SK1396A3 - 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: A = CN or CONH2; R1 = a gp. of formula (i)-(iv): R2-R12 = H, OH, halogen, 1-4C alkyl, morpholinyl, Ph, SPh or 3-6C cycloalkyl; a = 0 or 1.

Description

Pseudopeptides with trifluoromethyl substituted 2-azabicyclooctane of formula (I) wherein A is cyano or the radical of formula -CO-NH ₂ - and R ¹ is substituted heteroaryl or substituted aryl are used for the production of antiretroviral agents.

R'-CO-NH

H (D τι / η - 94

PSEUDOPEPTIDS WITH TRIFLUUMMETHYL-SUBSTITUTED 2-AZABICYCLOPACTANE, METHOD OF MANUFACTURING THEREOF AND ACTIVE SUBSTANCES CONTAINING

Technical field

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

BACKGROUND OF THE INVENTION

EP 528 242 discloses trifluoromethyl groups containing pseudopeptides as antiretroviral agents, some of the compounds of the present invention being included in the broadest sense in this publication.

SUMMARY OF THE INVENTION

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

in which

A represents a cyano group or a radical of the formula -CO-NH ₂ ^- and represents a radical of the formula

while

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and are phenyl, hydroxy, hydrogen, halogen, straight or a branched alkyl group having up to 4 carbon atoms, a morpholinyl group, a phenylthio group or a cycloalkyl group having 3 to 6 carbon atoms and a is 0 or 1, and salts thereof.

The compounds of the formula I according to the invention have a plurality of asymmetric carbon atoms.

Rest of Formula (A)

Nhh has 6 asymmetric carbon atoms (), which independently of one another occur 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 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. fumaric 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 from organic amines such as diethylamine , triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephedramine or methyl piperidine.

Preferred are compounds of formula I wherein:

A represents a cyano group or a radical of the formula -CO-NH ₂ - a

R @ 1 - represents a radical of formula wherein

R ⁴

R U t> 6 13 / T} O D χ X \ f £ \ f X \ / X \ / Xx f or. various and are phenyl hydroxy, hydrogen, fluorine, chlorine or bromine, straight or branched (C 3 -C 3) alkyl, morpholinyl, phenylthio, cyclopentyl or cyclohexyl, and

R ³ ,

R ⁴ > 8

R ⁹ ,

R ¹¹ and R ¹² are the same group, and are 0 or 1, and salts thereof.

Particularly preferred are compounds of formula I in which

A represents a cyano group or a radical of the formula -CO-NH ₂ - a

R ¹ is a radical of formula

, 10.9 R

(O-CH ₂ ) _and -

ch ₂ -opncom p2 p3 p4 p5 p6 p7 p8 p9 p10

X \ f X \ / X \ f X \ f X \ f X \ f X \ f X \ f X \!

R ¹¹ and R ¹² are the same phenyl, fluoro, chloro or morpholinyl, or different and represent hydroxy, hydrogen, bromo, methyl, phenylthio, cyclopentyl or cyclohexyl and J is 0 or 1, and their salt.

The present invention further provides a process for the preparation of novel 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

NH ₂ (ΠΙ) optionally with prior activation of the carboxylic acid, in inert solvents and in the presence of a base and / or adjuvant, and when A = CN, is finally reacted with dimethylcarbamoyl chloride also in one of the above solvents.

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

for example

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 furthermore 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 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 methanolate, organic amines such as 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 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 (II).

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 ¹ -diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N, N-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride, N-cyclohexyl-N '- (2-morpholinoethyl) -carbodiimidomethoxy 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-1,2-dihydroquinoline and propanephosphonic anhydride, isobutyl chloroformate, benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophobotate or 1-ethoxycarbonyl phosphate; .

The reactions may be carried out both at normal pressure and at elevated or reduced pressure, e.g.

0.5 MPa, 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 reaction with dimethylcarbamoyl chloride is preferably carried out in pyridine under a protective gas atmosphere.

The reaction is generally carried out at a temperature in the range of 80 ° C to 120 ° C, preferably around 100 ° C.

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 may 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 IV, C ₆ H ₅

W-NbL.CO — NH (IV)

NH ₂ in which

W represents an amino protecting group, preferably a tert-butoxycarbonyl group, i

they are first converted by the epoxidation reaction, optionally by means of base or phase transfer catalysis, to the compounds of formula (V)

W-NH

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

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

Suitable solvents are customary solvents, organic solvents such as 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 methylene chloride, dichloroethane (DCE), chloroform or carbon tetrachloride, and 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 chlorobenzoic acid, magnesium monoperoxyphthalate, dimethyloxirane or methyl (trifluoromethyl) dioxirane. Preference is given to m-chloroperbenzoic acid and magnesium monoperoxyphthalate (see P. Brongham et al., Synthesis (1987), 1015, W. Adam et al., J. Org. Chem. 52, 2800 (1987) and R. 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 tricaprylammonium amide (tricaprylamide) are used as adjuvants. 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 the formulas IV and V are for the most part known (EP 528 242).

The compounds of formula VI 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., Moling 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). The indicated IC ₅₀ values ^refer to the concentration of the substance to the said test conditions, causes a 50% inhibition of the protease.

Table I HIV-1 enzyme assay

Example Inhibition of HIV-1 protease IC ₅₀ (mol / 1) IC _g5 (mol / l) 1 1.8 x 10 ¹¹ 1.9 x ¹⁰ 2 1.7 x 10 ^-11 3.6 x 10 ^-11 3 2.4 x 10 ^-10 2.2 X 10 ⁷ 4 6.0 x ¹⁰ 3.3x10 ~ ⁸ 5 9.5 x 10 ^-11 2.1x10 ~ ⁹ 6 9.6 Oct 10 ^-8 3.3 x 10 “ ⁷ 7 1.3 x 10 ⁷ 3.2 x 10 “ ⁷ 8 2.4 X 10 ⁶ 3.2 X 10 ⁷ 9 ^{1.2.times.10@1} ° 2.6 x 10 ⁹ 10 9.6 x 10 “ ¹⁰ 3.1 x 10 ⁷ 11 1.6 x 10 ^-11 3.6 x 10 ¹¹ 12 1.1 Oct 10 ^-9 3.7 X 10 ¹⁰ 13 1.9 Oct 10 ¹¹ 2.5 X 10 ¹¹ 14 3.5 x 10 ^-9 1.8 X 10 ^-7 15 2.2 X 10 ¹⁰ 2.9 X 10 ⁷ 16 2.0 X 10 ⁷ 2.7 X 10 ⁷ 17 1.9 X 10 ⁷ ., 3.7 X 10 ⁵ 19 1.4 x 10 ^-11

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 in Ficol-Hypaque and stimulated in RPMI 1640 with 20% fetal calf serum with phytohemagglutinin (90 µg / ml) 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 the growth medium so as to contain 1.

C x 10 cells per ml. The infected cells 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 at various concentrations starting from the third vertical row of microtiter plates.

Test substances are incubated at 37 ° C until HIV viral control typically develops syncytes (between 3 and 6 days after infection), which is then 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 8.17 x 10 ~ ⁸ 2 3.85 x 10 “ ⁸ 3 3.5 x 10 ⁸ 4 2.25 x 10 ⁸ 5 6.4 x 10 ⁸ 6 5.8 x 10 ~ ⁸ 7 5.5 x 10 ^-7 8 1.2 x 10 ⁹ 9 2.4 x 10 ⁸ 10 8.0 x 10 ⁸ 11 7:55 x 10 ⁸ 12 7.74 x 10 ⁸ 13 7.3 x 10 ⁸ 14 6.0 x 10 ⁷ 19 6.74 x 10 ⁷

The compounds according to the 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. 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 compound or compounds 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 adjuvant to elucidate enzyme structures and reaction mechanisms, and use as reagents for diagnostics may be mentioned.

Examples of the invention

Starting compounds

Example I

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

HC-OH

HC-OH

I 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 (dec.)

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

Example II

6,7-Dimethylquinoxaline-2-carboxylic acid ₂ c

x '3

CH

CH.

'3

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).

The substituted quinoxaline-2-carboxylic acids listed in Table I are prepared analogously to Examples I and II.

Table I

R '

co ₂ h

Pr. (mixture of position 6 and 7 = 1: 1 X.X. (° C) ^R f ' yield (% xeor.) III ch ₃ 177 0.5 40 IV -about foam 0.5 47 IN foam 0.6 30

= dichloromethane / glacial acetic acid = 90: 10: 2

Example VI

3-Methyl-4,7-dichloroquinoline-2-carboxylic acid ethyl ester

g (0.0187 mol) of 3-methyl-4-hydroxy-7-chloroquinoline-2-carboxylic acid ethyl ester was heated in an oil bath at 140 ° C for 2 hours with 25 ml of phosphorous oxychloride under argon atmosphere. It is then distilled off under vacuum with POCl ₃ and poured carefully over ice water. The precipitate is filtered off, washed with water, dried and recrystallized from dichloromethane / cyclohexane (1: 1).

Yield: 3.8 g (71.0% of theory) of a colorless crystalline substance, m.p .: 104 DEG C. Rf (dichloromethane) = 0.9.

Example VII

3-Methyl-4-morpholinyl-7-chloroquinoline-2-carboxylic acid ethyl ester

Cl

g (3.5 mmol) of the compound of Example VI and 0.4 g (4.5 mmol) of morpholine are mixed with 2 drops of concentrated hydrochloric acid and refluxed in 5 ml of absolute ethyl alcohol for 6 hours. No reaction will take place. After the addition of 1 g (11.25 mmol) of morpholine, it is heated for an additional 12 hours. Concentrate in vacuo and partition the residue by column chromatography (silica gel 60, dichloromethane / ethyl acetate = 100: 5).

Yield: 100 mg (8.5% of theory) of a colorless crystalline substance, m.p .: 74 ° C

Rf (dichloromethane / ethyl acetate = 100: 3) = 0.45.

Example VIII

3-Methyl-4-morpholinyl-7-chloroquinoline-2-carboxylic acid

Dissolve 0.2 g (0.6 mmol) of the compound of Example VII in 5 ml of ethanol, heat to 50 ° C, mix with 1 ml of 1 N sodium hydroxide and stir for 10 minutes at 50 ° C. After cooling, the reaction mixture was treated with 1 ml of 1N hydrochloric acid to give a yellowish precipitate, which was filtered off and dried.

Yield: 130 mg (70% of theory) of a pale yellow crystalline solid, m.p .: 196 ° C

_Rf (methylene chloride / methanol 9: 1) = 0.5.

Example IX (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 was fluorinated with hydrogen fluoride and tetrafluoromethane and the dark brown alkaline suspension (about 200 ml) was filtered off, concentrated in vacuo to ca. The organic phase was 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 g). % of theory) of a slightly brownish oily liquid

Rf = 0.4 (dichloromethane).

Example X (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 oil bath at 130 ° C. 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 XI (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 XII (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 under argon in 5 ml of dimethylformamide, 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 further 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 solid

mp: 162 C HPLC: 97.53%.

Example XIII (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 (methylene chloride / methanol = 1Ó0: 5) (sprayed with ninhydrine).

Production examples

Example 1 (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

N H

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 XIII. The reaction mixture was allowed to stir overnight as the temperature rose to room temperature. The product is then precipitated with water and purified by column chromatography (silica gel 60, dichloromethane / methanol = 100: 5).

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

Example 2

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

The xHCI mg (0.142 mmol) of the compound of Example 1 was dissolved in 1 mL of methanol, treated with 1.42 mL of 0.1 N hydrochloric acid (0.142 mmol), and the resulting clear solution was lyophilized.

Yield: 89 mg (96% of theory) of a colorless foam.

Example 3 (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

NH,

Quinoline-2-carboxylic acid (0.014 g, 0.08 mmol) and HOBT (0.011 g, 0.08 mmol) were dissolved in 5 ml of DMF under argon, cooled to 0 DEG 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 XIII dissolved in 1 ml of dimethylformamide was added and the reaction mixture was allowed to stir overnight while raising the temperature to room temperature. The product is then precipitated by the addition of water, filtered off 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).

Example 4

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

xHCl prepared analogously to mmol) of the compound of the example

The title compound is obtained in Example 2 from 0.5 g (0.8175 3 and 0.82 ml of 0.1 N hydrochloric acid (0.82 mmol). Yield: 0.5 g (96% of theory) of a colorless glassy substances.

Analogously to the previous examples, the following pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane are prepared in Table 1 below.

way podlá pr. tn m m made of orig. zl. z pr. cs ΓΊ ΤΓ  yield. (% of theories) (WITH CM ABOUT m R / dichlórme- chloride / methanol = 100/5) ABOUT* Ό θ ' about G 4J • μ Colorless. foam Colorless. foam Colorless. foam lT * about υ and 1 about at ( 1 about υ 1 they * zz u o x ¹ * zH z z % x Q WHAT about # • M • n Ό C

Example 19

mg (0.08 mmol) of the compound of Example 3 was dissolved in 2 ml of pyridine, treated with 100 mg (0.92 mmol) of dimethylcarbamoyl chloride under argon and heated in a 100 ° C oil bath overnight. After cooling, the mixture was cooled to room temperature.

It is evaporated to dryness in vacuo and the residue is stirred with 5 ml of water and 5 ml of dichloromethane. The organic phase is separated, dried and evaporated to dryness and the residue is separated by column chromatography (silica gel 60, dichloromethane / ethyl acetate 1: 1). Yield: 26 mg (53.6% of theory) of a colorless foam Rf = 0.8 (dichloromethane / ethyl acetate = 1: 1).

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Claims (3)

Pseudopeptides with trifluoromethyl-substituted 2-azabicyclooctane of formula I H (I) wherein A represents a cyano group or a radical of the formula -CO-NH ₂ - a R ¹ represents a radical of formula wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and are phenyl, hydroxy, hydrogen, halogen, straight or a branched alkyl group having up to 4 carbon atoms, a morpholinyl group, a phenylthio group or a cycloalkyl group having 3 to 6 carbon atoms and a is 0 or 1, and salts thereof. Pseudopeptides according to claim 1 of the general formula I, in which A is cyano or a radical vzorca.-CO-NH ₂ - and R ¹ is a radical of formula N where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and are phenyl, hydroxy, hydrogen, fluoro, chloro or a bromine, a straight or branched alkyl group having up to 3 carbon atoms, a morpholinyl group, a phenylthio group, a cyclopentyl group or a cyclohexyl group and a is 0 or 1, and salts thereof. Pseudopeptides according to claim 1 of the general formula I, in which A represents a cyano group or a radical of the formula -CO-NH ₂ - a R ¹ is a radical of formula N where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and are phenyl, hydroxy, hydrogen, fluoro, chloro or bromine, methyl, morpholinyl, phenylthio, cyclopentyl cyclohexyl and group or * a is 0 or 1, T and salts thereof. 4. A method for producing pseudopeptides p substituted 2-azabicyclooctane in general trifluoromethyl of formula I according to The process of claim 1, wherein the carboxylic acids of formula II are reacted R 1 -COOH (II), wherein R ^{1 is} as defined above, with a compound of formula III NH ₂ optionally with prior activation of the carboxylic acid, in inert solvents and in the presence of a base and / or adjuvant, and when A = CN, is finally reacted with dimethylcarbamoyl chloride also in any of the above solvents.