NZ280729A

NZ280729A - Pseudopeptides having a trifluoromethyl-substituted 2-azabicyclooctane; medicaments

Info

Publication number: NZ280729A
Application number: NZ280729A
Authority: NZ
Inventors: Siegfried Raddatz; Hanno Wild; Dieter Habich; Wolfgang Roben; Jutta Hansen; Arnold Paessens; Kerstin Henninger
Original assignee: Bayer Ag
Priority date: 1995-01-04
Filing date: 1995-12-21
Publication date: 1996-08-27
Also published as: NO960016L; NO960016D0; CN1134940A; KR960029345A; IL116622A0; EP0720987A1; HUT74805A; CA2166374A1; HU9503927D0; FI960015A; PL312146A1; JPH08259594A; FI960015A0; DE19500120A1; AU4067895A; CZ1296A3; SK1296A3

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £80729 Priority Date(8):... Ari.:;.3£< Complete Specification Filed: .£.'.7 Claes: (6) Publication Date: &.fl..AU.G..f99& P.O. Journal No: ....!&£? N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION NEW ACYLATED PSEUDOPEPTIDES CONTAINING A TRIFLUOROMETHYL-SUBSTITUTED 2»AZABICYCLOOCTANE We, BAYER AKTIENGESELLSCHAFT, a Company registered under the laws of the Federal Republic of Germany of, D-51368 Leverkusen, Federal Republic of Germany, do hereby declare the invention, for which we pra > that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (Followed by 1A) N.Z. PATENT OFFICE 2 1 DEC 1995 RECEIVED f 280729 BAYER AKHENGESELLSCHAFT Konzemzentrale RP Patente Konzem New agylated pseudopeptides containing a trifluoromethvl-snhstitiited The present invention relates to new acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane, a process for their preparation and their use as antiretroviral agents. The publication EP 594 540 A1 discloses antiretroviral acyl compounds. The present invention relates to new acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane, of the general formula (I) -h 0) nha in which R1 represents a radical of the formula 280729 wherein A, D, E, L and T are identical or different and denote hydrogen, halogen, straight-chain or branched alkyl having up to 4 carbon atoms, morpholinyl, phenylthio or cycloalkyl having 3 to 6 carbon atoms, represents straight-chain or branched acyl having up to 20 carbon atoms, which is optionally substituted by carboxyl, by straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, represents a radical of the formula -CO-NR5R6 or P^XOR'XOR8), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched alkoxy having up to 6 carbon atoms, 280729 which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula -co-N'^Vs kP H3C CH, -N O HjC-^ ^ H3C or -CO-N^N W and their salts. The compounds of the general formula (I) according to the invention have several asymmetric carbon atoms. Hie radical of the general formula (A) has 6 asymmetric carbon atoms (*), which are present independently of one another in the R- or S-configuration. The configurations 1(R), 2(R), 3(S), 4(S), 5(S) and 6(S) are preferred Physiologically acceptable salts of the acylated pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane can be salts of the substances according 280729 to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are e.g. those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid Salts which may be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephedrinamine or methyl-piperidine. Preferred compounds of the general formula (I) are those in which R1 represents a radical of the formula wherein A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, straight-chain or branched alkyl having up to 3 carbon atoms, morpholinyl, phenylthio, cyclopentyl or cyclohexyl, R2 represents straight-chain or branched acyl having up to 17 carbon atoms, which is optionally substituted by carboxyl, straight-chain or branched alkoxycarbonyl wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, 5 represents a radical of the formula -CO-NR5R6 or PCOXORTXOR8), wherein 280729 having up to 4 carbon atoms or by a group of the formula -NR3R4, R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen or straight-chain or 10 branched alkyl having up to 3 carbon atoms, f or represents straight-chain or branched alkoxy having up to 4 carbon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula HjC OH, -C°-V'T) -NX0 ■ V-\-/ h,c -co -CO-N^N or w IS and their salts. Particularly preferred compounds of the general formula (I) are those -5- • 280729 in which R1 represents a radical of the formula A E L kj KX " SXX wherein 5 A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, phenylthio, cyclopentyl or cyclohexyl, R2 rqpresents straight-chain or brandied acyl having up to 15 carbon atoms, which is optionally substituted by carboxyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, represents a radical of the formula -CO-NR5R6 or PCOXOR^KQR8), wherein 15 R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, ^ 10 R7 and R8 are identical or different and denote hydrogen, methyl or ethyl, Jua no mi ruiLitJiimiii.i.iui -6- or represents straight-chain or brandied alkoxy having ujybQcAoireil<Qs,i which is optionally substituted by difluoromethyl, amuoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula -co h,c or and their salts. A process for the preparation of the compounds of the general formula (I) according to the invention has additionally been found, characterized in that first carboxylic acids of the general formula (H) R'-COj-H (ID in which R1 has the meaning indicated above, are converted by reaction with the compound of the formula (EI) 280729 H (in) in which R1 has the meaning indicated above, if appropriate with prior activation of the carboxylic acid, in inert solvents and in the 5 presence of a base and/or of an auxiliary, and in a second step an acylation is carried out in inert solvents, if appropriate in the presence of a base and/or of an auxiliary. The process according to the invention can be illustrated by way of example by the following reaction scheme: r into the compounds of the general formula (TV) ""YYl ♦ ""v co-NI H»C NH, MorphoCCH hobt r hp'j^m^co-nh^co-ni -i 2807 hjc-h,c- dmap h,c. tea H,C YYl X „,..Ci...,„ ;-1<^N^co-nh^co-N^Y^^N>J Tf, Suitable solvents for all process steps are the customary inert solvents which do not change undo: the reaction conditions. These preferably include organic solvents such as ethers, e.g. diethyl ether, glycol monomethyl or dimethyl ether, dioxane or tetrahydrofiiran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions, or halogenohydrocaibons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dimethylformamide and tetrahydrofiiran are particularly preferred. Suitable bases, depending on the individual process steps, are the customary inorganic or organic bases. These preferably include alkali metal hydroxide such as, for example, sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or alkali metal alkoxides such as, for example, sodium or potassium methoxide, or sodium or potassium ethoxide, or organic amines such as ethyldiisopropylamine, triethylamine, picoline, pyridine, dimethylaminopyridine or N-methylpiperidine, or amides such as sodium amide or lithium diisopropylamide or lithium N-silylalkylamides, such as, for example, lithium N-(bis)triphenylsilylamide or I T lithium alkyls such as n-butyliithium. The base is employed in an amount from 1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the compounds of the general formula (II). Suitable auxiliaries are preferably condensing agents which can also be bases, in particular if the carboxyl group is present in activated form as an anhydride. The customary condensing agents are preferred here, such as carbodiimides, e.g. N,"NP-diethyl-, N^-diisopopyl-, NjN'-dicyclohexylcarbodiimide, N-{3 -dimethylaminoiso-propyl)-N-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide metho-p-toluenesulphonate (CMCT or morpho-CDI), or caibonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium confounds such as 2-ethyl-5 -phenyl-1,2-oxazolium-3 -sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l -ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tri(dimethylamino)phosphanium hexafluorophosphate, 1-hydroxy-baizotriazole or dimethylaminopyridine. The reactions can be carried out either at normal pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at normal pressure. The reaction is in general carried out in a temperature range from -20°C to -+40°C, preferably from 0°C to room temperature. The acylation is in general carried out in one of the abovementioned ethers or halogenohydrocarbons, preferably tetrahydrofiiran or methylene chloride, in a temperature range from -30°C to +50°C, preferably from -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 base is employed in an amount from 1 mol to 10 mol, preferably from 1 mol to 3 mol, relative to 1 mol of the respective alcohol. if j'l JUU1I i'UIUIIWtUUiHnw -10- 280729 210729 ie carboxylic acids or In the case of the quinolines, phenyls, pyridyls and biphenyls, the carboxylic acids or the general formula (II) are known per se. The quinoxaline-carboxylic acids are known in some cases or are new and can then be prepared, for example, by reaction of the corresponding phenylenediamines with die osone of D-fructose - prepared in situ by reaction of the phenylhydrazone with NaNQ and hydrochloric acid - and subsequent oxidation using H2p2 solution [cf. for this G. Henseke, Chan. Ber. 91,1958, 1605-11 and DE 24 10 852]. The compound of the general formula (HI) is new and can be prepared, for example, by converting compounds of the general formula (V) W represents an amino protective group, preferably tert-butoxycarbonyl, first using an epoxidalion reaction, if appropriate with the aid of a base or a phase-transfer catalyst, into the compounds of the general formula (VI) c-h, (V) nh2 in which (VI) NHj in which 280729 W has the meaning indicated above, and then reacting with 3-trifIuoromethyl-2-azabicyclo[3.3.0]octane of the formula (VII) in solvents and removing the protective group according to customary methods. Suitable solvents are the customary organic solvents which do not change under the reaction conditions. These preferably include organic solvents such as alcohols, e.g. dimethyl ether, dioxane or tetrahydrofiiran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions, or halogenohydrocarbons such as methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Di chloromethane, dichloroethane, dimethylformamide and n-propanol are particularly preferred. Suitable reagents for the epoxidation are the compounds known from the literature, such as, for example, m-chlorobenzoic acid, magnesium monoperoxyphthalate, dimethyldioxirane or methyl(trifluoromethyl)dioxirane. m-Chloroperbenzoic acid and magnesium monoperoxyphthalate are preferred [cf. 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)]. H methanol, ethanol or n-propanol, ethers, e.g. diethyl ether, glycol monomethyl or If the epoxidation is carried out with the aid of the phase-transfer catalyst, the 280729 auxiliaries used are, for example, organic ammonium chlorides or bromides such as, for example, benzyltriethylammonium chloride or bromide, methyltrioctylammoniuni chloride, tetrabutylammonium bromide or tricapiylmethylammonium chloride (Aliquat 336). Benzyltriethylammonium chloride and bromide are preferred. The epoxidation is carried out in a temperature range from -10°C to +90°C, preferably from 0°C to +60°C. The reactions can be carried out either at normal pressure or at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at normal pressure. The compounds of the general formula (TV) are known and can be prepared, for example, as described above. The compounds of the general formulae (V) and (VI) are in the main known [cf. EP 528 242]. The compound of the general formula (VII) is new and can be prepared, for example, by fluorination of 2-azabicyclo[3.3.0]octane-3-carboxylic acid in the respective configuration using HF and SF4. It has surprisingly been found that the compounds of the general formula (I) have an extremely strong action against retroviruses. This is confirmed using an HIV-specific protease enzyme test The results of the examples shown below were determined according to the HTV test system described in the following literature references [cf. Hansen, J., Billich, S., Schulze, T., Sukrow, S. and Mftlling, K. (1988), EMBO Journal, Vol. 7, No. 6, pp. 1785 - 1791]: purified HTV protease was incubated with synthetic peptide which imitates a cleavage site in the Gag precursor protein and is an in vivo cleavage site of HTV protease. The resulting cleavage products of the synthetic peptide were analysed by means of reverse phase high performance liquid chromatography (RP-HPLC). The ICjo values indicated relate to the substance concentration which, under the I I 2807 abovementioned test conditions, causes a 50% inhibition of protease activity. Enzyme assay, HTV-1 Table I HIV-1-protease inhibition Example No. IQ» [mol/1] IG* [mol/I] 1 3.2 x 10"4 at 2 1.1 x 10* 3.3 x 10"5 3 1.5 x 10"9 2.5 x lO45 10 The compounds according to the invention additionally showed action in lentivirjs-infected cell cultures. It was possible to show this as exemplified by the HTV virus. HTV infection in cell culture The HTV test was carried out with slight modifications according to the method of Pauwels et al. [cf. Journal of Virological Methods 20, (1988), 309-321]. Normal human blood lymphocytes (PBLs) were enriched by means of Ficoll-Hypaque and stimulated in RPMI 1640 and 20% foetal calf serum with phytohaemagglutinin 15 (90 fig/ml) and interleukin-2 (40 U/ml). For infection with the infectious HTV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HTV virus adsorption solution and incubated at 37°C for 1 hour. 20 The virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium such that a concentration of 1 x 10s cells pa* ml was established. The cells infected in this way were pipetted into the wells of 96-well microtitre plates at 1 x 104 cells/well. ti a ?n - 14- 280729 The first vertical row of the microtitre plate contained only growth medium and cells which were not infected, but had otherwise been treated exactly as described above (cell control). The second vertical row of the microtitre plate contained only HIV-infected cells (virus control) in growth medium. The other wells contained the compounds according to the invention at different concentrations, starting from the wells of the 3rd vertical row of the microtitre plate, from which the test substances were diluted 210 times in steps of 2. The test batches were incubated at 37°C until, in the untreated virus control, the syncytia formation typical of HIV occurred (between days 3 and 6 after infection), which was then microscopically assessed. In the untreated virus control about 20 syncytia resulted under these test conditions, while the untreated cell control showed no syncytia. The ICjq values were determined as the concentration of the treated and infected cells at which 50% (about 10 syncytia) of the virus-inducted syncytia were suppressed by the treatment with the compound according to the invention. It has now been found that the compounds according to the invention protect HIV-infected cells from virus-induced cell destruction. Cell culture assay. PBT, Tabic It i i 280729 Example No. PBL IQo [mol/l] 1 1.08 x 10"7 2 6.12 x 10"7 3 1.2 x 10"7 The compounds according to the invention are useful active compounds in human and veterinary medicine for the treatment and prophylaxis of disorders produced by retroviruses. 10 Examples of indication areas in human medicine which can be mentioned are: 1.) The treatment and prophylaxis of human retrovirus infections. 2.) For the treatment or prophylaxis of disorders (AIDS) caused by HIV I (human immunodeficiency virus; earlier called HTLV IH/LAV) and HTV II and the stages associated therewith such as ARC (AEDS-related complex) and LAS 15 (lymphadenopathy syndrome) as -well as the immunodeficiency and encephalopathy caused by this virus. 3.) For the treatment or the prophylaxis of an HTLV-I or HTLV-D infection. 4.) For the treatment or the prophylaxis of the AIDS-carrier state (AIDS-transmitter state). Ffiniui mailTuM -16- 280729 Examples of indications in veterinary medicine which may be mentioned are: infections with a) maedi-visna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) 5 c) caprine arthritis encephalitis virus (in sheep and goats) d) zwoegerziekte virus (in sheep) e) infectious anaemia virus (equine) f) infections caused by feline leukaemia virus g) infections caused by feline immunodeficiency viius (FTV) 10 h) infections caused by simian immunodeficiency virus (SIV) From the indication area in human medicine the abovementioned items 2, 3 and 4 are preferred. The presort invention includes pharmaceutical preparations which, in addition to nontoxic, inert pharmaceutical^ suitable excipients, contain one or more compounds of the 15 formula (I) or which consist of one or more active compounds of the formula (I), and processes for the production of these preparations. The active compounds of the formula (I) should be present in the abovementioned pharmaceutical preparations in a concentration of approximately 0.1 to 99.5% by weight, preferably of approximately 0.5 to 95% by weight of the total mixture. 20 Apart from the compounds of the formula (I), the abovementioned pharmaceutical Tifi ™ 01 -17- 280729 preparations can also contain other pharmaceutical active compounds. The abovementioned pharmaceutical preparations are prepared in a customary manner by known methods, e.g. by mixing the active compound(s) with the excipient(s). In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound(s) according to the invention in total amounts of approximately 0.5 to approximately 500, preferably 1 to 100, mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably contains the active compound(s) in amounts of from approximately 1 to approximately 80, in particular 1 to 30, mg/kg of body weight. However, it may be necessary to depart from the doses mentioned, namely depending on the type and the body weight of the subject to be treated, the nature and the severity of the disorder, the type of preparation and administration of the medicament, and the period or interval within which administration takes place. The compounds according to the invention are enzyme inhibitors and can be employed as such for all purposes for which enzyme inhibitors are utilizable. By way of example, use as a label for affinity chromatography, use as an auxiliary for the elucidation of enzyme structures and reaction mechanisms and also use as a reagent for diagnostics can be mentioned here. A^bafrftwi'inuyii MilnTs -18 - I • I Starting compounds 280729 Example T 6,7-Dimethyl-2-[D-arabo-tetrahydroxy-butyl]quinoxaline HC-OH HC-OH CH2OH 2.0 g (5.58 mmol) of D-fructose phenylosazone (prepared according to C.L. Butler, J. Am. Chem. Soc. 51, 1929, 3163) are suspended in 12 ml of water, 12 ml of ethanol and 1.4 ml of conc. hydrochloric acid, warmed to 45°C and treated dropwise with a solution of 0.8 g (11.2 mmol) of NaNOj in 2.5 ml of water. A dark-red, clear solution is obtained, which is buffered at room temperature with sodium acetate. Everything is extracted by stirring with 15 ml of ethyl acetate, the dark-red organic phase is separated off, and the yellow, aqueous phase is concentrated somewhat and treated with 0.5 g (3.67 mmol) of 4,5-dimethylphenylenediamine. The mixture is heated on a boiling water bath for 20 minutes and the yellow precipitate is then filtered off. It is subsequently washed by stirring in some methanol, filtered again and dried. Yield: 0.3 g (29.4% of theory) of yellow crystals M.p.: 190°C (dec.) TLC: Rf (substance is very poorly soluble) = 0.4 (dichloromethane : methanol = 9:1) I " I Example g 6,7-Dimethylquinoxaline-2-carboxylic acid ,N 280729 ho2c n 0.3 g (1.08 mmol) of the compound from Example I are suspended in 10 ml of 10% strength HjOj solution. The mixture is treated with 0.6 g (15 mmol) of NaOH (solid) 5 with stirring. During the course of this foaming is observed. After stirring for about one hour, a clear solution is obtained On acidifying with conc. hydrochloric acid, a colourless precipitate is deposited It is filtered, washed with water and dried Yield: 160 mg (73.3% of theory) of colourless crystals Mp.: 203°C (dec.) 10 TLC: Rf = 0.5 (dichloromethane/glacial acetic acid/methanol = 90:10:2) Example III (S,S,S>3-Trifluoromethyl-2-azabicyclo[3.3.0]octane 55 g (0.355 mmol) of (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid are fluorinated using HF and SF4. The dark-brown, alkaline suspension (about 200 ml) is 15 filtered, concentrated to about 50 ml in vacuo and extracted three times with 50 ml of dichloromethane. The organic phase is dried, concentrated to a small volume in vacuo (dark-brown oil) and separated by column chromatography (silica gel 60, dichloromethane). Tr ft 30 fll 1 fun in I - 20 - 280729 Yield: 28.8 g (45.3% of theory) of slightly brownish oil Mp.: around 0°C, GC: 99% Rf = 0.4 (dichloromethane) Example IV (2R,3S)-3-(N-Benzyloxycarbonyl)amino-l-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane 0.3 g (1 mmol) of (2R)-[l-(N-benzyloxycarbonyl)amino-2-phenyl-(lS)-ethyl]oxirane and 0.15 g (0.84 mmol) of die compound from Example in are dissolved in 2 ml of 2-propanol and stirred for 12 h in a closed vessel in an oil bath heated to 130°C. After cooling, the contents are 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 colourless foam Rf = 0.2 (toluene/ethyl acetate = 100:5) Example V 280729 (2R,3S)-3-Amino-l-{(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 from Example IV are dissolved in 15 ml of methanol/THF (1:1), treated with some Pd/C (10% strength) and hydrogenated at room temperature for two hours. After filtering off the catalyst and evaporating the solvent, a slightly yellow oil is obtained. Yield: 80 mg (-quantitative) Rf = 0.6 (dichloromethane/methanol = 100:5) Example VI (2R,3S>3-[N-Ben2yloxycarbonyl-L-asparaginyl)amino-l-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane NHj 0.074 g (0.28 mmol) of Z-L-Asn-OH and 0.038 g (0.28 mmol) of HOBT (hydroxybenzotriazole) are dissolved in 5 ml of DMF undo: an argon atmosphere, cooled to 0°C in an ice bath and treated with 0.119 moipho-CDI with stirring. The mixture is stirred at 0°C for 3 hours and then treated with 0.08 g (0.234 mmol) of the compound from Example V, dissolved in 3 ml of DMF. Hie temperature is allowed to rise to RT and stirring is continued overnight After addition of water, a colourless precipitate is obtained. It is filtered, washed with water and dried Yield: 87 mg (63.0% of theory) of colourless crystals M.p.: 162°C HPLC: 97.53% Example VTT (2R,3S)-3-(L-Asparaginyl)amino-l-7(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-y 1} -2-hydroxy-4-phenylbutane 0.008 g (0.135 mmol) of the compound from Example VI are dissolved in 10 ml of methanol/THF (1:1), treated with some Pd/C (10% strength) and hydro genated at RT for 2 hours. After filtering off the catalyst and evaporating the solvent in vacuo, a colourless oil is obtained NH2 Yield 58 mg (95% of theory) Rf = 0.2 (dichloromethane/methanol = 100:5) (spraying with ninhydrin) I « I 280 Example VTIT (2R,3S)-3-(Quinoxalin-2-yl-L-asparaginyl)amino-l-{(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phaiylbutane n co—nh ^co nh v oh V NHj 0.095 g (6.7 mmol) of HOBT and 0.071 g (0.7 mmol) of triethylamine are dissolved 5 in 2 ml of DMF under an argon atmosphere, cooled to -40°C and treated dropwise with stirring with 0.14 g (0.7 mmol) of quinoxaline-2-carbonyl chloride in 3 ml of DM7. The mixture is allowed to react in an ice bath for 2 hours and is thai treated with 0.3 g (0.657 mmol) of the compound from Example VH. The mixture is stirred overnight, the temperature rising to room temperature. The desired product is thai 10 precipitated with water and purified by column chromatography (silica gel 60, eluent: dichloromethane/methanol = 100:5). Yield: 130 mg (2 32.3% of theory) of colourless foam Rf = 0.5 (dichloromethane/methanol = 100:5) Example IX 15 (2R,3S)-3-(Quinolin-2-yl-L-asparaginyl)amino-l-[(S,S,S)-3-trifluoromethyl-2-azabicyclo[3.3.0]octan-2-yl}-2-hydroxy-4-phenylbutane Tr RIAFmifi -24- 2807?o 0.014 g (0.08 mol) of quinoline-2-carboxylic acid and 0.011 g (0.08 mmol) of HOBT are dissolved in 5 ml of DMF under argon, cooled to 0°C in an ice bath and treated with 0.034 g (0.08 mol) of morpho-CDI. After stirring at 0°C for 3 hours, 0.03 g (0.657 mol) of the compound from Example VII, dissolved in 1 ml of DMP, are added and the mixture is stirred overnight, the temperature rising to room temperature. The desired product is then precipitated by addition of water, filtered, dried and purified by precipitation with methanol and diisqpropyl ether. Yield: 270 mg (67.2% of theory) of colourless glass Rf = 0.5 (dichloromethane/methanol = 100:5) In analogy to the above examples, the following new pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane are prepared, Table I: j? A V g14 Hrnrn rnnntri"" -25 - Table I; R1—CO—NH „ v v NHj CF, to On Ex.No. R1 Mp. (°C) Rf (dichloromethane/ methanol = 100:5) Yield (% of theory) prepared from starting Ex.No. process analogous to Ex.No. X H'cnN;i colourless foam 0.5 65 1 3 i\j co & ^4 40 Preparation Examples 280729 Example 1 (2R,3 S)-3-(Quinolin-2-yl-L-asparaginyl)-amino-1 - [(S, S, S)-3-trifluoromethy 1-2-azabicyclo[3.3.0]octan-2-yl}-2-(3-€tiioxycarfconyl)propionyl-4-phenylbutane 0.6 g (0.981 mmol) of the compound from Example IX is 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 ethyl succinyl chloride (d = 1.15) and 0.6 g (4.92 mmol) of dimethylaminopyridine (DMAP) in 15 ml of dried THF under argon. The mixture is treated with water, the precipitate is separated off, washed with water and dissolved in toluene, and the solution is dried and concentrated. Yield: 0.58 g (« 80% of theory) of colourless crystals M.p.: 138°C Rf ~ 0.6 (dichloromethane/methanol = 100;5) HPLC: 92.5% recrystallized from dichloromethane/diisopropyl ether => HPLC: 94.2% H In analogy to the procedure of Example 1, the compounds shown in Table 1 are prepared: </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 280729 NHs El No. Rl R? IVLpifQ/Rf** Yield (%of tiheoiy) 2 oa -coch3 colourless foam 0.7* - 93.6 3 -co-ch3 colourless foam 0.3* 93.9 4 oa -co-ccc*^ colourless foam 0.5* 26.5 5 oa -co<ch2)2-ch3 colourless foam 0.5** 89 6 oa -co-ch(ch3)2 colourless foam 0.5** 89 7 oa -co-(ch2)14ch3 colourless foam 0.5** 79 8 oa -COadamantyl colourless foam 0.6** 25 * (dichloromethane/methanol = 100:4) ** dichloromethane/ethyl acetate = 1:1 280729 WHAT WE CLSIM IS: 1. Pseudopeptides containing a trifluoromethyl-substituted 2-azabicyclooctane, of the general fopmila (I) (D in which R1 represents a radical of the formula fed * fcxx wherein A, D, E, L and T are identical or different and denote hydrogen, halogen, straight-chain or branched alkyl having up to 4 carbon 10 atoms, morpholinyl, phenylthio or cycloalkyl having 3 to 6 carbon atoms, R2 rqpresents straight-chain or branched acyl having up to 20 carbon atoms, which is optionally substituted by carboxyl, by straight-chain or Tr 1?if fill rniaijfii BMMihiuy - 29 - • 280 brandied alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or 5 straight-chain or brandied alkyl having up to 6 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(OXOR7XOR8), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, 10 R7 and R8 are identical or different and denote hydrogen or straight- chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or brandied alkoxy having up to 6 carbon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, 15 or represents a radical of the formula -co hgc ch3 7 "c°-^ 1^1 ..XL r/l or . H3CV • ^XJ h,c and their salts. t i 'i loniinniiLii ritm - 30 - 280 Compounds of the general formula (I), according to Claim 1 in which R1 represents a radical of the formula fed • "PCx D I wherein A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, straight-chain or branched alkyl having up to 3 carbon atoms, morpholinyl, phenylthio, cyclopaityl or cyclohexyl, R2 represents straight-chain or branched acyl having up to 17 carbon atoms, which is optionally substituted by carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 c?<rbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(OXOR7XOR8), wherein *60729 R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen or straight-chain or brandied alkyl having up to 3 carbon atoms, or represents straight-chain or brandied alkoxy having up to 4 carbon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula and their salts. Compounds of the general formula (I) according to Claim 1 in which R1 represents a radical of the formula -CO N pd - T wherein 280729 A, D, E, L and T are identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, phenylthio, cyclopentyl or cyclohexyl, R2 rqpresents straight-chain or branched acyl having up to 15 caibon atoms, which is optionally substituted by carboxyl, straight-chain or brandied alkoxycarbonyl having up to 6 carbon atoms or by a group of the formula -NR3R4, wherein R3 and R4 are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, represents a radical of the formula -CO-NR5R6 or P(OXOR7XORs), wherein R5 and R6 have the meaning of R3 and R4 indicated above and are identical to or different from this, R7 and R8 are identical or different and denote hydrogen, methyl or ethyl, or represents straight-chain or brandied alkoxy having up to 3 caibon atoms, which is optionally substituted by difluoromethyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl, or represents a radical of the formula f\ ing11r 'i 1 - 33 - 1 f 280729 -CO -co-r or -CO-N^N W H3C and their salts. A process for the preparation of the compounds of the general formula (I) according to Claim 1, characterized in that first carboxylic acids of the general formula (II) R'-CCVH ~ (II) in which R1 has the meaning indicated in Claim 1, are converted by reaction with the compound of the formula (HI) H (HI) NHj « 1 into the compounds of the general formula (IV) 280729 r'-co-nh^co-ni mvy- NH2 (IV) in which R1 has the meaning indicated in Claim 1, if appropriate with prior activation of the carboxylic acid, in inert solvents and in die presence of a base and/or of an auxiliary, and in a second step an acylation is carried out in inert solvents, if appropriate in the presence of a base and/or of £a auxiliary. Medicaments containing one or more compounds according to Claim I together with a pharmaceutically acceptable carrier. 6. A pseudopeptide of formula (I) according to claim 1 substantially as herein described or exemplified. 7. A process according to claim A substantially as herein described or exemplified. 8. A medicament according to claim 5 substantially as herein described or exemplified. / \ BAYER AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES Per: I </div>