystals R _f = 0.44 (dichloromethane / methanol = 9/1) Example XII

N _α- tert.Butyloxycarbonyl-N ^G -tosyI-S-arginyl-S-tert.butylglycine methyl ester

35.9 g (83.7 mmol) of N _α- tert-butyl-N ° -tosyI-S-arginine are dissolved in 160 ml of dichloromethane, cooled to 0 ° C and stirred with 22.6 g (167, 4 mmol)

HOBT moved. After 15 min, 18.9 g (91.4 mmol) of DCC are added and the mixture is stirred for a further 15 min. A solution of 12.1 g (83.7 mmol) of S-tert-butylglycine methyl ester in 200 ml of dichormethane is then added dropwise at 0 ° C. and the mixture is stirred overnight, the temperature rising to room temperature. It is washed twice with 5% citric acid, with water, with saturated sodium hydrogen carbonate solution, again with water and with saturated sodium chloride solution. After drying with sodium sulfate, the mixture is evaporated to dryness in vacuo and a colorless crystallizate is obtained. Yield: 33.2 g (71.3% of theory) R _f = 0.7 (dichloromethane / methanol = 95/5)

Example XIII

N _α- tert-butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycine

32.3 g (59.8 mmol) of the compound from Example XII are dissolved in 300 ml of methanol, mixed with 200 ml of sodium hydroxide solution and stirred overnight at room temperature. After evaporation of the solvent, the mixture is diluted with water and adjusted to pH = 6 with 1N hydrochloric acid. The precipitated substance is suctioned off and dried.

Yield. 19.7 g (60.8% of theory) colorless crystals R _f = 0.4 (dichloromethane / methanol = 95/5)

Example XIV

N _α- tert-butyloxy carbonyl- ^ -tosyl-S-arginyl-S-tert.butylglycl-L-leucinol

3 g (5,54 mmol) der Verbindung aus Beispiel XIII werden in 25 ml Dichlormethan gelöst, auf 0°C abgekühlt und mit 0,82 g (6,09 mmol) HOBT und 1,2 g (6,09 mmol) Morpho-CDI versetzt. Nach 15 min Rühren bei 0°C tropft man eine Lösung von 0,65 g (5,54 mmol) L-Leucinol in 25 ml Dichlormethan zu. Man läßt über Nacht rühren, wobei die Temperatur auf Raumtemperatur ansteigt. Nach Zu¬ satz von 50 ml Dichlormethan wäscht man mit gesättigter Natriumhydrogencarbo- natlösung, mit Wasser und mit gesättigter Kochsalzlösung. Man engt die Lösung i.V. auf ein kleines Volumen ein und säulenchromatographiert (Kieselgel 60, Lauf¬ mittel: Dichlormethan : Methanol = 9/1). Ausbeute: 2,1 g (59,2% d.Th.) farblose Kristalle R_f = 0,78 (Dichlormethan / Methanol = 9/1)

3 g (5.54 mmol) of the compound from Example XIII are dissolved in 25 ml of dichloromethane, cooled to 0 ° C. and with 0.82 g (6.09 mmol) of HOBT and 1.2 g (6.09 mmol) of morpho -CDI offset. After stirring for 15 minutes at 0 ° C., a solution of 0.65 g (5.54 mmol) of L-leucinol in 25 ml of dichloromethane is added dropwise. The mixture is stirred overnight, the temperature rising to room temperature. After 50 ml of dichloromethane have been added, the mixture is washed with saturated sodium hydrogen carbonate solution, with water and with saturated sodium chloride solution. The solution is concentrated in vacuo to a small volume and column chromatographed (silica gel 60, mobile phase: dichloromethane: methanol = 9/1). Yield: 2.1 g (59.2% of theory) of colorless crystals R _f = 0.78 (dichloromethane / methanol = 9/1)

Example XV

N ^G -Tosyl-S-arginyl-S-tert.butylglycyl-S-leucinol

2.07 g (3.23 mmol) of the compound from Example XIV are stirred for 2 hours with 20 ml of hydrogen chloride-saturated dioxane at room temperature. Then it is adjusted to pH 8-9 with 1N sodium hydroxide solution and extracted with ethyl acetate. After neutral washing, dry with sodium sulfate and evaporate to a small volume. The individual components are separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1). Yield: 1.5 g (86.2% of theory) Example XVI

N _α -3-pyridylmethyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycyl-S-leucinol

In analogy to the procedure of Example VII, the title compound is prepared from 0.88 g (1.63 mmol) of the compound from Example XV and 0.89 g (3.26 mmol) of 3-pyridylmethyl-4-nitrophenyl carbonate (prepared as in Example VI) produced. Yield 0.58 g (52.7% of theory) of colorless crystals R _f = 0.75 (dichloromethane / methanol = 9/1)

Example XVH

(2 R, S) -3-cyclohexyl-2-aminopropanol hydrochloride

45.7 g (0.178 mol) of (2 R, S) -N-tert-butoxycarbonyl-3-cyclohexyl-2-aminopropanol are dissolved in a little methanol, and the solution is cooled to 0 ° C. For this, 100 ml of methanol saturated with hydrogen chloride are added dropwise. All are left to stand overnight, the temperature rising to room temperature

The solution is evaporated to dryness in vacuo, the residue is stirred with toluene, separated and dried in vacuo. Yield 33.8 g (98.3% of theory) of colorless crystals Example XVm

(2R, S) -N- [N _α -tert.Butyl-N ^G -tosyl-S-arginyl-S-valyl] -3-cyclohexyl-2-amino-ρropanol

^Ω

4 g (7.6 mmol) of the compound from Example III are dissolved in 35 ml of dichloromethane. At 0 ° C., 2.05 g (15.2 mmol) of HOBT are added with stirring. After stirring for 15 min, 1.6 g (8.36 mmol) of morpho-CDI are added, and after stirring for a further 15 min, a solution of 1.47 g (7.6 mmol) of the compound from Example is added dropwise at 0.degree XVII and 2.8 ml (15.96 mmol) diisopropylethylamine in 40 ml dichloromethane. The mixture is stirred overnight, the temperature rising to room temperature. The reaction mixture is washed with saturated sodium bicarbonate and with saturated sodium chloride solution, dried with sodium sulfate, i.V. evaporated to a small volume and separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5) yield diastereomer A = 1.51 g (29.8% of theory)

| 68.7% of theory colorless crystals

Yield diastereomer B = 1.97 g (38.9% of theory) R _f = 0.82 and 0.66 (dichloromethane / methanol = 9/1)

Example XIX

(2R, S) -N- | ^ -Tosyl-S-arginyl-S-valyl] -3-cycloallςyl-2-aminopropanol

1.96 g (2.94 mmol) of the diastereomer B from Example XVIII are stirred for 12 min overnight with hydrogen chloride-saturated dioxane at room temperature. The reaction mixture is then made alkaline with 1 N sodium hydroxide solution (pH = 8-9), all in conjunction. evaporated to dryness and the residue was stirred intensively twice with 5 ml of water and 50 ml of ethyl acetate for 1 hour. The organic phase is washed with saturated saline, dried with sodium sulfate and reduced to a small volume i.V. vaccinated. The residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 9/1).

Yield: 1.4 g (84.3% of theory) of colorless crystals R _f = 0.15 (dichloromethane / methanol = 9/1).

Example XX

(2R, S) - [(N _α -2,5-dimethylbenzyloxycarbonyl-N ^G -tosyl) -S-arginyl-S-valyl] -3-cyclohexyl-2-aminopropanol

In Analogie zur Vorschrift des Beispiels VII wird die Titelverbindung aus 1,4 g (2,19 mmol) der Verbindung aus Beispiel XIX und 1,32 g (4,38 mmol) 2,5-Dime- thylbenzyl-4-nitrophenylcarbonat hergestellt. Ausbeute: 1,0 g (62,7% d.Th.) farblose Kristalle R_f = 0,46 (Dichlormethan / Methanol = 9/1)

In analogy to the procedure of Example VII, the title compound is prepared from 1.4 g (2.19 mmol) of the compound from Example XIX and 1.32 g (4.38 mmol) of 2,5-dimethylbenzyl-4-nitrophenyl carbonate. Yield: 1.0 g (62.7% of theory) of colorless crystals R _f = 0.46 (dichloromethane / methanol = 9/1)

Example XXI

(2R, S) - [(N _α -2,5-dimethylbenzyloxycarbonyl-N ^G -tosyl) -S-arginyl-S-valyl] -R- leucinal

1 g (1.453 mmol) of the compound from Example VII is dissolved in 5 ml of dry dichloromethane and 5 ml of dry DMSO, cooled to 0 ° C. and with 0.95 ml (6.83 mmol) of triethylamine and 1.09 g (6 , 83 mmol) of sulfur trioxide-pyridine complex. After stirring at 0 ° C. for 1.5 h, 30 ml of dichloromethane are added and the mixture is stirred vigorously for 30 min with 50 ml of saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution, dried and evaporated in vacuo. The residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5). Yield: 0.7 g (70.2% of theory) of colorless crystals R _f = 0.61 / 0.58 (dichloromethane / methanol = 9/1) Example XXII

(2R, S) -N _α -3-pyridylmethyloxycarbonyl-N TÖ-tosyl-S-arginyl-S-tert.butylglycyl-leucinal

In analogy to the procedure of Example XXI, the title compound is made from 0.58 g

(0.85 mmol) of the compound of Example XVI and 0.67 g (4.23 mmol) of sulfur trioxide-pyridine complex. This creates a mixture of diastereomers that has not been separated.

Yield: 0.25 g (42.6% of theory) of colorless foam

R _f = 0.56 and 0.5 (dichloromethane / methanol = 9/1)

Example XXEQ

(2R, S) -N- [N _α -2,5-dimethylbenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl] -3-cyclohexyl-2-aminopropanal

In Analogie zur Vorschrift des Beispiels XXI wird die Titelverbindung aus 1,0 g

In analogy to the procedure of Example XXI, the title compound is made from 1.0 g

(1.37 mmol) of the compound from Example XX and 1.12 g (7.05 mmol) of sulfur trioxide-pyridine complex.

Yield diastereomer A: 0.23 g (23.1% of theory) of colorless foam

Yield diastereomer B: 0.18 g (18.1% of theory) of colorless foam

R _f , diastereomer A: 0.46 (dichloromethane / methanol = 95/5)

R _f , diastereomer B: 0.40 (dichloromethane / methanol = 95/5)

Example XXIV

(2R, S) -2- [N _α - (3-pyridylmethyloxycarbonyl) -N ^G -tosyl-R-arginyl-S-tert.butylglycyl] - amino-3-phenylpropanal

The title compound with D-arginine is prepared analogously to the instructions in Example XXXIII and publication EP 64 547.

Example XXV

a) (2R, S) -N- [N _α - (2,5-dimethyl-pyridyl-3-methyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-3-phenyl -2-aminopropanol

In Analogie zur Vorschrift des Beispiels VII wird die Titelverbindung aus 2 g (3,57 mmol) N^Tosyl-S-arginyl-S-valin-S-phenylalaninol und 2,16 g (7,14 mmol) 2',5'-Dimethyl-3-pyridylmethyl-4-nitrophenyl-carbonat (hergestellt analog Daniel F. Veber, J. Org. Chem. 42, 20, 1977 p. 3286-8) aus 13,4 g (0,044 mol) Dinitro- phenylcarbonat und 3 g (0,0218 mol) 2,5-Dimethyl-3-hydroxymethylpyridin in 90 %iger Ausbeute erhalten. Ausbeute: 1,94 g (75,0% d.Th.) farblose Kristalle R_f = 0,5 (Methylenchlorid/Methanol = 9/1)

In analogy to the procedure of Example VII, the title compound is made from 2 g (3.57 mmol) of N ^ tosyl-S-arginyl-S-valine-S-phenylalaninol and 2.16 g (7.14 mmol) of 2 ', 5' -Dimethyl-3-pyridylmethyl-4-nitrophenyl carbonate (prepared analogously to Daniel F. Veber, J. Org. Chem. 42, 20, 1977 p. 3286-8) from 13.4 g (0.044 mol) of dinitrophenyl carbonate and 3 g (0.0218 mol) of 2,5-dimethyl-3-hydroxymethylpyridine obtained in 90% yield. Yield: 1.94 g (75.0% of theory) of colorless crystals R _f = 0.5 (methylene chloride / methanol = 9/1)

b) (2R, S) -N- [N _α - (2,5-dimethyl-3-pyridylmethyl-oxycarbonyl) -N ^G- tosyl-S-arginyl-S-valyl] amino-3-phenylpropanal

In analogy to the procedure of Example XXI, the title compound is made from 1.8 g

(2.4865 mol) of the above compound, 1.86 g (1 1.686 mmol = 4.7 eq) pyridine-SO _r

Complex and 1.61 ml (11.686 mmol = 4.7 eq) triethylamine at 0 ° C and two

Hours response time.

Yield: 1.48 g (82.5% of theory) of colorless crystals

R _f = 0.35 (double spot) (dichloromethane / methanol = 100/7)

Manufacturing examples

example 1

(IR, S) -l- [N _α - (2,5-dimethyl-3-pyridylmethyloxy-carbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-1 - (1, 3- dithian-2-yl) -2-phenylethane

150 mg (0.208 mmol) of the diastereomeric aldehyde of the compound from Example XXV are dissolved under an argon atmosphere with 5 ml of methanol and with stirring at room temperature with 0.083 ml, d = 1.078 (0.83 mmol, 4 eq.) 1,3-Di - Mercaptopropan and 0.22 ml (2.08 mmol, 10 eq) BF ₃ x Et ₂ θ were added. After 2 hours, 5 ml of ethyl acetate and 5 ml of 10% NaHCO ₃ - are added.

Solution. After briefly stirring vigorously, the organic phase is separated off, dried with Na ₂ SO ₄ , evaporated to a small volume in vacuo and the remaining residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane - »dichloromethane / methanol = 100/7 ). Yield: 80 mg (47.5% of theory) of colorless foam

R _f (dichloromethane / methanol 100/7) = 0.48 MS (FAB) m / z = 812 (M + H) ⁺

Example 2

(IR, S) -l- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-tert-butylglycyl] amino-l- (1,3-dithian-2-yl ) -2-phenylethane

The title compound was prepared in analogy to the procedure of Example 1 from the corresponding aldehyde (prepared analogously to Example XXTV with L-arginine instead of with

D-arginine) and 23 ml (d = 1.078, 4 equivalents) 1,3-dimercaptopropan.

Yield: 220 mg (49.1% of theory), colorless foam

R _f (dichloromethane / methanol 100/7) = 0.5

MS (FAB) m / z = 798 (M + H) ⁺

Example 2a

(lR, S) -l- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -R-arginyl-S-tert.butyl-glycyl] amino-l- (l, 3-dithian-2-yl ) -2-phenylethane

Die Titelverbindung wurde in Analogie zur Vorschrift des Beispiels 1 aus dem entsprechenden Aldehyd der Verbindung aus Beispiel XXIV und 0,083 ml (d = 1,078, 4 Äquivalente) 1,3-Dimercaptopropan hergestellt. Ausbeute: 95 mg (60,1% d.Th ) farbloser Schaum R_f (Cyclohexan / Essigester / Methanol = 2/2/1) = 0,7 MS (FAB) m/z = 798 (M+H)⁺

The title compound was prepared in analogy to the procedure of Example 1 from the corresponding aldehyde of the compound from Example XXIV and 0.083 ml (d = 1.078, 4 equivalents) of 1,3-dimercaptopropane. Yield: 95 mg (60.1% of theory) of colorless foam R _f (cyclohexane / ethyl acetate / methanol = 2/2/1) = 0.7 MS (FAB) m / z = 798 (M + H) ⁺

Example 3

(1 R, S) - (2R, S) - 1 -acetoxy- 1 - ({2R, S} -2-methylbutyl) thio-2-rN _α - (2,5-dimethyl-3-pyridylmethyloxycarbony ^ -N ^ tosy ^ -S-arginyl-S-valylJamino-S-phenylpropane

100 mg (0.1385 mmol) of the diastereomeric aldehyde from Example XXV are dissolved in pa acetonitrile under an argon atmosphere and with stirring with 19 μl, d = 0 848 (0.1565 mmol, 1.2 eq) (2R, S) -2 -Methylbutyl mercaptan and 4 μl, d = 0.73 (0.1565 mmol, 1.2 eq) triethylamine added After 4 h stirring at room temperature, the mixture is cooled to -70 ° C., mixed with 20 μl (0.78 mmol ) Triethylamine, 8 mg

(0.06 mmol) dimethylaminopyridine (DMAP) and 30 μl, d = 1 08 (0.317 mmol) acetic anhydride. The temperature is allowed to rise slowly to room temperature and the mixture is stirred overnight. The reaction solution is evaporated down to a small volume in vacuo and the rest is chromatographed separated (silica gel 60, eluent dichloromethane -> dichloromethane / methanol = 10/1)

Yield 35 mg (29.2% of theory) colorless foam R _f (dichloromethane / methanol = 10/1) = 0.6 MS (FAB) m / z = 868 (M + H) ⁺ Example 4

(lR, S) - (2R, S) -l-acetoxy-l- (3-methylbutyl) thio-2- [N _α - (2,5-dimethyl-3-ρyridylmethyloxycarbonyl) -N ^ (tosyl) -S-arginyl-S-valyl] amino-3-phenylpropane

In analogy to the procedure of Example 3, the title compound is obtained from 100 mg (0.1385 mmol) of the compound of Example XXV, 19 μl, d = 0.835 (0.1565 mmol, 1.2 eq) 3-methylbutyl mercaptan, 4 μl / 20 μl, d = 0.73 (0.1565 mmol / 0.78 mmol) triethylamine, 30 μl, d = 1.08 (0.317 mmol) acetic anhydride and 8 mg (0.8 mmol) DMAP. Yield: 23 mg (19.2% of theory) of colorless foam R _f (dichloromethane / methanol = 10/1) = 0.6 MS (FAB) m / z = 868 (M + H) ⁺

Example 5

(lR, S) - (2R, S) -l-acetoxy-l- (3-methylbutyl) thio-2- [N _α - (3-pyridylmethyl-oxycarbonyl) -N ^G - (tosyl) -S- arginyl-S-tert.butylglycyl] amino-3-phenylpropane

In Analogie zur Vorschrift des Beispiels 3 wird die Titelverbindung aus 100 mg (0, 141 mmol) (2R,S)-2-[N_α-3-Pyridylmethyloxycarbonyl)-N^G-(tosyI)-S-argiιιyl-S- tert.butylglycyl]amino-3-phenyl-propan-2-al, 19 μl, d = 0,835 (0,1565 mmol, 1,1 eq) 3-Methylbutylmercaptan, 4 μl / 20 μl, d = 0,73 (0,1565 mmol / 0,78 mmol) Triethylamin, 30 μl, d = 1,08 (0,317 mmol) Essigsaureanhydrid und 8 mg (0,06 mmol) DMAP hergestellt. Ausbeute: 52 mg (26,5% d.Th.) farbloser Schaum R_f (Dichlormethan / Methanol = 100/7) = 0,6 MS (FAB) m/z = 854 (M+H)⁺

In analogy to the procedure of Example 3, the title compound from 100 mg (0.141 mmol) (2R, S) -2- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyI) -S-argiιιyl-S- tert .butylglycyl] amino-3-phenyl-propan-2-al, 19 μl, d = 0.835 (0.1565 mmol, 1.1 eq) 3-methylbutyl mercaptan, 4 μl / 20 μl, d = 0.73 (0, 1565 mmol / 0.78 mmol) triethylamine, 30 μl, d = 1.08 (0.317 mmol) acetic anhydride and 8 mg (0.06 mmol) DMAP. Yield: 52 mg (26.5% of theory) of colorless foam R _f (dichloromethane / methanol = 100/7) = 0.6 MS (FAB) m / z = 854 (M + H) ⁺

Example 6 and Example 7

(lR, S) - (2R, S) -l-acetoxy-l- (3-methylbutyl) thio-2-N- [N _α - (2,5-dimethylbenzyloxy- carbonyl) -N -tosyl-arginyl-S -S-valyl] amino-3-cyclohexylpropane

The title compound is prepared analogously to the procedure of Example 1 from 80 mg (0.1 1 mmol) of the compound from Example XXIII, 17 μl (0.132 mmol) of 3-methyl-1-butanethiol, 4 μl of triethylamine in 10 ml of acetonitrile.

Yield Example 7: 45.6 mg (47.5% of theory) of colorless foam

Yield: Example 8: 3.6 mg (3.7% of theory) of colorless foam

R _f Example 6 = 0.78 (dichloromethane / methanol 9/1) R _f Example 7 = 0.72 (dichloromethane / methanol 9/1) Example 8 and Example 9

(1R, S) - (2R, S) -1 -acetoxy- 1 - (3 -methylbutyl) thio-2-N- [N _{0 [} -2,5-dimethylbenzyloxycarbonyl-N ^ tosyO-S-arginyl- S-valylJamino-S-isopropylpropane

In analogy to the procedure of Example 1, the title compound is 150 mg

(0.233 mmol) of the compound from Example XXI, 33 μl (0.268 mmol) 3-methyl-1-butanethiol and 8 μl triethylamine in 10 ml acetonitrile.

Yield Example 9 = 100 mg (53.9% of theory) of colorless foam

Yield Example 10 = 38 mg (20.5% of theory) of colorless foam

R _f Example 8 = 0.70 (dichloromethane / methanol 9/1)

R _f Example 9 = 0.64 (dichloromethane / methanol 9/1)

Claims

claims 1. pseudopeptides with mercaptal or thioether function of the general Formula (I)

in which R represents tert-butyloxycarbonyl or a radical of the formula -R ⁶ -CH, -O-CO- or R ⁷ -CO-, wherein R ⁶ and R ^{7 are} identical or different and are phenyl or a 5- to 7-membered aromatic, optionally benzocondensed heterocycle with up to 4 heteroatoms from the series S, N and / or O, the ring systems optionally up to 3 are substituted in the same way or differently by halogen or by straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, R ^{2 represents} hydrogen or methyl, R represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms, R ^{4 represents} straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by phenyl, R ^{5 represents} a radical of the formula -OCO-R ⁸ , where o R is straight-chain or branched alkyl having up to 6 carbon atoms, benzyl or aryl having 6 to 10 carbon atoms, or R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical form the formula ^ (CR R) _a , woπn R ⁹ and R ^{10 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, a represents a number 1, 2 or 3, and their salts. 2. Compounds of the general formula (I) according to Claim 1, in which R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁶ -CH ₂ -O-CO- or R ⁷ -CO-, wherein R ⁶ and R ^{7 are the} same or different and are phenyl, pyridyl, Quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or Are pyrimidyl, which are optionally substituted up to 2 times identically or differently by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, R ^{2 represents} hydrogen or methyl, R ^{3 represents} straight-chain or branched alkyl having up to 3 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R ^{4 represents} straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R ^{5 represents} a radical of the formula -OCO-R ⁸ , wherein R ^{8 is} straight-chain or branched alkyl having up to 4 carbon atoms, benzyl, phenyl or naphthyl, or R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical form the formula ^ ( ^{CR R} ) a, - p wherein R ⁹ and R ^{10 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, a represents a number 1, 2 or 3, and their salts. 3. Compounds of the general formula (I) according to claim 1, in which R ¹ for tert-butyloxycarbonyl or for a radical of the formula -R ⁶ -CH ₂ -O-CO- or R ⁷ -CO-, woπn R ⁶ and R ^{7 are the} same or different and are phenyl, pyridyl, Quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which are optionally substituted up to 2 times identically or differently by fluorine, chlorine, bromine or by straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, R ^{2 represents} hydrogen or methyl, R ^{3 represents} straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, R ^{4 represents} straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl, R ^{5 represents} a radical of the formula -OCO-R ⁸ , wherein R ^{8 is} straight-chain or branched alkyl having up to 3 carbon atoms, or R ⁴ and R ⁵ together with the sulfur atom represent a heterocyclic radical form the formula ^ ( ^{CR R} ) _a , - p wherein R ⁹ and R ^{10 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, a represents a number 1, 2 or 3, and their salts. 4. A process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that aldehydes of the general formula (HI)

in which R ¹ , R ² and R ^{3 have} the meaning given above, depending on the meanings of R ² and R ³ given above Mercaptans of the general formula (IV) or (IVa) HS-R ⁴ (I \ 0 or HS- (CR ⁹ R ¹⁰ ) _a -SH (IVa) in which R ⁴ , R ⁹ , R ¹⁰ and a have the meaning given above, in inert solvents and in the presence of a base, if appropriate under a protective gas atmosphere, and in the case of the compounds of the general formula R ⁵ O-CO-R ^{8 is followed by} acylation by customary methods.