SK1296A3 - Acyled pseudopeptides with trifluoromethyl-substituted 2-azabicyklooctane, manufacturing process thereof and medicaments containing these substances - Google Patents

Abstract

3-Trifluoromethyl-2-azabicyclo(3,3,0)octane peptide analogues of formula (I) and their salts are new: R1 = a gp. of formula (i) or (ii): A, D, E, L and T = H, halogen, 1-4C alkyl, morpholinyl, SPh or 3-6C cycloalkyl; R2 = 1-20C acyl opt. substd. by COOH, 2-6C alkoxycarbonyl or NR3R4; CONR3R4 or P(O)(OR7)(OR8); 1-6C alkoxy (sic) opt. substd. by CHF2, OOCHF2, OCF3 or CF3 or a gp. of formula (iii)-(vi): R3 and R4 = H, Ph or 1-6C alkyl; R7 and R8 = H or 1-4C alkyl.

Description

ACYLATED PSEUDOPEPTIDES WITH TRIFLUUMMETHYL-SUBSTITUTED 2-AZABICYCLOPACTANE, METHOD OF MANUFACTURE AND ACTIVE SUBSTANCES CONTAINING THESE SUBSTITUTES

Technical field

The present invention relates to novel acylated pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane, to a process for their preparation and to antiretroviral agents containing them.

BACKGROUND OF THE INVENTION

EP 594 540 A1 discloses antiretroviral acylated compounds.

SUMMARY OF THE INVENTION

The present invention provides novel acylated pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane of formula I

in which is the remainder of the formula

or

T taking

A, D, E, L and T are the same or different and represent a hydrogen atom, a halogen atom, a straight or branched alkyl group of up to 4 carbon atoms, a morpholinyl group, a phenylthio group or a cycloalkyl group of 3 to 6 carbon atoms;

^R2 is straight or branched acyl having up to 20 carbon atoms optionally substituted with carboxyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or a group of the formula -NR ³ R ^4, wherein

R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 6 carbon atoms, furthermore a radical of the formula -CO-NR ⁵ R ⁶ or P (O) (OR ⁷ ) ( OR ⁸ ), whereby

R ⁵ and R ⁶ have the meanings given for R ³ and R ⁴ and are the same or different with and

R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or a straight or branched alkoxy group of up to 6 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl or the remainder of the formula

-WHAT

and salts thereof.

The compounds of the present invention have multiple asymmetric carbon atoms.

of the general formula

Rest of Formula (A)

(A) has 6 asymmetric carbon atoms (), which independently exist in the R- or -S configuration. Preferred configurations are 1 (R), 2 (R), 3 (S), 4 (S), 5 (S), and 6 (S).

Physiologically acceptable salts of the pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane may be salts of the compounds of the present invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, citric acid. , maleic acid or benzoic acid.

Salts include salts with the usual bases such as alkali metal salts (e.g. sodium or potassium), alkaline earth metal salts (e.g. calcium or magnesium), or ammonium salts derived from ammonia or organic amines such as diethylamine , triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephedrine or methyl piperidine.

Preferred are compounds of formula I wherein:

R ¹ is a radical of formula

while A, D, E, L hydrogen, and T are the same or fluorine, chlorine

a branched alkyl group is morpholinyl, cyclopentyl or various and is hydrogen or bromine, straight or up to 3 carbon atoms, phenylthio or cyclohexyl; and

^R2 is straight or branched acyl having up to 17 carbon atoms optionally substituted with carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -NR ³ R ^4, wherein

R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 4 carbon atoms, furthermore a radical of the formula -CO-NR ⁵ R ⁶ or P (O) (OR ⁷ ) ( OR ⁸ ), whereby

R ⁵ and R ⁶ have the meanings given for R ³ and R ⁴ and are the same or different with and

R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 3 carbon atoms, or a straight or branched alkoxy group of up to 4 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethoxy or the remainder of the formula

-CO-N

-CO-N and their salts.

Particularly preferred are compounds of formula I in which

R ¹ is a radical of formula

while

A, D, E, L and T are the same or different and are a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a phenylthio group, a cyclopentyl group or a cyclohexyl group, and

^R2 is straight or branched acyl having up to 15 carbon atoms optionally substituted with carboxyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or a group of the formula -NR ³ R ^4, wherein

R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 3 carbon atoms, furthermore a radical of the formula -CO-NR ⁵ R ⁶ or P (O) (OR ⁷ ) ( OR ⁸ ), whereby

R ⁵ and R ⁶ have the meanings given for R ³ and R ⁴ and are the same or different with and

R ⁷ and R ⁸ are the same or different and are hydrogen, methyl or ethyl, or are straight or branched alkoxy of up to 3 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or the remainder of the formula

-WHAT

and salts thereof.

The present invention further provides a process for the preparation of novel acylated pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane of formula I, which comprises reacting carboxylic acids of formula II

R ¹ -COOH (II), wherein R ^{1 is} as defined above, with a compound of formula III

(ΙΠ) to the compound of formula IV

wherein R ^{1 is} as defined above, optionally with prior activation of the carboxylic acid in inert solvents and in the presence of a base and / or composition, and in a second step acylation in solvents, optionally in the presence of a base and / or composition.

The process of the present invention can be illustrated by the following reaction scheme.

acid, auxiliary inert auxiliary e.g.

Suitable solvents for all process steps are customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol monoethyl ether, glycodimethyl ether, dioxane or tetrahydrofuran, hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions, halogenated hydrocarbons such as methylene chloride, chloroform or tetrachloride dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Particularly preferred is dichloromethane, dimethylformamide or tetrahydrofuran.

Suitable bases are the customary inorganic or organic bases, depending on the individual process steps. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkali metal alcoholates such as sodium or potassium ethanolate or sodium or potassium methoxide, organic amines such as is, for example, ethyldiisopropylamine, triethylamine, picoline, pyridine or N-methylpiperidine, amides such as sodium amide or lithium diisopropylamide, lithium N-silylalkylamides such as lithium N- (bis) -triphenylsilylamide or lithium alkyls such as for example n-butyllithium.

The bases are used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of the compound of the general formula (ΙΓ).

Suitable adjuvants are preferably condensing agents, which may also be bases, especially when the carboxyl group is activated in the anhydride form. Preferably, conventional condensing agents such as carbodiimides are used herein, for example

N, N'-diethylcarbodiimide, dicyclohexylcarbodiimide, carbodiimide hydrochloride,

N, N'-diisopropylcarbodiimide, N, N'N- (3-dimethylaminoisopropyl) -N'-ethyl-N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide meto-p-toluenesulfonate (CMCT or morpho CDI), carbonyl compounds such as carbonyldiimidazole,

1.2-Oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl 2-dihydroquinoline and propanephosphonic anhydride, isobutyl chloroformate, benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, 1-hydroxybenzotriazole or dimethylaminopyridine.

The reactions can be carried out both at normal pressure and at elevated or reduced pressure, for example in the range of 0.5 to 5 bar, but preferably at normal pressure.

The reactions are generally carried out at a temperature in the range of -20 to 40 ° C, preferably 0 ° C to room temperature.

The acylation is generally carried out in one of the aforementioned ethers or halogenated hydrocarbons, preferably tetrahydrofuran or methylene chloride, at a temperature in the range of -30 ° C to 50 ° C, preferably -10 ° C to room temperature.

Suitable bases and / or auxiliaries for the acylation are in general the abovementioned organic amines and pyridines. Triethylamine and dimethylaminopyridine are preferred.

The bases are used in an amount of 1 mol to 10 mol, preferably 1 mol to 3 mol, based on 1 mol of the corresponding alcohol.

The carboxylic acids of the formula II are known in the case of quinolines, phenyls, pyridyls and biphenyls. Quinoxaline carboxylic acids are partially known or novel and can then be prepared, for example, by reaction of the corresponding phenylenediamines with ozone D-fructose, produced in situ by reaction of phenylhydrazone with sodium nitrite and hydrochloric acid followed by oxidation with hydrogen peroxide solution (see, for example, G. Henseke, Chem. Ber. 91, 1958, 1605-1611 and DE 24 10 852).

The compounds of formula III are new and can be prepared, for example, the compounds of formula V c _p h ₅

W-NK, CO-NH 7 nh ₂ (IN) in which W represents a protecting group butoxycarbonyl, amino groups, preferably

they are first converted into compounds of formula VI by means of an epoxidation reaction, optionally by means of a base or by phase transfer catalysis

W-NH

O ^

(VI)

NH 3 in which W is as defined above and then reacted with 3-trifluoromethyl-2-azabicyclo [3.3.0] octane of formula VII

CF, (VII) in the solvent and the protecting group are cleaved by conventional methods.

Suitable solvents are customary solvents, organic solvents which do not change under the reaction conditions. These include alcohols such as methanol, ethanol or n-propyl alcohol, ethers such as diethyl ether, glycol monomethyl ether, glycol dimethyl ether, dioxane or tetrahydrofuran, hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions, halogenated hydrocarbons such as chlorine , dichloroethane (DCE), chloroform or carbon tetrachloride and further dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane, dimethylformamide and n-propyl alcohol are particularly preferred.

Suitable epoxidation reagents are those known from the literature, such as m-chlorobenzoic acid, magnesium monoperoxyphthalate, dimethyloxirane or methyl (trifluoromethyl) dioxirane. M-chloroperbenzoic acid and magnesium monoperoxyphthalate are preferred (see P. Brongham et al., Synthesis (1987), 1015, W. Adam et al., J. Org. Chem. 52, 2800 (1987) and Curci et al., J Org. Chem., 53, 3890 (1988)).

When the epoxidation is carried out by phase transfer catalysis, for example, organic ammonium chlorides or ammonium bromides such as benzyltriethylammonium chloride or benzyltriethylammonium bromide, methyltrioctylammonium chloride, tetrabutylammonium bromide, or tricapatrylmethylamide36 are used as excipients. Benzyltriethylammonium chloride and benzyltriethylammonium bromide are preferred.

The epoxidation is carried out at a temperature in the range of -10 ° C to 90 ° C, preferably 0 ° C to 60 ° C.

The reactions can be carried out both at normal pressure and at elevated or reduced pressure, for example in the range of 0.5 to 5 bar. Preferably, it is operated at normal pressure.

The compounds of formula (IV) are known and can be prepared, for example, as described above.

The compounds of formulas V and VI are for the most part known (EP 528 242).

The compounds of formula VII are novel and can be prepared, for example, by fluorination of 2-azabicyclo [3.3.0] octane-3-carboxylic acid in the corresponding configuration with HF or SF ₄ .

Surprisingly, it has been found that the compounds of formula I have a markedly potent action against retroviruses. This is demonstrated by the HIV-specific protease enzyme assay.

The results of the examples below were determined using the HIV-testing system described by Hansen, J., Schulze, T., Sukrow, T., Mölling S. and K. (1988), EMBO Journal, 7, no. 6, p. Suitable HIV proteases were incubated with a synthetic peptide that mimics the cleavage site in the gag precursor protein and represents the in vivo HIV protease cleavage site. The resulting synthetic peptide cleavage products are analyzed by RP-HPLC (reverse phase high performance liquid chromatography). Reported _IC50 values applicable to ^the concentration of the substance to the said test conditions, causes a 50% inhibition of the protease activity.

Table I HIV-1 enzyme assay

inhibition HIV-l protease Example IC _5Q (mol / 1) IC _g5 (mol / 1) 1 3.2 x 10 ^-4 not been established 2 1.1 x 10 ⁶ 3.3 x 10 ⁵ 3 1.5 x 10 ⁹ 2.5 X 10 ⁷

In addition, the compounds of the present invention exhibit activity in lentivirus-infected cell cultures. This can be shown in the example of HIV-virus.

HIV-infection in cell culture

The HIV test is carried out with slight modifications according to the method of Pauwels et al. (see Journal of Virological Methods 20 (1988), 309-321).

Normal human blood lymphocytes (PBL) are enriched with Ficol-Hypaque and stimulated in RPMI 1640 with 20% fetal calf serum with phytohemagglutinin (90 μ9 / π »1) and interleukin (40 U / ml). For infection with infectious HIV, PBLs are pelleted and the cell pellets are then suspended in 1 ml of HIV-virus adsorption solution and incubated for 1 hour at 37 ° C.

The viral adsorption solution is centrifuged and the infected cell pellets are introduced into a growth medium such that it contains

x 10 cells per ml. The cells so infected are pipetted into 96-well microtiter plate dishes at 1 x 10 ⁴ cells / dish.

The first vertical row of the microtiter plate contains only growth medium and cells that were not infected but were treated as above (cell control). The second vertical row of the microtiter plate contains only HIV-infected cells (virus control) in the growth medium. The other dishes contain the compounds of the present invention in various concentrations, starting with the third vertical row of microtiter plate dishes.

The test substances are incubated at 37 ° C until the typical viral formation of HIV in the untreated virus control (between days 3 and 6 after infection) is evaluated microscopically. In the unprocessed viral control, about 20 syncytes result under these test conditions, whereas the unprocessed cell control contains no syncytes.

IC ₅₀ values were determined as the concentration of processed and infected cells at which 50% (about 10 syncytes) of virus-induced syncytes were suppressed by treatment with a compound of the present invention.

It has been found that the compounds of the present invention protect HIV-infected cells from virus-induced disruption.

Table II PBL cell culture assay

Example PBL IC _5Q (Mol / 1) 1 1,08 x 10 ~ ⁷ 2 6,12 Draw 10 ^-7 3 1,2 x 10 ⁷

The compounds of the present invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.

Indicative areas in human medicine include:

1. Treatment and prophylaxis of human retroviral infections.

2. Treatment or prophylaxis of diseases caused by HIV I (human immunodeficiency virus, first called HTLV III / LAV) and HIV II (AIDS) and their associated stages such as ARC (AIDS related complex) and LAS (Lymphadenophathy-Syndrome) such as the virus-induced immune deficiency and encelophathy.

3. Treatment or prophylaxis of HTLV-I or HTLV-II infection.

4. Treatment or prophylaxis of the AIDS carrier stage (AIDS carrier status).

Indications in veterinary medicine include:

1. Maedivisna infection (in sheep and goats).

2. Progressive pneumonia virus (PPV) infection (in sheep and goats)

3. Infection of caprine arthritis encephalitis virus (in sheep and goats). ⁴

4. Zwoegerziekte infection with virus (sheep).

5. Anemia virus infection (in horses).

6. Infections caused by feline leukemia virus.

7. Infections caused by feline immunodeficiency virus (FIV).

8. Infections caused by simian immunodeficiency virus (SIV).

Preferred for the indication areas in human medicine are those listed in points 2, 3 and 4.

The present invention also relates to pharmaceutical compositions which, in addition to non-toxic, inert, pharmaceutically acceptable carriers, contain one or more compounds of the formula I or consist of one or more active compounds of the formula I as well as a process for the preparation of such compositions.

The active compounds of the formula I should be present in the pharmaceutical compositions in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight of the total mixture.

In addition to the compounds of formula (I), the above pharmaceutical compositions may also contain other pharmaceutical active ingredients.

The production of the aforementioned pharmaceutical compositions is carried out in a customary manner by known methods, for example by mixing the active compound (s) with the carrier or carriers.

In general, both in human and veterinary medicine, it has proven advantageous to administer the active ingredient or active ingredients in a total amount of about 0.5 to about 500 mg / kg, preferably 1 to 100 mg / kg of body weight per 24 hours to achieve the desired results. , optionally in the form of multiple individual doses. One unit dose contains the active compound (s) preferably in an amount of about 1 to 80 mg / kg, in particular 1 to 30 mg / kg body weight. Depending on the type and body weight of the object being treated, the type and severity of the disease, the type of preparation and the drug being administered, as well as the period or interval at which it is administered, it may be necessary to deviate from the indicated doses.

The compounds of the present invention are enzyme inhibitors and as such may be used for all purposes for which enzyme inhibitors are useful. For example, use in affinity chromatography, use as an aid to elucidate enzyme structures and reaction mechanisms, and use as reagents for diagnostics may be mentioned.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example X

6,7-dimethyl-2- (D-arabo-tetrahydroxy-butyl) quinoxaline

HC-OH

CH ₂ OH

2.0 g (5.58 mmol) of D-fructose-phenylsazone (produced according to CL Butler, J. Am. Chem. Soc. 51, 1929, 3163) are suspended in 12 ml of water, 12 ml of ethyl alcohol and 1.4 ml. of concentrated hydrochloric acid, the suspension is heated to 45 ° C and treated dropwise with a solution of 0.8 g (11.2 mmol) of sodium nitrite in 2.5 ml of water. A dark red clear solution is obtained, which is buffered at room temperature with sodium acetate. It is stirred with 15 ml of ethyl acetate, the dark red organic phase is separated, the aqueous yellow phase is concentrated slightly and mixed with 0.5 g (3.67 mmol) of 4,5-dimethylphenylenediamine. The reaction mixture is heated for 20 minutes on a boiling water bath! and then the yellow precipitate is filtered off. This was stirred with a small amount of methanol, filtered again and dried.

Yield: 0.3 g (29.4% of theory) of a yellow crystalline solid

mp: 190 C (decomposition)

DC: Rf ₍ very poorly soluble) = 0.4 (dichloromethane: methanol = 9: 1).

Example II

6,7-Dimethylquinoxaline-2-carboxylic acid

0.3 g (1.08 mmol) of the compound of Example I is suspended in 10 ml of 10% hydrogen peroxide solution. While stirring, 0.6 g (15 mmol) of solid sodium hydroxide is added while foaming is observed. After stirring for about one hour, a clear solution was obtained. Upon acidification with concentrated hydrochloric acid, a colorless precipitate precipitates, which is filtered off, washed with water and dried.

Yield: 160 mg (73.3% of theory) of a colorless crystalline substance, m.p .: 203 DEG C. (decomposition)

DC: Rf = 0.5 (dichloromethane / glacial acetic acid / methanol = 90: 10: 2).

Example III (S, S, S) -3-Trifluoromethyl-2-azabicyclo [3.3.0] octane

g (0.355 mmol) of (S, S, S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid is fluorinated with hydrogen fluoride and tetrafluoromethane. The dark brown alkaline suspension (about 200 ml) was filtered off, concentrated to about 50 ml in vacuo and extracted three times with 50 ml of dichloromethane. The organic phase is dried, concentrated in vacuo to a small volume (dark brown oil) and separated by column chromatography (silica gel 60, dichloromethane).

Yield: 28.8 g (45.3% of theory) of a slightly brownish oil

Rf = 0.4 (dichloromethane).

Example IV (2R, 3S) -3- (N-Benzyloxycarbonyl) amino-1 - {(S, S, S) -3-trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl) -2-hydroxy-4-phenylbutane

0.3 g (1 mmol) of (2R) - [1- (N-benzyloxycarbonyl) amino-2-phenyl (1S) -ethyl] -oxirane and 0.15 g (0.84 mmol) of the compound of Example IX are dissolved in 2 ml of 2-propanol and stirred for 12 hours in a sealed vessel on a 130 ° C oil bath. After cooling, the contents were concentrated to a small volume and separated by column chromatography (silica gel 60, toluene / ethyl acetate = 100: 5).

Yield: 72 mg (18% of theory) of a colorless foam Rf = 0.2 (toluene / ethyl acetate = 100: 5).

Example V (2R, 3S) -3-Amino-1 - {(S, S, S) -3-Trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl} -2-hydroxy-4-phenylbutane

112 mg (0.235 mmol) of the compound of Example X are dissolved in 15 ml of a mixture of methanol and tetrahydrofuran, palladium on carbon (10%) is added and the mixture is hydrogenated for 2 hours at room temperature. Filtration of the catalyst and evaporation of the solvent gave a slightly yellow oily liquid.

Yield: 80 mg (quant.)

_Rf = 0.6 (dichloromethane / methanol 100: 5).

Example VI (2R, 3S) -3- [N-benzyloxycarbonyl- (L-asparaginyl) amino] - {(S, S, S) -3-trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl) -2-hydroxy -4-phenylbutane

0.074 g (0.28 mmol) of ZL-Asn-OH and 0.038 g (0.28 mmol) of hydroxybenzotriazole are dissolved in 5 ml of dimethylformamide under argon, cooled to 0 ° C in an ice bath and mixed with stirring. 0.119 g (0.28 mmol) of morpho-CDI. The reaction mixture was allowed to stir for 3 hours at 0 ° C and then treated with 0.8 g (0.234 mmol) of the compound of Example XI dissolved in 3 mL of dimethylformamide. The mixture was allowed to warm to room temperature and stirred overnight. Upon addition of water, a colorless precipitate precipitates, which is filtered off, washed with water and dried.

Yield: 87 mg (63.0% of theory) of a colorless crystalline substance m.p .: 162 DEG C. HPLC: 97.53%.

Example VII (2R, 3S) -3 - ((L-asparaginyl) amino-1- (S, S, S) -3-trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl} 2-hydroxy-4- phenylbutane

0.008 g (0.135 mmol) of the compound of Example XII are dissolved in 10 ml of a 1: 1 mixture of methanol and tetrahydrofuran, Pd / C (10%) is added and hydrogenated at room temperature for 2 hours. Filtration of the catalyst and evaporation of the solvent in vacuo gave the product as a colorless oil; Yield: 58 mg (95% of theory)

_Rf = 0.2 (dichloromethane / methanol 100: 5) (sprayed with ninhydrine).

Example VIII (2R, 3S) -3- (quinoxalin-2-yl-L-asparaginyl) amino-1- (S, S, S) 3-trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl) 2-hydroxy-4-phenylbutane

HOBT (0.095 g, 6.7 mmol) and triethylamine (0.071 g, 0.7 mmol) were dissolved in DMF (2 mL) under argon, cooled to -40 ° C and treated dropwise with 0.14 g with stirring. (0.7 mmol) of quinoxaline-2-carboxylic acid chloride in 3 ml of dimethylformamide. The reaction mixture was allowed to react for 2 hours in an ice bath and then treated with 0.3 g (0.657 mmol) of the compound of Example VII. The mixture was allowed to stir overnight while leaving the room. Then, the desired product was subjected to column chromatography (silica gel 60, dichloromethane / ethyl alcohol = 100: 5).

Yield: 130 mg (32.3% of theory) of a colorless foam Rf = 0.5 (dichloromethane / methanol = 100: 5).

The temperature rises to the temperature with water precipitation and cleans

Example IX (2R, 3S) -3- (quinolin-2-yl-L-asparaginyl) amino-1 - {(S, S, S) -3-trifluoromethyl-2-azabicyclo [3.3.0] octan-2-yl } 2-hydroxy-4-phenylbutane

Quinoline-2-carboxylic acid (0.014 g, 0.08 mmol) and HOBT (0.011 g, 0.08 mmol) were dissolved in 5 ml of dimethylformamide under argon, cooled to 0 ° C in an ice bath and treated with 0.034. g (0.08 mol) morpho-CDI. After stirring at 0 ° C for 3 hours, 0.03 g (0.0657 mol) of the compound of Example VII dissolved in 1 ml of dimethylformamide was added and the reaction mixture was allowed to stir overnight at room temperature. The desired product is then precipitated by the addition of water, filtered off, dried and purified by precipitation with methanol and diisopropyl ether.

Yield: 270 mg (67.2% of theory) of a colorless glass Rf = 0.5 (dichloromethane / methanol = 100: 5).

The pseudopeptide with the trifluoromethyl-substituted 2-azabicyclooctane shown in Table I is prepared analogously to the previous examples.

way podlá pr. m made of orig. zl. z pr, yield % teór. j ⁶⁵ s C 'Π>! ζ + J o (U o and ^w -r. 1 ^g O d +) K 6 * about at 0 » • + J • + J Ibezf areb. foam they 2 2 $ o o r> n 2 I • M X

Production examples

Example 1 (2R, 3S) -3- (quinolin-2-yl-L-asparg) aginyl) amino-1 - {(S, S, S) -3-trifluoromethyl-2-azabicyclo [3.3.0] octane- 2-yl) -2- (3-ethoxycarbonyl) propionyl-4-phenylbutane

0.6 g (0.981 mmol) of the compound of Example IX was stirred overnight at room temperature with 0.4 g (3.93 mmol = 0.54 ml) of triethylamine (d = 0.73), 0.32 g (1). 96 mmol = 0.278 ml) of succinic acid ethyl ester (d = 1.15) and 0.6 g (4.92 mmol) of diethylaminopyridine (DMAP) in 15 ml of dried tetrahydrofuran under argon. The batch is then mixed with water, the precipitate is separated, washed with water, dissolved in toluene, dried and concentrated.

Yield: 0.58 g (80% of theory) of a colorless crystalline substance, melting point: 138 DEG C .;

_Rf = 0.6 (dichloromethane / methanol 100: 5)

HPLC: 92.5% recrystallized from dichloromethane / diisopropyl ether => HPLC: 94.2%.

Analogous to that of Ex. 1, the compounds shown in Table 1 are prepared.

Pr. R R ² about ** m.p. (C) / ^ / yieldfbacc.) 1 2 Ολ -CO-CH-, ^k jezf. foam 0,7 * 93.6 3 -co-ch ₃ BEZFO. foam 03 * 93.9 4 -CO-C (CH ₃ ) i BEZFO. foam 03 * - 26.5 5 -CO- (CH ₂ ) ₂ -CH ₃ BEZFO. foam 0,5 ** 89 6 οα -CO-CHICHE ^ BEZFO. foam 03 ** 89 7 -CO-CH ^ CCH- BEZFO. foam 03 ** 79 8 -CO-Adamaatyl BEZFO. pene 0,6 ** i 25

** (dichloromethane / methanol = 100: 4) (dichloromethane / ethyl acetate = 1: 1)

Claims (5)

PATENT CLAIMS Acylated pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane of formula I wherein: R ¹ represents a radical of formula wherein And, D, E, L, and T are the same or different and are hydrogen, halogen, straight or branched alkyl of up to 4 carbon atoms, morpholinyl, phenylthio or cycloalkyl of 3 to 6 carbon atoms, and is straight or branched acyl having up to 20 carbon atoms optionally substituted by a carboxy group, a straight or branched alkoxycarbonyl group having up to 6 carbon atoms or a group of the formula -NR ³ R ⁴ , wherein: R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 6 carbon atoms, furthermore a radical of the formula -CO-NR ⁸ R ⁸ or P (O) (OR 2) ( OR ⁸ ), wherein r ⁵ and R ⁸ have the meanings given for R ³ and R ⁴ -a are the same or different thereto and R? and R ⁸ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or a straight or branched alkoxy group of up to 6 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl the rest of the formula -CO and their salts. Acylated pseudopeptides according to claim 1 of the general formula I, in which R ¹ represents a radical of formula wherein And, D, E, L and T are the same or different and are hydrogen, fluorine, chlorine or bromine, straight or branched (C 3 -C 3) alkyl, morpholinyl, phenylthio or cyclopentyl or cyclohexyl, and ^R2 is straight or branched acyl having up to 17 carbon atoms optionally substituted with carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -NR ³ R ^4, wherein R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 4 carbon atoms, furthermore a radical of the formula -CO-NR 4 R ⁶ or P (O) (OR ⁷ ) ( OR ⁸ ), whereby R ⁵ and R ⁶ have the meanings given for R ³ and R ⁴ and are the same or different with and R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 3 carbon atoms, or a straight or branched alkoxy group of up to 4 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethoxy or the remainder of the formula -WHAT -CO-N -CO-N ^ N V = / and salts thereof. The acylated pseudopeptides of claim 1, wherein: R ¹ represents a radical of formula wherein A, D, E, L and T are the same or different and are a hydrogen atom, a fluorine, chlorine or bromine atom, a methyl group, a phenylthio group, a cyclopentyl group or a cyclohexyl group, and ^R2 is straight or branched acyl having up to 15 carbon atoms optionally substituted with carboxyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or a group of the formula -NR ³ R ^4, wherein R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 3 carbon atoms, furthermore a radical of the formula -CO-NR ⁵ R ⁶ or P (O) (OR ⁷ ) ( OR ⁸ ), whereby R ⁵ and R ⁶ have the meanings given for R ³ and R ⁴ and are the same or different with and R ⁷ and R ⁸ are the same or different and are hydrogen, methyl or ethyl, or are straight or branched alkoxy of up to 3 carbon atoms optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or the remainder of the formula -CO-N HaC CH, -WHAT -CO-N N = J HaC and their salts. Process for the preparation of acylated pseudopeptides with trifluoromethylsubstituted 2-azabicyclooctane of the formula I according to claim 1, characterized in that the carboxylic acid of the formula II is first R @ 1 -COOH (II), in which R ^{@ 1 is} as defined above, is converted by a reaction with a compound of formula III (III) to a compound of formula IV N 1 (IV) wherein R ^{1 is} as defined above, optionally with prior activation of the carboxylic acid, in inert solvents and in the presence of a base and / or adjuvant, and in a second step acylating in inert solvents, optionally in the presence of a base and / or aids. A medicament comprising one or more compounds according to claim 1.