WO1997030075A1

WO1997030075A1 - Oxime- and nitron-substituted pseudopeptides with an anti-viral action

Info

Publication number: WO1997030075A1
Application number: PCT/EP1997/000470
Authority: WO
Inventors: Siegfried Raddatz; Dieter Häbich; Thomas-Joachim Schulze; Thomas Schenke; Jürgen Reefschläger
Original assignee: Bayer Aktiengesellschaft
Priority date: 1996-02-16
Filing date: 1997-02-03
Publication date: 1997-08-21
Also published as: AU1599497A

Abstract

The invention concerns oxime- and nitron-substituted pseudopeptides with an anti-viral action 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 cytomegalviruses.

Description

ANTIVIRAL EFFECTIVE OXIME AND NITRONE SUBSTUTUATED PSEUDOPEPTIDES.

The present invention relates to new antivirally active oxime- and nitrone-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 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-488 041] are known as classes of compounds with anti-cytomegaly activity. The present invention now relates to new antivirally active oxime- and nitrone-substituted pseudopeptides of the general formula (I)

in which

R ^{1 represents} tert-butyloxycarbonyl or a radical of the formula -R ⁴ -CH ₂ -O-CO- or R ⁵ -CO-, in which R ⁴ and R ^{5 are the} same or different and phenyl

or a 5- to 7-membered aromatic, optionally benzo-fused heterocycle with up to 4 heteroatoms from the

Row S, N and / or O stands, the ring systems optionally being substituted up to 3 times identically 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 ^{3 represents} phenyl or straight-chain or branched alkyl having up to 7 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms,

A for a radical of the formula N-OR ⁶ or

in which R ^{6 is} hydrogen or straight-chain or branched alkyl having up to 6

Means carbon atoms which is optionally substituted by phenyl,

R ⁷ denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, 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 such as hydrofluoric acid, hydrochloric acid and Hydrobromic acid, especially hydrofluoric and hydrochloric acids, also 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, lactic acid and sorbic acid and sorbic acid Sulfonic acids such as 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-condensed unsaturated 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. Particularly preferred are: quinolyl, quinoxalinyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl or tetrazolyl.

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

shows at least 3 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 those in which

R ^{1 represents} tert-butoxycarbonyl or a radical of the formula -R ⁴ -CH ₂ -O-CO- or R ⁵ -CO-, in which R ⁴ and R ^{5 are} identical or different and are phenyl, pyridyl, quinolyl,

Furyl, thienyl, pyrryl, pyrimidyl 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 for hydrogen or methyl stands,

R ^{3 represents} phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

A for a radical of the formula N-OR ⁶ or

stands in what

R ⁶ denotes hydrogen or for straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl,

R ⁷ denotes straight-chain or branched alkyl having up to 5 carbon atoms or benzyl, and their salts.

Compounds of the general formula (I) in which

R ^{1 is} tert-butoxycarbonyl or a radical of the formula -R ⁴ -CH ₂ -O-CO- or R ⁵ -CO- in which R ⁴ and R ^{5 are} identical or different and phenyl, pyridyl, quinolyl, or quinoxalinyl mean, which are optionally 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 is} hydrogen or methyl,

R ^{3 represents} phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl or cyclopentyl or cyclohexyl, A for a radical of the formula N-OR ⁶ or

stands in what

R ⁶ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl,

R ⁷ straight-chain or branched alkyl having up to 4 carbon atoms or

Benzyl means, and their salts. Compounds according to the invention of the general are very particularly preferred

Formula (I) in which

R ^{3 represents} isobutyl, benzyl, phenyl or cyclohexylmethyl.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that

Compounds of the general formula (III)

in which

R ¹ , R ² and R ^{3 have} the meaning given above, with compounds of the general formulas (IV) or (IVa) H ₂ NOR ⁶ (IV) R ⁷ -NH-OH (IVa) in which

R ⁶ and R ^{7 have} the meaning given above, in inert solvents and in the presence of a base.

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

Oxime over (IV)

Nitrone over (IVa)

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. 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, dimethyl formamide, hexamethyl aminophosphate, triamethyl aminophosphate, triamethyl aminophosphate, triamethyl aminophosphate, or picolin. 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 for the oxime production, and in the case of the nitrones also pyridine.

Suitable bases are organic amines, trialkyl (C ₁ -C ₆ ) amines such as, for example, triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorphohn. 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 at normal pressure, but also at elevated or reduced pressure (e.g. 0.5 to 3 bar). Generally one works at normal pressure.

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

[A] compounds of the general formula (V)

)

in which

R ^{2 has} the meaning given above,

D represents an amino protecting group, preferably Boc, Fmoc and Z, and E represents benzyl or C ₁ -C ₄ alkyl, first converted into the free carboxylic acids, then with compounds of the general formula (VI)

in which

R ^{3 has} the meaning given above, after removal of the protective group D in a last step, with compounds of the general formula (VII)

R ¹ -L (VII)

in which

R ^{1 has} the meaning given above and

L represents hydroxyl, 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, and finally oxidizes the alcohol group, or

[B] Compounds of the general formula (VIII)

in which

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

E '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 with compounds of the general formula (V) in inert solvents, if appropriate in the presence of a base and / or an auxiliary, and the oxidation is carried out as described above.

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, 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, hexamethylidium triethyl aminophosphate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate, triamethylphosphinate . 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, in each case based on 1 mol of the compounds of the general formulas (V) and (VIII).

The reactions can be carried out at normal pressure, but also at elevated or reduced pressure (e.g. 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 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 potassium permanganate, bromine, Jones reagent, pyridinium dichromate, pyridinium chlorochromate,

Pyridine-sulfur trioxide complex / DMSO or with chlorine and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) [Org. Synth. 69, 212 (1990)] or oxalyl chloride [Swern oxidation (ClCOCOCl / DMSO / CH ₂ Cl ₂ / NEt ₃ ), for example according to RE Ireland et al., J. Org. Chem. 50, 2199 (1985)]. The oxidation with pyridine-sulfur trioxide complex in dimethyl sulfoxide is preferably carried out in the presence of triethylamine

(J.R. Parikh et W.v.E. Doering, 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 present as an activated anhydride. The usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminopropyl) -N ', are preferred here. ethyl carbodiimide hydrochloride, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl -1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 1-hydroxybenzotriazole (HOBT) and as a base, e.g. 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 hydroxides or alkaline earth 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 (for example 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 (VI) and (VII) are known per se or can be prepared by customary methods.

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

in which

R ^{2 has} the meaning given above and

T includes the scope of E and E 'given above, with amino acid derivatives of the general formula (X)

in which

X includes the above-mentioned scope of D and R ¹ , 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, cleaves the amino protecting group, specifically 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.

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

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

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

The anti-HCMV activity was determined in a screening test system in 96-well microtiter plates 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 of the 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 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 × 10 ⁴ non-infected HELF cells in Eagle's MEM (Minimal Essential Medium) with 10% fetal calf serum is placed in each well given and the plates are at

Incubated 37 ° C in a CO ₂ incubator for 6 days. After this time, the cell law 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:

It has now been found that compounds of the invention, the increase of HCMV in HELF cells in some cases lower concentrations inhibit 10-50fach as Cymevene ^® Sodium and partly also act selectively.

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 develop life-threatening HCMV pneumonitis, encephalitis, and gastrointestinal and systemic HCMV infections.

2) Treatment and prophylaxis of HCMV infections in AIDS 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, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the 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 approximately 0.001 to 10 mg / kg, preferably approximately 0.01 to 5 mg / kg of body weight in the case of intravenous administration, in order to achieve effective results, and in the case of oral administration

Application 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 application route, on the individual behavior towards the medicament, the 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.

Starting compounds Example I and Example II

(2R, S) - [N _α -tert.Butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valy1] -3-phenyl-propane-2-al

1 g (1.51 mmol) [N _α -tert.butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-phenyl-alaninol] are dissolved in 5 ml of dry dichloromethane and 5 ml of dried DMSO, to 0 ° C cooled and mixed with 0.98 ml (7.097 mmol) triethylamine and 1.13 g (7.097 mmol) 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 with sodium sulfate and evaporated down in vacuo. The residue is separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5).

There are two diasteromers.

Diastereomer A: Yield = 0.58 g (58% of theory) of colorless foam

Diastereomer B: Yield = 0.31 g (31% of theory) of colorless foam

Diastereomer A: R _f - = 0.2 (dichloromethane / methanol = 95/5)

Diastereomer B: R _f = 0.14 (dichloromethane / methanol = 95/5) Example III and Example IV

(2R, S) -N- [N _α -BenzyloxycarbonyI-N ^G -tosyl-S-arginyl-S-valyl] -3-phenyl-propane-2-al

Analogously to the instructions of Examples I and II, the title compound from 5 g

(7.2 mmol) [N _α -Benzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-phenylalaninol],

4.7 ml (33.84 mmol) of triethylamine and 5.39 g (33.84 mmol) of sulfur trioxide-pyridine complex were obtained.

There are two diastereomers.

Diastereomer A: Yield = 35.1% of theory colorless foam

Diastereomer B: Yield = 17.0% of theory colorless foam

Diastereomer A: R _f = 0.37 (dichloromethane / methanol = 95/5)

Diastereomer B: R _f = 0.32 (dichloromethane / methanol = 95/5)

Example V

(2R, S) -N- [N _α -quinoxalin-2-yl-N ^G -tosyl-S-arginyl-s-valyI] -3-phenyl-propane-2-al

Analogously to the instructions from Examples I and II, the title compound is made

2.3 g (3.21 mmol) (N _α -quinoxaline-2-yl-N ^G -tosyl-S-arginyl-S-valyl) -S-phenylalaninol, 4.03 ml (28.88 mmol) triethylamine and 3.89 g (24.44 mmol) of sulfur trioxide-pyridine complex obtained.

A mixture of diastereomers is obtained which is not separated.

Yield: 1.59 g (69.3% of theory) of light pink crystals

Mp: 107-108.5 ° C

R _f = 0.47 and 0.43 (eluent: dichloromethane / methanol = 9/1).

Example VI

(2R, S) -N- [N _α -tert.Butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycyl] -3-phenyl-propane-2-al

Analogously to the instructions in Examples I and II, the title compound is made from 17.6 g

(26.08 mmol) (N _α -tert.Butyloxycarbonyl-N ^G -S-arginyl-S-tert.butylglycyl) -S-phenylalaninol, 12.4 g = 17 ml (122.58 mmol) triethylamine and 19.5 g (122.58 mmol) sulfur trioxide-pyridine complex.

A mixture of diastereomers is obtained which is not separated.

Yield: 3.91 g (22.3% of theory) of colorless crystals

R _f = 0.52 and 0.46 (eluent: dichloromethane / methanol = 95/5)

Example VII

(2R, S) -N- [N _α -2,6-dichlorobenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycyl] -3-phenyl-propane-2-al

Analogously to the instructions of Examples I and II, the title compound is made from 0.66 g

(0.85 mmol) (N _α -2,6-dichlorobenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycyl-S-phenylalaninol, 1.07 ml (7.64 mmol) triethylamine and 608 mg (3, 82 mmol)

Sulfur trioxide-pyridine complex produced.

The resulting mixture of diastereomers is not separated.

Yield: 640 mg (97.2% of theory) of colorless foam

R _f = 0.31 and 0.26 (eluent: dichloromethane / methanol = 9/1)

Example VIII

(2R, S) -N- [N _α -3-pyridyl-methyloxycarbonyl-N ^G -tosyl-R-arginyl-S-tert.butylglycyl] -3-phenyl-propan-2-al

Analogously to the instructions of Examples I and II, the title compound from 0.571 g

(0.8044 mmol) (N _α -3-pyridylmethyloxycarbonyl-N ^G -tosyl) -R-arginyl-S-tert.butylglycyl-S-phenylalaninol, 1.01 ml (7.25 mmol) triethylamine and 0.577 g

(3.62 mmol) sulfur trioxide-pyridine complex. A mixture of diastereomers is obtained which is not separated.

Yield: 200 mg (35.1% of theory) of colorless foam

R _f (double spot) = 0.49 (eluent: dichloromethane / methanol = 100/7)

Example IX

(2R, 2S) -N- [N _α -3-pyridyl-methyloxycarbonyl-N ^G -tosyl-S-arginyl-S-tert.butylglycyl] -3-phenyl-propan-2-al

Analogously to the instructions in Examples I and II, the title compound is made from 1 g

(0.1408 mmol) (N _α -3-pyridyl-methyloxycarbonyl-N ^G -tosyl) -S-arginyl-S-tert.butylglycyl-S-phenylalaninol, 1.83 ml (13.16 mol) triethylamine and 1 g ( 6.28 mmol) sulfur trioxide-pyridine complex. A mixture of diastereomers is obtained which is not separated.

Yield: 657 mg (65.9% of theory) of colorless foam

R _f = 0.33 and 0.15 (eluent: toluene / ethyl acetate / methanol = 40/40/15)

Example X

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

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 purpose, 100 ml of methanol saturated with hydrogen chloride are added dropwise. Allow to stand overnight, the temperature rising to RT. The solution is used i.V. evaporated to dryness, the residue was stirred with toluene, separated and i.V. dried.

Yield: 33.8 g (98.3% of theory) of colorless crystals, not further characterized.

Example XI

(2R, S) -N- [N _α -tert.Butyl-N ^G -tosyl-S-arginyl-S-valyl3-3-cyclohexyl-2-aminopropanol

4 g (7.6 mmol) of N _α- tert-butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valine 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 RT. The reaction mixture is washed with saturated sodium bicarbonate and with saturated sodium chloride solution, dried with sodium sulfate, evaporated in vacuo to a small volume and separated by column chromatography (silica gel 60, mobile phase: dichloromethane / methanol = 95/5)

R _f = 0.82 and 0.66 (dichloromethane / methanol = 9/1) Example XII

(2R, S) -N- [N ^G -Tosyl-S-arginyl-S-valyl] -3-cycloalkyl-2-aminopropanol

1.96 g (2.94 mmol) of the diastereomer B from Example XI are stirred overnight in 12 ml with dioxane saturated with hydrogen chloride at RT. 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

(Kieselgel 60, eluent: dichloromethane / methanol = 9/1).

Yield: 1.4 g (84.3% of theory) of colorless crystals

R _f = 0.15 (dichloromethane / methanol = 9/1).

Example XIII

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

In analogy to the procedure of Example XI, the title compound is prepared from 1.4 g (2.19 mmol) of the compound from Example XII 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 XIV

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

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

(1.37 mmol) of the compound from Example XIII 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 XV

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. With stirring, the mixture is cooled to 0 ° C. and 38.6 g (0.152) of iodine, dissolved in 100 ml of THF, are added dropwise. The mixture is then heated to boiling overnight. After cooling, methanol is added until a clear solution is obtained. After evaporation of the solvents i.V. (Rotavapor) is taken up in 300 ml of 20% potassium hydroxide solution. The mixture is stirred for 3 hours at room temperature, extracted three times with 100 ml of dichloromethane, the combined dichloromethane solution is shaken 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 = 1.45 1

Example XVI

N _a -tert.Butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valine

91.48 g (0.148 mol) N _α -butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valine-S-benzyl ester are dissolved in 800 ml of ethanol, 9.34 g of Pd / C are added under an argon atmosphere and Hydrogenated at RT overnight (6.5 l added). The catalyst is filtered off and the filtrate is evaporated to dryness.

Yield: 78 g (quantitative) colorless crystals

R _f = 0.75 (dichloromethane / methanol = 9/1)

Example XVII

N _α- tert-butyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-leucinol

9.6 g (18.22 mmol) of the substance from Example XVI, 2.7 g (20 mmol) of HOBT and 3.83 g (20 mmol) of N-cyclohexyl-N '- (2-morpholinoethyl) 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 XV and 2.59 g of Δ 3.5 ml (20 mmol) of diisopropylethylamine in 100 ml of dichloromethane is then added dropwise at 0.degree. The mixture is stirred overnight, the temperature rising to RT. 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 XVIII

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

10.5 g (16.77 mmol) of the compound from Example XVII are stirred overnight at RT with 200 ml of dioxane saturated with hydrogen chloride. Then you steam i.V. the solvent is removed, the residue is taken up in 200 ml of ethyl acetate and the mixture, which is initially heterogeneous, is stirred for one hour with saturated sodium bicarbonate solution. The organic phase is separated off, the aqueous phase is extracted twice more 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 i.V. to dry out.

Yield: 8.5 g (96.3% of theory) of colorless crystals

R _f = 0.23 (dichloromethane / methanol = 9/1)

Example XIX

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

Analogous to Daniel F. Veber, J. Org. Chem. 42, 20, 1977 p. 3286-8 the title compound is prepared 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 XX N _α -2,5-Dimethylbenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl-S-leucinol

3.85 g (7.32 mmol) of the substance from Example XVIII and 3.3 g (10.98 mmol) of the substance from Example XIX are dissolved in 20 ml of dioxane, mixed with 20 ml of water and stirred at RT for 48 hours. The solvents are used i.V. evaporated and the residue 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 XXI

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

1 g (1.453 mmol) of the compound from Example XX 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 added. 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 i.V. evaporated. 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

(2S) -2- [N _α - (3-pyridinyl-methoxycarbonyl) -N ^G - (4-tosyl) -R-arginyl-S-tert.butylglycinyl] amino-3-phenyl-propan-1-ol

A stirred suspension of 1.3 g (2 mmol) of (2S) -2- [N ^G - (4-tosyl) -R-arginyl-S-tert.butylglycinyI] -amino-3-phenylpropan-1-ol [prepared according to methods known from the literature, using the commercially available Boc- (R) Arg (Tos) -OH [see DE 43 31 134 Example 2] and 1.1 g (4 mmol) of 4-nitrophenyl-3-pyridinylmethyl carbonate [prepared by DF Veber et al., J. Org. Chem. 42, 1977, 3286] in 10 ml of dioxane and 10 ml of water is obtained by the constant addition of aqueous 2N sodium hydroxide solution

(approx. 2.5 ml) kept at pH 7.5 and stirred overnight at room temperature. The reaction mixture is then stirred into a mixture of 25 ml of 1N citric acid and 20 ml of ethyl acetate. The aqueous phase is separated off, adjusted to pH 9 by adding 2N sodium hydroxide solution and extracted three times with 20 ml of ethyl acetate each time. The combined organic extracts are dried over magnesium sulfate, the solvent i.V. evaporated and the residue precipitated with dichloromethane / diethyl ether.

Yield: 1.1 g (77.4% of theory) of colorless crystals

Fp .: from 95 ° C (decomp.)

R _f = 0.15 (dichloromethane / methanol = 9/1)

MS (FAB) m / z = 710 (M + H) ⁺ Example XXIII

(2R, S) -2- [N _α - (3-pyridinyl-methoxycarbonyl) -N ^G - (4-tosyl) -R-arginyl-S-tert.butylglycyl] amino-3-phenylpropan-1-al

In analogy to the procedure of Example I, the title compound is prepared from 2.0 g (2.82 mmol) of the compound from Example XXII and 2.1 g (13.2 mmol) of sulfur trioxide-pyridine complex.

Yield: 1.52 g (76.4% of theory) of colorless foam as a mixture of diastereomers R _f (dichloromethane / methanol = 4/1) = 0.38 or 0.2

Example XXIV

N _α- tert-butoxycarbonyl-N ^G - (4-tosyl-R-arginyl-S-tert-butylglycyl-S-2-amino-2-phenylethanol

5.4 g (10 mmol) of the substance from Example (XVI), 2.7 g (20 mmol) of HOBT and

2.11 g (1 1 mmol) of N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide are combined at 0 ° C. and stirred for 20 minutes at this temperature. Then 1.37 g (10 mmol) of S-2-aminophenylethanol and 1.9 ml (11 mmol) of diisopropylethylamine in 30 ml of dichloromethane are added dropwise at 0 ° C. and the mixture is stirred overnight at room temperature. It is washed with saturated sodium bicarbonate solution, with

Water and with saturated sodium chloride solution, dried over sodium sulfate, concentrated and chromatographed (silica gel 60, methylene chloride / methanol 95: 5).

Yield: 2.74 g (41% of theory)

R _f = 0.53 (methylene chloride / methanol = 95: 5)

Example (XXV)

N ^G - (4-Tosyl) -S-arginyl-S-tert-butylglycyl-S-2-amino-2-phenylethanol dihydrochloride

2.46 g (3.7 mmol) of the compound from Example (XXIV) are dissolved in 30 ml of dioxane saturated with HCl and stirred overnight at room temperature. The mixture is concentrated, taken up in methanol / toluene and concentrated again. It is then dried in a high vacuum.

Yield: 2.65 g (quantitative)

Example XXVI

N _α -2,5-Dimethylbenzyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-tert-butylglycyl-S-2-amino-2-phenylethanol

Analogously to Example (XX), the title compound is prepared from 2.6 g (3.6 mmol) of the substance from Example (XXV) and 2.46 g (8.18 mmol) of the substance from Example (XI).

Yield: 2.14 g (72% of theory)

R _f = 0.55 (dichloromethane / methanol = 95: 5)

Example (XXVII)

(2R, S) - [(N _α -2,5-dimethylbenzyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-tert-butylglycyl] -2-aminophenylacetaldehyde

Analogously to Example (XXI), the title compound is prepared from 2.13 g (2.95 mmol) of substance from Example (XXVI) with 2.21 g (13.9 mmol) of sulfur trioxide-pyridine complex in 20 ml each of dichloromethane and dimethyl sulfoxide.

Yield: 1.62 g (76% of theory)

R _f = 0.56 (dichloromethane / methanol = 95: 5)

Manufacturing examples

Example 1 and Example 2

(R or S) - (E / Z) - [N _α -tert.Butyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-valyl] -3-phenyl-propanaloxime-O-methyl ether

0.5 g (0.759 mmol) of the compound from Example I are dissolved in 2.95 ml (12.14 mmol) of pyridine and 75 mg (0.896 mmol) of O-methylhydroxylamine hydrochloride are added with stirring. After 4.5 h, the starting compound is still present according to the DC. A further 37 mg (0.448 mmol) of O-methylhydroxylamine hydrochloride are added and the mixture is left to react overnight. After dilution with 50 ml of water, the mixture is extracted 3 times with 30 ml of ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated to a small volume in vacuo. The residue is separated by column chromatography (silica gel 60, dichloromethane / methanol = 95/5)

Diastereomer A, R or S, E or Z product, yield: 30 mg (5.7% of theory) color.

foam

Diastereomer B, R or S, Z or E product, yield: 330 mg (63.2% of theory) of color foam

Diastereomer A, R or S, E or Z product, R _f = 0.43 (dichloromethane / methanol 9/1)

Diastereomer B, R or S, Z or E product, R _f = 0.39 (dichloromethane / methanol 9/1)

The compounds listed in Table 1 are prepared in analogy to the instructions in Examples 1 and 2:

Example 33 and Example 34

(2R or S) - (1E or Z) -N- [N _α -2,5-dimethylbenzyloxycarbonyl-N ^G - (4-tosyl-) S-arginyl-S-valyl] -3-cyclohexyl-2-aminopropanal- oxime and (2S or R) - (1Z or E) -N- [N _α -2,5-dimethylbenzyloxycarbonyl-N ^G -tosyl-S-arginyl-S-valyl] -3-cyclohexyI-2-aminopropanal oxime

Analogously to the instructions in Examples 1 and 2, the title compounds are prepared from 80 mg (0.11 mol) of the compound from Example XIV, 0.4 ml (5.28 mmol) of pyridine and 9 mg (0.13 mmol) of hydroxylamine hydrochloride .

Diastereomer A, yield; 44 mg (53.9% of theory) fbl. foam

Diastereomer B, yield: 7.7 mg (9.4% of theory) fbl. foam

Diastereomer A, R _f = 0.54 (dichloromethane / methanol = 9/1)

Diastereomer B, R _f = 0.48 (dichloromethane / methanol = 9/1)

Example 35 and Example 36

N- [N _α -2,5-Dimethylbenzyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-valyl] - (R, S) -leucinal- (E and Z) -oxime

In analogy to the instructions in Examples 1 and 2, the title compound is prepared from 100 mg (0.146 mg) of the compound from Example XXI, 0.6 ml (6.99 mmol) of pyridine and 12 mg (0.175 mmol) of hydroxylamine hydrochloride.

Yield: 46 mg (45.0% of theory) of colorless foam

R _f = 0.45 (dichloromethane / methanol = 9/1)

Example 37 and Example 38

(R, S) -N- [N _α -3-pyridylmethyloxycarbonyl-N ^G - (4-tosyI) -R-arginyl-S-tert.butylglycyl] phenylalaninal (E or Z) oxime

In analogy to the instructions of Examples 1 and 2, the title compounds are prepared from 200 mg (0.283 mmol) of Example XXII, 1.1 ml (13.56 mmol) of pyridine and 24 mg (0.34 mmol) of hydroxylamine hydrochloride.

E or Z, R or S, fbl. Foam, yield: 15 mg (7.3% of theory)

Z or E, S or R, fbl. Foam, yield: 34 mg (16.6% of theory)

E or Z, R or S, R _f = 0.31 (dichloromethane / methanol = 9/1)

Z or E, S or R, R _f = 0.251 (dichloromethane / methanol = 9/1)

Example 39

R, SN- [N _α -3-pyridylmethyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-tert.butylglycyl] phenylalaninal (E / Z) oxime

In analogy to the instructions in Examples 37 and 38, the title compound is prepared from 200 mg (0.283 mmol) of the compound from Example VIII, 30 mg (0.426 mmol) of hydroxylamine hydrochloride and 3.5 ml (0.43 mmol) of pyridine. There is an E / Z mixture that is not separated.

Yield: 177 mg (86.7% of theory) of colorless foam

R _f = 0.5 (eluent. Dichloromethane / methanol = 100/7).

Example 40

2- (R / S) - [N _α -Benzyloxycarbonyl-N ^G - (4-tosyl) -S-arginyl-S-valyl] phenylalaninal-N-methylnitrone

0.5 g (0.72 mmol) of the compound from Example (III) / (IV) are placed in 2.8 ml of pyridine, and a total of 144 mg (1.73 mmol) of N-methylhydroxylamine hydrochloride are added. The mixture is stirred overnight at room temperature, water is added and the mixture is extracted with ethyl acetate. It is dried with sodium sulfate, concentrated and chromatographed (silica gel 60, dichloromethane / methanol = 95: 5).

Yield: 0.23 g (46% of theory)

R _f = 0.45 (dichloromethane / methanol = 9: 1)

The compounds listed in Table 2 are prepared in analogy to the procedure of Example 40.

Claims

claims

1 pseudopeptides of the general formula (I)

in which

R ^{1 is} tert-butyloxycarbonyl or a radical of the formula -R ⁴ -CH ₂ - O-CO- or R ⁵ -CO-, in which

R ⁴ and R ^{5 are the} same or different and 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 being up to 3 times the same or different by halogen or by straight-chain or branched alkyl or acyl are each substituted with up to 6 carbon atoms,

R ^{2 represents} hydrogen or methyl,

R ^{3 represents} phenyl or straight-chain or branched alkyl having up to 7 carbon atoms, which is optionally substituted by phenyl or cycloalkyl having up to 6 carbon atoms, A represents a radical of the formula N-OR ⁶ or

stands in what

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

R ⁷ denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, and their salts.

2. Compounds of general formula (I) according to claim 1, in which

R ^{1 is} tert-butoxycarbonyl or a radical of the formula -R ⁴ -CH ₂ -O- CO- or R ⁵ -CO-, in which

R ⁴ and R ^{5 are the} same or different and are phenyl, pyridyl, quinolyl, furyl, thienyl, pyrryl, pyrimidyl or

Are 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 ^{3 represents} phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, A for a radical of the formula N-OR ⁶ or

stands in what

R ⁶ denotes hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by phenyl,

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

R ^{1 represents} tert-butoxycarbonyl or a radical of the formula -R ⁴ -CH ₂ -O- CO- or R ⁵ -CO-, in which R ⁴ and R ^{5 are} identical or different and are phenyl, pyridyl,

Are quinolyl or quinoxalinyl, 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 for phenyl or for straight-chain or branched alkyl with up to

5 carbon atoms, which is optionally substituted by phenyl or cyclopentyl or cyclohexyl, A for a radical of the formula N-OR ⁶ or

stands in what

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

R ⁷ denotes straight-chain or branched alkyl having up to 4 carbon atoms or benzyl, and their salts.

4. Compounds of general formula (I) according to claim 1, in which

R ^{3 represents} isobutyl, benzyl, phenyl or cyclohexylmethyl.

5. Compounds of the general formula (III)

in which

R ¹ , R ² and R ^{3 have} the meaning given above, with compounds of the general formulas (IV) or (IVa)

H ₂ NOR ⁶ (IV) R ⁷ -NH-OH (IVa) in which

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

7. Compounds according to claim 1 for combating diseases.

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