WO1997030071A1

WO1997030071A1 - Triazolidin-2-yl- and 1,3-thiazan-2-yl-substituted pseudopeptides

Info

Publication number: WO1997030071A1
Application number: PCT/EP1997/000474
Authority: WO
Inventors: Siegfried Raddatz; Thomas-Joachim Schulze; Dieter Häbich; Wolfgang Kanhai; Jürgen Reefschläger
Original assignee: Bayer Aktiengesellschaft
Priority date: 1996-02-16
Filing date: 1997-02-03
Publication date: 1997-08-21
Also published as: DE19605767A1; AU1599597A

Abstract

The invention concerns thiazolidin-2-yl- and 1,3-thiazan-2-yl-substituted pseudopeptides with an anti-viral action and having general formula (I) in which the substituents area 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

Thiazolidin-2-yl and l, 3-thιazan-2-yl-substituted pseudopeptides

The present invention relates to novel antiviral thiazolidin-2-yl and 1,3-thiazan-2-yl substituted pseudopeptides, processes 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 HIV protease or 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 derivatives, cobalt complexes, macrolides and acyl peptides [EP 488041] are known as classes of compounds with anti-cytomegaly activity.

The present invention now relates to novel antiviral thiazolidin-2-yl and 1,2-thiazan-2-yl-substituted pseudopeptides of the general formula (I)

in which

R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁸ -CH ₂ -O-CO- or R ⁹ -CO-, wherein

R ⁸ and R ^{9 are} identical or different and are phenyl or a 5- to 7-membered aromatic, optionally benzocondensed heterocycle having up to 4 heteroatoms from the series S, N and / or O, the ring systems optionally up to 3 times the same or different 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 ^{3 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 and R ^{5 are the} same or different and represent hydrogen or methyl,

a represents a number 1 or 2,

R ^{6 represents} hydrogen, benzyl or straight-chain or branched alkyl having up to 6 carbon atoms,

R ^{7 represents} hydrogen or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms,

and their salts

The compounds of general formula (I) according to the invention can also in

Form of their salts are present. In general, salts with organic and inorganic bases or acids may be mentioned here

The acids which can be added preferably also include hydrohalic acids, such as, for example, the hydrofluoric acid, hydrochloric acid and the hydrobromic acid, in particular the hydrofluoric and chlorine acids

Phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids such as 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 p-toluene sulfonic acid, 1,5-naphthalene disulfonic 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. Sodium, potassium, magnesium or calcium salts, as well as ammonium salts which are 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 may contain up to 4 oxygen, sulfur and / or nitrogen atoms as heteroatoms. 5- and 6 are preferred -linked rings with one oxygen, sulfur and / or up to 4 nitrogen atoms. Are particularly preferred.

Quinolyl, quinoxalinyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl or tetrazolyl.

The compounds of the general formula (I) according to the invention have, like the general formula (II)

shows at least 5 asymmetric carbon atoms (*). They can be present independently of one another in the D or L form, or R or S configuration The invention encompasses 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 ⁸ -CH ₂ -O-CO- or R ⁹ -CO-,

wherein

R ⁸ and R ^{9 are the} same or different and are phenyl, pyridyl, quinolyl,

Quinoxalinyl, furyl, thienyl, pyrryl or pyrimidyl, which may be up to 2 times the same or different by fluorine,

Chlorine, bromine or substituted 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 5 carbon atoms, which may be substituted by phenyl or cyclopropyl, cyclobutyl,

Cyclopentyl or cyclohexyl is substituted,

R ⁴ and R ^{5 are the} same or different and represent hydrogen or methyl,

a represents a number 1 or 2,

R ^{6 represents} hydrogen, benzyl or straight-chain or branched alkyl having up to 5 carbon atoms, R ^{7 represents} hydrogen or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms,

and their salts.

Compounds of the general formula (I) according to the invention are particularly preferred

in which

wherein

R ⁸ and R ^{9 are the} same or different and are phenyl, pyridyl, quinolyl, or

Quinoxalinyl, which are optionally substituted up to 2 times the same or different 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 ^{J represents} straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl or cyclβpentyl or cyclohexyl,

R ⁴ and R ^{5 are} identical or different and represent hydrogen or methyl,

a represents a number 1 or 2,

R ^{6 represents} hydrogen, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,

R ^{7 represents} hydrogen or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, and their salts.

The compounds of the general formula (I) according to the invention can be prepared by:

Aldehydes of the general formula (III)

in which

R ¹ , R ² and R ^{3 have} the meaning given above,

with cysteine derivatives of the general formula (IV)

HS- (CR ⁴ R ⁵ ) _a - (NHR ⁷ ) -CO ₂ R ⁶ (IV)

in which

a, R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,

in inert solvents, if appropriate in the presence of a base.

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

The usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps. These preferably include 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 dimethylsulfoxide, dimethylformamide, hexamethylphosphoric acid, hexamethylphosphate Ethyl acetate, pyridine, triethylamine or picoline It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, dioxane and dioxane / water 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 1 mol to 3 mol, based in each case on 1 mol of the compounds of the general formula (III). The reactions can be carried out under normal pressure, but also under elevated or reduced pressure (for example 0.5 to 3 bar). Generally one works at normal pressure.

The reactions are carried out in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and at normal pressure.

The compounds of the general formulas (IV) and (V) are known or can be prepared by customary methods.

Some of the compounds of the general formula (III) are known or new as species and can be prepared by

[A] compounds of the general formula (VI)

in which

.->

R "has the meaning given above,

D represents an amino protecting group, preferably Boc, Fmoc or Z,

and

E represents benzyl or C, -C ₄ -alkyl, first converted into the free carboxylic acids, then with compounds of the general formula (VII)

in which

R ^{3 has} the meaning given above,

implements

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

R * -L (vm)

in which

R ^{1 has} the meaning given above

and

L is hydroxy, C _j -C ₄ - alkoxy, phenoxy or nitrosubstituiertees a typical carboxylic acid activating radical such as chlorine,

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

Implement tools,

and finally oxidizes the alcohol function,

or

[B] Compounds of the general formula (IX)

in which

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

and

has the meaning of E given above and is the same or different with this.

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

The usual inert solvents which do not change under the reaction conditions are suitable as solvents for all process steps. These preferably include 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 Hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline It is also possible to use mixtures of the solvents mentioned, if appropriate also with water. Methylene chloride, tetrahydrofuran, dioxane and

Dioxane / water. Suitable bases are organic amines, trialkyl (C, -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 1 mol to 3 mol, in each case based on 1 mol of the compounds of the general formulas (VII) and (IX)

The reactions can be carried out under normal pressure, but also under elevated or reduced pressure (for example 0.5 to 3 bar). In general, the reaction is carried out under normal pressure

The reactions are carried out in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and at 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, pyridinium dichromate, pyridinium chlorochromate,

Pyπdin-Schwefeltπoxid-complex or with chlorine and 2,2,6,6-tetramethyl-pιpeπdιn-1-oxyl (TEMPO) [Org Synth 69, 212 (1990)] or Oxalylchloπd [Swern-Oxidaüon (C1COCOC1 / DMSO / CH ₂ C1 ₂ / NEt ₃ ) eg according to RE Ireland et al, J Org Chem 50, 2199 (1985)] The oxidation is preferably carried out with pyridine-sulfur trioxide complex in dimethyl sulfoxide in the presence of triethylamine

[J R Paπkh and W v E Doeπng, J Am Chem Soc 89, 1967, 5505-7]

The oxidation generally takes place 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 carboxyl group is activated as the anhydride. The usual condensation agents, such as carbodiimides such as BN, N'-dimethyl, N, N'-dipropyl, are preferred here -, N, N'-Dιisopropyl-, N, N'-Dιcyclohexylcarbodπmιd, N- (3-Dιmethylamιno- ιsopropyl) -N'-ethylcarbodamιd-Hydrochloπd, or carbonyl compounds such as Carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2 ~ oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l -ethoxy carbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphobate, or 1-hydroxybenzene triazole onates, 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, N-methylmorpholine and 1-hydroxybenzotriazole are particularly preferred.

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 to convert the salts initially formed into the free carboxylic acids by treatment with acid.

The usual inorganic bases are suitable as bases for the saponification.

These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali 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.

The saponification is generally 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 such as 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 formulas (VII) and (VTII) are known per se or can be prepared by customary methods.

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

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 (XI)

in which

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

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

and then, likewise by customary methods, the amino protective 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 (X) and (XI) are known or new and can then be prepared by customary methods

The compounds show an antiviral activity against representatives of the Herpetoviridae group, especially against the human cytomegalovirus

(HCMV)

The anti-HCMV activity was determined in a screening test system in 96-well microplates with the aid of human embryonic pulmonary fibroblasts (HELF) cell cultures. The influence of the substances on the spread of the cytopathogenic effect was compared to that Reference substance

Ganciclovir (Cymevene® sodium), a clinically approved anti-HCMV chemotherapy drug The substances (100 or 50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on microtitre 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 microtitre 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 is added to each well and the plates are incubated at 37 ° C in a CO ₂ incubator for 6 days. After this time, the cell lawn in the substance-free virus controls, starting from 50 - 100 infectious centers, is 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 anti-cellular activity

1) CIC ₅₀ = highest concentration that shows no obvious anti-cellular effects

2) IC ₅₀ = concentration of the compound according to the invention, which has a 50% inhibition

of the CPE

CIC 50

3) SI = selectivity mdex

IC, 50 It has now been found that the compounds of the Vermeh¬ tion of HCMV in HELF cells in some cases inhibit 10-50fach lower concentrations than Cymevene ^® Sodium and partly also are more selective.

The compounds according to the invention are therefore valuable active substances for the treatment and prophylaxis of diseases caused by the human cytomegalovirus. Examples of indications which may be mentioned are:

1) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who often suffer from life-threatening HCMV pneumonitis, encephalitis, and gastrointestinal and systemic HCMV infections

2) Treatment and prophylaxis of HCMV infections in AJDS 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, dragées, 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, that is to say 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 to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg of body weight for intravenous administration to achieve effective results, and for oral administration

Application the dosage is about 0.01 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 route of administration, on the individual behavior towards the drug

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

(2R, S) -N-rN _α - (2,5-dimethyl-pyridyl-3-methyloxycarbonyl) -N ° - (tosyl) -S-arginyl-S-valyl] amino-3-phenyl-propanol

^IX

The title compound is obtained from 2 g (3.57 mmol) N ° tosyl-S-arginyl-S-valine-S-phenylalaninol and 2.16 g (7, 14 mmol) 2 ', 5'-dimethylpyridyl-3-methyl -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) Obtained 2,5-dimethyl-3-hydroxymethylpyridine in 90% yield. Yield: 1.94 g (75.0% of theory) of colorless crystals (without mp) R _f = 0.5 (methylene chloride / methanol = 9/1)

Example II

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

The title compound is prepared from 1.8 g (2.4865 mol) of the compound from Example I, 1.86 g (1 1.686 mmol = 4.7 eq) pyridine-SO ₃ complex and 1.61 ml (11.686 mmol = 4 , 7 eq) Triethylamine at 0 ° C and two hours reaction time. Yield: 1.48 g (82.5% of theory) of colorless crystals R _f = 0.35 (double spot) (dichloromethane / methanol = 100/7).

The compounds listed in Table I were prepared in analogy to the procedure of Example II and the methods which are published in EP 646 597 and EP 646 598.

Table I

3

INS

^{r ζ Λ} n

Manufacturing examples

example 1

(lR, S) -l- [N _α - (2,5-dimethyl-3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-l - ({2R, S} - {4S} -4-carboxythiazolidin-2-yl) -2-phenylethane

^oO

20 mg (0.0277 mmol) of the diastereomeric aldehyde of compound II, (2R, S) -2- [N _α - (2,5-dimethyl-3-pyridylmethyloxycarbonyl-N ^G - (tosyl) -S-arginyl-S -valyl] - amino-3-phenylpropan-al, and 2.5 mg (0.02 mmol) of L-cysteine are dissolved in 5 ml of absolute methanol under an argon atmosphere, heated to 50 ° C. for 2 h and then mixed with water. The precipitate which has separated out is filtered off with suction, washed with water, dried and purified by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 7/3). Yield: 8 mg (22.9% of theory) of colorless foam R _f - (dichloromethane / Methanol = 7/3) = 0.5 MS (FAB) m / z = 825 (M + H) ⁺

Example 2

(lR, S) -l- [N _α - (2,5-dimethyl-3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-l - ({2R, S} - {4S} -4-methoxycarbonylthiazolidin-2-yl) -2-phenylethane

Analogously to the procedure of Example 1, the title compound is prepared from 70 mg (0.097 mmol) of the compound from Example II and 13.1 mg (0.097 mmol) of L-cysteine methyl ester in 10 ml of methanol under an argon atmosphere. Yield: 23 mg (28.3% of theory) of colorless foam R _f (dichloromethane / methanol = 9/1) = 0.5 MS (FAB) m / z = 839 (M + H) ⁺

Example 3

(lR, S) - l - [N _α - (2,5-dimethylbenzyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-l - ({2R, S} - {4S} - 4-methoxycarbonylthiazolidin-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is prepared from 70 mg (0.097 mmol) of the compound from Example III and 13.1 mg (0.097 mmol) of L-cysteine methyl ester in 10 ml pa of methanol under an argon atmosphere. Yield: 40 mg (40.8% of theory) of colorless foam R _f (dichloromethane / methanol = 9/1) = 0.5 MS (FAB) m / z = 838 (M + H) ⁺ Example 4

(lR, S) - l - [N _α - (2,5-Dimethylbenzyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-l - ({2R, S} - {4S} - 4-carboxythiazolidin-2-yI) -2-phenylethane

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

(0.208 mmol) of the compound from Example III and 30 mg (0.2476 mmol) L-

Cysteine in 15 ml methanol p.a. produced under an argon atmosphere.

Yield: 38 mg, colorless foam

R _f (dichloromethane / methanol = 7/3) = 0.5

MS (FAB) m / z = 824 (M + H) ⁺

Example 5

(lR, S) -l- [N _α -2,5-dimethyl-3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] amino-l - ({2R, S} - {4R, S} -4-carboxy-l, 3-thiazan-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is prepared from 100 mg (0.1385 mmol) of the compound from Example II and 18.7 mg (0.1385 mmol) of D, L-homocysteine in 10 ml pa methanol under an argon atmosphere. Yield: 80 mg (68.8% of theory) colorless foam R _f (dichloromethane / methanol = 9/1) = 0.4 MS (FAB) m / z = 839 (M + H) ⁺

Example 6

(l R, S) - l - [N _α -3 -Pyridylmethoxycarb onyl) -N ^G - (tosyl) -S -arginyl -S- tert.butylglycyl] amino-l - ({2R, S} - {4S} -4-carboxythiazolidin-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is prepared from 100 mg (0.141 mmol) of the compound of Example IV and 18 mg (0.148 mmol) of L-cysteine in 10 ml of methanol pa under an argon atmosphere. Yield: 30 mg (26.2% of theory) of colorless foam MS (FAB) m / z = 811 (M + H) ⁺

Examples 7 and 7a

(lR, S) -l- [N _α -3-pyridylmethoxycarbonyl) -N ^G - (tosyl) -R-arginyl-S-tert.butylglycyl] - amino-l - ({2R, S} - {4R} - 4-carboxy-5,5-dimethylthiazolidin-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound

Diastereomer A and diastereomer B and C as a mixture of 50 mg (0.071 mmol) of the compound from Example V and 12 mg (0.08 mmol) of D - (-) - penicillamine in 10 ml of methanol p.a. produced under an argon atmosphere.

Yield: Diastereomer A: 17 mg (28.7% of theory), colorless foam

Rf = 0.5

Dichloromethane / methanol = 4/1

Diastereomer B and C (B / C = 1/2): (40.5% of theory) 24 mg, colorless foam

Rf = 0.35 (running as above)

R _f (dichloromethane / methanol = 4/1) = 0.5

MS (FAB) m / z = 839 (M + H) ⁺

Example 8

(IR or S) -l- [N _α -2,5-DimethylbenzyloxycarbonyI) -N ° - (tosyl) -S-arginyl-S-valyl] - amino-l - ({2R, S} - {4S} - 4-carboxythiazolidin-2-yl) -2-cyclohexylethane

In analogy to the procedure of Example 1, the title compound is made from 70 mg

(0.096 mmol) of the diastereomer B of the compound from Example VI and 12.2 mg

(0.101 mol) L-cysteine.

Yield: 52 mg (65.1% of theory) of colorless foam

R _f = 0.56 (eluent: dichloromethane / methanol = 9/1)

MS (FAB) m / z = 831 (M + H) ⁺

Example 9

(l R, S) - l - [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl-S- tert.butylglycyl] -amino-l - ({2R, S} - {4S} -4-carboxythiazolidin-2-yl) -3-methylbutane

In analogy to the procedure of Example 1, the title compound is 80 mg

(0.1 19 mmol) of the compound from Example VII and 15 mg (0.125 mmol) L-

Made of cysteine.

Yield: 50 mg (54.2% of theory) of colorless foam

R _f = 0.52 (eluent: dichloromethane / methanol = 9/1)

MS (FAB) m / z = 777 (M + H) ⁺

Example 10

(1 R, S) - 1 - [N _α -3-pyridylmethyloxycarbonyl) -N ^G -tosyl-R-arginyl-S-tert.butylglycyl] - amino-l - ({2R, S} - {4R, S} -l, 3-thiazan-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is prepared from 100 mg (0.141 mmol) of the aldehyde from Example V (with D-arginine instead of L-arginine) and 20 mg (0.148 mmol) of D, L-homocysteine. Yield: 18 mg (15.5% of theory) of colorless foam R _f = 0.9 (dichloromethane / methanol = 85/15).

Example 11

(lR, S) -l- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-tert.butyl-glycyl] -amino-l - ({2R, S} - {4R, S} -4-carboxy-l, 3-thiazan-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is prepared from 300 mg (0.424 mmol) of the compound from Example IV and 150 mg (1.1 mmol) of D, L-homocysteine in 20 ml of methanol pa under an argon atmosphere. Yield: 35 mg (10.9% of theory) of colorless foam R _f = (dichloromethane / methanol = 85/15) = 0.12 MS (FAB) m / z = 825 (M + H) ⁺

Example 12

(lR, S) -l- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-tert.butyl-glycyl] -amino-l - ({2R, S} - {4R} -4-carboxy-5,5-dimethylthiazolidin-2-yl) -2-phenylethane

^

In analogy to the procedure of Example 1, the title compound is prepared from 300 mg (0.424 mmol) of the compound of Example IV and 75 g (0.5 mmol) of D - (-) - penicillamine in 20 ml of methanol pa under an argon atmosphere. Yield: 305 mg (85.7% of theory) of colorless foam R _f = (dichloromethane / methanol = 4/1) = 0.5 MS (FAB) m / z = 839 (M + H) ⁺

Example 13

(IR, S) -l- [N _α -3-pyridylmethoxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-tert.butyl] -amino- l - ({2R, S} -3-acetyl- {4S} carboxythiazolidin-2-yl) -2-phenylethane

40 mg (0.049 mmol) of the compound of Example 6 are dissolved in 1 ml of pyridine, 1 ml of water and 1 drop (N15 mg Δ 0.15 mmol) of acetic anhydride are added and the mixture is stirred at room temperature overnight. Everything will be to

Evaporated to dryness, the residue was stirred with 2 ml of water, filtered and dried.

Color Crystals, yield: 20 mg (47.5% of theory)

MS (FAB) m / z = 853 (M + H) ⁺

Example 14

(lR, S) -l- [N _α -3-pyridylmethyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-tert.butyl-glycyl] -amino-l - ({2R, S} - {4R} -4-carboxythiazolidin-2-yl) -2-phenylethane

In analogy to the procedure of example 1, the title compound is prepared from 300 mg (0.424 mmol) of the compound of example IV and 54 mg (0.444 mmol) of D-cysteine in 30 ml of methanol pa under an argon atmosphere. Yield: 200 mg (58.1% of theory) colorless foam R _f = (ethyl acetate / methanol / toluene = 3/4/3) = 0.35 MS (FAB) m / z = 811 (M + H) ⁺

Example 15

(lR, S) -l- [N _α -2,5-dimethylbenzyloxycarbonyl) -N ^G - (tosyl) -S-arginyl-S-valyl] - amino-l - ({2R, S} - {4R , S} -4-carboxy-l, 3-thiazan-2-yl) -2-phenylethane

In analogy to the procedure of Example 1, the title compound is made from 0.4 g

(0.555 mmol) of the compound of Example III and 0.19 mg (0.139 mmol) D, L-

Homocysteine in 25 ml methanol p.a. produced under an argon atmosphere.

Yield: 220 mg (47.4% of theory) of colorless foam

R _f = (dichloromethane / methanol = 85/15) = 0.65 and 0.73

(Diastereomers not separated)

MS (FAB) m / z = 838 (M + H) ⁺

Claims

claims

1. thiazolidin-2-yl and l,

2-thiazan-2-yl-substituted pseudopeptides of the general formula (I)

in which

R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁸ -CH ₂ - O-CO- or R ⁹ -CO-,

woπn

R ⁸ and R ^{9 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 times the same or different are substituted by halogen or by straight-chain or branched alkyl or acyl each with 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 and R are identical or different and represent hydrogen or methyl,

a represents a number 1 or 2,

R for hydrogen or for straight-chain or branched alkyl or

Is acyl each having up to 6 carbon atoms,

and their salts.

Compounds of the general formula (I) according to Claim 1

in which

wherein

R ⁸ and R ^{9 are the} same or different and phenyl, pyridyl. Quinolyl, quinoxalinyl, furyl, thienyl, pyrryl or pyimidyl, 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 5 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

R ⁴ and R ^{5 are the} same or different and represent hydrogen or meth \ 1. a represents a number 1 or 2,

R ^{6 represents} hydrogen, benzyl or straight-chain or branched alkyl having up to 5 carbon atoms,

R represents hydrogen or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms,

and their salts.

3. Compounds of general formula (I) according to claim 1

in which

wherein

R ⁸ and R ^{9 are} identical or different and are phenyl, pyridyl,

Are quinolyl or quinoxalinyl, which are optionally substituted up to 2 times in the same or different manner 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 4 carbon atoms, which is optionally substituted by phenyl or cyclopentyl or cyclohexyl,

R ⁴ and R ^{5 are the} same or different and represent hydrogen or methyl,

a represents a number 1 or 2, R ^{6 represents} hydrogen, benzyl or straight-chain or branched alkyl having up to 4 carbon atoms,

R ^{7 represents} hydrogen or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,

and their salts.

4. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that

Aldehydes of the general formula (III)

in which

R ¹ , R and R have the meaning given above,

with cysteine derivatives of the general formula (IV)

HS- (CR ⁴ R ⁵ ) _a - (NHR ⁷ ) -CO ₂ R ⁶ (IV)

in which

a, R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,

in inert solvents, if appropriate in the presence of a base

5. Medicament containing one or more compounds according to claim 1.

6. Compounds according to claim 1 for combating diseases.

7. Use of compounds according to claim 1 for the manufacture of medicaments.