SK115193A3 - Antiretroviral active acylderivatives - Google Patents

Abstract

The invention relates to compounds of the formula I <IMAGE> in which R1 is acyl, and salts thereof, which have antiretroviral activity, in particular against AIDS.

Description

Anti retrο virally active acyl derivatives

Technical field

The invention relates to novel antiretroviral tin compounds, to a process for the preparation of these compounds, to pharmaceutical compositions containing the compounds, to these compounds for use in a method of therapeutic treatment, to the use of the compounds or to the animal body preparations.

BACKGROUND OF THE INVENTION The human or animal body and for the therapeutic treatment of the human or for the manufacture of pharmaceuticals

There are a number of diseases that, according to current scientific knowledge, are caused by the disease.

To date, AIDS is a disease of the immune system induced by the HIV retrovirus (Human Immunodeficiency Virus). It is estimated that about 10 million people suffer from this disease, while the number of infected people continues to increase and the disease virtually always leads to the death of the patient.

To date, retroviruses HIV-1 and HIV-2 have been identified and molecularly biologically characterized as the cause of the disease (HIV means Human Immunodeficiency Virus). In addition to the limited possibilities of reducing the symptoms of AIDS so far and certain preventive options, the search for such agents is desirable for the treatment of the disease. which will adversely affect the multiplication of the virus itself without damaging the virus-free cells and tissue of the patient.

The retroviral protease is a proteolytic enzyme, which is counted as an aspartate protease relative to the aspartate residue present in the active center, and that enzyme participates in the reproductive cycle of a number of retroviruses in the grains of new infectious virions within infected cells.

For example, the HIV-1 and HIV-2 retroviruses always have a region in their genobes that encodes a gag protease. This gag protease is responsible for the correct proteolytic cleavage of protein precursors that originate from genomic grafts encoding Group Specific Antigens (gag). This releases the structural proteins of the viral core. Gagprotease itself is part of a protein precursor encoded by the p 1 genomic graft of HIV-1 and HIV-2, which also contains reverse transcriptase and integrase grafts and is likely to be autoproteolytically cleaved.

The gag-Protease cleaves the major core protein of p24 HIV-1 and HIV-2 retroviruses, preferably at the non-terminal proline residue position, for example, to the bivalent Phe-Pro, Leu-Pro or Tyr-Pro radical. It is a protease with a catalytically active aspartate residue in the active center, i.e. a so-called aspartate protease.

Given the central role of the gag protease in the processing of said core protein, it is believed that effective inhibition of this enzyme in vivo can be achieved by preventing the formation of mature virions and that the corresponding inhibitors can be therapeutically used for this purpose.

In general, to combat retroviral diseases such as AIDS, research teams have been working for some time to produce compounds that are effective as inhibitors of in vivo anti-retroviral gag proteases, in particular against the HIV-1 retrovirus gag protease. (HIV-1-protease), but also against the HIV-2 retrovirus protease or other AIDS virus proteases.

At present, the main task is to provide such compounds that possess as far as possible the best pharmacokinetic properties.

A prerequisite for in vivo therapeutic efficacy is the good attainability of these inhibitors for the body, for example, good resorbability and / or high levels of these inhibitors in blood plasma, also when administered enterally, especially orally, to achieve a high concentration of inhibitory active agent in infected cells. The favorable distribution of inhibitors to the organism is also important.

It is an object of the invention to possess properties which are even effective and which even have antiretrovirally effective properties.

SUMMARY OF THE INVENTION

In the case of the compounds of formula I, it is to provide structural compounds with improved compounds that exhibit better unmodified antiretroviral enteral, especially oral, higher levels to be achieved with the corresponding compounds.

new antiretropharmacodynamic resorption as a compound by administration, and / or in the bloodstream, than by administration of the unmodified invention are compounds

(I) wherein R 1 is an acyl compound.

In European patent application EP 0 432 695 (published

June 19

1991), a compound of formula II is disclosed

(II) in European

19 June 1991) and also generically included

EP 0 346 847 (published patent application 0 This compound is also where, for example, it is also described in European patent 432 694 which is a synthesis application (published December 11, 1989). in vivo, as well as the structure of this compound for its activity: Tucker TJ et al., J. Med. Chem., 35, 2525-2533 (1992); Robert NA et al., Bochem. Soc.Tranact. 2 0.5 1 3-5 16 (1 99 2), Krausslicn H.-G., J. Virology 66,567-572 (1992); Martin JA et al., Biochem. Commun. 17 6.1 80-188 (1999), Krohn et al., J. Med.

Chem. 34.3340-3342 (1991); Holmes H.C. et al. Antiviral Chem. and Chemother. 2,287-293 (1,991); Graig J.C. et al., Antivirus

Chem. and Chemother. 2.181 to 186 (1991); Graig J.C. et al ..

Antivíral Res. 16.295-305 (1991); 248.358 to 361 (1990); Overton H.A. (1990); Muírhead G.J. et al., 170P (1992); W 1 am am P.E.O. and 34 (2), 15P (1929); Shaw et al.

Roberts N.A. et al., Sucence et al., Virology 179,508-511

Brit.J.Clin.Pharmacol. 34 (2), et al., Br et al., J. Pharm.

Brit. J. Cl. Pharmacol.34 (2),

166P (1,992); Johnson V.A. et al., J. Infectious Dis. 166 (5), 1143 (1992); Phylip L.H. FEBS Lett. 3 4 (3), 449 (1,992); EP 0 432 695 (published Jun 19, 1991); EP 0 513 917 (published

19.11.1992); ľhompson W.J. 15,801 (1,993) and EP 0 346 847 (published Dec. 20, 1989).

None of these publications disclose or suggest compounds that contain a different radical on the free hydroxy group of compounds of formula II.

Surprisingly, it has now been found that the compounds of formula II, when administered to mammals, in particular orally, are found in the blood at a significantly higher concentration when a compound of formula I with a hydroxy group modified with the general substituent R 1 is administered. compared to administration of the corresponding free compounds of formula II.

The general terms and designations used in the description of the invention preferably have the following meanings.

The compounds of the formula I according to the invention can be present in different isomeric forms if the radical R 1 is present in different isomeric forms. Thus, asymmetric carbons present in the R 1 substituents independently of one another may occur in the (R), (S) or (R, S) configuration and / or on cis / trans isomerism on multiple bonds such as double bonds. Accordingly, the compounds of formula I may exist as diastereomeric mixtures or as racemic mixtures or as pure isomers, in particular as pure enantiomers.

The term lower used in the definition of groups or residues, such as lower alkyl or (lower alkoxy) carbonyl, means that the groups or residues so defined, unless specifically defined otherwise, contain at most 7, preferably at most 4 carbon atoms . In the case of a lower alkenyl group and a lower alkynyl group, the specification means a lower presence of at least and at most 7 carbon atoms, preferably 2 to 4 carbon atoms, and in the case of a lower alkenoyl group or lower alkyinoyl group, 3 to 7, preferably 3 or 4 carbon atoms.

For example, the acyl group R 1 has up to 25, preferably up to 19 carbon atoms, and is in particular an acyl group of a carboxylic acid or an unsubstituted or substituted amino acid linked through its carbonyl group, furthermore an aminocarbonyl group or a N-subsubstituted carbamic acid residue. bonded via its aminocarbonyl group, or the remainder of the half-carbonic acid ester bonded via its carbonyl group.

Preferred acyl groups R 1 of the carboxylic acid include, for example, unsubstituted alkanoyl, alkenoyl or alkinoyl or substituted alkanoyl, alkenoyl or alkinoyl, especially octanoyl, decanoyl, dodecanoyl or palmitoyl, unsubstituted, unsubstituted, unsubstituted, or a lower alkyinoyl group, the substituents of which are, for example, one or more groups, preferably at most three, in particular one or two groups selected from the group consisting of hydroxy, lower alkoxy, (lower and 1 alkoxy) (lower and 1 alkoxy) (lower alkoxy) -group, (lower and 1-alkoxy) (lower and 1-alkoxy) (lower alkoxy) -group, phenoxy, naphthoxy, phenyl (lower alkoxy) -group, 2-halogen (lower alkane) an aryl group such as 2-chloroacetyl an amino, (lower alkyl) amino- or di (lower alkyl) amino (lower and 1 alkoxy) -2- (lower alkane) oyl group such as dimethylamino ( lower alkoxy) acetyl, amino-, (lower alkyl) amino- or di (lower alkyl) amino (lower and 1-alkoxy) (lower and 1-alkoxy) -2- (lower alkane) -yl, such as dimethylamino- [2- (lower and 1-alkoxy) ethyl] acetyl, (lower alkane) oyloxy, phenyl (lower alkane) oyloxy, such as benzoyloxy or phenylacetyloxy, atom halogen, such as fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, carboxy, (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, such as benzyloxycarbonyl, carbamoyl , (lower and 1 alkyl) carbamoyl, hydroxy (lower alkyl) carbamoyl, di (lower and 1 alkyl) carbamoyl, b is / hydroxy (lower and 1 alkyl) / carbam an aryl group, a carbamoyl group whose nitrogen atom is part of a 5- to 7-membered heterocyclic ring which may contain yet another heteroatom selected from the group consisting of oxygen, sulfur, nitrogen and nitrogen substituted by a lower alkyl group such as methyl or ethyl, for example pyrrolidinocarbonyl, morpholino-inocarbonyl, thiomorpholino-carbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl or 4- (lower and 1-alkyl) piperazine A 1-yl-carbonyl group such as a 4-methylpiperazin-1-ylcarbonyl group, a cyano group, an oxo group, a cycloalkyl group, for example a C 3 -C 8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, a bicycloalkyl group, for example a 6 to 12 carbon atoms cycloalkyl group a decahydronaphth-2-yl group, an endo- or exo-2-norbornyl group, bycicle (2.2.2) an oct-2-yl group, or a bicyclo (3.3.1) non-9-yl group, triacrylate C 9 -C 14 tricycloalkyl such as 1- or 2-adamantyl, cycloalkenyl such as C 4 -C 8 cycloalkenyl such as 1-cyclohexenyl or 1,4-cyclohexadienyl, bicycloalkenyl , for example, a 5-norbornen-2-yl group or a bicyclo [2.2.2] octen-2-yl group, a heterocyclyl group which means a saturated, partially saturated or unsaturated ring per se or in a single or double benzene, cyclopenta-, cyclohexa- or cycloheptane-containing form containing 3 to 7, preferably 5 to 7, ring atoms and at most 4 heteroatoms selected from the group consisting of nitrogen, sulfur and / or oxygen and which is unsubstituted substituted or substituted, in particular by a lower alkyl group, a lower alkanoyl group, a hydroxy group, a lower alkoxy group, a phenyl (lower alkoxy) group such as a benzyloxy group, a hydro (lower alkyl) group such as a hydroxymethyl group, halogen, cyano and / or tri fluoromethyl, such as pyrrolyl, 2,5-dihydropyrrolyl, furanyl, thienyl, tetrahydrofuran, cyclopenta (b) pyrrolyl , pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolinyl, pyrazolidinyl, triazolyl such as 1,2,3-, 1,2,4- or 1,3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, nu, indolyl, isool, isoquinolyl, benzo furanyl, pyridine piperidinyl group, tetrahydroisoxazolyl group, tetrahydroisothiazolyl group-indolyl group, quinolyl group, benzimidazolyl group, yl group, pyrimidinyl group, piperazin-1-yl group, thiomorpholine group, and phenyl group. , folin, 1,2-dihydro- or 1-yl or quinolyl, or substituted

1,2-dihydro- or wherein the above-mentioned nu, S, Sdioxo-oxo-4'-tetrahydroisoino-4,4-tetrahydroisone is unsubstituted by a process, in particular by a lower alkyl group than in the case of 4- (lower) 1) piperazin-1-yl such as 4-methyl-1- or 4-ethylpiperazin-1-yl, (lower alkan) oyl, such as, for example, 4- (lower alkane) oylpiperazin-1-yl such as a 4-η-1-yl group, or as an acetylpiperazine, a 1-carbonyl group containing a naphthyl and a nanyl group, such as a hydroxy (lower alkyl) 5-hydroxymethylfuran-2-aryl group 1, n-phenyl or fluorenyl, for example in the case of a group, preferably carbon, for example or 2-naphthyl

A 2-indanyl group, n up to up

Aryl groups such as or inden-1-yl such as fluoren-9-yl, wherein the aryl group is unsubstituted or mono- or poly-substituted, for example lower alkyl, for example methyl, halogen (lower and lower alkyl) a halogen atom such as a fluorine atom or a chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, a (lower and 1-channel) oxyoxy group, a carboxyl group, a (lower and 1alkyl) group, such as a chloro or bromomethyl group; ) oxycarbonyl, phenyl (lower and 1-alkoxy) carbonyl, carbamoyl, mono- or di (lower alkylcarbamoyl), mono- or dihydroxy (lower alkyl) carbamoyl, haogene (n) lower alkyl) such as tri-fluoromethyl, heterocyclyl (lower alkyl) in which the heterocyclyl radical has the abovementioned meanings, in particular heterocyclyl Imethyl in which the heterocyclyl radical is bonded via a ring nitrogen atom, for example piperidinomethyl, piperazin-1-ylmethyl, 4- (lower alkyl) piperazinyl with a methyl group such as 4-methyl- or a 4-ethylpiperazin-1-ylmethyl group, a 4- (lower alkanoylpiperazin-1-ylmethyl) group such as a 4-acetylpiperazin-1-ylmethyl group, morpholinomethyl group or thiomorpholinomethyl group by cyano and / or nitro group, in particular phenyl 1 an o-group which is substituted in the para-position by one of the abovementioned groups, for example a lower alkanoyl group such as a hunting group, an acetyl group, a propionyl group, a butyryl group, a methylpropionyl group, a pivaloyl group, a n-pentanoyl group , hexanoyl or heptanoyl, such as n-heptanoyl, hydroxy (lower alkanjoy, for example beta-hydroxypropionyl, (lower al (lower alkanjoyl, for example (lower alkoxy) acetyl or ('lower alkoxy) propionyl, such as methoxyacetyl, 3-methoxypropionyl or n-butyloxyacetyl, (lower alkoxy) (lower alkoxy) (lower alkanjoy) such as 2 (2-methoxyethoxy) acetyl, (lower and alkoxy) (lower alkoxy) (lower alkoxy) (lower alkanjoy, such as 2- (2- (2methoxyethoxy) ethoxy) acetyl) , phenoxyin-alkanilyl, for example phenoxyacetyl, naphthoxy (lower alkanjoyl, for example alpha- or beta-naphthoxyacetyl, phenyl (lower alkoxy) (lower-alkanjoyl, such as benzyloxyacetyl), 2-halogen (lower alkanjoyl, such as 2) -chloroacetyl, amino-. (lower alkyl) amino- or di (lower alkyl) amino (lower alkoxy) -2- (lower alkanjoyl group, such as dimethylamino (lower alkyl)

An alkoxy] acetyl group, an amino- (lower alkylamino- or di (lower alkyl) amino) (lower 1 alkoxy) (lower 1 alkoxy) - 2- (lower alkanoyl) group such as dimethylamino- 2- (lower alkoxyethoxy / acetyl), (lower and 1-channel) oxyoxy (lower alkanoylacetyl, or (lower alkanoylacetyloxypropionyl) such as acetoxyacetyl or beta-acetoxypropionyl, halogen (lower alkanoyl, e.g. an alpha-haloacetyl group, such as an alpha-chloro, alta-bromo, alpha-iodo, and 1 fa, and 1 fa, alpha-trifluoro- or alpha, alpha, alpha-trichloroacetyl group, or naiogenpropionyio group, such as beta- a chloro- or beta-bromopropionyl group, a carboxy (lower alkanoyl group, for example a carboxyacetyl group or a 3-carboxypropionyl group), (a lower alkoxycarbonyl (lower alkanoyl group, for example (lower alkoxy) carbonylacetyl or (lower alkoxycarbonylpropionyl), such as methoxycarbonyl acetyl, beta-methoxycarbonylpropionyl, ethoxycarbonylacetyl, beta-ethoxycarbonylpropionyl, tert-butoxycarbonylpropionyl, or lower-carbonyl for example carbamoylacetyl or beta-carbamoylpropionyl, (lower alkyl) carbamoyl (lower alkanoyl, for example methylcarbamoyl acetyl or beta- / N- (lower alkyl) carbamoylpropionyl, such as beta- (N-methyl) -, beta- (N-ethyl-, beta- (N- (n-propyl)) carbamoyl- or beta- (N- (n-hexyl)) carbamoyl propionyl, di (lower and alkylcarbamoyl (lower alkanoyl), for example dimethylcarbamoylacetyl, beta- (N, N- / di (lower and alkyl / carbamoylpropionyl) such as beta- (N, N-dimethyl) -, beta- (N, N-diethyl) -, beta- ( N, Nd - (n-propylcarbamoyl) - or beta (N, N, - di- (n-hexylcarbamoylpropionyl group, beta-pyrrolidinocarbonylpropionyl group, beta-morphol) 1-inocarbonylpropionyl, beta-thiomorpholino-inocarbonylpropionyl, beta-piperidin-1-ylcarbonylpropionyl, beta-piperazin-1-ylcarbonylpropionyl or beta- / 4- (lower) alkyl (perazin-1-ylcarbonyl) propionyl, such as beta- (4-methylpiperazin-1-ylcarbonylpropionyl), oxo (lower alkanoyl group, e.g. acetoacetyl or propionylacetyl) a hydroxycarboxy lower alkanjoy group, for example a α-hydroxy-α-β-carboxyacetyl group or an altahydroxy-beta-carboxypropionyl group, a hydroxy (lower alkoxy) carbonyl group (lower alkanjoy group, for example alpha-hydroxy-alpha-ethoxy- or methoxycarbonylacetyl or alpha-hydroxy-beta-ethoxy- or -methoxycarb an onylpropionyl group, an alpha-acetoxy-alpha-methoxycarbonylacetyl group, a dinydroxycarboxy (lower alkanjoyl group, for example a 11a, a beta-dihydroxy-beta-carboxypropionyl group, a dihydroxy (lower alkoxy) carbonyl (lower alkanjoyl group, for example alpha, beta-dihydroxy- beta-ethoxy- or -methoxycarbonylpropionyl, alpha, beta-diacetoxy-beta-methoxycarbonylpropionyl, alpha-naphthyloxycarboxy (a lower alkanjoyl group, for example 2-alta-nattoxy-4-carboxybutyryl, alpha-naphthoxy (lower and 1 alkoxycarbonyl 1 (a lower alkanjoyl group, for example a 1 phtha-naphthoxyethoxycarbonyl acetyl group, 2alpha-naphthoxy-3-ethoxycarbonylpropionyl group, or a 2-allyloxytoxy-4-tert-butoxycarbonylbutyryl group, e.g. 2alpha-naphthoxy-3-benzyloxycarbonylpropionyl, alpha-ethoxycarbamoyl (lower alkanjoyl group, e.g. 2-alpha-naphthyl) an oxy-4-carbamoyibutyryl group, an alpha-naphthoxycyano (lower alkanjoyl group, for example, an alpha-naphthoxycyanoacetyl group or a 2-alpha-naphthoxy-4-cyanobutyryl group, alpha-nattoxyoxo (lower alkanjoyl group, for example 2-altaanaphthoxy-4) -oxopentanoyl, neterocyclyl (lower alkanjoyl, for example optionally substituted pyrrolylcarbonyl, for example 2- or 3-pyrrolylcarbonyl, furylcarbonyl, for example 2-furylcarbonyl, 5-hydroxymethylfuran-2-yl, thienylcarbonyl, for example 2-thienylcarbonyl, pyridyl (lower alkanjoyl, such as pyridyl carbonyl, for example 2-, 3- or 4-pyridylcarbonyl, pyridylacetyl) a 2-pyridylacetyl group, or a pyridylpropionyl group, for example a 3- (2-pyridylpropionyl group), a quinolylcarbonyl group such as quinolyl-2-yl a ronyl group, an isoquinolinecarbonyl group, such as an isoquinolin-3-ylcarbonyl group, optionally substituted indolyicarbonyl group, for example 2-, 3- or

5-indolylcarbonyl, 1-methyl-1,5-methyl-, 5-methoxy-,

5-benzyloxy-, b-chloro- or 4, b-dimethyl-indyl-2-carbonyl, cyclohepta (b) pyrrole-1-b-carbonyl, pyrrolidine- (2-buto-3- ) - y 1 carbonyl group (wherein pyrrolidines 1

The 2-carbonyl group (= prolyl group) preferably has the D or L configuration, a hydroxypyrrolidinylcarbonyl group, for example a 3- or 4-hydroxypyrrolidinyl-2-carbonyl group, an oxopyrrolidinylcarbonyl group, for example a b-oxopyrrolidinyl-2-carbonyl group. a piperidinyl carbonyl group, for example a 2-, 3- or 4-piperidinylcarbonyl group,

A 3,4-tetrahydroquinolylcarbonyl group, for example a 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl group, or

A 1.2.3.4-tetrahydroisoquinolylcarbonyl group, for example

A 1,2,3,4-tetrahydroisoquinolyl-2-, -3-buto-4-carbonyl group or a 1,2,3,4-tetrahydroisoquinolylcarbonyl group, for example i, 2,3,4-tetrahydroisoquinolyl-i-, -3- or - A carbonyl group, an imidazolylcarbonyl group, for example an imidazol-1-ylcarbonyl group or an imidazol-4-ylcarbonyl group, for example an imidazolylcarbonyl group, for example an imidazolylcarbonyl group, for example 4 -imidazolylacetyl or imidazolylpropionyl, for example 3- (4-imidazolyl) propionyl, morpholinocarbonyl, thiomorpholino-inocarbonyl, morpholino-acetyl, 11-morpholino-acetyl, 4- (lower and lower) A 1-piperazinoacetyl group such as a 4-methylpiperazinoacetyl group, an indolyl acetyl group or a benzofuranyl acetyl group, a lower alkenoyl group, for example an acryloyl group, an inyl acetyl group, a crotonoyl group, or a 3- or 4-pentenoid group; lower alkinoyl, for example propioloyl or 2- or 3-butinoyl, cycloalkylcarbonyl, for example cyclopropyl, cyclo butyl, cyclopentyl or cyclohexylcarbonyl, bi-cycloalkylcarbonyl, for example decahydronattyl-2 carbonyl - or an exo-norbornyl-2-carbonyl group, a cyclic (2,2,2) oct-2-ylcarbonyl group or a bicyclo [3.3.1] non-γ-ylcarbonyl group, tr1cycloalkylcarbonyl

- 1 to 3, for example, a 1-cyclo-adamantylcarbonyl group, a cycloalkenylcarbonyl group, for example a 1-cyclonexenylcarbonyl group, or a 1,4-cyclonicadienylcarbonyl group, a bicycloaikenylcarbonyl group, for example a 5-norbornene / bicycloylcarbonyl group; (octen-z-ylcarbonyl) a cycliopropylacetyl group, a cyclopentyiacethyl group, a cyclohexyl acetyl group or a 3-cyclonexylpropionyl group, a cycloalkyl group (for example, a cyclohexylacryloxy group, for example a cycloalkenyl group, a cycloalkenyl group), e.g. onexenes I acetyl group; or

A 1,4-cyclonexadienylethyl group, a reny (lower alkyl group) group such as a benzoyl group, a reriyiacetyl group, or a 3-renyipropionyl group which is unsubstituted on the phenyl residue or one or more times substituted by a lower alkyl group such as methyl a halogen (lower alkyl) group such as a chloro- or bromomethyl group, a naiogen atom, for example a hydrogen atom or a chlorine atom, a nydroxy group, a lower alkoxy group, for example a methoxy group, a piperidinomethyl group, or a piperidinyl group . 4- (lower alkylpiperazin-1-ylmethyl) such as 4-methyl- or 4-ethylpiperazin-1-ylmethyl, 4- (lower alkanipiperazin-1-ylmethyl) such as 4-acetylpiperazin-1-ylmethyl a mortoinomethyl group, a thiomortol in a methyl group, a cyano group and / or a nitro group, or an alpha-naphthyl or beta-naphthyl (lower and icanjoy group, wherein the naphthyl residue is unsubstituted or one or more substituted) a lower alkyl group such as a methyl group, a phenyl group, a halogen atom such as a chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, and / or a nitro group, the lower alkanoyl group in the phenyl- or an alpha-naphthyl (lower alkanoyl) or beta-naphthyl (lower alkanoyl) residue is unsubstituted or substituted, for example, by a nydroxy group, a lower α (coxy group) , (lower alkanjoyioxy, carboxyl, (lower and icoxy) carbonyl, phenyl (lower alkoxy) carbonyl, such as oenzyloxycarbonyl, carbamoyl, (lower alkylcarbonyl), di C lower alkyls such as carbamoyl, cyano and / or oxo and is optionally branched, such as 4-chloromethyl, 4-bromomethyl-1,4-fluoro, 4-chloro, 4-methoxy-, 4-morpholinomethyl-, 4-thiomorpholinomethyl-, 4-cyano or 4-nitrobenzoyl, and Ifa-naphthylacetyl, o-naphthylacetyl, (lower alkylthenylacetyl, such as 4-methyl); Renylacetyl, (lower alkoxy) phenylacetyl, such as 4-methoxythenyiacetyl, 2 (lower and 1 alkoxy) -2-phenylacetyl, such as (R) - or (S) -2-methoxy-2-phenylethyl hunting. group, 3- (p-nydroxyrenyl) propionate hunting group, children of lacety hunting group, di - (4-methoxytenyl) acetyl group, triteny la Hunting group, 3-a 11 a- or 3-oethanatylpropionyl group, 3-thenyi or 3-a 11a-natty 1-2-trihydroxypropionyl group, 3-renyi or 3-air alpha-naphthyl-2 (lower alkoxy) propionyl, such as 3-1-enyl- or 3- and itanatyl-2-neopentyloxypropionyl, 3-thienyl-2-pivoyloxy- or 2-acetoxypropionyl 3-thienyl or 3-aliphenyl-2-carboxymethyl propionyl, 3-thienyl or 2-acetoxypropionyl, 3-thienyl or 2-acetoxypropionyl; aita-naphthyl 1-2- (lower alkoxy) carbonyipropiononyl group such as 3-aita-naphthyl-2-ethoxycarbonyl ipropionyl group, 3-thenyl- or 3-aitynaphthyl-2-benzyloxycarbonyimethylpropionyl group, 3-1 enylene-1 or 3-allyl-naphthyl-2-carbamoylpropyl group, 3-1-enyl-aieno 3-aita-naphthyl-2-tert-butylcarbamoyl propionyl group, 3-thenyl- or 3-alpha- naphthyl-2-cyanopropionyl, 3-thenyl- or 3- and 1'-naphthyl-2-cyanomethylpropi onion, 3-thenyl- or 3-a11a-naphthyl-2-acetonyropropionyl, 2-benzyl- or 2-ata-naphthyimethyl-4-cyanobutyryl, 4-phenyl- or 4-a11a-naphthyl 3-carboxybutyryl, 4-1-enyl or 4-aita-naphthyl-3-benzyloxycarbonyibutyryl, 2-benzyl or 2-alpha-naphthyl Methyl-4-oxopentanoyl, phenyl (lower alkanedio, e.g. a beta-tenylacryloyium or betathenyl group in an inyl acetyl group, a naphthylcarbonyl group, for example an alpha-or beta-naphthylcarbonyl group, an indenylcarbonyl group, for example a 1-, 2- or 3-indenylcarbonyl group, or an indanyicaroonyl group, for example 1 or 2-indanylcarbonyl.

Preferred acyl groups R 1 of the carbonic acid half ester are, for example, C 1-4 unsubstituted and substituted and alkyloxycarbonyl, especially (lower alkoxyalkoxy) carbonyl, for example methoxy, ethoxy and tertiary (lower and IKoxy) carbons. Donyl, such as tert-butoxycarbonyl, 2-naogeno (lower alkoxycarbonyl, for example 2-chloro, 2-oromo-, 2-iodo-ally 2,2,2-trifluoroethoxycarbonyl, aryl (lower alcohols) alkoxycarbonyl, for example ary Imethoxycarbonyl, in which the aryl radical contains B to 14 carbon atoms and is unsubstituted or one or more, preferably one, substituted, for example, by a lower alkyl group, for example methyl, to iogen ( a lower alkyl group such as a chloro- or di-methyl group, a halogen atom such as a fluorine atom or a chlorine atom, a nydroxy group, a lower and 1 alkoxy group such as a methoxy group, (lower aikanjoyioxy group, carboxyl group, (lower alkyl) oxycarbonyl group, phenyl 1 (lower alkoxy) carbonyl group, carbonyl group, mono- or di (lower and IKyl) caroamoyl group , mono or dihydroxy (n 1 of the carbamoyl group), haiogen (lower alkyl group such as trifluoromethyl group, neterocyclic (lower group 1)) radical has the meanings in which the heterocyclic group as above for a lower alkanoyl heteroaryl group, in particular a non-heterocyclic methyl group, in which the heterocyclic radical is bonded via a ring nitrogen atom, for example piperidin-1-ylmethyl, piperazin-1-ylmethyl 4- (m-alkyl) piperazin-1-ylmethyl, such as 4-methyl or 4-ethylpiperazin-1-ylmethyl,

4- (lower aikanjoylpiperazin-1-ylmethyl, 4-acetyl piperazin-1-ylmethyl, morpholinomethyl or thiomorpholinomethyl, cyano or / anthroethyl, and in particular is thenyl; - or 2-naphthyl, thiorenyl or thenyl, mono- or polysubstituted by lower alkyl, for example methyl or tert-butoxy, lower alkoxy, for example methoxy, ethoxy or tert-butoxy, hydroxy , atoms

A halogen atom, for example a fluorine atom, a chlorine atom or a bromine atom, and a nitro group, for example a phenyl (2-alkoxy) carbonyl group such as a benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, di-phenyls (lower alkoxy) carbonyl groups such as diphenyloxycarbonyl, di- (4-methoxythenylmethoxycarbonyl), triethyloxycarbonyl or thiorenyl (lower alkoxy) carbonyl; or a heterocyclyl (lower alkoxycarbonyl group which is mentioned in which it is known to have a non-heterocyclic radical, higher for a non-heterocyclic group forming a substituent of an alkanoyl group, for example a ruran-1'-imethoxycarbonyl group) pyridin-ζ-, -3- or -4-ylmethoxycarbonyl is tested for.

a preferred acyl group of the N-substituted carbamic acid includes an amine carbonyl moiety in which the amino acid bears 1 or from substituents independently of one another selected from unsubstituted or substituted lower alkyl groups which substituents are selected from substituents which have been for the substituted lower alkanoyl group, and the number thereof corresponds to the number defined therein, for example substituents selected from the group consisting of nydroxy, lower aicoxy, phenoxy, (lower alkanjoyioxy, phenyl (lower aikan'joyioxy) such as a benzoyloxy group or a phenylacetoyloxy group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, in particular a fluorine or chlorine atom, a carboxyl group, a (lower alkoxy) carbonyl group, phenyl 1 ( a lower alkoxycarbonyl group, such as a benzyloxycarbonyl group, a carbamoyl group; upine, (lower alkylcarbamoyl, hydroxy (lower carbamoyl group), di (lower alkylcarbamoyl, bis / hydroxy (lower alkyl) carbamoyl group, cyano, oxo group and aryl group containing 6 to 6) 12 carbon atoms, for example a phenyl group, a naphthyl group such as an i- or 2-naphthyl group, an indanyl group such as a 1- or 2-indanyl group, an indenyl group such as an inden-1-yl group, or a fluorine a aryl group such as a fluoro-9-yl group, wherein the aryl group is unsubstituted or one or more times, preferably one, substituted, for example, by a lower alkyl group, for example a methyl group, to 1 ogene (lower alkyl group such as chlorine- a bromomethyl group, a nalogen atom, for example a thorium or chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, (a lower aikanjoyioxy group, a carboxy group, (a lower alkyl group) ) oxycarbonyl, phenyl (lower and alkoxy) carbonyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, mono- or dihydroxyphenyl alkyl) carbamoyl, to an ogen (lower alkyl, such as trifluoromethyl, cyano and / or nitro), in particular the phenyl group substituted in the para position with one of said groups, said substituents being the most unsubstituted lower alkyl group such as methyl or an ethyl group, and an aryl group which has a radical of up to 14 carbon atoms and which is unsubstituted or one or more, preferably one, substituted, for example, by a lower alkyl group, for example methyl, naiogen (lower alkyl group such as cnior- or bromomethyl) an alkoxy atom, for example a thio atom or a chlorine atom, a hydroxyl group, a lower alkoxy group, if o methoxy, (lower aikanjoyioxy, carboxyl, (lower alkyloxycarbonyl, thenyl (lower and alkoxycarbonyl) carbonyl, carbamoyl, mono- or di (carbamoyl) a mono- or di-pyridyl group (with a carbamoyl group, a nagene (lower alkyl group such as a trifluoromethyl group), a heterocyclic group (lower alkyl group in which the non-heterocyclic group has a the meanings given above for the heterocyclic group forming the substituent of the lower aikanoyl group, in particular the heterocyclylmethyl group in which the heterocyclic radical is bonded via a crown nitrogen atom, for example pi per imidomethyl, e.g. 1-ylmethyl, 4- (lower alkylpiperazin-1-ylmethyl), such as 4-methyl- or 4-ethylpiperazin-1-yl, 4- (lower alkanoyl) piperazinyl - a methyl group such as a 4-acetyl or piperazinimethyl group, a morpholomethyl group or a thiomorpholine group, a cyano group, and / or a tri group, a correspondingly suitably substituted thenyl group or an i- or 2-naphthyl group, the remainder The N-substituted carbamic acid may carry at most one of the above-mentioned aryl groups on the nitrogen atom, the acyl group R1 of the N-substituted carbamic acid being in particular a mono- or di (mercapto and alkyl) aminocarbonyl group such as Ν. -methyl-, N-ethyl-, Ν, Ν-dimethyl- or N, N-diethylaminocarbonyl, or phenyl (a lower alkylamino aminocarbonyl group in which the thenyl radical is unsubstituted or substituted by the groups mentioned for the detinary aryl group) , for example a lower alkyl group, for example a methyl group, to an ogen (. n is an alkyl group such as a chloro or bromomethyl group or a trifluoromethyl group, a naiogen atom, for example a fluorine atom or a chlorine atom, a hydroxyl group, a lower alkoxy group such as a methoxy group, a carboxyl group and / or cyano group, at most three of these substituents, in particular one of mcn, for example in the para position, such as in N-benzyl-, N- (4-fluoro-benzyl), N- (4-trifluoromethylbenzyl) -, N- (4-trifluoromethylbenzyl) - or - N - (4-cyanobenzylamino) -carbonyl group.

Especially. Preferred is an aminocarbonyl group which is substituted on the nitrogen atom with only one substituent, for example an N- (lower alkylaminocarbonyl group such as N-methyl or N-ethylaminocarbonyl), or a thenylimino alkylamino aminocarbonyl group in which the Tenyl radical is unsubstituted or substituted by groups mentioned in the definition of an aryl group, for example a lower alkyl group such as a methyl group, a halo (lower alkyl group such as a chloro- or bromomethyl group), and a fluoromethyl group, a halogen atom such as a thorium or chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, a carboxyl group and / or a cyano group, optionally substituted by at most three mutually independent groups selected of these substituents, in particular one of them, for example in the para position, such as in Ν-benzyl-, N - (, 4-fluoroyl) i-, n- (. 4-cn i oro) benzyl) -, N- (4-trifluoromethylbenzyl or N- (1,4-cyanobenzyl) ammonium carbonyl).

preferably the acyl groups R 1 unsubstituted by amino acids include amino acids but no alpha, beta, -gamma- or deita-amino acid residues 11n linked through their carbonyl group, in particular naturally occurring L-configuration amino acids normally found in proteins, or in an emitter of such an amino acid, i. having an unnatural U configuration, or icn isomerically a mixture of D, L, an amino acid homologue in which the amino acid ocular chain is extended or truncated by, for example, one or two methyl groups, wherein the amino group is in beta, gamma or delta halftone or wherein the aromatic radical has from 6 to 14 carbon atoms, for example, substituted thenyiaiamine or phenylengine, where the phenyl is replaced by one or more κ rats, the lower alkyl group, for example the methyl group, may be lower, hydroxy, lower alkoxy, for example methoxy, (lower aikanjoyioxy, for example acetoxy, amino, (lower alkylamino), for example methylamino-group, di (lower) alkylamino group, for example dimethylamino group, (lower and kan) oylamino group, for example acetyl amine -coupled or brewed amino, (lower alkoxycarbonylamino, for example tert-butoxycarbonylamino, aryl 1 methoxycarbonylamino, wherein the aryl radical has from 6 to 14 carbon atoms, such as benzyloxycarponylamino, or 9-fluorenyimethoxycarbonylamino, halogen, such as fluorine, chlorine, bromine or iodine, carboxyl and / or meth, or benzanated phenyleneamino or thioamino, or thioamino, or thienyl amine or thioamino, or thienyl amine or thienyl amine 1 g of iycin such as cyclohexyl amine or cyclonexyl gycin. Within the above definitions, the aforementioned acyl groups of amino acids such as propyl, indol-2-carbonyl, 1,2,3,4-tetrahydro-11n3-carbonyl and trans-3- and the trans-4-hydroxypropyl group already present in the definition of the substituted lower aikanoyl group R 1 for the sole purpose of avoiding overlapping of these deticines.

These amino acid residues may be substituted at one of the free amino function or hydroxy function, preferably one free aimnotunction, by one of the radicals mentioned above under the acyl group R 1 forming an acyl carboxylic acid group or a half-carbonic acid ester, unsubstituted or substituted by an alkyl group. , in particular lower alkyl, such as methyl, ethyl, isopropyl, n-propyl or n-butyl, the substituents being, for example, one or more groups, preferably at most three, at least one group selected from the group consisting of hydroxyl, lower alkoxy, tenoxy, to 11-oxy, (lower and kan) oxyoxy, halogen and halogen such as toro, chloro, bromo or iodo, in particular chlorine atom, carboxy group hunting, inoxidation of alkoxycarbonyl a group, such as a benzyloxycarbonyl group, such as a benzyloxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, a oxycarbamoyl group, a di-lower alkylcarbamoyl group, bis / hydroxy (. a U-carbamoyl group, an oxo group, a cycloalkyl group, for example a C 3 -C 8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl cyclohexyl group, a bicycloalkyl group a decahydronaphth-2-yl group, an endo group, a cyclopentyl group, or a hunting group, for example, up to 12 carbon atoms, such as a bicycloalkyl containing 6 or exo-2-norbyrnyl group, bicyclo (2.2.2) oct-2-yl group or a bicyclo [3.3.1] non-9-yl group, a tricycloalkyl group, for example, a tricycloalkyl group such as a 1- or 2-adamantyl group, a cycloalkylene group , for example, cycloalkenyl having 4 to 8 carbon atoms, such as 1-cyclohexenyl or 1,4-cyclohexadienyl, bicycloalkenyl, for example 5-norbornen-2-yl or bicyclo [2.2.2] octen- A 2-yl group, a heterocyclic group that is saturated, partially unsaturated or unsaturated circle, which is i

as lacquers or in single or double, in particular jeunoductive, oenz-, cycliopenta-, cyclionexa- and oococio-hepta-anelated torms containing 3 to 6, optionally 5 to 1 ring atoms and at most four heteroatoms selected from the group consisting of atorn nitrogen, a sulfur atom and / or an oxygen atom, which is exemplified by a teroatomic moiety which is substituted by another group, is not particularly substituted by an aikanoyl group, a lower hydroxy group, a lower alkoxy group, a theny (lower alkoxy) group. such as benzyloxy, nydroxy (a lower group such as a naryloxymethyl group, atornoine halogen, cyano group and / or trifluoromethyl group such as pyrrolidine group, 2,5-dihydropyrrolidine group , tura ny hunting group, women group, tetran yd roruranyi group, cyclionepta / 0 / 'pyrroiyiov u group, p y r i o i i y y i o v group, i i d i z o i i o u group, i i d i z o 11 d i n i i o u group, p yra z o i n i i o u s p i n, pyrazoiidinyi group, three i z o i i o o

A 1,2,4-alyl 1,3,4-triazolyl group such as an i- or 2-tetrazolyl group, a tetrazolyl group, a tetrahydrooxazolyl group, a tetranyaro isoxazolyl group, and a tetrazolyl group. group, tetranydroisothiazole, indoyl, isoindoyl, chnoyl, hunting, oenzimidazolium, benzoturanyl, pyridynyl, pyrimidinyl, ion, piperazin-i-yi, plague 1-0 ii novu thiomorpholino, S, Sd, oxothiomorpholino, 1,2-dihydro- or i, 2,3,4-tetranyrocyninyl, or 1,2-dihydro- or i, 2,3,4-tetranydroiso said group being unsubstituted and substituted by the above process, in particular by a lower alkyl group such as in a 4- (lower alkyl) piperazin-1-yl group such as 4-methyl or 4-ethylpiperazine-1-yl; or mzso an alkanoyl group, for example in a 4-methyl group and a 1-chloroyl group per azin-1-yl group, such as a 4-acetyl group in a perazinyl group, and an aryl group, preferably an aryl group containing 6 to 6 alkyl atoms, for example a phenyl group, a naphthyl group as well as a 2-naphthyl group, an indyl group such as or a given hunting group, an inenyl group such as a n-1-fluorenyl group, or a fluorophenyl group , the yi group, while the uveoenearyl groups are unsubstituted aneaneoeaeaeneans c, rac, nodeeaen, substituted, for example, by a lower and γ κ yi group, such as κ iao methyl, naiogen m z, and κ κ i skupinou, and κ ω a, a dromomethyl group, such as an atom of the ion, for example atomic riuoruaiepoato in tonic, nydroxy, mzs an alkoxy group, such as a methoxy group, an i n i z i i i n i n i y y x y group, a carboxyl group, a t, m zsi and i y y x y κ a r o n y i o o group, r e n y i i. lower than the γ oxyy κ ardonyl group, the κ aroamoyl group, the rnono-aiooo anmzsi ai Kyu Karoamoyl group, the mono-aloooainyaroxy (. nizsia kyl) caroamoyl group, the naiogen (nizsia ι κ yu group). a triuromethyl group, a non-ocylyl and a nizsiaicyl group in which the neterocyloxy group is as defined above, in particular a maneterocyloxymethyl group in which the neterocyclyl group is bonded via a krill nitrogen, such as piperazine and piperazine; 4- (lower-alkyl) piperazin-1-ylmethyl, and 4-methyl-4-methyl-4-ethylpiperazin-1-ylmethyl, 4 - (lower-alkyl) piperazin-4-yl; yimethyl group, axo 4-acetyl ipi perazi niy 1 metyl group a morto-inomethyl group and one or more ortho-11-methyl groups, a cyano group, an aryoo group or a tri-group, especially a group substituted in the field by one of the aforementioned groups, in particular the corresponding msp δ salt substituted with an alkyl group, in particular a correspondingly substituted methyl group, preferably a pension group, an air-methyl group, a β- group,

The 3- or 4-pyrimidoyl group, or further one of the groups in the description, relates to the manner of the axo-protective group, or may be civivatized to the carboxylate group.

Especially preferred is a carbonyl group linked to an amino acid selected from the group consisting of glycine n (h-G 1 y-OH), and 1 and n i n (h-A1 and -O H), n-aminobutyric acid,

k y s e i i n u 3-in i n o in a s i o v u, Kyse i i i n u 4-ain i núia s i o v u, kyse i i n u 3-arn and nopentane kyse i i i n u 4-am inopentane k y s e i i i n u 5-arni nopentane Kyse i i i n u 3 - a m i n o n e Kyse i 11 n u 4-aminohexanoic acid, Kyse i i i n u 5-ain i nonexane,

va iin (. H-va i-OH), norvaiin (Acid and 11a-amine no va v era va), ieucine (n-Leu-Qh), isoucine (h - ϊ ie - 0 h), norieucine ( [alpha] 11a-aminonexanoic acid, n-ni-eh), serine (H-Ser-UH), nomoserine ([alpha] 11a-amino-gamma-nyaroxymasioic acid, threonine (h-T hr-O hj) , me 11 onin (h - met - h h), cysiein (h - ϋ ys - ϋ hj, hair dryer la ianin (HP not-0 h), tyrosin n (H-iyr-úHj,

4-aminoethenes i and i or n,

- c n i o r r i n i i i n i n,

- carboxytenyialanine, oeta-thienylserine (p-ayaroxyrenesin}, phenyigiycin, allyl-naphthylanine (hN ai-OH), cyclionexyiaianine (H-Cn-uHj, cyclionionyl glycine, tryptophan (h - T rp - O) h),

Aspartic acid (H-Asp-OH), asparagine (.H-Asn-OH),

k y s e 1 i n a am inorna i onova, rn o n o a m i a amine and ononic acid, k y s e 1 i n a glutamic (H-Glu-OH), g i utamin (H-Gi n-OH) hi s 11 ci í n (H-H1S-OH J,

a rinin (H-Arg-UHi, yin) (H-Lys-OH),

Ž 4 a e ita-nyoroxy-y sin, orniiin (Acid a-a, oeita-oi am i novelova ;,

3-ain i nopr opanova,

Aira acid, gamma-d i aim nornas io va aa ira, oeta-αlaminopropionic acid, o last-aliphatic and inocyanates selected from the group consisting of I anin, va 11 n, ieucine, Acid 3 - and lineage, opioid 2-Amino Acid, 3-Amino Acid, 4-Arm Amino Acid, 3-Amino-Nopentanoic Acid, Acid

4-aim nopentanoic acid, 5-aminopentanoic acid, 3-aminonexanoic acid

5-amino n e x a n o a, o o o u c i, o o o amino amino n o z o n g i y g c y, s p a r a g i n, g u utamini y s i a a n e n, p r c 0 Hl

Kazaa zpaipaauaosencieasymecni ckenoun i i a) may have at least one or more guraciu alta-aimnosKUpina, if present, unsubstituted aiecojeoen aieoo ava κ rat N-alkylated, such as an alkyl group, such as an alkyl group i ov and try for, n-propyl group and n-propyne group, and less than lower group such as 3-aminopropyl group, enenyi-aoo to thi amino (lower group, such as 3 -thienylthio-propyl, renylthiisylicyl, such as oenzyl, oitenylmethyl, trityl, aryo / aneterocyclyl (lower alkyl), in which it has no K i y radical residue the meanings given above for the acyl group R 1 of the carboxylic acid, in particular a non-cytoklyl group, e.g. for example, ruranyl, mzsi alklyl, such as z-ruranylmethyl, thienyl-alkyl, such as 2-1-methylmethyl, imidazolyl alkyl, such as imiaazo-1-4-ylmethyl, or 2 -, 3- or 4-pyrimidyl (lower alkyl) such as

2-, 3- or 4-pyriaylmethyl; and N-acylated with acyl groups which are, for example, mentioned in the case of R1, in particular unsuccolated or substituted by a lower and 1K yesyl group, as defined above, in particular acetyl, propi group, pivaioyi group, neterocyki y 1 (lower and iKanjoy1 group, axo was already

- aer ο aerated above for ac yi R1, for example, iaa ruran-γ a aroonyiovous upin, - - hyaroxy and ethyl-2-γ κ arbonyi skú, 2-, 3-aiedo 4-pyriayicaroony sCupin , a morto-carboxylic acid group, 11 an omorromic and aroonyl group, a niaciacylic group, a niacinuroyl acetyl group, an aryl group (lower-anionic anyl group, such as a Denzoyl group, and an aiDO acetylenic acid group). ii already mentioned above for Ki aerospace, in particular (lower ai κ oxyj κ aroonyi group, ie cd cd utox ykar Dony up group, aieoo aryi. nizsia ι oxy oxy) κ ar D onyi group, and κ ooenzyioxy κ aroonyi Nou,

Karooxy-SKUpina docnenoretazca is a free trial aieoo is in a lot and a lot of it, eg κ iaoa κ o (nizsiai k. Yi) escerovas up upina, and κ omethoxy and aroonyi group aieoo t-group, atoxycaroonyi κ oa ry Ϊ esters sxupin aieoo sk y n / í a i up up up up up up up up up up up,,,,,,,, tor tor K tor K tor a a a iκ iaaa κ o 4 - n 11 rorenyioxy ar ardonyiovas up upina, denzyioxy ar ardony skupina group aieoo y - u rorenyi n r ethoxy ar ardony ova Group aieoo a κ ar ar D am oyi group, and κ o (nizsi a i i uKaroamoy hunting group such as 1Karoamoy hunting group such as aiinizsi aikyi / Karoamoyi group as d imethyiKarbamoy hunting group as mono- aieDO di / nyaroxy (ni zs ia 1 Ky'u Karoamoyova group, as nyaroxymethyi Karoamoyi group aieoo ai (nyaroxymethy ij Kar Dainoy i group aieDO aKo mono- aieoo ai / Carboxy (lower ai Ky u Karoamoy group, as carooxymethylcarbamoyl group aieoo ai (Carooxymevy i / Caroamoyl group, an amine of an O-chain group not found in the polar group, is a free group and is in an alkylated form, e.g. a group such as n-oucyi am ino-supup to aieoo ui methy 1 am ino-group, aieoo in acylated form, for example axo (lower and icanjoy laimine sxupine, as keto acetylamine group aieoo beivoyl amine group, aKo am i no (nizsia ι κ an / oyiaminovas κ upina, such as 3 - amino - 3, 3

Z baimetyipropionyia rm novasgroup, and κ o ar yi (lower ι κ an) oyia im nova group, in which aryi residue oosanujebazi 4 atoms un'lika and means, for example, renyi group and ioo r iuoreny hunting group, while the nesuost i tuosyy A lower alkoxy group, a carboxy group, a carboxylic acid group and a suit suitoyoyl group such as a tert-alkoxycarbonylamino group, such as an aryimecoxycarbonylamino group, in which the aryl moiety is about 14 amino acids, such as the oenzyloxycarponyne aieoo yt iuorenyimethoxy group and arbonyia inova group, such as piperioyi - i - ony arponyl group, mor ó io in io aroonyi group, 11 omortoiin oKarDonyi group aieoo as b, S-aioxothioniofroinokaroonyi group a, pi to Docneno chain is a duo in another sk The upine aieoo is in the threefold of the j aieoo still r 11 rated jorme, for example, and a lower than a x o - s κ u p i n, as m e t o x y - s u p i n a aoooo t-thioxy, such as a r y i aiKoxy as

i. n i z s is an alkoxy group, in particular an oesyloxy group, such as inizsi x y - s k p i n, such as acetox y-group, aieoo a i κ yi yxyxy a r o n y i x x y - s u u p i n, n a p r i κ i a o t e r c. b u t y i x y κ a t 'o n y toxy-SKU p i n a.

The cyano groups R @ 1 are in particular unsubstituted and substituted amino acids selected from the group consisting of an arylalkyl group, a n-lower alkyl group, a n-methyl group, an aynyl group, a tenyiaianyl group, a N - (, oenzyioxycaroonyl, urenyiaiani group). γ-fluorenylimethoxycarbonyl (phenylthio), aminoacetyl, thiycyl), N - (lower and lower) aminoacetyl, n, n, ai (lower and lower amino groups, N - (lower lower alkyls) ) -N-phenyl (lower alkyl) amino, N-lower alkyl-N-imidazoyl The lower alkyl amine no-acetyl group, N-lower alkyl and N-pyridyl group, N-lower alkyl group, N - lower and a cy N - (may have alkoxycarbonylaminoacetyl group, N-phenyl (lower and 1-alkoxy; carbonyls N - (lower isocyanate), N-morto-amino-N-11-morpholine-11) ( a lower alkylamino group, for example N-methylamines N, N-imethylamino and N-methyl-N-methyl. N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl-N-methyl ovu -N- (2-Amino-3-pyrimidylmethyl aminoacetyl-4-ylmethyl) n-methylaminoacetyl group,

N-inets and N-terc.DutoxyKar'oony´iaimnoacety hunting oon y N--N- (n i zsi a κ y i j am inoacety hunting try to n y i am inoacety iovu

3-aini nopr'op and they hunt

2- a m i n o u t y r y group,

- m m i i i i i i i i i i i i i i i i

- (n, n - a i m e t y i m i n o j o u t yr y i v u

-a m i n o p e nt a n o y hunting group, 4-a m i n o p e n t a no yi

- a i n i n o p e n t a n o p y i v u group, 3-a m i n o n e x a n o yi group

4a m a n i n e a n o y i o v a group a i o o 5-a m i n o ne s a n i a n i n a n i n a n e n i n a n i n i n a n n a n i n a n i n a n i 3 -1 e n y i p o o o y i i o o s s u pi n u, N - í.

a i o o 4 - p o r i o i i i o v i i i i o v i s n i, m - t o x y i a n o i n i i o t o x y i a i o i i i i s i s i,

Nt er cb ut ox yk aroo ny y va y y group, n-1 er co utox y y y ro y yy y y y group, n-oenzyioxy and aroonyivaiy group, n- (mort οι ino κ aroonyijvaiyi group, norvaiyi group, ieucyi group , n-acetyloxy, n-z-, 3-amino-4-pyridoxydione, n-1-denzyloxycarbonyl, iso-butyl, to cetyl, N-propioryloxy, N-thioxy, , tutoxy and ardonyuizo-sucyl, with an onyl group, an iysyl group, a giutamyl group, a gamma- (N-benzyloxycarbonyl and γ-butynyl group, an asparagylic group, and beca- (N-oenzyioxycaric) an aspartic group, wherein the amino κ yseine residues of iocrempripa α, κ e and neoDsanuju z i a d n asymmetrically u n i i k, it is a n i n i i n i i n i n i n i n i n o i n i i o o o (D, L).

If n a c n o o z a nydroxyaieoo armno-Group, which

They contain a free hydrogen atom, on a carbon atom which is protruding from a two to two, such as, for example, in a substituted moiety of the formula x, but it is also possible.

o s i e d κ e e e e t i i i----------,

alkenyl or lower aikinyl group, then z and u are -.

eto ietoaoooobneta utonie ry, although the existence is common to the eye and in that eye it is common to fall within 11 ez and the extent of the compound yield in all the formulas in which there is no possible ziaanatautomerism does not exist - Oh and leoo -nh na- atomocn κ torycnvycnaazaavo jna vazoa j.

in all cases, the compounds are not sufficient. Sufficiently suited to the taxation of the compound, which can be processed into the preparation.

oo i am i zucenin in s o o e o n e n o n o n s and i m i m i s, s i s i s i d i i ooo i ooo i i o i i s i o s i s o s i o s i o s i o s i o n i s n o s.

The salts may be a salt of a compound of formula (I) with a Kysioune and a salt of, for example, a carboxylic acid and a carboxylic acid.

METALS oavoaene oa metals ia, groups of eriodicated elements of the first element, ions and ets of metals, for example 11 salts, potassium salts, salts of metals and 1 κ and 11 zem earths, ai eoo iaa norate or calcium, as well as salts of organic and fatty acids such as mono-, e-alkali, and amine, which may optionally be formed with hydroxy or tri- and 1-cyanamines, in particular mono-, oi or with quaternary ammonium sulfide and N-methyl-N-erylamine amines, diethylamines, such as mono-, or ammonium, ammonium, ethoxy, or amine,

- n y and r o x y -1 e r c. outy amino amino in aieoo tr is (.hydroxymethymethylaminamines, n, n- and i (mzsi ai Ky 1 jN- / hyaroxy (n n iss 1-phy 1 spring), such as triethylamine, mono-, bi- or tris - (2 / nyaroxy (lower than, n - aimeuy) N - (z-nyaroxyethyl) aminomaieootri - (z - nyaroxyethylamine, Nm ethyl-ug iu-amine aieoo Quaternary ammonium salts such as tetrabuty ammonium salts

Compounds of all formulas having a contaminated group such as amine groups, cerebellum 11, aionic salts of sanitary substances, such as sulfuric acid and sulfuric acid, and the like. xyioic acid, it is inactive,

S U I t o o o o s s o i i n i i o s s i i n i i n i i n i n i n i m i, n i p i i n i with acetic acid, p r o o o o,

kyse i inou giykoi, κ y s e i i nou succinic Kyse and others other i e i no- acid, kyse i other n yoroxyma i e i with a new, acidic acid e i no o o u, kyse i i nou t u m a r o v o u, κ y s e i another jap i onou, κ y with e i other in i n nou, kyse! i inou g i u k o n o o u, κ y s e i another g lUKarovou , Acid g i uκ u-

and other oeizoic acid, lonic acid, citric acid,

Acid different Acid different Acid and another

- a i n i n o s i i c y i v o, β-acetoxyoenzo,

Acidic acid with another other saicicic, phenoxyoenzoic, and eoic acidic zonicotinic acid.

a i eoo napt 'i k i a so i r a-am

Kyse and other towns, Kyse and other towns

Acidic thiaroxyethanesuiron,

Acid and other ethane (s) with benzosuifonic acid,

Acidic acid or other naphthalene-2-succinic acid

2a ieoo

3-tostoglycerate, giucoso-6-tartrate, with succinic acid (to form cyclamates; or with sulfuric compounds such as ascorbic acid, compounds of the formula with acids and basic groups may also form Pharmaceutically unsuitable salts can also be used internally for isolation and purification purposes.

the terms compound and salt of z and h are also expressly as individual compounds or individual salts.

The compounds of formula (I) have valuable pharmacological properties. Of the compounds, after the warm-blooded animal has been exposed to the ocular, in particular, it is inactivated and expressed by the compound of formula (i), which are described and can be obtained effectively in aspartate proteases, which also include ii. A iu $ aKo aspartatprotease n 1 v - ί aieoo / a <apr 'ipaoneaaisic retroviruses that induce symptoms,

Which s g o c g e c e s s y m p t o m i i i s S j i. o to m v i u eh u 4 4 4 i

(.published i 9. j u n i i y 9 i) and o i i s i n e u e n e u u 11 k a c j e. The formula i x to ni v-1-proteasy is n a p i i i o o o o i i i j. m e a. C n e m. 3 4,3 3 4 ô - 3 3 4 2 (i y y i), h i v - 2 - th e y a n n i v i i y y described in Science 46 46, 3 ó δ - 3 o i compounds of formula x I

zati et al what i n n i o i c i a H and V - 1 - a u c i n o κ on the p u n e c n e ku 11 u r y They are d. i y y o).

whilst in the throat treated with heat, blood-warmed eyes in the eye, she, in the eye, in the eye of the formula.

By virtue of the general formula (i), it is possible to react, especially in the case of enterain, to eliminate the need for other treatments, and to improve the resorption of the compound of formula (ii) and to increase the blood concentration of the compound of formula (Ii). 1 even under otherwise κ ycn conditions. It is also possible for example to distribute the active ingredient in the desired manner. The use of the aforesaid method is to provide the above described description of providing precursors for the treatment, including the treatment with the antisense treatment.

the above mentioned properties can be proved by the following s o o o o o.

The test compounds of formula (I) and the comparative formula (DmSO) at a concentration of 2400 ing / ml. The solutions obtained are diluted

0% n (n / a. Of the nyaroxypropyl-beta-cycloaexyl compound of formula II used as a control) is dissolved three times in order to obtain a test substance from mg / in.

The solution is then taken as mg / k g. 30 minutes after using 3 to 4, the experiments were attempted

For each of the animals in the animal, the animal is animal, that the animal is also an anaalyse and it is processed once by us.

They fit the first method and the blood is mixed by mixing the blood with one volume volume of 11 ri. After centrifugation, the supernatant was reversed with a liquid-pressure liquid chromatographic supernatant.

Appropriate methods, κ unpaired from the blood bath, add the internal s t a n a and r α k a s a n n 11 u 11 n a i n e 4 u m concentration. the blood is then oastreoi. The piazine is then removed, which is then treated with the same one and the same. After centrifugation, the supernatant is dried under vacuum and the residue is suspended in a pH of 3.0 mm 3 / ml. The suspension is extracted first and then 0.2 ml of aisopropylether. The obtained aisopropyl-propylene solution is evaporated by evaporation and the residue is dissolved in> 10% aqueous acetonitrile (iodine / op.). This solution is then heated to a high temperature with a liquid solution.

Anaiyza High Pressure Liquid Chromatography is converted to a column of N ucieosii C ₁₈ c in dimensions of ž 5 x 4.6 mm (Reverse Stamping Material i by Macnerey-Nage i, Duren, Federal Republic of Germany on the Siikaic Oasis Aerivatized with 18 Hydrocarbon Remains (1) (k), which is in comparison with a divisible tie formed by a 40% solution of acetonitrile in a solution containing 0.1% of trifluoroacetic acid. The column flow rate is imi / min. Detection is performed at 5 nm. As well as blood samples, standards were used for the blood compounds that could be used to plot the standard curves based on the in vivo concentration determined.

In comparison, all of formula 1 is compared with the compounds of formula 11 (efficiently) by about 11 obtained in the formula. the concentration of δ inactive compounds of formula 1 in the blood of the mouse is after perorainompo or even a compound of the formula I, for example a compound of the formula I in which K is acetyl, all of the above more than three times as high as it is native and, moreover, the absorption of the compound is in the general formula of formula I in which R is

Of the formula 11, for example more than four times, it is possible to achieve a blood-efficient blood pressure at the blood level

III of a compound of formula i i.

can be commercially available comparative agents for testing in other aspartate proteases, for example animals and animals, for example

In practice, as in practice, the determination of the concentration of the effective blood concentration in the blood depends on the specific activity of the blood.

On the one hand, the aforementioned mouse modeioin not mentioned here can be used as a comparative substance for comparison with the compound tested in the animal.

In the following, the compounds of formula (I) may be meaningful to use more definitive definitions in order to overcome more general oetinitics by more specific definitions, but individual substituents may also be omitted.

Preferred are compounds of formula (I) wherein R 1 is octanoyl, oekanoyl, dooecanoyl, palmitoyl, non-succinated, or a sostituated lower aikanoyl group, lower aikenoyl group with a lower and aneonium group, is in the aieoo meKOiKyrm groups, not more than the third group, most of them is aieoo aaiejavom 1 groups, from the group clear j nyaroxy group, lower aiKoxy-SKUpine, (lower ai κ oxy λ lower aiKoxyj (lower lower alkoxy) (lower lower alkoxy) - a group, a renoxy group and a nonartoxy group, a group such as a ioxyoxy group, and aoxyoxy 2- group (lower aikari) ) oyiovuzsi aikoxyjacetyi group, am i no v

n u i

i n u, z-n and i o - i 0 in u group and Ky i j am i no- than ci 11 n e t y i- i z s 1 and i k y u -

z s i i i aoooo a n n i z s i a i κ y

- i n i z s i i i k i n i o i u u group as imet i i m i no- (aiKoxyjetoxy) acety hunting group

Group i (n i z s i and ι κ a n) o y i o x y - s k u p

The group aieoo t e n y i c e t y i x y - s κ u p i n u, t o in n a i u y e n, such as o o o o o o o o o o o, atom i o u u. i.

group, ten y κ o x y j k a r D o n y io group, loxyKar'pony io k k p i n u, (n k a r o and in o y i o u k i i)

(i) / kar ausi o o m o y i o u u s

A group which is a member of a non-heterocyclic ring of a ring which can be further selected from the group consisting of an oxygen atom, a sulfur atom, a nitrogen atom and a nitrogen atom substituted by a lower alkyl group such as a methyl group and an ethyl group, e.g. 11, aortho-1-inocarbonyl group, a piperidino-1-yloxycarbonyl group, a piperazin-1-ylcarbonyl group, and a 4- (lower arylamino-1-ylcarbonyl) group such as 4-methyl-piperazin-4-ylcarbonyl, cyano, oxo, cycloalkyl, for example cycloalkyl of 3 to 8 carbon atoms, such as cyclopropyl, cycloethyl and cycloexyl, oicycyclic and oai κ yi, such as an oicyKioalkyl group having from 6 to 2 ato m o u n i i a, e e e a h y e r o n a r t - y i o u u, e n a o- aieoo e x o-234 n o r n o r 'n y i o u s up, 1 / n o n - o - y i o u group, a tricyclic group, for example a tricycloalkyl group having 9 and z 4 uric acid atoms, as well as a 2-adainantium group, a cycloalkenyl group

group for example c y k i o a 1 κ e n y 1 o u a group o 4 to δ

and t o m i n i i, a κ o i-cyclionexenyl group and i o o o i, 4-c y i n i o, a dicycloai kenyi group, n a p i i n ior n n-2-y hunting group a i e o 2

group which means saturated, partially saturated aieoo

which is like taxa and i e d i i n i n i n i n z -, cyciopenta-, cyclionexa- aoo cyclionepta-aneiated th e r i, e i s i n i i n i s i n i s

r o a t o m y selected from the group consisting of ausica, a sulfur atom

or / or an oxygen atom, which is unsubstituted or substituted by an unsubstituted or substituted suds 11 tuent am izvoien ym isosine for a lower or lower alkyl group, lower ai-anoyl group, nyarox ys κ upin, lower aikox γ- with κ upin, renyiiinizsiai κ oxy) - with κ upin, and κ luxy-

s κ u p i n u, n y d r o x y (. n i z s i i y y i j u u group, as n y a r o x y m e t y i v u u group atom n a i o g e n u, k y and n o- s κ u p i n u a i e o / a t r i t o r m e t y i v u group n a p r i o o y y y o o - s u p i n u, 2, 5 - o o y y o o y y y o o group turanyl group, tien y hunting group, tetranyoroTU- r and n y i o u u group, c y 1 e t t t t r t t,,,

n i i o i u group, i i n i i o i i i o i v i i i ididolidinyl group, pyrazolinyl group, p y r a z d i n y 1 o u group, three a-

zo i y i o in u a group such as 1,2,3-, 1,2,4- or 1,3,4-triazole group a tetrazolyl group such as i-aleoo of 2-tetrazolyl group t e c r a n y o r o x o z 1 y 1 o u u, tetranyoroisoxa- of hunting a group, tetrahyarothiazole, t e t r a-

nydroisothiazolyl group, i n d o 1 y 1 o u u group,

group a cynoyl group, an isocylamino group, o e n z i -

m i d a z i y i n a group, benzoturans of the hunting group, a p i r i y i n a group, a pyrimidinyl group, a p i r i d i n i i n e group, a p i r azin-i-yl group, morpholino group

p i n u, p , b-dioxothiomortoline, 1,2-oinyoro- or

1.2.3.4-tetranydrocninolyl or 1,2,2-o n y and r o-aleoo

1.2.3.4- a tetrahyaroisoquinolinyl group, wherein the substance is

p i n y are unsubstituted or especially substituted lower

An alkyl group such as a 4 - (lower alkyl) piperazin-1-yl group such as the 4-methyl-4-ethylpiperazin-1-yl group, a lower aikanoyl group, such as the 4-i, lower aikanjoylpiperazine-1-yl group; a 4-acetyipiprazin-1-yl group such as a 4-acetyipiprazin-1-yl group, such as a 5-nayloxymethyl group, aaryl group containing at least 11 catenyi, nartyiovu

SKUp'l what i - aieoo

A 2-naphthyl group, an inanyanyl group such as a 2-inoanyl nu, an inoenyl group, such as an ini n-i y y group, and an eoriuorenyl group, such as a thiorene y y group, wherein the aryi group is nesuDS c 1t uu boil aieuú je uen aieoo v

SUDST i tuentam i tuentam i selected from the group include a different group, such as a methyl group, a haiogen (lower ai y y i OV a group such as a rummet y group, and that of a halogen, e.g. o atoinfluorua has been involved in the respect of iota, a ny oroxy group, a lower α1-oxy group, such as a mecoxy group,

(a) aikanjoyioxy-carboxyxy group and aryloxy group, aryloxy group, aryloxy group, aryloxy group, aryloxy group, aryloxy group, aryloxy group, and aryloxy group. nizsiaoamoy hunting group, the iogen (nizsiaiky i.) group, ri uormet yi group, neterocykiyi (. ri izsiaikyi) group, in which the maneterocykiy 1 residue of the above is known, especially the neterocyk 1 yi met y 1 group, in which the non-cyclocycle is a 1-yl radical bonded via a ring atom such as a piperazinomethyl group, a piperazin-1-yimethyl group, and a 1-cyanepiperazin-ynyl group such as 4-methyl4; - i. n i

4e-piperazin-1-ylmethyl-once-i-ylmethyl group morpholefins of the cyano group and thus a group of three, in particular a para group substituted by a jeone group, a group, a group, 4-thiocyanjoyipipeako 4-acetyl ipiprazin-1-methyl group and thiomorpholinomethylenedioxy from the above-mentioned groups, further (lower and alkoxy) carbonyl groups, for example methoxy, ethoxy or tertiary (lower and lower alkoxy) carbonyl groups. 1 a alkoxycarbonyl group, such as a tert-butoxycarbonyl group, a naphiogen (lower alkoxy) carboxy group, for example 2-cn 1 or 2-b ron, 2-joo or 2, 2, 2 -1 ricoxoxycarbones 1; ov ii group, aryl (lower alkoxy) carbonyl, carbon and from a number of up to 14 atoms or fluorine of pin, xyl (lower substituents for example methylo chloro or for example an arylmethoxycarbonyl radical contains or a substituted alkyl group, and an alkyl group, a halogen atom, such as an alkoxy, carbo, phenyl, halogen, lower nu, hydroxy, (lower alkane) oyloxy (lower and lower) 1) Oxycarbonyl examines a carbamoyl assay as a trifluoromethyl group having the aforementioned group, aryl is unsubstituted including a lower group, halogen ((bromomethyl group or chlorine, such as methoxy, group, and 1-alkoxy) carbonyl) or a di- (lower alkyl) carbamoyl dihydroxy (lower alkyl) carbamoyl alkyl) group, alkyl), in particular a group which has been linked via a mono-halogen group to form a substituent of a heterocyclylmethyl radical, heteroaryl lower group, ring perazine (lower heterocycles). 1y1 (lower cyclyl radical of the heterocyclyl group, heterocyclyl such as piperidinomethyl group, 4- (lower alkyl) piperaz such as 4-methyl- or 4-ethyl-4- (lower, piperazin-1-) ylmethyperazin-1-yl, -ra-1-chloro-1-yl-piperazin-1-ylmethyl

A 4-acetylpiperazin-1-ylmethyl group is tested and / or a phenyl group or a phenyl group which is substituted several times by a lower alkyl tert-butyl methoxy group of a hydroxy group for a 1 kanoyl group in which the nitrogen atom is .

A 1-ylmethyl group methyl group such as morphol inomethyl cyano, in particular means fluorenyl or nu or thiomorphol inomethyl, nitro, the aryl radical being a group of 1- or 2-naphthyl one group, lower for example methyl or alkoxy, for example or tert-butoxy fluorine, for example atom and / or nitro group, such as alkoxycarbonyl, diphenyl (lower and 1-alkoxy) carbonyl carbonyl a group, nu, tri-oxycarbonyl, ethoxy, halogen, or bromine, for example phenyl (lower and 1-alkoxy) carbonybenzyloxycarbonyl, 4-methoxybenzyl-4-nitrobenzyloxycarbonyl, such as diphenylmethoxyphenyl (4-methoxyphenyl) methoxy a methoxycarbonyl group, or a fluorenyl (lower alkoxy) carbonyl group, such as a 9-fluorenylmethoxycarbonyl group, or a heterocyclyl (lower alkoxy) carbonyl group wherein the heterocyclyl radical is as previously defined for a heterocyclic group forming a substituent of a lower alkanoyl group, for example a furan-2-ylmethoxycarbonyl group, or a pyridine-2-, -3- or -4-ylmethoxycarbonyl group, or via and 1-a-carbonyl-linked amino acid radical selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norvaline, leucine, iso-eucine, norleucine, serine, homoserine, threonine, methionine, cystine, phenylalanine, tyrosine, 4- aminophenyl and 1,4-chlorophenyl and 1,4-carboxyphenylalanine, beta-phenylserine, phenylglycine, alpha-naphthylamine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, asparagine, acid elin am inomonic acid, am inomonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, delta-hydroxylysine, ornithine, 3-aminopropanoic acid, aa fa, gamma-diamine inomasic acid and alpha acid, beta-diaminopropionic, particularly preferably an aliphatic amino acid radical selected from the group consisting of alanine, valine, norvaline, leucine, 3-aminopropionic acid, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid

5-aminopentanoic, hexanoic acid, glutamine, 3-aminohexanoic acid, 4-amino acid, 5-aminohexanoic acid, and isoleucine or aminofunctional methionine from the group consisting of lysine and phenylalanine, glycine, asparagine, each of which has no asymmetric carbon atom. unless it is not in form D,

L or (D, L), preferably in the form of L, and the 1 -amino group, if present, is unsubstituted or one or two times N-alkylated from the group consisting of a lower alkyl group such as a methyl group, n-propyl or n-butyl, amino (lower alkyl group such as 3-aminopropyl group, phenyl or naphthylamino) (lower alkyl group such as 3-phenyl amine) an inopropyl group, a phenyl (lower alkyl group such as a benzyl group), and / or a heterocyclyl (n-rocyclyl radical for a substituted heterocyclymethyl group such as an alkyl group), wherein said nu R 1 group is more preferably especially diphenylmethyl, trityl lower alkyl, meanings which have already been the alkanoyl group, for example furanyl (lower alkyl) 2-furanylmethyl, thienyl (lower than 2-thienylmethyl, imidazolyl (lower) alkyl ) a group such as an imidazolyl-4-ylmethyl group or a 2-, 3- or 4-pyridyl (lower alkyl) group such as a 2-, 3- or 4-pyridylmethyl group, and / or N- acylated with, for example, unsubstituted or substituted lower alkanoyl radicals as previously defined in the definition of R 1, in particular acetyl, propionyl, pivaloyl, heterocyclyl (lower alkan) aryl, as defined above for the substituted lower alkanoyl group R 5, for example furan-2-ylcarbonyl, 5-hydroxymethylfuran-2-ylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, folinocarbonyl, thiomorpholinocarbonyl, indolyl-acetyl or benzofuranyl acetyl, aryl (lower alkan) oyl such as benzoyl or phenylacetyl, (lower alkoxy) carbonyl such as t-butoxycarbonyl or an aryl (lower alkoxy) carbonyl group as previously defined, for example, a phenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group, the side chain group being a (lower alkyl) ester group or a tert. a butoxycarbonyl group or as an aryl group (lower aryl group of which is carboxyl) a carbonyl aryl ester group is present, in a nitrophenyl group, a naphthyl group or a biphenyl group, for example as a free group or a group such as methoxy, such as an alkyl ester of scfenyl, 4-fluorophenyl 4-nitrophenyloxycarbonylcarbamoyl, such as (lower than methylcarbamoyl, such as dimethylcarbamoyl alkyl) carbamoyl, such as mono- or di / hydroxy (lower alkyl) / carbamoyl, such as hydroxymethylcarbamoyl or di (hyrie) yyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, such as a (1) alkyl) carbamoyl, di (lower group, droxymethyl) carbamoyl group, or as mono- or di / carboxy (lower and 1 alkyl) carbamoyl group such as carboxymethy1carbamoyl or di (carboxymethy1) carbamoyl, am i no-s kupi na bo of a side chain, alpha, is a free group or a di (lower alkyl) amino group, or a methylamino group, a group such as an acetylamine moiety that is not in the position occurs as a mono- or n-butylamino group such as (lower and 1 kan) oylamine or beers, a loylamino group such as an amino (lower and 1 chanoyl) amino group such as a 3-amino-3,3-dimethylpropionylamino group such as ary 1 (lower and 1 ch) oylamino in which the aryl group has 6 to 14 carbon atoms means, for example, a phenyl group, a naphthyl group or a fluorenyl group and is unsubstituted or substituted by a lower alkyl group, a hydroxy group, a lower alkoxy group, a carboxyl group, a carbamoyl group or a sulfamoyl group such as a 4-hydroxyphenylbutyryl group, such as a (lower and 1-alkoxy) carbonylamino group, such as a tert-butoxycarbonylamino group, such as an arylmethoxycarbonylamino group wherein the aryl group contains 6 to 14 carbon atoms, such as benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, such as piperidyl-1-carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or S, S-dioxothiomorpholino-carbonyl 1 The side chain group and / or the hydroxy group of the side chain is a free group or occurs as a lower alkoxy group, such as a methoxy group or a tert-butoxy group, such as a phenyl (lower alkoxy) group, such as a benzyloxy group , as (lower alkane) oyloxy, as acetoxy, or as (lower alkyl) oxycarbonyloxy, for example tert-butoxycarbonyloxy, in

and salts thereof, in particular their pharmaceutically usable salts

Further, the salts thereof, be preferred where R _t and 1 am Anilinocarbonyl AC radical, to 2 substituents from the group consisting of an alkyl group, a (lower-phenylacetyloxy group, a bromo or a group of the formula a compound of the bearing 1 is aminocarbonyl wherein innovators am a group independently of one another comprising an unsubstituted group of which the hydroxyl group of the naphthoxy group, the alkane) oyloxy group (the group selected and substituted by the lower substituents selected from the group consisting of lower and 1 cox y group is alkane) oyloxy group such as a benzoyloxy fluorine group, a chlorine atom, a group (phenyloxycarbonyloxy) carbamoyl group, lower (lower alkyl) / carbamino phenoxy phenyl or carboxylic acids 1 (lower and (1) carbamoyl, halogen such as fluorine or iodine, alkoxy) carbonyl, carbamoyl, (lower hydroxy (lower alkyl) carbamoyl); bis / hydroxy ((especially (lower alkoxycarbonyl, such as, moyl, cyano, oxo, and aryl) such as phenyl, naphthyl, such as 1- or 2 naphthyl, indanyl, such as 1- or a 2-indanyl group, an indenyl group such as an inden-1-yl group, or a fluorenyl group such as a fluoro-1-9-yl group, wherein the aryl group is unsubstituted or one or more, preferably one, substituted with substituents selected from m comprising a lower alkyl group such as methyl, a halo (lower alkyl) group such as a chloro or bromomethyl group, a halogen atom such as a fluorine or chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group , (lower alkane) oyloxy, carboxyl, (lower and alkyl) oxycarbonyl, phenyl (lower alkoxy) carbonyl, mono- or di (lower and alkyl) carb an amoyl group, a mono- or dihydroxy (lower and alkyl) carbamoyl group, and a halogen (lower alkyl) group such as a trifluoromethyl group, a cyano group and / or a nitroskune, in particular a phenyl group which is substituted in the para position by one of the aforementioned groups, and an aryl group which

1 contains 6 to 14 carbon atoms and is unsubstituted or one or more, preferably one, substituted with substituents selected from the group consisting of lower alkyl, for example methyl, halogen (lower and 1-alkyl), such as chloro or bromomethyl a halogen atom, for example a fluorine atom or a chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, a (lower alkane) oyloxy group, a carboxyl group, a (lower alkyl) oxycarbonyl group, a phenyl (lower alkoxy) carbonyl group , a carbamoyl group, a mono- or di (lower alkyl) carbamoyl group or a dihydroxy (lower alkyl) carbamoyl group and an alkyl group of 1 or less. y 1) o in the meaning of which the group consisting in particular of the heterocyclyl radical bonded with piperidinylmethyl

- (lower alkyl) carbamoyl as a trifluoromethyl group, boon, monosodium monohydrate, wherein said c,

J tests a heterocyclyl for a heteroalkanoyl of which h is a nitrogen atom, n-1-y-1-methylcarbonyl, such as

- (lower assayed via a ring group, for example, alkyl) piperazin-1-ylmethyl (lower cycloyl) (the residue has a cyclic group, a tertiaryyl group, for example,

4-methyl- or 4-ethylpiperazin-1-ylmethyl, alkanilylpiperazin-1-ylmethyl, such as 4-acetylpiperazin-1-ylmethyl, morpholinomethyl or thiomorpholinomethyl, cyano a group and / or a nitro group, preferably a correspondingly substituted or 1- or 2-naphthyl group, substituents of an aminocarbonyl group, in particular an aminocarbonyl alkyl) aminocarbonyl diethylaminocarbonyl carbonyl group, a group of which the rest may be a group such as a phenyl group of at most one of the aryl mono- or di (lower N-methyl 1 -),

J or pheny1 (below is a phenyl radical or substituted with the groups mentioned above)

N-ethyl, N, Nalkyl) and nonesubstituted by the definition of an aryl group, for example substituted by substituents selected for example as chloro, chloro, lower alkyl, (lower alkyl), nu or trifluoromethyl or fluorine a group selected from methyl, halogen

or a bromomethyl group of a halogen atom, for example a hydroxy group, a lower alkoxy group such as a methoxycarbonyl group and / or a cyano group, preferably substituted by these groups, in the para position with up to three substituents independently selected from one of these substituents, e.g. Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-1-fluoromethylbenzyl) - or especially as

J

N- (4-chlorobenzyl-, cyanobenzyls) of the springcarbonyl group, particularly preferably carbonyl groups, for example as Nm ethyl or ny (lower lower unsubstituted or, for the definition of the aryl group, by substituents selected from nu, as a methyl group, and substituted on the nitrogen atom,

N- (4-amino-one), or a fector, is a group of the phenylene groups mentioned above

N- (lower alkyl) amino amino bonyl

N-ethylaminocarbonyl groups are alkyl, substituted for example substituted by a lower alkyl group (lower alkyl) such as chloro or bromomethyl, or trifluoromethyl. a halogen atom, such as a fluorine atom or a chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group, a carboxyl group and / or a cyano group, preferably substituted by up to three substituents independently selected from these groups, in particular one among these substituents, for example in the para position, such as in Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N - (4-cyanobenzyl) aminocarnonyl.

Particular preference is given to compounds of the formula I in which R @ 1 represents unsubstituted or substituted lower alkanoyl, lower alkenoyl or lower and quinoyl, the substituents of which comprise one or more groups, preferably at most three groups, in particular one group, selected from the group consisting of hydroxy, lower alkoxy, phenoxy, naphthoxy, (lower alpha) oxyoxy-up, phenyl 1 (lower and lower); A 1-alkoxy oxy group such as a benzoyloxy group or a phenylacetyl group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, in particular a fluorine or chlorine atom, a carboxyl group (lower) alkoxycarbonyl, phenyl (lower and 1-alkoxy) carbonyl, such as benzyloxycarbonyl, carbamoyl, (lower and 1 ') carbamoyl, hydroxy (lower and alkyl) carPamoyl a di (lower and 1 alkyl) carbamoyl group, a bis / hydroxy (lower and alkyl) / carbamoyl group, a carbamoyl group whose nitrogen atom is part of a 5- to 6-membered heterocyclic ring which may still contain a further heteroatom selected from the group consisting of oxygen, sulfur, nitrogen and nitrogen substituted by lower alkyl, such as methyl or ethyl, for example pyrrolidinocarbonyl, morpholinocarbonyl, 11-morpholino-carbonyl, piperidin-1-ylcarbonyl, piperazine-1 -ylcarbonyl or 4- (lower alkyl) piperazin-1-ylcarbonyl, such as 4-methylpiperazin-1-ylcarbonyl, cyano, oxo, cycloalkyl, e.g. cyclopropyl, cyclopentyl or bicycloalkyl containing from δ to 1 of en a lo / zzz / oct-z-yl moiety such as a bicyclic carbon atom, such as deca or exo-2-norbornyl, or a bicyclo group, such as Cκ-4 carbon atoms,

1- or z-adamantyl, cycloalkenyl, nu, cyclobutyl hexyl, alkyl hydronaphth-2-yl, (3.3.1) non-9-yl, three cycloalkyls the C 9 -C 8 -cycloalkyl group, such as a C 4 -C 8 cycloalkenyl group, such as a 1-cyclohexenyl or 1,4-cyclohexadienyl group, a bicycloalkenyl group such as a 5-norbornen-2-yl group or a biocycloalkyl group A heterocyclic group which preferably represents a saturated, partially saturated or unsaturated ring, which occurs as such or in a simple benzo-, cyclopenta-, cyclohexa- or cyclo-heptane-anelated group. a form containing at most four heteroatoms selected from the group consisting of a t. a nitrogen atom, a sulfur atom and / or an oxygen atom, preferably 1 or 2 of said heteroatoms, and b to 7 ring atoms, and which is unsubstituted or substituted by at least substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy -phenyl 1 (lower alkoxy) such as benzyloxy, hydroxy (lower alkyl) such as hydroxymethyl, halogen, cyano and / or trifluoromethyl, e.g. pyrrolyl, 2, 5-di 44 hydropyrrolyl, furanyl, thienyl, tetrahydrofuranyl, cyclohexyl / pyrrolidinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolines a pyrazolidinyl group, a triazolyl group such as 1,2,3-, 1,2,4- or

1,3,4-triazolyl, tetrazolyl, such as or 2-tetrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, indolyl, isoloyl, quinolyl benzimidazolyl, , pyrimidinyl piperazin-1-yl,

S, S-dioxothiomorpholine, 2,3,4-tetrachinolyl or 2,3,4-tetrahydroisoquinolyl, are unsubstituted or substituted by the above-substituted lower alkyl (lower alkyl) piperazin-1-yl moieties as described above. an ethylpiperazin-1-yl group, such as in 4- (lower and 1-chanoyl) -piperazine in 4-acetyl-perazinoyl group, a carbonyl carbon atom, a nu or a 3,4-tetrachinolyl group in a manner such as a 1- or yyl group, an isoquinolyl benzoturanyl group, a piperidinyl group, such as a pyrimidine N, N-thiomorpho, 2-dihydro, 2-dihydro-urea, referred to in the 4-ethyl-alkanoyl

-yl groups and hydroxy (lower by selected changes such as in the 41- or non-alkyl group) such as in a b-hydroxymethyl-furan-2-ylaryl group containing 6-12 phenyl, naphthyl, indanyl, as 1-indenyl, as inde n-1-fluorenyl, as fluorenyl-9aryl is unsubstituted or preferably one, substituted substituent, and for example 2-naphthyl

A 2-indanyl group, group, or group, wherein or more than one selected from the group consisting of a lower alkyl group such as a methyl group, a halo (lower alkyl) group such as a chloro- or bromomethyl group, a halogen atom such as a fluorine or chlorine atom, a hydroxyl group, a lower alkoxy group such as a methoxy group, a (lower alkane) oyloxy group, a carboxyl group, a (lower alkyl group) oxycarbonyl group, a phenyl (lower alkoxy) group carbonyl, carbamoyl

4b, a mono- or di (lower alkyl) carbamoyl group, a mono- or dihydroxy (lower alkyl) carbamoyl group, halogen (lower alkyl) such as trifluoromethyl, heterocyclyl (lower alkyl in which the non-heterocyclyl radical is as defined above, in particular heterocyclylmethyl in which the heterocyclyl radical is bonded via a ring nitrogen atom, piperazin-1-ylmethyl, for example pi a peridomethyl group, a 4- (lower alkyl) piperazin-1-ylmethyl group such as a 4-methyl- or 4-ethylpiperazin-1-ylmethyl group, a 4- (lower alkane) oylpiperazin-1-ylmethyl group such as 4-acetylpiperazin-1-ylmethyl, morpholomethyl or thiomorpholinomethyl, cyano and / or nitro, in particular phenyl substituted in the para position by one of the abovementioned groups (lower alkoxy) carbonyl, e.g. methoxy, ethoxy or tert, (lower alkoxy) carbonyl, such as tert-butoxycarbonyl, z-halo (lower alkoxy) carbonyl, for example z-chloro, z-bromo, z- iodo- or z, z, z-1, chloroethoxycarbonyl, aryl (lower alkoxy) carbonyl, for example arylmethoxycarbonyl, in which the aryl radical contains from 6 to 14 carbon atoms and is unsubstituted or one or more, preferably one times substituted by substituents selected a lower group such as methyl, halogen (lower group such as a chloro- or bromomethyl group, an atom such as a fluorine atom and a 1-alkoxy group, a carboxylic acid 1 (lower mono- or alkyl alkyl halogen) , a group, an alkanjoyloxy group a carbonyl group, a carbamoyl group, a mono- or a pin, a halogen (lower or chlorine atom, a hydroxy-like methoxy group, (a lower (lower and alkyloxycarbonyl), di (lower alkylcarbamoyl dihydroxy (lower and alkylcarbamoyl) alkyl, such as trifluoromethyl, heterocyclyl (lower alkyl) of the rocyclyl radical having the meanings forming the heterocyclyl group wherein the lower and the 1-a-1-noyl substituent mentioned above, in particular the heterocyclylmethyl group, in which the heterocyclyl radical is bonded via a ring nitrogen atom, for example a piperidine methyl group, a n-1-ylmethyl group in the case of n-ylmethyl 4-ethylpiperazin-1-ylmethyl, morpholinomethyl cyano and / or 1'-naphthyl phenyl, substituents such as lower ethoxy, halogen, bromine, and / or an alkoxycarbonyl group, such as

4-methoxybenzyloxycarbonyl, diphenyl (lower diphenylmethoxycarbonyl, alkoxycarbonyl, which have already been 4 - (lower)

4-methyl- or alkanilylpiperazin-1-ylmethyl of trans-1-ylmethyl, morpholinomethyl, in particular phenyl, or multiple-substituted lower alkyl tert-butyl methoxy, hydroxy, chloro and chloro; enylene (lower benzyloxycarbonyl group in the group such as xyphenyl 1-methoxycarbonyl pin or fluorene 1 (lower fluorenylmethoxycarbonyl (lower alkoxycarbonyl radical has the meanings, for example 1 ', 3' - or 3-carbonyl)) sets of aminopentanoic acid, pentanoic acid, norleucine 5, serine tenylalanine, tyrosine, 4-carboxyphenylalanine, naphthalene and naphthalic acid, aspartic acid, asparagine, aminomalonic acid amide, histidine, arginine lysine, a lower furan-2-ylmethoxycarbonyl substituent

A 4-ylmethoxycarbonyl-linked radical including glycine, alanine, amino-inasonic acid, 4-aminopentanoic acid, 3-aminohexanoic acid, aminohexanoic acid, valine, norvaline, nomoserine, threonine, 4-aminophenylalanine, beta-phenylserineine, beta-phenyl-phenylalanine , such as a 4- (lower than 4-acetylpiperazo or thio nitro group), the fluorector is one or a methyl or alkoxy group, for example, or a t-butoxy group, for example a fluorine atom, a nitro group , benzyloxykarbonyskupinu e.g., 4-nitroa 1 koxyjkarbony one of the group, di (4-methoxy r 11 s 1 s 1 oxycarbonyl group Item D, since such θά ^d: further heterocycles? neterocyklylový wherein the heterocyclyl, and the 1 kanoyiovej group, a group or a pyridine group, or via an alpha amino acid selected from z-aminobutyric acid, aminotrimoric acid, 3-amino-5-amino-4-aminonexanoic acid, eucine, iso -ucine, methionine, cysteine, 4-chlorophenylalanine, phenylglycine, α 1 acyclohexylglycine, tryptophan, aminomalonic acid, glutamic acid, glutamine, delta-hydroxylysine, arable tin, i

3-aminopropanoic acid, alpha, gamma-diamino butyric acid and 1α, beta-diam inopropionic acid, particularly preferably an aliphatic amino acid residue selected from the group consisting of aianine, valine, norvaline, ieucine, 3-aminopropionic acid, 2- aminobutyric acid, 3-aminobutyric acid, 4 aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid and isoleucine, or the amino acids selected from the group consisting of glycine, asparagine, g utamine, methionine, lysine, and phenyl and lani n, each of said amino acids (except when there is no asymmetric carbon k, such as glycine) in the form of U, L or (U, L), preferably in the form of L, and 1? -Amino group, if present, is unsubstituted or one or two N-alkylated groups selected from the group consisting of a lower alkyl group, such as a methyl group, a n-propyl group or an n-bur, an yl group, an amine (lower alkyl) group, such as a 3-aminopropyl group, a phenyl- or naphthyl-amino group ( a lower alkyl group such as a 3-phenylaminopropyl group, phenyl (a lower alkyl group such as a benzyl group, a diphenyl methyl group, a trityl group, and / or a heterocyclyl (lower alkyl) group having a neterocyclyl radical as defined above for the substituted lower alkanoyl group

K i, in particular a heterocyclylmethyl group, for example a furan (lower alkyl) group, such as a 2-fluoromethyl group, a thienyl (lower and alkyl) group, such as a thienylmethyl group, or a -, 3- or A 4-pyridyl (lower and 1-yl) group, such as a 2-, 3- or 4-pyridylmethyl group, and / or N-acylated with, for example, the unsubstituted or substituted lower and 1-canoyl radicals mentioned above for the definition of K i, in particular from the group consisting of acetyl, propionyl, pivaloyl, heterocyclyl (lower alkanjoyl as defined above for the substituted lower alkanoyl, e.g. furan-2-ylcarbonyl, 5-hydroxymethylfuran-2-ylcarbonyl)

4 ', 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, indolylacetyl or benzofuranylacetyl, ar y 1 (lower alkanjoyl such as benzoyl or phenylacetyl, (lower alkoxy) carbonyl as a tert-butoxycarbonyl group, or an aryl (lower alkoxy) carbonyl group as defined above, for example, a phenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group, the side chain carboxyl group is free or occurs as (lower alkyl ester, such as methoxy caroonyl or tert-butoxycarbonyl, such as aryl (lower alkyl ester, wherein aryl is phenyl, 4-nitrophenyl, naphthyl, fluorenyl or biphenylyl, for example as 4- nitrophenyloxycarbonyl, benzyloxycarbonyl or a 9-fluorenylmethoxycarbonyl group, such as a carbamoyl group, such as a (lower alkylcarbamoyl group, such as a methylcarbamoyl group, such as a di (lower alkyl) carbamoyl group, such as a dimethyl carbamoyl group, such as a mono- or di hydroxy (lower and lower) carbamoyl, such as hydroxymethylcarbamoyl or di (hydroxymethyl) carbamoyl, or as mono- or di / carboxy (lower alkylcarbamoyl, such as carboxymethylcarbamoyl or di (carboxymethyl) carbamoyl, amino a side chain that is not in the alpha position is a free group or occurs as a mono- or di (lower and alkyl) amino group such as an n-butylamino group or a dimethylamino group such as (lower alkanjoylamino, such as acetylamino or pivaloylamino, such as amino (lower alkanjoylamino, such as 3-amino-3,3-dimethylpropionyloamino, such as aryl) a kanjoylamino group in which the aryl radical contains from 1 to 14 carbon atoms is, for example, a phenyl group, a naphthyl group or a fluorenyl group and is unsubstituted or substituted by a lower alkyl group, a hydroxy group, a lower group and a 1-alkoxy group;

A carboxy group, a carbamoyl group, or a sulfamoyl group such as a 4-hydroxyphenylbutyryl group such as a (lower alkoxycarbonylamino group, such as a tert-butoxycarbonylamino group, such as an arylmethoxycarbonylamino group, in which the aryl radical contains b to carbon atoms such as benzyloxycarbonyl amine methoxycarbonyl group, such as a mortolinocarbonyl group, or as a 9-fluorenylpiperidyl-1-carbonyl thiomorpholinocarbonyl group or as a s-dioxothiomorpholinocarbonyl group, and / or a the side chain nydroxy group is a free group or occurs as a lower alkoxy group, such as a methoxy group or a tert-butoxy group, such as a phenyl (lower and 1 alkoxy) group, such as a benzyloxy group, such as (lower alkanjoyloxy) a group, such as an ac ethoxy group, or as a (lower alkyl) oxycarbonyloxy group, for example tert-butoxycarbonyloxy oxides, and salts thereof , in particular their pharmaceutically usable salts.

Furthermore, compounds of the general formula and salts thereof in which

K i represents an amocarbonyl group or an aminocarbonyl radical in which the amino group bears i or substituents independently selected from the group consisting of unsubstituted lower alkyl, substituted lower alkyl, the substituents of which are selected from hydroxy; a lower alkoxy group, a tenoxy group, a naphthoxy group, (a lower alkanjoyloxy group, a phenyl (lower a.1 channel) oxy group such as a benzoyloxy group or a phenylacetyloxy group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, in particular a fluorine or chlorine atom, a carboxyl group, a (lower alkoxycarbonyl group, a phenyl (lower and 1-alkoxy) carbonyl group such as a benzyloxycarbonyl group, a carbamoyl group, and (1) carbamoyl, hydroxy (lower alkyl) carbamoyl, di (lower and carbonyl) carbamoyl, bis / hydroxy ( lower (1 ') (1-carboxy), cyano, oxo and aryl groups containing from 1 to 3 carbon atoms, phenyl, naphthyl, such as i- or 1 ', indanes wherein the aryl group is tested several times, preferably by an alkyl group, a alkyl group, for example a naphthyl group or a nu, such as 1- or 1'-indanyl as indene-i-. halogeno (lower, such as chloro or bromomethyl, halogen, such as fluoro or chloro, hydroxy, lower alkoxy) a group such as (lower alkanjoyloxy, carboxyl (lower alkyl) oxyl carbonyl, carbamoylcarbamoyl) carbamoyl, such as trifluoromethyl, as is unsubstituted substituted by methoxybiphenyl 1 (lower, mono-o- or di-halogen (lower, cyanocyanate, alkoxy) carbonyl or di (lower alkyl hydroxy (lower alkyl and alkyl)) and / or a nitro group, in particular a phenyl group, in the para position is substituted by one of said groups, in particular an unsubstituted lower alkyl, group or ethyl group, and contains from 1 to 14 carbon atoms and one or more times, preferably one, as a methyl aryl group which is unsubstituted or substituted by substituents selected from the group consisting of lower alkyl, for example methyl, to 1-enene (lower alkyl such as chloro or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower) an alkoxy group, such as a methoxy group, (lower alkanoyl ox y-, carboxyl, (lower alkyl) o xycarbonyl groups, phenyl (lower alkoxycarbonyl, carbamoyl, mono- or di (lower and 1-alkyl) carbamoyl, mono- or dihydroxy (lower and 1-alkyl) carbamoyl, halogen (lower alkyl, such as a trifluoromethyl group, a heterocyclyl (lower alkyl group) in which the heterocyclyl radical has the meanings given above for the non-heterocyclyl group representing a lower alkanoyl substituent, in particular the heterocyclylmethyl group in which the heterocyclyl radical is bonded via a ring nitrogen atom, for example piperidinomethyl, piperazin-1-ylmethyl b, 4- (lower alkyl) piperazin-1-ylmethyl group such as

4-methyl- or 4-ethylpiperazin-1-ylmethyl, 4- (lower alkanoylpiperazin-1-ylmethyl) such as 4-acetypiperazin-1-yl, morpholinomethyl, or thiomorph o inomethyl, cyano and / or nitro, preferably correspondingly substituted phenyl or 1- or z-naphthyl, wherein at most one of said substituents of the aminocarbonyl radical may be an aryl group, in particular an aminocarbonyl, mono- or a di (lower alkyl) am inocarbonyl group, such as a Ν-methyl-, N-ethyl-, Ν, Ν-dimethyl- or N, N-diethylcarbonyl group, or a phenyl (lower alkyl) aminocarbonyl group wherein the phenyl moiety is unsubstituted and edo substituted by the groups mentioned in the definition of the aryl group, for example substituted by a lower alkyl group, for example a methyl group, by halo (lower alkyl) group. a pin, such as a chloro- or bromomethyl group, or a trifluoromethyl group, a halogen atom, for example a fluorine atom or a chlorine atom, a hydroxyl group, a lower alkoxy group such as a methoxy group, carboxyl group and / or cyano group, preferably at most three substituents independently selected from these groups, in particular substituted by one of these groups, for example in the para position, such as in N-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- ( 4-1 (fluoromethylbenzyl) or N- (4-cyanobenzyl) aminocarbonyl group, particularly preferably an aminocarbonyl group substituted on the nitrogen atom by only one residue, for example an N- (lower alkyl aminocarbonyl group such as N-methyl- or N-) an ethylaminocarbonyl group, or a phenyl (lower alkyl) aminocarbonyl group in which the phenyl residue is unsubstituted or substituted by the groups mentioned in the definition of an aryl group, e.g. lower alkyl, such as methyl, nalogen (lower alkyl, such as chloro or bromomethyl or trifluoromethyl, halogen, such as fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, carboxyl) and / or cyano, preferably substituted by up to three substituents independently selected from these groups, in particular substituted by one of these groups, for example in the polona para, such as in Ν-benzyl-, N- (4-fluorobenzyl) -, N - (4-chlorobenzyl) -, N - (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyl.

more particularly preferred are compounds of formula I wherein K 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, unsubstituted lower alkanoyl, substituted lower alkanoyl, the substituents of which are one or up to three groups, with at least one group or two groups selected from the group consisting of hydroxy, lower and 1 cox y, (lower and 1 coxy) (lower 1 coxy) -group, (lower and 1 coxy) (lower alkoxy) (lower alkoxy), phenoxy.

naphthoxy, phenyl 1 (lower alkoxy) -group, 2-halo (lower alkanjoyl such as 2-chloroacetyl, amino- (lower alkyl) amino or di (lower alkyl) amino (lower alkoxy) -2- (lower alkanjoyl group such as dimethylamino (lower alkoxy) acetyl, amino-, (lower alkyl) amino or di (lower alkyl) amino (lower alkoxy) (lower alkoxy) -2 (lower alkanjoyloxy group such as dimethylamino-2- (lower alkoxyjetoxy) acetyl group, (lower alkanjoyloxy group, phenyl (lower alkanjoyloxy group such as benzoyloxy group or phenylacetyloxy group), halogen atom such as fluorine atom, chlorine atom, a bromine or iodine atom, in particular a fluorine or chlorine atom, a carboxyl group, (lower alkoxycarbonyl), phenyl (lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, (lower and 1-alkyl) carbamoyl, hydroxy (n) lower and 1k y1) a caramoyl bis / hydroxyoxo-carbon such as carbon, such as a cycloalkyl cyclopropyl group or a di (lower and 1-alkyl) carbamoyl group, a (lower and 1-alkyl) carbamoyl group, a cyano group, a cycloalkyl group containing 3 to An 8-atom group having from 3 to 8 atoms, a cyclobutyl group, a cyclopentyl cyclohexyl group, a cycloalkenyl group having from 4 to 8 carbon atoms, such as i-cyclohexenyl or 1,4-cyclonexadienyl, pyrrolyl,

3

2,5-dihydropyrrolyl, turanyl sulfine, thienyl, tetrahydrofuran, pyrrolidinyl, imiaazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, tetrahydrooxazolyl, tetranydrothiazolyl, tetranydroisothiazolyl, indolyl, indolyl, quinolyl, isocynyl, benzimidazolyl, benzofuranyl, pyridyl, pyrimidinyl, piperidinyl, piperidinyl piperazin-1-yl, morpholino, thiomorpholino, S, N-oxothiomorpholino, 1,2-dinydro- or 1,2,3,4-tetranydroquinolyl or 1,2-dinydro - or a 1,2,3,4-tetrahydroisoquinolyl group, said non-heterocyclic radicals being unsubstituted or substituted lower alkyl, lower alkanoyl, nydroxy, lower alkoxy, phenyl (lower alkoxy, such as benzyloxy, hydroxy (lower and alkyl), such as nydroxymethyl, halogen, cyano or and / or three fluoromethyl, especially substituted by lower alkyl, such as in the 4- (lower and alkyl) piperazin-1-yl, such as in the 4-methyl or 4-ethylpiperazin-1-yl group, by lower alkanoyl, for example in a 4- (lower alkane) piperazin-1-yl group such as a 4-acetylpiperazin-1-yl group or a hydroxy (lower alkyl) group, for example a 6-hydroxymethylfuran-2-ylcarbonyl group, and an aryl group selected from from the group comprising a phenyl group, a naphthyl group, such as a 1- or 2-naphthyl group, an indanyl group, such as. 1- or 2-indanyl, indenyl, such as inden-1-yl, and fluorenyl, such as fluorenyl

A 9-yl group, wherein the radicals are unsubstituted or one or more, preferably one, substituted, for example, with substituents selected from the group consisting of lower alkyl, for example methyl, such as chloro or halogen, for example fluorine, lower and lower alkyl; alkoxy, alkanjoyloxy, carboxyl, halogen (lower alkyl) bromomethyl, chlorine or chlorine, hydroxy and methoxy, (lower, lower and lower) oxyl 54 carbonyl, 1 (lower carbamoyl mono- or alkoxy) carbonyl, di (lower alkyl) carbamoyl, mono- or pin, halogen (lower dihydroxy (lower and lower) 1) carbamoyl skualkyl group, such as trifluoromethyl, piperidinomethyl, piperazin-1-ylmethyl, 4- (lower alkyl) piperazin-1-ylmethyl, such as 4-methyl- or 4-ethylpiperazin-1-ylmethyl a 4- (lower and 1-alkyl) oyl group in the n-1-ylmethyl group such as a 4-acetylpiperazin-1-ylmethyl group, morpholinomethylmethyl, thiomorpholinomethyl group, cyano group and / or nitro, the most mathenyl, which is substituted in the para para with one of said groups, or an alpha-carbonyl radical of an amino acid radical selected from the group consisting of glycine, alanine, z-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, acid

3-amino hexanoic acid, 4nexanoic acid, valine, norvaline, serine, nomoserine, threonine, thiamine, 4-aminophenyl and 1-anine, phenylalanine, beta-phenylserine, cyclonexylalanine, cyclonexylgagic acid, asparagine, acid aminomaonic acid, amine hexanoic acid, 5-amino-eucine, iso-eucine, nor-eucine, methionine, cysteine, phenyl and 1-anine, 4-chlorophenylalanine, 4-carboxyphenylglycine, alpha naphthylalanine, ytin, tryptophan, aspa aminoaminonic acid, glutamic acid monoamide, glutamine, histidine, arginine, lysine, dithanedroxylanine, ornithine, 3-aminopropanoic acid, αα, gamma-amine inosonic acid and alpha, beta-diamine inopropionic acid, preferably an aliphatic amino acid residue. selected from the group consisting of alanine, valine, norvaline, acid

3-aminopropionic acid, .gamma.-aminobutyric acid, or amino acids selected from the group consisting of glycine, asparagine, glutamine, methionine, lysine, and phenylalanine; and also amino acids selected from the group consisting of 3-aminobutyric acid, 4-aminobutyric acid, 3- aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, and 5-aminohexanoic acid, but in all cases (except asymmetric carbon, such as glycine), of said amino acids found in

In the form u, L or (u, L), and 1 a-amino group, if present, is unsubstituted or one or two N-alkylated groups selected from the group consisting of a lower alkyl group such as a methyl group, n -propyl or n-butyl, amino (lower alkyl), such as 3-aminopropyl, phenyl or naphthylamino (lower alkyl), such as 3-phenyl 1 (lower alkyl), methyl, trityl, such as 2-turylmethyl as benzyl, diphenylamine, furan (lower alkyl), thienyl 1 (lower alkyl), such as 2 -thienylmethyl, imidazolyl (lower alkyl), such as imidazo 1-4-ylmethyl and / or 2-, 3- or 4-pyridyl (lower alkyl) and / or Na cyanated by lower and 1 kanoyl moieties as defined above for the definition. R 1, especially groups selected from the group consisting of acetyl, propionyl, pivaloyl, furan-1-ylcarbonyl, 5-hydroxymethyl-furan-1-ylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholino a phenyl, indolylacetyl or benzofuranyl acetyl group, a phenyl 1 (lower alkanjoyl group such as a benzoyl group, or a phenylacetyl group, a (lower alkoxy) carbonyl group, such as a tert-butoxycarbonyl group, or a phenyl (lower and 1 alkoxy) carbonyl group A benzyloxycarbonyl group, and pharmaceutically acceptable salts thereof.

becnéno

Further, the formula I may be more preferred, and also their compounds familiar with the aminocarbonyl group and the inocarbonyl group, such as the N-methyl-1-, monosalts in which R1 or di (lower alkyl) aminocarbonyl

N-ethyl- Ν, Ν-dimethyl- or Ν, Ν-diethyl preferably a mono (lower alkyl) aminocarbonyl group or a phenyl (lower alkyl) aminocarbonyl group in which the phenyl residue is unsubstituted or substituted by groups mentioned in the definition of an aryl group, for example substituted by a lower alkyl group,

- b 6 for example with methyl, halo (lower alkyl) such as chloro or bromomethyl or trifluoromethyl, halogen, for example fluorine or chlorine, hydroxy , lower alkoxy such as methoxy, carboxy and / or cyano, preferably substituted with up to three substituents independently selected from these groups, in particular one of these, for example in the para position, such as in Ν-benzyl-, N (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyl.

more particularly preferred are those compounds of formula I wherein R 1 is unsubstituted lower alkanoyl, substituted lower alkanoyl, of which there are from 1 to 3 groups, especially one group. selected from the group consisting of hydroxy, lower alkoxy, phenoxy, naphthoxy, lower alkanjoyloxy, phenyl (lower alkanjoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, in particular a fluorine or chlorine atom, a carboxyl group, a (lower and 1-alkoxy) carbonyl group, a phenyl (lower alkoxy) carbonyl group such as a benzyloxycarbonyl group, a carbamoyl group, 1-alkyl) carbamoyl, hydroxy (lower alkyl) carbamoyl, di (lower alkyl) carbamoyl, bis / hydroxy (lower and 1-alkyl) / carbamoyl, cyano, oxo, cycloalkyl containing 3 up to 8 carbon atoms, such as a cyclopropyl group, a cyclopentyl group, a cyclopentyl group or a cyclohexyl group, a cyclopentyl group containing from 4 to 8 carbon atoms such as

1-cyconexenyl or 1,4-cyclohexadienyl, pyrrolyl,,, 5-dinydropyrrolidinyl, furanyl, thienyl, tetranycurfuranyl, pyrrolidinyl, imidazolyl, imidazolinyl, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole, pyrazole; pyrazolidinyl, tetranydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, indolyl, and indolyl;

a cinnamolyl group, a benzimidazolyl group, a benzofuranyl group, a pyridyl group, a pyrimidinyl group, a piperidinyl group, a group, a thiomorpholine, or a new or a pin, or a piperazin-1-yl group, a morpholine group, a S, S-dioxothiomorpholino 2,3,4-tetrahydroisoquinolyl, 2,3,4-tetrahydroisoquinolyl, 1,2-dinydro-1,2-d, and the non-heterocyclic moieties mentioned are unsubstituted substituted by lower alkyl, n-hydroxy-alkoxy; and alkyl or cyano substituted or non-methyl, such as methyl, lower, lower alkanoyl, benzyloxy, hydroxymethyl, and / or trifluoromethyl lower. an alkyl group such as an alkyl) piperazin-1-yl group such as a 4-lower and 1 canoe such as a 4- (lower alkane) oylpiperazine-1 like a 4-acetylpiperazin-1-yl group, and an alkyl group such as phenyl (lower alkoxy), especially in the 4- (lower or 4-ethylpiperazin-1-yl) group, the group, the yl or the hydroxy (lower a 5-hydroxymethylfuran-1'-ylcarbonyl group, and an aryl group selected from the group consisting of a phenyl group, a naphthyl group such as 1- or 2-naphthyl group, an indanyl group, and a 1- or 2-indanyl group, an indenyl group such as indene A 1-yl group, and a fluorenyl group, such as a fluoren-9-yl group, which groups are unsubstituted or one or more, preferably one, substituted with substituents selected from the group consisting of lower alkyl, for example methyl, and halogen (lower alkyl group such as chloro or bromomethyl group, halogen atom such as fluorine or chlorine atom, nyroxy group, lower alkoxy group than methoxy group, (lower alkane joyloxy, carboxyl, (lower alkyloxycarbonyl, phenyl (lower and 1-alkoxy) carbonyl, carbamoyl, mono- or di (lower alkylcarbamoyl), mono- or dinydroxy (lower halo (lower alkyl), nu , piperidinyl, alkylcarbamoyl, such as trifluoromethylpiperazin-1-ylmethyl, 4- (lower and lower alkyl) perazin-1-ylmethyl, such as 4-methyl- or 4-ethylpiperazine-1; 4-acetylpiperazin-1-ylmethyl, morpholinomethyl, thiomorpholinomethyl, cyano and / or nitro, in particular phenyl-1-ylmethyl, 4- (lower alkane) oylpiperazin-1-ylmethyl, such as 4-acetylpiperazin-1-ylmethyl; a group which is substituted in the para position by one of the abovementioned groups, or by an alpha-carbonyl group linked to an amino acid radical selected from the group consisting of glycine, and n, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid,

3-aminonexanes, 4-aminohexanoic acid, o-amino nexanoic acid, valine, norvaline, serine, nomoserine, threonine, tyrosine, 4-aminophenylalanine, phenylalanine, beta-phenyl 1-serine, cyclohexylalanine, cyclonexylgage, asagin, eucine, iso-eucine, noreucine, methionine, cysteine, phenylalanine,

4-chlorophenylalanine, 4-carboxyphenyls 1 g 1-ycin, and 1 phth-naphthalene and 1-ananine, 1-ycin, tryptophan, α-α and aminomalonic acid, aminomalonic acid mono amide, glutamic acid, glutamine, histidine, arginine, lysine, delta-hydroxylysine, ornithine, 3-aminopropanoic acid, α-fa, gamma-diamine-butyric acid and alpha, beta-diaminopropionic acid, particularly preferably an aliphatic amino acid residue selected from alanine, valine, norvaline , leucine, 3-aminopropionic acid, 2-aminobutyric acid and isoleucine or amino acids selected from the group consisting of glycine, asparagine, glutamine, methine, lysine and phenylalanine, and also amino acids selected from the group consisting of 3-aminobutyric acid, 4- aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, acid

5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid and 5-aminohexanoic acid, each of which (except for asymmetric carbon, such as glycine) may each have the form D , L or (D, L), preferably form L, the alpha-amino group, if present, is unsubstituted or mono- or N-alkylated by one or more of a lower alkyl group such as a methyl group

- n-propyl or n-butyl and alkyl groups such as 3-aminopropyl naphthyl and amino (lower alkyl groups than those in the phenyl group) lower alkyl groups 1 (lower alkyl group, and / or 2-, 3- or 4-pyridyl) (lower alkyl group);

2-, 3- or 4-pyridylmethyl group by unsubstituted or substituted radicals, in particular the group, ylcarbonyl-, alkyl, alkyl, alkyl, trityl, such as 2-methylmethyl, as previously mentioned, amino (lower, phenyl- or 3-phenylaminopropyloako benzyl, furanyl, thi-2-thienylmethyl acid, and / or N-acylated with lower alkanoyl groups as defined above for a pivaloyl group comprising a group

R 1, preacetyl furan - 2 groups selected from propionyl, group, 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, indole 1 acetyl or benzofuranyl acetyl, phenyl (lower and lower); a canolyl group such as a benzoyl group; or

A 5-hydroxymethylfuran-2-ylcarbonyl phenylacetyl group (a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group, or a lower alkoxycarbonyl group such as a benzyloxycarbonyl group, and pharmaceutically acceptable salts thereof.

Compounds of formula I and their salts in which R @ 1 is aminocarbonyl, mono- or di (lower alkyl) aminocarbonyl, such as Ν-methyl-, N-ethyl-, Ν, Ν-dimethyl- or an N, N-diethylaminocarbonyl group, preferably a mono (lower alkyl aminocarbonyl group or phenyl (lower alkyl aminocarbonyl group) in which the phenyl group is unsubstituted or substituted by the radicals defined in the aryl group, for example substituted by substituents selected from the group consisting of lower alkyl, e.g. halo (lower alkyl, such as chloro or bromomethyl or trifluoromethyl, halogen, e.g. fluoro or chloro, nydroxy, lower alkoxy, such as methoxy, carboxyl and / or cyano) , preferably substituted with at most three substituents

6ϋ therein independently selected from these groups, in particular substituted by one of these groups, for example in the para position, such as in Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyl group.

Even more preferred are compounds of formula I wherein R 1 is octanoyl, decanoyl, aodecanoyl, palmitoyl, lower and 1 carboxylic acid, such as formyl, acetyl, butyryl, methyl 1-propionyl , n-pentanoyl, pivaloyl, nonxanoyl or heptane, for example (lower alkoxy) propionyl

3-methoxypropionyl nonyl ynyl group, nydroxy (lower alkanjoyl group, ice beta-nydroxypropionyl group, alkanjoyl group) or (lower acetyl group,

An oxyacetyl group an alkanjoy group, (a lower alkyl alkoxy) (a lower group such as a (lower and 1 alkoxy) (lower alkoxy) acetyl group such as a methoxy group or n-buty, (a lower and 1-alkoxy (lower and 1-alkoxy) (lower than 2- (2-methoxyethoxy) acetyl, and 1-alkoxy j (lower alkoxy)

2- (2- (2-methoxy) ethoxy) acetyl, phenoxy (lower alkanjoy, for example phenoxyacetyl, phenyl (lower alkoxy) (lower alkanjoy, such as benzyloxyacetyl), 2-nalogen (lower alkanjoy, such as 2-chloroacetate) amino, (lower alkyl) amino, or di (lower alkyl) amino (lower alkoxy) -2- (lower alkanjoyl, such as dimethylamino (lower alkoxy) acetyl, amino- (lower alkyl) amino or di ( lower alkyl) amino (lower and 1-alkoxy) (lower and 1-alkoxy) -2- (lower alkanjoyl, such as dimethylamino- / 2- (lower alkoxy) acetyl, (lower alkane) oyloxy (lower alkanjoyl, for example (lower) an alkanjoyloxyacetyl group or (a lower and 1-chanoyl oxypropionyl group such as an acetoxyacetyl group or a beta-acetoxypropionyl group, a carboxy (a lower alkanjoyl group such as a carboxyacetyl group or a 3-carboxypropionyl group, oxo (n)) lower alkanjoyl, for example acetoacetyl or propionyl acetyl, 5-hydroxymethyl furan-2-ylcarbonyl, 2- or 3-pyrrolidinylcarbonyl, furylcarbonyl, for example 2 furylcarbonyl, thienylcarbonyl,

2-thienylcarbonyl, pyridyl (lower alkanjoyl, such as pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, pyridylacetyl, for example 2-pyridylacetyl or pyridylpropionyl, for example 3- (2-pyridyl) propionyl a quinoyl carbonyl group such as a quinolin-2-ylcarbonyl group, an isocninolylcarbonyl group such as an isoquinolin-3-ylcarbonyl group, a 2-, 3- or 5-indolylcarbonyl group, pyrrolidinyl 1 (2- or 3- carbonyl, 2-, 3- or 4-piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-tetrahydroisoquinolinyl; 1-, -3- or -4-carbomyl, imidazolyl (lower alkanjoyl such as imidazolylcarbonyl, for example imidazol-1-ylcarbonyl or imidazol-4-ylcarbonyl, imidazolylacetyl, for example 4-imidazolyl acetyl) or imidazolylpropionyl, for example 3- (4-imidazolyl) propionyl, pyrazolyl (lower alkanjoyl, such as 1-pyrazolylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, morpholinoacetyl, thiomorpholinoethyl, thiomorpholinoethyl) - (lower alkyl) -1-piperazinoacetyl, such as 4-methylpiperazinoacetyl, indolylacetyl, benzofuranylacetyl, phenyl 1 (lower alkanjoyl, for example benzoyl, phenylacetyl or 3-phenylpropionyl), which is unsubstituted or mono- or multiply substituted by a substituent selected from the group consisting of a lower group, such as a methyl group, nalogen (lower group such as a chloro- or bromomethyl group, an atom such as a fluorine or chlorine atom, the most hydroxy and 1-alkoxy group) , for example methoxy, p coupler, piperazin-1-ylmethyl, and alkylpiperazin-1-ylmethyl such as 4-methyl, morpholinomethyl alkyl.

alkyl) halogen, a group of piperidinyl

- (lower or 4-ethylpiperazin-1-ylmethyl, thiomorpholinomethyl, cyano and nitro, for example 4-chloromethyl-, 4-bromomethyl-, 4-fluoro-,

4-chloro-, 4-methoxy-, 4-morpholinomethyl-, 4-thiomorpholinomethyl-,

4-cyano- or 4-nitrobenzoyl, 4-methylphenylacetyl, 4-methoxyphenylacetyl, 3- (p-hydroxyphenyl) propionyl or 2- (lower and 1-alkoxy) -2-phenylacetyl, as (R) - or (S) -2-methoxy-2-phenylacetyl, an aliphatic amino acid or via alpha-carbonyl groups of leucine, sucrose acid 2 aminobutyric lysines

from the set

4-ami nomas1,

4-aminopentane, 3-aminohexane,

5-aminohexane, each of which is asymmetric to be in the form of D, L ny comprising and phenylalanic comprising an acidic acid of another acid of said carbon, such as or (D, L) a radical of a radical of 3-aminopropionic or asparagine amino acids , glutamine, also amino acids

3-aminobutyric acid, acidic acid with glycine, furthermore

3-aminopentane, 5-aminopentane

The 4-aminohexane amino acid is preferably in the form, for example, in which the acid in the selected acid (except for the glycine) can

L, when the alpha-amino group in the form of one or a group such as methyl n-butyl, benzyl, imidazol-4-ylmethyl pyrimidine 1 (lower alkane is present, N-alkylated) a n-propyl phenyl group (lower by 1 y 1 (n by a test group, twice an alkyl or lower alkyl group) and / or 2-, such as 2-, 3- or 4-pyridyl is not substituted by the more severe alkyl group or group , as a trial, 3- or as

4-methyl, and / or acylated (lower and 1-alkoxycarbonyl, such as tert-butoxycarbonyl, or benzyloxycarbonyl, such as in any alkyl, N- (lower and 1-alkyl), and 1-aryl, such as N-methyl); a tylalanyl group, a phenylalanyl group, an aminoacetyl group (glycyl group), N- (lower alkyl group or N, N-di (lower and alkylamino group) such as N-methylaminoacetyl group, N, N -dimethylaminoacetyl or N-methyl-N (n-butyl) amine acetyl, N- (lower alkyl) -N-phenyl (lower alkyl) aminoacetyl, such as N-methyl-N-benzyl amine acetyl, N- (lower alkyl) 63

An N-pyridyl (lower alkyl) amine acetyl group, for example

N-methyl-N - [(2-, 3- or 4-) pyridylmethyl] -aminoacetyl group, such as N-methyl-N- (2- or 3-pyridylmethyl) amine acetyl group, N - (imidazolyl) (lower alkyl) -N - (lower alkyl amino amino) such as N- (imidazol-4-ylmethyl) -N-methyl amine acetyl, N -phenyl (lower alkoxy) carbonyl-N- (lower alkyl) amino group such as N-benzyloxycarbonyl-N-methylaminoacetyl, 2-aminobutyryl, 4 (N, N-dimethylamino) butyryl, va1 yyl, norv and 1 yl, leucyl, isoleucyl, methionyl, lysyl, glutamyl or aspartyl, the amine acid residues (except glycine) are preferably in the form of (L), and pharmaceutically acceptable salts thereof.

In addition, compounds of the formula I and their salts in which R @ 1 represents a mono or di (lower alkyl) aminocarbonyl group such as N-methyl-, Ν-ethyl-, N, N-dimethoxy may also be more particularly preferred. y 1- or N, N-diethylaminocarbonyl, preferably a mono (lower alkyl) aminocarbonyl, or phenyl (lower alkyl aminocarbonyl) in which the phenyl radical is unsubstituted or substituted by the groups mentioned in the definition of an aryl group, for example substituted by a lower alkyl group such as a methyl group, a halogen (lower alkyl group such as a chloro- or bromomethyl group or a trifluoromethyl group, a halogen atom such as a fluorine atom or a chlorine atom, a hydroxy group, a lower alkoxy group such as a methoxy group) carboxyl and / or cyano, preferably substituted by up to three substituents independently selected from these groups, especially substituted one of these groups, for example in the para position, such as in Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4 -cyanobenzyl · aminocarbonyl.

More particularly preferred are compounds of formula I wherein R 1 is lower alkanoyl, such as acetyl, proplonyl, butyryl, pivaloyl, hexanoyl or heptanoyl, hydroxy (lower alkanjoyl, e.g., betahydroxypropionyl, ( lower and 1-alkoxy) (lower and 1-canolyl), for example (lower alkoxy) acetyl or (lower and 1-alkoxy) propionyl, such as methoxyacetyl or beta-methoxypropionyl, phenoxy (lower an alkanoyl group, for example a phenoxyacetyl group, (lower and 1 channel) alkoxy (lower alkane) oyl group, for example 1 ad (lower alkane) oyloxyacetyl group or (lower alkane) oyloxypropionyl group an acetoxyacetyl group or a betaacetoxypropionyl group, an oxo (lower alkane) oyl group, for example an acetoacetyl group but bo propionylacetyl, 5-hydroxymethylfuran-2-ylcarbonyl, 2- or

3-pyrrolylcarbonyl, furylcarbonyl, for example 2-furylcarbonyl, thienylcarbonyl, for example 2-thienylcarbonyl, pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, 2-, 3- or 5-indolylcarbonyl, pyrrolidinyl

3-carbonyl, 2-, 3- or 4-piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-tetrahydroisoquinolyl-1 -, -3- or -4-carbonyl, imidazolylcarbonyl, such as imidazol-1-yl to arbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, morpholinoacetyl, thiomorpholinoacetyl, 4- (lower and 1alkyl) -1 -pi a perazinoacetyl group, such as a 4-methylpiperazinoacetyl group, an indyl acyl group, a benzofuranyl acetyl group, a phenyl 1 (lower alkane) oyl group, for example a benzoyl group, a phenylacetyl group or a 3-phenylpropionyl group which is on the phenyl residue unsubstituted or mono- or poly-substituted by a lower alkyl group, for example a methyl group, a halo (lower alkyl) group such as a chloro- or bromomethyl group, a halogen atom, for example a fluorine atom or a chlorine atom u, hydroxy, lower alkoxy, for example methoxy, piperidinylmethyl, piperazin-1-ylmethyl, 4- (lower alkyl) piperazine-1- ylmethyl such as 4-methyl- or 4-ethyl

5 moieties with η-1-ylmethyl, morpholomethylmethyl, thiomorpholomethyl, cyano and / or nitro, for example 4-chloromethyl-1,4-bromomethyl-4-fluoro-4-chloro-4 -methoxy-, 4-morpholinomethyl-, 4-thiomorpholinomethyl-, 4-cyano- or 4-nitrobenzoyl, 4-methylphenyl acetyl, 4-methoxyphenylacetyl or 3- (p-hydroxyphenyl) propionyl, or an aliphatic amino acid radical bound via an alpha-carbonyl group selected from the group consisting of alanine, valine, norvaline, leucine, 3-aminopropionic acid, 2-aminobutyric acid and isoleucine or amino acids selected from the group consisting of glycine, asparagine, glutamine, methionine, lysine and phenylalanine, furthermore amino acids selected from the group consisting of 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid,

4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid and 5-aminohexanoic acid, each of which may be asymmetric in the form of the above-mentioned carbon atom,

D, L or (D, acidic) as preferably (except when in the case of glycine) form L, tethered or with a group such as methyl n-butyl benzyl alkynyl group, as present, N-alkylated. n n-propyl alkyl of 3- or α 1 -amino group when one or two times with a group, a phenyl group (lower group and / or 2-, a group and / or N-acylated group (lower tert, butoxycarbonyl) is unsubstituted alkyl group or group,

4-pyridyl (or alkoxycarbonyl) or as benzyloxycarbonyl, such as in the alanyl group of N- (lower alkyljalanyl group, such as N-methylalanyl group, phenyl and 1anyl group, amine acetyl group (glycyl group), - (lower alkyl) aminoacetyl and 1 or

N, N-di (lower alkylamino) acetyl, such as N-methylaminoacetyl, N, N-dimethylaminoacetyl, and / or

N-methyl-N- (n-butyl amine acetyl), N- (lower alkyl) N-phenyl (lower alkyl) aminoacetyl, such as N-methyl-N benzyl amine acetyl, N- (lower and 1-alkyl) -N -pyridyl (lower alkyl amino-acetyl group, for example N-methyl-N- [66 (2-, 3- or 4-) pyridylmethyl) -aminoacetyl group such as N-methyl-N- (3-pyridylmethyl) amino-acetyl, N-phenyl (lower and 1-alkoxy) carbonyl-N- (lower-alkyl) amino-acetyl, such as N-benzyloxycarbonyl-N-methylaminoacetyl, 2-aminobutyric acid a group, a valyl group, a norvalyl group, a leucyl group, an isoleucyl group, a methonyl group, a yyl group, a glutamyl group or an aspartic group, said amino acid residues (except g 1 ycine) are preferably in the form of L , and pharmaceutically acceptable salts thereof.

In addition, compounds of the formula I and their salts in which R @ 1 is aminocarbonyl, mono- or di (lower alkyl aminocarbonyl), such as Nm ethyl-, N-methyl-, Ν, Ν-dimethyl- or N, N a diethylaminocarbonyl group, preferably a mono (lower alkyl) aminocarbonyl group or a phenyl (lower alkyl) am inocarbonyl group in which the phenyl radical is unsubstituted or substituted by the groups already mentioned above for the definition of an aryl group, preferably for example lower alkyl, for example methyl, halogen (lower alkyl), such as chloro or bromomethyl, or three fluoromethyl, halogen, for example fluoro or chloro, hydroxy, lower alkoxy such as methoxy, carboxyl and / or cyano a group, preferably at most three substituents independently selected from these groups upine, in particular by one of these groups, for example in the para position, such as in Ν-benzyl-, N- (4-fluorobenzyl) -, N- (4-chlorobenzyl) -, N- (4-trifluoromethylbenzyl) - or N- (4-cyanobenzyl) aminocarbonyl.

Particularly preferred are compounds of formula I wherein R 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, lower alkanoyl, such as acetyl, propionyl, butyryl, methylpropionyl, n-pentanoyl, hexanoyl, or a hepta noyl group, (lower than methoxyacetyl or 4-butoxyacetyl xyl) (lower acetyl group, alkanjoy group, phenoxy group (lower hunting group, phenyl 1 (n as benzyloxyacetyl hunting group, and 1 alkoxy) group and group, try to test the ginseng

3-methoxypropionyl, (lower and 1-alkoxy) (lower and 1-co as 2- (2-methoxyethoxy) ethoxyalkoxy) (lower and 1-alkoxy) (lower and 1-channel) o (n as a 2- (2- (2-methoxyethoxy) ethoxy) acetyl alkanjoyl alkoxy) (n group, 2 as a 2-chloroacetyl group, such as phenoxyacetyl alkanjoyl, halogen (lower alkanjoyl, amino-, (lower alkyl)) amino- or di (lower alkyl) amino (lower alkoxy) -2- (lower alkanjoyl) such as dimethylamino (lower alkoxy) acetyl, amino- (lower alkyl) amino- or di (lower alkyl) amino ( lower alkoxy) (lower and 1 alkoxy) -2- (lower alkanjoyl, such as dimethylamino- (2-lower alkoxyethoxy) -acetyl; 2- (lower alkoxy) -2-phenylacetyl such as (R j or (S) - 2-methoxy-2-phenylacetyl, furylcarbonyl, for example furan-2-ylcarbonyl, piperides 1 (lower alkanjoy, for example pyperidylcarbonyl) yyl such as 2-, 3- or 4-pyridylcarbonyl, pyisoquinolylcarbonyl,

D-propyl ridylacetyl, such as pyridylpropionyl, quinolylcarbonyl, nyl

1-l-3-ylcarbonyl, especially L- or alkanjoyl, such as imidazolylacetyl, or imidazolylpropiazolylpropionyl,

2-pyridylacetyl or as a 3- (pyridin-2-ylpropionyl group, such as quinolin-2-ylcarbonyl, as well as a pyrrolidinyl-2-carbonyl group, imidazolyl (lower)

A 4-imidazolylcarbonyl group, for example a 4-imidazolylacetyl onyl group such as 3- (4-imidopyrazolyl) (lower alkanjoyl group such as a 1-pyrazolylcarbonyl group, women) 1 (lower alkanoyl, for example benzoyl, phenylacetyl or 3-phenylpropionyl, 4-chloromethylbenzoyl, 4-morpholinomethylbenzoyl, 4-thiomorpholinomethylbenzoyl, aminoacetyl) (f) alkyl) aminoacetyl or N, Nd 1 (lower alkyl) aminoacetyl such as N-methylaminoacetyl,

N, N-dimethylaminoacetyl or N-methyl-N (n-butyl) aminoacetyl, N- (lower alkyl) -N-phenyl (lower alkyl) aminoacetyl, such as N-methyl-N-benzyl; inoacetyl, N- (lower alkyl) -N-benzyloxycarbonylaminoacetyl, such as N-methyl-N-benzyloxyaminoacetyl, N-imidazolyl (lower alkyl) -N- (lower alkyl) aminoacetyl, such as N - (imidazole-4) -ylmethyl) -N-methylaminoacetyl, N (lower alkyl) -N-pyridyl (lower alkyl) aminoacetyl, for example N-methyl-N - / (2-, 3- or 4-) pyridylmethyl / aminoacetyl such as N a methyl-N- (2- or 3-pyridylmethyl) aminoacetyl or 4- (N, N-dimethylamino) butyryl group, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I, wherein R _t is a lower alkanoyl group such as acetyl group, propionyl group, butyryl group, pivaloyl group, hexanoyl group, or furyl group, e.g., furan-2-ylcarbonyl, pyridylcarbonyl, for example 2- , 3- or 4-pyridylcarbonyl, phenyl (lower alkanjoyl, for example benzoyl, phenylacetyl or 3-phenylpropionyl, 4-morpholinomethylbenzoyl, 4-1-fluoromethylbenzoyl, aminoacetyl, N - (lower) alkyl) aminoacetyl, N, Nd i (lower alkyl amino amino) such as N-methylaminoacetyl, N, Nd methyl aminoacetyl, N-methyl-N- (n-butyl) aminoacetyl, N- (lower) (lower alkyl) -N-phenyl (lower alkyl) aminoacetyl, such as methyl-N-benzyl amino aminoethyl, or N- (lower alkyl) N-pyridyl (lower alkyl); and a minoacetyl group, for example Nmethyl-N - [(2-, 3- or 4-) pyridylmethyl] amine acetyl group such as N-methyl-N- (3-pyridylmethyl) aminoacetyl group, and pharmaceutically acceptable salts thereof.

Particularly preferred are compounds of formula I wherein R 1 is lower alkanoyl, such as acetyl, (lower alkoxy) (lower alkanoyl), such as methoxyacetyl, pyridylcarbonyl, such as pyridin-2-ylcarbonyl, or a furylcarbonyl group, such as a furan-2-ylcarbonyl group, and pharmaceutically acceptable salts thereof.

použivzorca

Particularly preferred are compounds of the general formula in which R1 represents a lower alkanoyl group than a furylcarbonyl group such as furan-2-yl,

Or a carbonyl group, and a pharmaceutical thereof

Useful salts.

Also particularly preferred are compounds of formula I wherein R 6 is (lower alkoxy) (a lower alkanjoyl group such as methoxyacetyl group, a group such as pyridin-2-ylcarbonyl group, and a pharmaceutically acceptable salt thereof.

or pyridylcarbonyl pharmacy is a particularly preferred group, and their pharmaceuticals are compounds of the formula (I) to an alkanoyl group, particularly useful with

Very preferred are the compounds

I, in the pharmaceutical specification.

salts of formula (I) and exemplified in the Examples

Compounds having at least one, for example, a salt of formula I and a group of such salts are obtained in a manner known per se,

a) reacting a compound of formula II above with a carboxylic acid of formula III as defined above with an acid of general formula

OH (III) wherein R 1 has this acid, of formula II and of the general reaction, are, if necessary, in the meanings indicated, or with a reactive derivative of a functional group in the starting compounds of formula III not to participate in the protected form, the protecting groups present are split off, or

(b) an amine apprentice of formula IV

wherein R 1 is as defined above, or a reactive derivative thereof, amidated with a carboxylic acid of formula V

(V) or a reactive derivative thereof, wherein the free functional groups in the starting materials of formula (IV) and (v) which are not to be involved in the reaction are in protected form if necessary, subsequently protecting groups present are cleaved, or

c) a compound of formula VI

1 (VI)

wherein R 1 has the above-mentioned meanings, or a reactive derivative thereof and mends a carboxylic acid of the formula VII

(VII) or a reactive derivative thereof, wherein the free functional groups in the starting materials of formula VI and VII which are not to be involved in the reaction are, if necessary, in a protected form, followed by cleavage of the protective groups present, subsequently optionally of a compound of the formula I having at least one salt-forming group obtained by one of the above processes is converted into its salt and / or the obtained salt is converted into the free compound or another salt and / or the isomeric mixtures of the compounds of the formula I and converting a compound of the invention of formula I to another compound of the invention of formula I.

In the following, the methods defined above will be described in more detail.

Method a) Preparation of an acylated compound

For example, the preparation of the ester is carried out in a manner known per se using an acid of formula III wherein R 1 has the meanings given above except for the aminocarbonyl group or the N-substituted carbamic acid residue, or a reactive derivative thereof. A reactive derivative is, for example, a compound of the formula IIIa

R 1 -Z 1 (IIIa) wherein R 1 has the latter meanings and Z 1 is in particular a reactively activated hydroxy group.

The free carboxylic acid of the formula III can be activated, in particular also in situ, for example with strong acids such as hydrohalic acid, sulfuric acid, sulphonic acid or carboxylic acid or with acidic ion exchangers, for example hydrochloric acid, hydrobromic acid or acid. hydrocyanic acid, alkanoic acid optionally substituted, for example, by a halogen atom, or an acid of formula

III, preferably an excess of the acid of formula III, if necessary during binding of the resulting reaction water with a water binding agent, during azeotropic distillation of the reaction water or during extra esterification, anhydride acids, in particular inorganic anhydrides, anhydride carboxylic acids such as anhydrides (lower alkane) ) carboxylic acids (except formic anhydride), for example acetan hydride, or suitable activating or coupling agents of the type mentioned below. The compound of formula R1-Z1 may also be a carboxylic acid azide (which can be obtained, for example, by reacting the corresponding acid ester to the corresponding hydrazide and reacting it with nitrous acid), a carboxylic acid halide, in particular an acid chloride or bromide, e.g. organic acid halides, in particular with oxalyldiphenyl halides, such as oxalyldichlorides, or especially with inorganic acid halides, for example phosphorus or sulfur halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus pentachloride , phosphorus tribromide, phosphorus pentachloride, phosphorus tribromide, thionyl chloride or thionyl bromide, or, in particular, under gentle conditions, the reaction of a lower (1 &apos;) -alpha-1-phenylene amine such as is tetramethyl-alpha-halenenamine, especially 1-chloro-N, N, 2-trimethyl-1-propenamine (preferably by reaction in an inert solvent, in particular a chlorinated hydrocarbon such as methylene chloride or chloroform, or an ether such as diethyl ether, dioxane or tetrahydrofuran, at a preferred temperature of -78 to 50 ° C, in particular at -60 to 30 ° C, e.g. temperature between -10 ° C and ambient temperature (see Devos A. et al., JCSChem.Commun. 1979, 1180-81, and H et al., B. et al.,

Or g. Synth. 59, 26 (1980)), whereby the acid halide obtained, for example the acid chloride of the formula 111a in which Z 1 is a chlorine atom, can also be directly further processed, for example by reaction with a compound of the formula II in the presence of a tarium. nitrogenous bases such as pyridine and / or 4-dimethylaminopyridine (DMAP, which is preferably added in a catalytic amount), preferably at a temperature between -20 and 50 ° C, in particular at a temperature between 0 ° C and ambient temperature), an activated ester, wherein Z 1 is in particular a cyanomethoxy group, a nitrophenoxy group such as a 4-nitrotenoenoxy group or a 2,4-dinitrophenoxy group, or a polyhalophenoxy group such as a pentachlorophenoxy group, or symmetrical or preferably asymmetric an acid anhydride, which may be obtained, for example, by reacting a salt, for example an alkali metal salt such as a sodium or potassium salt, an acid of formula III, or a reaction partner thereof to form an anhydride preferably a (lower alkane) carboxylic acid, such as acetic acid, with a partner acid halide, and thus in particular either by reacting a carboxylic acid salt of formula III with a carboxylic acid halide, for example a carboxylic acid chloride such as acetyl chloride id, or by reaction of a carboxylic acid halide of the formula 11a, in which Z 1 is a halogen atom, for example a chlorine atom or a bromine atom, with a (lower alkane) carboxylic acid salt, in particular sodium or potassium acetate.

In particular, carboimides, for example Ν, Ν'-dialkylcarbodiimide, the alkylated radical of which contains from 1 to 4 carbon atoms, or N, N'-di-cycloalkylcarbodiimide, may be used as activating and coupling agents for the in situ activation of carboxylic acids of the formula III. wherein the cycloalkyl radical contains 5 to 7 carbon atoms such as diisopropylcarbodiimide or Ν, Ν'-dicyclohexylcarbodiimide, preferably with the addition of an activating catalyst such as N-hydroxysuccinimide or optionally with a halogen atom, an alkyl group containing 1 to 7 atoms C 1 -C 7 -alkoxy, substituted N-hydroxybenzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, alkyl haloformate having an alkyl radical of 1 to 4 carbon atoms, for example isobutyl chloroformate, suitable carbonyl compounds, e.g. N, N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, e.g. 2-e 5-methyl-1,2-oxazol-3-sulphonate or 2-tert-butyl-5-methylisoxazolium perchlorate, suitable acylamino compounds, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline or suitable phosphoryl cyanamides or azides, for example, diethyl phosphoryl cyanamide or diphenylphosphoryl azide, and also triphenylphosphine disulfide or 1-alkyl-2-halopyridinium halide, the alkyl group of which contains 1 to 4 carbon atoms, e.g. 1 methyl-2-chloropyridinium iodide.

The general substituent Z <preferably as a chlorine atom or a bromine atom, for example (a lower alkanjoyloxy group, represents a halogen atom as well as an acyloxy group, such as an acetyloxy group).

For the special case of an ester of carbonic acid, oxygen through its carbonyl group, n of the general formula as a chlorine atom, the additional alcohols, substituted alkyl alcohols, heterocyclic 1 (lower and 1 alkyl) and 1 of whom 1 ον, as defined in the definition the moiety of the half-bonding atom is suitable for halogen compounds, by reaction of the introduction of an acyl moiety attached to the moiety

For example, Hla in which Z 1 is an atom may be prepared, for example, by unsubstituted or subsalkyl) alcohols or having residues of an unsubstituted or substituted alkoxycarbonyl group, an aryl (lower alkoxy) carbonyl group or a heterocyclyl (lower alkoxy) carbonyl group R 5, with phosgene or also with its analogues which contain other halogen atoms in place of chlorine, in particular bromine, preferably in the presence of tertiary nitrogen bases such as pyridine or triethylamine, and in inert solvents such as chlorinated hydrocarbons such as methylenediamine or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxane, or carboxylic acid amides, for example in dimethylformamide. Also suitable are the corresponding N-carbonylazolides of the formula 111a (Z1 = nitrogen-containing heherocyclyl, such as 1-imidazolyl), which can be obtained, for example, by reaction of the corresponding N, N'-carbonyldiazoles, such as Ν, Ν -carbonyldiimidazole, under the conditions described for phosgene and its analogs with other halogen atoms. The reaction of the compounds of formula II with the corresponding compounds of formula 111a is also carried out under these conditions (see Staab H.A., Angew.Chemie 74, 407 (196 2)).

For the particular case of the introduction of an aminocarbonyl group R 1 or an acyl group R consisting of an N-substituted carbamic acid residue, the corresponding isocyanate of the general formula 111b is particularly suitable as an activated acid derivative.

Q-N = C-O (IIIb) wherein Q is a protecting group, for example a tri-haloacetyl group, such as a trifluoromethyl or trichloroacetyl group, or any of the unsubstituted or substituted (lower alkyl) or aryl radicals which have been mentioned above for the definition of the aminocarbonyl group R 1 in which the amino group carries 1 to 2 substituents, whereby when Q represents an amino function protecting group, the corresponding compounds of formula I in which R represents free amine-carbones can be obtained 1, after reaction with a compound of formula II by cleavage of said protecting group Q, as further described below for the release of an amyl group protected by an acyl group, in particular by acid hydrolysis, or obtainable when Q is any of said substituted or unsubstituted (lower alkyl) residues corresponding to? A compound of formula I having an aminocarbonyl group:

L which is mono-substituted at the nitrogen atom. Both the aminocarbonyl group and the N-mono-substituted aminocarbonyl group can be converted to the N-disubstituted aminocarbonyl group by alkylation under the conditions described below in connection with the additional measures of the methods for preparing the compounds of the invention.

These reactions may be carried out under known reaction conditions, at conventional temperatures, in the presence of inert solvents or diluents or in the absence of these solvents and diluents, in particular in the case of using (lower alkane) oylanhydrides to activate carbonic acid of formula III. for example, acid amides, for example, carboxylic acid amides, such as dimethylformamide, dimethyl acetamides or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), or amides inorganic acids such as hexamethylphosphoric triamide, ethers such as cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers such as diethyl or ethylene glycol dimethyl ether, halo genic hydrocarbons such as halogen lower alkanols such as methylene chloride or chloroform, ketones such as acetone, nitriles such as ace tonitrile, acid anhydrides such as acetic anhydride, esters such as ethyl acetate, bis-alkarisulfines such as dimethylsulfoxide, nitrogen heterocycles such as pyridine, or mixtures of these solvents, in particular anhydrous solvents, for which the solvents described above may be selected for the above reactions. the particular reaction, optionally using salts of the compounds used, in particular the metal salts of the carboxylic acids used, such as alkali metal or alkaline earth metal salts, for example sodium or potassium salts, in the absence or presence of catalysts, condensing agents or neutralizing agents, the type of reaction and / or reactants, at atmospheric pressure or in a closed vessel, at normal pressure or at elevated pressure, for example at a pressure that is formed in a sealed tube in the reaction mixture using the reaction conditions and / or inert atmosphere, for example under argon or nitrogen. The solubilizing agent itself may also serve as the solvent, e.g., a carboxylic acid or carboxylic acid. The reaction is carried out by conventional thin layer analytical methods.

in particular, the acid anhydride is suitably monitored by chromatography on

The reaction is not otherwise mentioned, at moderate to 60 ° C, for example at elevated temperature to about ambient. In the case of the general formula R 1 -Z 1, in which Z 1 with the activated derivative of the compound having the ester is carried out in particular, the reaction is carried out at a temperature of 0 or slightly

5 ° C, for example, carried out with a halogen atom or formula II such as chlorofluoric acid in order to prepare a reaction of a compound of formula I in which R 6 represents an amino-carbonyl group or an N-substituted carbonic acid residue The reaction is preferably carried out in the presence of an acid-binding agent, such as a non-acylatable base, in particular a tertiary nitrogenous base, such as N-methylphosphine, 4-dimethylaminopyridine, triethylamine or ethyldiisopropylamine. In particular, in the reaction with a carboxylic acid halide of formula (IIa) in which Z 1 is a halogen atom such as a chlorine or bromine atom, in the reaction with an anhydride, in particular a symmetrical anhydride (Z i = OR), an excess of the corresponding compound of formula IIIa is used. (ha 1 ogenide or R 1 = OR i), for example more than 1.05 times the excess. The reaction conditions specifically mentioned are always preferred.

The protective groups of the functional groups present in the starting materials to be reacted, in particular the carboxyl, amine, hydroxy and / or mercapto groups, include in particular those conventional protecting groups usually used in synthesis of peptide compounds, but also of cephalosporins and penicillins, as well as nucleic acid and sugar derivatives. These protecting groups may already be present in the precursors of the reactants and should protect the functional group against undesirable side reactions such as acylation, etherification, esterification, oxidation, oxidation, silane, etc. In addition, in some cases, protecting groups may influence the selective, for example, stereoselective, course of the reaction. Protecting groups are characterized by being easy, i.e. without side reactions, cleavable, for example, solvolytically, reducing, photolytically, or else enzymatically, for example under physiological conditions. Only those radicals which are not present in the end products are designated as protecting groups.

Protection of functional groups by such protecting groups, the protecting groups themselves, as a reaction leading to the cleavage of these protecting groups are publications such as:

Organic Chemistry, Plenum Press,

Th.W.Greene, Protective Grays in The Peptides,

London and New

If

New York 1981

Academis Press nischen Chemie

II described, for example, in standard

J.F.W.-McOmie, Protective Groups in

London and New York 1973

Yor k r g a n i c S y n t h e s, W i 1 e y (E.G r s a j.Meinhofer)

Methoden der o rg a 15/1, Georg T h e m e Am i nosäu1981,

4.vy d. .

Jakubke and H.Jescheit,, Houben-weyl,

Verlag, Stuttgart 1974, H.D.

ren, Pr e t i d e, Proteine, Verlag Chemie, Weinheim, D e r f i e 1 d

Beach a B a s e 1 1982 and Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharides and Derivatives, Georg Thieme Verlag, Stuttgart 1 9 74.

For example, the carboxyl group is protected as an ester group that is selectively cleavable under gentle conditions. The carbonyl group protected in the esterified form is preferably esterified with a lower alkyl group which is branched at the 1-position of the lower alkyl group or substituted by suitable substituents at the 1- or 2-position of the lower alkyl group.

A protected carboxyl group which is esterified with a lower alkyl group is, for example, a methoxycarbonyl group or an ethoxycarbonyl group.

A protected carboxyl group which is esterified by a lower alkyl group, a branched alkyl group, a carbonyl group, for example which is in the 1-lower position, is in particular a tert (lower and 1-oxo) tert-butoxycarbonyl group.

A protected carboxyl group which is esterified with a lower alkyl group which is substituted at the 1-position or at the position by suitable substituents is, for example, an arylmethoxycarbonyl group having one or two aryl radicals, the aryl group being unsubstituted or substituted by, for example, lower alkyl, e.g. a lower alkyl group such as a tert-butyl group, a lower alkoxy group such as a methoxy group, a hydroxy group, a halogen atom such as a chlorine atom and / or a nitro group, and in particular represents a phenyl group substituted one or three times such a benzyloxycarbonyl a benzyloxycarbonyl group such as a 4-nitrobenzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group, or a diphenylmethoxycarbonyl group substituted by a substituent; an example of a di- (4-methoxyphenyl) methoxycarbonyl group, further a lower alkyl esterified carboxyl group wherein the lower alkyl group is in the 1 or 2 position substituted with suitable substituents such as 1- (lower and 1-alkoxy) (lower alkoxycarbonyl, e.g. methoxymethoxycarbonyl); 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1- (lower alkyl) thio (lower alkoxy) carbonyl, for example 1-methylthiomethoxycarbonyl or i-ethyl 11 ethoxycarbonyl, aroylmethoxycarbonyl in which the aroylmethoxycarbonyl group is an ayl group. a benzoyl group optionally substituted by, for example, a bromine atom, for example a phenacyloxycarbonyl group, 2-halogen (lower alkoxycarbonyl, for example 2,2,2-trifluoromethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl) as well as 2- (trisubstituted siyl) (lower a larger alkoxycarbonyl group, wherein said substituents are, independently of one another, aliphatic, aralkyl, cycloaliphatic or aromatic hydrocarbon radicals which are optionally substituted, for example, by a lower alkyl group, an aryl group, a halogen atom or an anro group; for example optionally substituted lower alkyl, phenyl (lower alkyl, cycloalkyl, or phenyl) as described above, such as 2-1 ri (lower alkyljsilyl (lower alkoxy) carbonyl such as 2 tri (lower alkyljsilylethoxycarbonyl) such as 2 tri a methylsilylmethoxycarbonyl group or a 2- (di-butylmethylsilyl) oxycarbonyl group or a 2-triarylsilylethoxycarbonyl group such as a triphenylsilylethoxycarbonyl group.

The carboxyl group is also protected as an organic silyl oxycarbonyl group.

Such an organic silyloxycarbonyl group is, for example, a tri (lower alkyl) silyloxycarbonyl group, for example a trimethylsilyloxycarbonyl group. The silicon atom of the silyloxycarbonyl group may also be substituted by two lower alkyl groups, for example methyl groups, and one amino or carboxy group of a second molecule of formula I. Compounds with such protecting groups may be prepared using, for example, dimethylchlorosilane as a silylating agent.

a suitable xyl ester

The carboxyl group is also internally protected with a hydroxy group

Protected in gamma position, ie. in the form of a lactone, for example a carboxyl group, an alkoxycarbonyl group, for example a group, benzyloxycarbonyl, nyl, phenylmethoxycarbonyl.

is preferably in the molecule relative to k a r b o preferably gamma-lactone.

is preferably tert. (lower tert-butoxycarbonyl 4-nitrobenzyloxycarbonyl-9-fluorenylmethoxycarbonyl or di The protected amino group is protected with an amino function protecting group, for example in the form of an acylamino group, an γ-methylamino group, an etherified mercaptoamino group, 2acyl ( lower and 1-k-1-enyl-amine or si-1-amine or as azido.

In an acyl amino group, the acyl group is, for example, an acyl residue of an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular a (lower alkane) carboxylic acid, optionally substituted, for example, by halogen or aryl, or benzoic acid optionally substituted for example, a halogen atom, a lower alkoxy group or a nitro group, or preferably a half-carbonate ester. Such acyl groups are preferably (lower alkane) oyl, such as formyl, acetyl, propionyl or pivaloyl, halogen (lower alkane), such as 2-haloacetyl, such as 2-chloro, 2-bromo-, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally with, for example, a halogen atom, a lower alkoxy group or a nitro substituted benzoyl group such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4 nitrobenzoyl, (lower alkoxyjcarbonyl, preferably in the 1-position of the lower alkyl radical branched or in the 1- or 2-position suitably substituted (lower alkoxyjcarbonyl, e.g. tert, (lower alkoxy) carbonyl a tert-butoxycarbonyl group, an arylmethoxycarbonyl group having one, two or three aryl radicals, which may be for example a lower alkyl group, in particular a tert (lower alkyl group such as methoxy, halogen, such as chlorine and / or nitro mono- or polysubstituted phenyl group, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl) a 9-fluorenylmethoxycarbonyl group or a di- (4-methoxyphenyl) methoxycarbonyl group, an aryloxymethoxycarbonyl group, in which the aryl group preferably represents, optionally, a halogen atom such as bromine, a substituted benzoyl group, for example phenacyloxycarbonyl, 2-halo ( and 1-alkoxycarbonyl, for example 2,2,2-trifluoroethoxycarbonyl, 2-bromomethoxycarbonyl or 2-iodoethoxycarbonyl, alkoxycarbonyl,

A 2-tri (lower and 1-alkyl) 1-yl (lower alkoxycarbonyl than 2-three methylsilyl-ethoxycarbonyl group or group, or three, for example, 2-tri2- (trisubstituted 1-yl) ( lower group,

2- (di-n-butylmethylsilyl) oxycarbonyl aryl 1-yl (lower alkoxy) carbonyl, phenylsilylethoxycarbonyl.

In the arylmethylamino group, in particular the triarylmethylamino group, substituted, for example, benzyl especially mono-, radicals of such di- or especially p-risk are examined for or, for example, in aryl by phenyl radicals.

a 1-methyl tritylamino group.

pi var 1 (n represents etherified mercaptoam firstly occurs with a lower alkylthio group optionally with, for example, a group or a tertiary, such as a methoxy group, where the higher mercaptoamers 11o-or inanapric 1 ad than the methyl group of the chlorine group; An itro group, for example, as a 4-nitrophenylthio group, is substituted by an aryl group with an alkyl group, a butyl group, a lower group, a halogen atom such as an enyl group, a substituted atom, and a 1 alkoxy atom. £ · i

In 2-acyl (lower and 1-k-1-enyl), the corresponding amino-protecting group, for example the corresponding methyl or tert-butyl group which is used as the acyl radical, functions (lower alkanecarboxyone such as lower alkyl) , a lower alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom, and / or an anro substituted benzoic acid or, in particular, a half-carbonic acid ester, in particular (lower alkyl-half-carbonic acid ester). - (lower and 1-chan-1 (lower and 1-k-1-en-2-yl), for example 1- (lower alkane) oylprop-1-en-2-yl such as 1-acetylprop-1-en- 2-yl, or (lower alkoxy) carbonyl (lower alk-1-ene) -2-yl, for example (lower alkoxy) carbonylprop-1-en-2-yl such as 1-ethoxycarbonylprop-only-2-yl.

the group is, for example, a tri (lower and 1-yl) silane such as a trimethylsilylamino group or a ylamino group. Silicon atom silylaminot i e ž

The silylamino amino group, the t-butyl imethyl group, may be groups, for example, or carboxyls with such, for example, using lances, substituted with two methyl groups of the second protecting group silylating, for example dimethylsilane.

by probing molecules that have been hydrogenated

The amino group may also be of a form. As appropriate considerations, strong anions of sulfuric acid, e.g.

Preferred protecting groups are amino and amino

I. Of one of the formulas, a large number of chlorosprotected to protonation in inorganic phosphorylates or a lower (lower alkoxy) carbonyl group may be

- (lower (or lower) or a 1-canolyl (lower alkoxy) -carbonyl (n particularly preferred benzyloxycarbonyl) is preferably a 1-anionic acid, bromo is p-tol n such as halo-1 or fluorocyclic amine phenyl (lower alkoxy) carboalkoxycarbonyl, group or group, fluorenyl (lower and 1-k-1-en) -2-yl-higher alk-1-ene) - The 2-yl is a t-butoxycarbonyl group.

For example, a hydroxy group such as a chlorine atom may be unsubstituted or protected

J, as an acetyl or substituted lower group and / or 2, in particular by an acyl atom, tests in particular with the direct testing of the carbine selines mentioned for protected amino groups. a hydroxyethoxycarbonyl protecting group, a diphenylmethoxycarbonyl xcarbonyl group. Hydroxy group (lower and alkyl) with 1-yl group, dimethylsilyl, lightly acyl halo, alkanoyl, 2-dichloroacetyl moiety of half ester The 4-nitrobenzyloxycarbonyl or triphenylmethone may further be protected, for example, with a trimethylsilylotriisopropylsilyl group or with a tert-butyl-cleavable etherified group, for example an alkyl group, such as a tertiary (lower alkyl) group, for example tert. butyl, oxa or thiaaliphatic or -cycloaliphatic, especially 2-oxa or 2-thaliphatic or -cycloaliphatic hydrocarbon radicals, for example 1- (lower and 1-alkoxy) (lower alkyl) (1- (lower alkyl)) or 1- ('lower) (C1-C6) alkylthio (lower alkyl) such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl with 5 to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl or the corresponding thiaanologues, such as 1-phenyl (lower alkyl) such as benzyl, diphenylmethyl phenyl phenyl halogen , for example, a group or triethyl radicals may be substituted by, for example, a methoxy, chlorine, lower and / or nitro group, for example by an alkoxy, n, ou.

Two, in particular adjacent, hydroxy or adjacent hydroxyl groups and an amino group contained within a single molecule, may be protected, for example, with a divalent protecting group, such as preferably a methylene group substituted with one or two lower alkyl groups or an oxo group, for example unsubstituted or substituted alkylidene, for example lower alkylidene, such as isopropylidene, cycloalkylene, especially cyclohexylidene, carbonyl or benzylidene.

The hydroxyl group adjacent to the carboxyl group can be protected by the formation of an internal ester (1 to 1), in particular gamma-1actone.

Preferably, the hydroxy group is protected by a tri (lower alkyl) silyl group or as a lactone, in particular a tert-butyldimethylsilyl group.

The mercapto group, such as in cysteine, may in particular be protected by S-alkylation with optionally substituted alkyl residues, silylation, thioacetal formation, S-acylation or formation of asymmetric disulfide moieties, mercapto-protecting groups such as benzyl optionally substituted on the phenyl group a methoxy or diphenylmethyl radical, for example, a three-phenylmethyl group, a trimethylsilyl tetrahydropyranyl group, an acetamidomethyl group, a 2-chloroacetamidomethyl group, a benzyloxycarbonyl alkyl group, an aminocarbonyl group, as well as an i (lower and (1) 1-S-tert-butylthio or

Preferred nitro, such as optionally methoxy,

4-methoxybenzyl, substituted on phenyl as di- (4-methoxyphenyl) methyl, pyridyldiphenylmethyl, benzylthiomethyl, na, acylaminomethyl, such as isobutyl-acetamidomethyl, benzoyl, or alkyl, especially (lower carbones, such as ethylamino) a group such as S-ethyl 11- or S-sulfo.

The cleavage of the protecting groups which are not part of the desired end product of the general formula I, for example the carboxyl, amine, hydroxy and / or mercapto function, is carried out in a known manner, for example by solvolysis, in particular hydrolysis, alcoholysis or acidolysis or Other reducing agents, as well as photolysis, optionally sequentially or simultaneously, may also be used as enzymatic methods to protect the protective groups of the groups mentioned by the protective group. Shade, for example, described in the standard previous section by us.

Thus, for example, a tertiary (lower alkoxy) carbonyl substituted by the description in, for example, an alkoxycarbonyl, substituted silyl or alkoxy or lower alkylthio group substituted diphenylmethoxycarbonyl free carboxyl group by a (lower three protected carboxyl group, lower 1 or optionally) a group converted to a suitable acid such as formic, trifluoroacetic acid, acid, optionally with phenol or anisole.

hydrochloric acid or acid by addition of a nucleophilic compound,

For example, an optionally substituted benzyloxycarbonyl group can be liberated by hydrogenolysis, i. by hydrogen in the presence of a metal hydrogenation catalyst such as a palladium catalyst.

Further, a free carboxyl group such as a 4-nitrobenzyloxycarbonyl group may also be suitably substituted also by reduction of sodium dithionite, or by or reducing chromium, for example, hydrogen k-releasing hydrogen at birth and alkaline use with a carboxylic acid salt or metal carboxylic acid, e.g. of a reducing metal, to a benzyloxycarbonyl group to be converted, for example, by treatment with a dithionite such as zinc, ova, for example a chromium (II) salt, usually in the presence of which it produces with the metal is an acid, particularly suitable acetic acid, diphenylglycolic acid, acid or thio. , glycolic acid, lactic acid, acid such as, for example, mandelic acid, tartaric acid or alcohol preferably adds water.

4-chloromethanedioic acid, or wherein

By treatment with a reducing metal or 2-halogen (lower after conversion 2-bromo (lower corresponding 2-iodo) (lower or aroylmethoxycarbonyl carboxylic acid) can also be used.

By reducing the metal salt as previously described, the alkoxyjcarbonyl group attempts to convert the alkoxyjcarbonyl alkoxyjcarbonyl group to the free β group as described above, the (optionally 1-group) group can also be preferably or sodium iodide.

2- (trisubstituted as, for example, p on carbonyl silyl) (lower and 1-alkoxy) carbonyl group 2-three (lower and 1 kyl) with 11 y 1 (lower alkoxy) can be converted to the free carboxyl group

Aroylmethoxycarbonyl by nucleation is a sodium thiophenoxide salt-forming agent, also a hydrofluoric acid salt group providing a fluoride anion such as an alkali metal fluoride such as sodium fluoride or potassium fluoride, optionally in the presence of a macrocyclic polyether (crown ether) or fluoride an organic quaternary base such as tetra (lower alkyl) ammonium chloride or three (lower and alkyl) aryl (lower and alkyl) ammonium fluorides such as tetraethylammonium fluoride or tetrabutylammonium fluoride in the presence of an aprotic polar solvent such as N, or dimethylsulfoxide methyl 1 acetam i.

A carboxyl group protected as an organic silyloxycarbonyl group such as a tri (lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl group) can usually be released solvolytically, for example by treatment with water, alcohol or acid, or else with fluoride, as described above.

The esterified carboxyl group can, as is also the case, be released enzymatically, for example by esterases or suitable peptidases.

For example, an esterified or lysine, such as a lysine nmethyl ester, may be treated with trypsin.

The carboxyl group protected as an internal ester, for example gamma-lactone, can be liberated by hydrolysis in the presence of hydroxide bases such as alkaline earth metal hydroxides or, in particular, alkali metal hydroxides, for example sodium hydroxide, potassium hydroxide or lithium hydroxide, in particular lithium hydroxide. at the same time removes the correspondingly protected hydroxy groups.

The protected amino group is liberated in a manner known per se, selected according to the nature of the protecting group, preferably by solvolysis and / or reduction.

A (lower alkoxy) carbonylamino group, a tert-butoxycarbonylamino group, can be cleaved, for example, in the presence of acids, for example mineral acids, for example hydrohalic acids, such as phosphorous bromide, solvents, as in particular also for hydrochloric or hydrobromic acid, or sulfuric acid, preferably hydrochloric acid such as water or carboether, preferably cyclic alkoxycarbonylamino-2-bromo (lower alkoxycarbonylalkoxy) carbonylamino), na or 4-n (optionally acetic or

2-halogen (lower conversion after

2-iodo (lower or acid in polar xyl ethers, amino group on aroylmethoxycarbonylamino amino group reagents such as acids which can be cleaved by treatment is zinc in the presence of acetic acid.

itrobenzoylcarbonyl of a suitable reducing carboxylic acid may also be cleaved

The aroylmethoxycarbonylamino group is treated with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxy, while the 4-nitrobenzyloxycarbonylamino trial can also be cleaved by treatment with an alkaline dithionite such as sodium dithionite.

on metal,

Optionally substituted diphenylmethoxycarbonylamino, (lower alkoxycarbonylamino) or 2- (trisubstituted as alkoxy) carbonylamino, by treatment with a suitable acid, for example trifluoroacetic acid.

(lower alkoxy) carbonylamino group (lower can be 1 y y) with 1 y 1 (lower release form or

Alternatively, it can be cleaved, for example, by the presence of a suitable palladium catalyst such as lower (methylformamide) and alcohols, preferably methanol.

possibly

2-trisubstituted benzyloxycarbonylaminomethylsulfonate, i.e. hydrogenolysis; by treatment with hydrogen in a hydrogenation catalyst, preferably polar (1) (n ethers such as ethanol or alkane) oyl amides, cyclic methanol such as solvents, for example dimers, for example dioxane, or propanol , in particular or a triarylmethylamino group, can be cleaved, for example, by treatment with an acid, for example hydrochloric acid, for example a substituted formylamino group, with acids such as mineral diacid or organic acids such as formic, acetic or trifluoroacetic acid. water.

The amino group is released, for example, protected as by hydrolysis

Amino-protected silylamino-group, with or by alcoholysis.

For example, a 2-haloacetyl group may be liberated by treatment with a thiourea in the presence of a base or a thiolate salt such as an alkali metal thiolate derived from thiourea, followed by solvolysis, in particular alcoholysis or hydrolysis of the resulting substitution product.

An amino group protected with a 2- (trisubstituted silyl) (lower alkoxy) carbonyl group, such as a 2 -1 R (lower alkyl) silyl (lower alkoxy) carbonyl group, can also be converted to the free amino group by treatment with a hydrofluoric acid salt. providing a fluoride anion, as discussed above in connection with the release of a similarly protected carboxyl group. Likewise, a silyl group, such as a trimethylsilyl group attached to a heteroatom such as a nitrogen atom, can be cleaved directly by fluoride ions.

The amino group protected to the free amino acid by catalysed hydrogenation such as nickel, thiotreitol or the presence of an acid, hydrogenation as a naphtha catalyst, or Rane in the form of an azido group by reduction, for example, can be palladium compounds also by treatment with zinc acetic acid. . A catalytic solvent such as halogenated methylene chloride or also in water or some solvent such as alcohol or such as, for example, hydrogen in the presence of hydrogen, for example platinum oxide, by reduction using mercaptomer mercaptoethanol, or as the acid is preferably carried out %, for example in a mixture of water and orgadioxane, at a temperature of about 20-25 ° C, or else with cooling or heating.

A hydroxy or mercapto group protected with a suitable acyl group, a tri (lower alkyl) silyl group or an optionally substituted 1-phenyl (lower alkyl) group, is liberated analogously to the correspondingly protected amino group.

For example, a hydroxy group or a mercapto group protected with a 2,2-dichloroacetyl group is released by basic hydrolysis.

The hydroxy or mercapto group protected with a tertiary lower alkyl group or a 2-ox α- or 2-thiaaliphatic or cycloaliphatic residue is liberated, for example, by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid such as tri- fluóroctcvá.

The phenyl-protected mercapto-protected mercapto group can be released by mercury salts at pH 2-6 or by a zinc / acetic acid system or by electrolytic reduction.

The mercapto group protected with an acetamidomethyl group or an isobutylamidomethyl group can be released by reaction with mercuric salts in the

PH

Mercapto-group protected

The 2-chloroacetamethylmethyl group can be released, for example, by treatment with 1-piperidinoothiocarboxamide.

The mercapto group protected with S-ethylthio, S-1-tert-butylthio and S-sulfo can be liberated by thiolysis by treatment with thiophenol, thioglycolic acid, sodium thiophenoxide or 1,4-diotriol.

Two hydroxy groups or an amine group and an adjacent hydroxy group which are jointly protected by a two-valence protecting group, preferably a methylene group, which is preferably mono- or di-substituted, for example, by a lower alkyl group such as (lower alkyl iiden group, for example isopropyl) an idene group, a cycloidene group, for example a cyclohexylidene group, or a benzylidene group, can be liberated by acid solvolysis, particularly in the presence of a mineral acid or a strong organic acid.

The tri (lower alkyl) sulfonyl group can also be cleaved by acidolysis, for example with a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid.

The 2-halo (lower alkoxy) carbonyl group is cleaved by the abovementioned reducing agents, for example, a reducing metal such as zinc, or a reducing salt of divalent chromium, or sulfur compounds, such as sodium dithionite or preferably sodium sulfide. and carbon disulphide.

Esterified hydroxy groups such as a (lower alkane) oyloxy group, such as an acetyloxy group, can also be released by esterases. The acylated amino group can also be released by suitable peptidases.

The temperatures at which the release of the protected functional groups is carried out preferably lie in the temperature range of -80 to

100 ° C, particularly preferably in the temperature range from -20 to 50 ° C, for example in the temperature range from to 35 ° C, especially at a temperature close to ambient temperature.

In the presence of a plurality of protected functional groups, the protective groups may, if desired, be selected by simultaneously removing at least two protecting groups, for example acidolytically, in particular by treatment with trifluoroacetic acid or hydrogen in the presence of a hydrogenation catalyst such as palladium on. coal. Protecting groups, on the other hand, can be chosen so that they are not simultaneously cleaved, but in the desired order, whereby the corresponding intermediates are obtained.

The starting compound of formula II can be obtained from 2- [3 (S) amino-2 (R) -hydroxy-4-phenylbutyl] -N-tert-butyldecahydro- (4aS, 8a) -quinolin-3 (S). 1-carboxamine (prepared according to the procedure described in Example 33 of European patent EP 0 432 595), which can also be obtained, for example, by reaction of compound 92 (VIII)

wherein P 1 is an amine function protecting group as defined above in relation to process A), in particular a tert-butoxycarbonyl or benzyloxycarbonyl group, which may be prepared by the process described in E et al. in J. Org. Chem. 50, 4615-4625 (1985), with N-tert-butyldecahydro (4aS, 8aS) -isoquinoline-3 (S) carboxamide (prepared according to European patent EP 0 432 694), e.g. a polar solvent such as an alcohol at elevated temperature

Temperature, e.g. reflux, e.g. methanol or ethanol,

IX at a temperature of 40 to a compound in ° C, in particular of the general formula

(IX) in which Pi has the latter meaning, followed by cleavage of the amino function of the Pi function, for example in the case of tert-butoxycarbonyl P, by cleavage with an acid such as a mineral acid such as hydrohalic acid, in particular hydrochloric acid, or in the presence of a strong organic acid such as formic acid in organic solvents such as ethers, for example in a cyclic ether such as dioxane or without solvent in the case of a liquid organic acid such as formic acid or in the case of benzyloxycarbonyl acid by hydrogenation in the presence a catalyst, for example a noble metal catalyst, for example on a support such as coal, silica or alumina, preferably palladium on carbon, at normal or elevated pressure, for example at normal pressure, in a polar solvent such as an alcohol such as methanol or ethanol, at a temperature of 0 to 5 0 ° C, preferably at about ambient temperature, and the obtained compound (N- tert -butyl-decahydro-2 - //2(R)hydroxy-4- phenyl-3(S)amino/butyl/-(4aS,8aS)-isoquinoline -3 (S) carboxamide / or a salt thereof, for example the salt of the latter, is amidated with either L-asparagine on a nitrogen protected P c amine protecting group, for example alpha- (N-benzyloxycarbonyl) -L-asparagine, or its reactive a derivative, in particular a p-nitrophenyl ester, as described in connection with amidation in process b), preferably in the presence of a tertiary nitrogen base such as triethylamine or N-ethyldiisopropylamine, in particular in an acid amide, for example dimethylformamide, at a temperature of from 0 to 50 ° C, preferably at ambient temperature to give a compound of formula X

wherein P <- represents a group protecting the amine function, which was defined for process a), in particular a benzyloxycarbonyl group, which is then removal of the protecting group is converted to the corresponding free amino-z1účeninu, while in the case of benzyloxycarbonyl L _£ this group is cleaved off e.g. by hydrogenation in the presence of a catalyst such as a noble metal catalyst, for example on a support such as coal, silica gel or alumina, preferably palladium on activated carbon, at normal or elevated pressure, preferably at normal pressure, in a polar solvent such as an alcohol such as methanol or ethanol at a temperature of 0 to 50 ° C, preferably at near ambient temperature, which is then amidated by reaction with quinoline-2-carboxylic acid under reaction conditions analogous to those described in the process b), to form a compound of formula II.

Alternatively, a compound of the formula I may be used

II can also be obtained by the process disclosed in EP 0 432

695 (published on 19.06.1991).

Starting compounds of formula

III are commercially available or known, or can be prepared by known methods

By way of example, the preparation of aryl 1 (lower and 1 channel) substituted with a heterocyclylmethyl radical in which the heterocyclyl radical is bonded via a ring nitrogen atom, which is preferably carried out by reaction of an aryl (lower alkanjoyl radical substituted with a halomethyl group), such as chloromethyl or bromomethyl, such as chloromethylbenzoyl or bromomethylbenzoyl with the corresponding heterocyclic nitrogen base such as peridine, piperazine, 1- (lower and 1-yl) piperazine, 1- (lower oylpiperazine) or in particular morpholine or leophilic substitution of a halogen atom.

The preparation of the amino acid derivatives of formula III in which the alpha-amino group is alkylated with a radical of phenyl (lower alkyl) and heterocyclyl (lower alkyl) can be carried out, for example, by reductive amination an amino acid (of which other groups that should not be involved may be protected if desired) having a primary or secondary alpha-amino group, phenyl (lower and 1 kyljketone or -aldehyde such as benzaldehyde, or heterocyclyl (lower alkyljketone) or an aldehyde, such as a heterocyclylaldehyde, for example a furanaldehyde, such as furan-2-aldehyde, or a piridine aldehyde, such as pyridin-3-aldehyde, or an imidazolylaldehyde, such as imidazol-4-ylaldehyde (optionally N-protected for example with trityl) cleavage as described above for the compound of formula III or the protected final product in general I), for example under catalytic hydrogenation conditions, for example in the presence of a heavy metal catalyst such as Raney nickel, at normal pressure or at a pressure of about 10 to 10 MPa, preferably at about 10 MPa, or under reducing conditions. a complex borohydride such as sodium borohydride d.

For example, isocyanates of formula (111b) can be prepared from the corresponding amine precursors by converting the amino group to an isocyanate group, for example by reaction with heat phosgene, for example under reflux conditions, or dropwise addition of liquid or solvent dissolved primary, secondary or tertiary amine excess of phosgene in a suitable solvent (toluene, xylene, igroin, chlorobenzene, and 1-chloronaphthalene, etc.) while cooling (e.g. to -50 to 0 ° C) to form a carbamoyl chlorine intermediate. The mixture is then phosgenated (for example at 50 ° C to reflux) until all solids dissolve, while eliminating the resulting hydrochloric acid.

Method b) Amidation (condensation to form an amide bond).

In the starting compounds of the formulas IV and / or V, the functional groups which are not to be involved in the reaction are protected, if necessary. The protective groups and their deployment are described above in relation to method a).

The carboxylic acid of formula V occurs either with a free carboxy group or as a reactive derivative thereof, for example, as an activated ester derived from a free carboxy compound, as a reactive anhydride or further as a reactive cyclic amide. Said reactive derivatives may also be formed in situ.

In particular, the active esters of the compound of formula V are esters unsaturated on a carbon atom, for example a vinyl ester (which may be prepared, for example, by esterification of the ester ester-reacting vinyl ester such as the corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl ester ( which may be prepared, for example, by reacting the corresponding acid with an isoxazolium reagent; 1,2 oxazolium or Woodward method), or 1- (lower alkoxyvinyl ester) (which may be prepared, for example, by reacting the corresponding acid with (lower alkoxyjacetylene; ethoxyacetylene method) or amidine type esters N, N'-disubstituted amidino esters (which may be prepared, for example, by reaction of the corresponding acid with a suitable Ν, Ν'-disubstituted carbo diimide, for example N, N'-dicyclohexylcarbonyl; carbodiimide method) or Ν, Ν -disubstituted amidino esters (which may be prepared, for example, by reaction of the corresponding acid with Ν, Ν-disubstituted k y and n and m i d o m; cyanamide. method), suitable aryl esters, especially phenyl esters substituted with electron affinity substituents (which can be prepared, for example, by reacting the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol,

4-methylsulfonylphenol, 2,4,5-trifluorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide; activated aryl ester method), cyanomethyl ester (which may be prepared, for example, by reacting the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioesters, especially the phenyl 11 esters optionally substituted by e.g. nitro group other methods, for example substituted nitro groups, among methods; meamino- or amidopromide with anhydride or carboxylic acid thiol ester) or esters (which are chenic acid such as peridine, non-2,3-dicarboxylic acid,

3,4-dihydro-1,2,3-benztriazin-4-one, can be prepared with N-hydroxyam such as

N-hydroxyphthalic acid,

1-hydroxybenzotriazole by reaction of N-hydroxyamidine-N-hydroxypine, in particular no-

N-hydroxysuccinimide, N-hydroxy-5-norboric acid, or 3-hydroxyn acid, for example, the anhydride or carbide method;

The active N-hydroxy method as well as internal esters, for example gamma-lactone, can be used.

be symmetric acids, for example acid halides by reaction or preferably anhydrides with a particularly corresponding or oxa acid anhydrides can be mixed anhydrides of such inorganic acids such as acid rides (which can be prepared with thionyl chloride, phosphorus pentachloride; acid chloride method) e.g. and treating it with a half acidic acid, for example by reacting with chloroformic acid or a 1-alkoxy acid, in particular to prepare the acidic acid to prepare the hydrazoic anhydride with (lower of the corresponding, as well as dy esterudusi to u;

of the corresponding phosphoric anhydride containing o / X i d f o s (which can be via the corresponding azide method)

1 d

2-dihydroch

O-alkyl alcohol and dichloromethane with e. chlorides by other methods to prepare alkyl) esters (higher alkoxy) carbonyl-2- (ntoda mixed anhydride with dihalogenated (which can be acid-chloride-acid method), phosphoric anhydrides (for example, derivatives of phenyl-N-phenylphosphoramidochloridates acid and phosphoric acid in the presence of acids and / or racemization of the lower hydroxybenzotriazole, cyantostonic acid) or with anhydrides with an organic silane such as titanium (lower and 1-channel) carboxylic acid such as phenylacetic acid, the pivaloyl acid method of mixed anhydrides which may be, for example, an alkali salt with a suitable organic halogen, for example a lower alkane chloride or derivatives which may be reacted with or in the presence of a derivative of an acid, a sulfonic anhydride additive, for example a phosphoric acid diethyl ester or as mixed anhydrides (which can be prepared with organic carboxylic acids) other reaction of the corresponding acids with an optional acid sub-halide in j;

with an organic sulfonic acid, for example by reacting salts, such as the acid, with sulfonic acids such as (lower and 1 kan) - or phenyl is an acid chloride or trifluoroacetocarboxylic acid) or to prepare a metal with an aryl acid such as methane or p-t. uenesulfonic acid; the mixed anhydride method with 1 tonic acid) as well as symmetrical anhydrides (which can be prepared, for example, by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylaminopropion; symmetric anhydride method).

Suitable cyclic amides are, in particular, amides with five-membered aromatic diazacyclides, such as amides with imidazoles such as imidazole (which may be prepared, for example, by reaction of the corresponding acid with N, N'-carbonyldiimidazole; imidazole method) or pyrazole such as 3,5-dimethylpyrazole. which can be prepared, for example, via an acid hydrazide by reaction with acetylacetone; the pyrazolide method).

As mentioned above, the carboxylic acid derivatives used as acylating agents can also be prepared in situ. Thus, for example, N, N'-di substituted amidinoester can be prepared in situ by reacting a mixture of the starting material of formula V and the acid of formula V used as acylating agent in the presence of a suitable N, N'-di substituted carbodiimide, e.g. in the presence of a suitable base such as triethylamine.

Further, it is possible to form the amino or amido ester of the acid used as acylating agent in the presence of the starting material of formula IV to be acyclated by reacting a mixture corresponding to the starting acid and the amino compound in the presence of Ν, Ν'-disubstituted carbodiimide, Ν'-dicyclohexylcarbodiimide, and N-hydroxyamine or Nhydroxyamide, for example N-hydroxysuccinimide, optionally in the presence of a suitable base such as 4-dimethylaminopyridine.

Further, in situ activation can be achieved by reaction with N, N, N ', N' - 1-ethylcarbonyl compounds such as O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate.

Finally, the phosphoric and carboxylic acid anhydrides of formula V can be prepared in situ by reacting a phosphoric acid amide such as hexamethylphosphoric amide in the presence of a sulfonic anhydride such as 4- with a salt such as tetrafluoroborate, for example sodium tetrafluoroborate, or with another hexamethylphosphoric amide derivative, such as benzotriazol-1-yl-oxytris (dimethyl amino) phosphonium hexafluoride, preferably in the presence of a racemizing agent, preferably in the presence of a racemic agent, preferably in the presence of is N-hydroxybenztriazole.

The amino group of the compounds of formula IV involved in the reaction preferably carries at least one reactive hydrogen atom, especially when the carboxy group reacting therewith is in reactive form. However, the compound of formula IV may also be in the form of a reactive derivative, i. with an amino group in reactive form, for example by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene-fluorophosphite or tetraethyl pyrophosphite. For example, a derivative of such an amino group compound is also a carbamic acid halide, wherein the amine group involved in the reaction is substituted with a halocarbonyl group, such as a chlorocarbonyl group.

The condensation to prepare the amide compound can be carried out in a manner known per se, for example as described in standard publications, including Houben-Weyl, Methoden der organischen Chemie, 4th Ed., Vol. 15/11 (1974), vol.IX (1955), vol.

E 11 (1985), Georg Thieme Ver e a g, Stuttgart,

The Peptides (E. Gross and J. Meienhofer, H. g.), Vol. 1 and 2, A c a demic Press, London and New York, 1979/1980 or M. Bodansky,

Principles of Peptide Synthesis, Springer-Verlag, Berlin 1,984.

The condensation of the free carboxylic acid with the corresponding amine can advantageously be carried out in the presence of one of the usual condensing agents. Conventional condensing agents are, for example, carbodiimides, for example diethyl-, dipropyl-, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or, in particular, dicyclohexylcarbodiimide, further suitable carbonyl compounds,

100, for example, carbonyl imidazole, 1,2-oxazole compounds, for example 2-ethyl-1-5-phenylene-1,2,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazole iumperchorate, or a suitable acylamino compound, for example, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N, N, N'-N'-tetraalkyluronium compounds such as O-benzotriazole-1. -ylΝ, Ν, Ν ', N'-tetramethyluronium hexafluorophosphate, other activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis- (2-oxo-3-oxazolio) triazolinylbenzenesulphinylbenzoylidyl chloride - (dimethylamino) phosphonium hexafluorophosphate.

If desired, an organic base, for example tri (lower alkyl) amine with free-radical residues, for example ethyldiisopropylamine, and / or a heterocyclic base, for example pyridine, 4-dimethylaminopyridine or preferably N, is added. -methy 1 morpholine.

The condensation of the activated ester, reactive anhydride or reactive amide with the corresponding amine is usually carried out in the presence of an organic base, for example a simple tri (lower alkyl) amine, for example triethylamine or tri-butylamine, or one of the abovementioned bases. If desired, a condensing agent as described for free carboxylic acids is also used.

The condensation of the acid anhydride with the amines can be carried out, for example, in the presence of inorganic carbonates, for example in the presence of ammonium carbonate or alkali metal carbonates, or ammonium hydrogen carbonate or alkali metal hydrogen carbonates, for example hydrogen carbonate or sodium carbonate. or potassium (usually together with sulfate), while the reaction of sulfonic acid halides such as chlorides with 1 tonic acids is carried out in the presence of hydroxides such as alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.

The carboxylic acid halides, for example the chloroic acid derivative derived from the acid of formula V, are condensed with the corresponding amines preferably in the presence of an organic amine, for example the above three (lower alkyl) amines or heterocyclic bases, optionally in the presence of hydrogen sulphate.

The condensation is preferably carried out in an inert, preferably anhydrous solvent or in a mixture of such solvents, for example carboxylic acid such as formamide or dimethylformamide, and a halogenated hydrocarbon such as methyl chloride, carbon tetrachloride or chlorobenzene a ketone such as acetone, a cyclic ether such as tetrahydrofuran, an ester such as ethyl acetate, or a nitrile such as acetonitrile, or mixtures of these solvents, optionally at a reduced or elevated temperature, for example at a temperature of about - 40 to about 100 ° C, preferably at a temperature of from about -10 ° C to about 50 ° C, and without an inert gas or an inert gas atmosphere, for example under nitrogen or argon.

Aqueous, for example alcoholic (for example ethanol) or aromatic solvents or solvent mixtures, for example benzene or toluene, may also be used. Acetone can also be added in the presence of alkali metal bases.

Said condensation may also proceed according to a method known as solid phase synthesis and is ascribed to R. Merifield, which is described, for example, in Angew. Chem. 97,801-81 2 (1985), Naturvissenschaftten 71, 252-258 (198 4) or in R.A. Houghten, Proc. Natl. Acad. Sci. USA 82: 5131-5135 (1985).

in the compounds of the formula obtained, the groups are optionally carried out after

a).

Release of functional groups that are protected by the protective use of one or more of the methods described in the method

The process starts with the preparation of the starting compound of the formula from the compound of the formula VI described in process c) and proceeds

Advantageously, the IV can be prepared by forming

102 this compound is amidated by either L-asparagine, which is protected on the nitrogen by an amine function P _; , for example alpha- (N-benzyloxycarbonyl) -L-asparagine, or a reactive acid derivative thereof, in particular a p-nitrophenyl ester, preferably in the presence of a tertiary nitrogen base, triethylamine or N-ethyldiisopropylamine, the amidation being carried out as described above, particularly in the amide an acid such as dimethylformamide at a temperature of 0 to 50 ° C, preferably at ambient temperature, to give a compound of formula IV which is protected on nitrogen by P; and which can be converted to a compound of formula

IV by cleavage of the protecting group of the conditions set forth for cleavage of the protecting group from the compound of formula IX.

Method c) Amidation (condensation for preparation and binding)

In the starting materials of formula (VI) and / or (VII), the functional groups which are not to be involved in the reaction are protected, if necessary, by protecting groups. Protective groups suitable for this purpose and their introduction are described above in connection with method a).

The free carboxylic acids and their reactive derivatives, as well as the methods used for the amidation (condensation), are quite analogous to the carboxylic acids, their derivatives and α and m a d i n i m e. according to method b), when the corresponding compounds of the formula VI are used instead of the amino compounds of the formula IV and the corresponding compounds of the formula VII are used instead of the carboxylic acids of the formula V.

Optionally, the release of the functional groups in the obtained protected compounds of formula I is carried out using one or more of the methods described in process a).

It should be taken into account that this reaction will possibly be inhibited by shifting the residue R 1 to the free amino group in the

103. The process variants are advantageously limited to those starting materials and reaction conditions which permit the reaction without disturbing the shift of the acyl residue.

The preparation of the starting compound of formula (VI) is preferably carried out by reacting the compound of formula (IX) above with a carboxylic acid also of formula (III) or a reactive derivative thereof under reaction conditions analogous to those described in process (a). protected with a protecting group Pi from which a protecting group such as a tert-butoxycarbonyl or benzyloxycarbonyl group is cleaved under conditions analogous to those described for the cleavage of a protecting group from a compound of formula IX to give a compound of formula VI.

for example, the starting compound of formula VII is obtained by amidating a carboxyl-protected L-asparagine derivative, for example protected by one of the carboxyl-protecting groups mentioned in method a), with quinoline-2-carboxylic acid under the above amidation conditions, preferably under conditions which have already been mentioned for the preparation of the compounds of the formula II from the compound of the formula X after cleavage of the protecting group P2, then the carboxyl-protecting group is cleaved to give the compound of the formula VII.

In order to obtain the compounds of the formula I, process variant c) is preferably not used, but one of processes a) or c) is used instead.

All other starting compounds mentioned for any of the above methods are either commercially available or known or can be prepared by a known method.

they may be converted under known conditions, in the presence or absence of diluents, for example in amides

All of the above reactions of the reaction conditions, preferably / at conventional temperatures, in inert solvents or

104 acids, for example in carboxylic acid amides, such as dimethylformamide, diethyl acetamide, or 1,3-dimethyl-3,4,5,6-tetrahydro- (2- (1H) -pyrimidine ( Or in amides of inorganic acids such as hexamethylphosphoric triamide, in ethers, for example in cyclic ethers such as tetrahydrofuran or dioxane, or in acyclic ethers such as diethyl ether or ethylene glycol dimethyl ether, in halogenated hydrocarbons such as halogenated hydrocarbons, such as 1 cans, for example methylene chloride or chloroform, in ketones such as acetone, in nitriles such as acetonitrile, in acid anhydrides such as acetic anhydride, esters such as ethyl acetate, in bisalkansulfinines such as dimethylsulfoxide, in nitrogen heterocycles, such as pyridine, or mixtures of these solvents, in particular anhydrous solvents or mixed solvents, each of which is If appropriate, a suitable solvent is used, using salts of the solvents used, in particular the metal salts of the used carboxylic acids, such as alkali metal and alkaline earth metal salts, for example sodium or potassium salts, in the absence or presence of catalysts, condensation agents or neutralizing agents, and depending on the type of reaction and / or reactants at atmospheric pressure or in a closed vessel, at normal pressure or further under elevated pressure, for example at a pressure which is formed in the reaction mixture in the closed vessel under reaction conditions; atmosphere, such as under argon or nitrogen. Preference is given to reaction conditions analogous to those set forth in the Examples. The acylating agent itself, for example a carboxylic acid halide or carboxylic acid anhydride, may also serve as the solvent. The reactions are suitably monitored by conventional analytical methods, in particular by thin-layer chromatography.

Additional modalities

In the additional process steps that are carried out, if desired, the functional groups of the starting compounds which are not to be involved in the reaction can be

105, if desired, in a protected form, for example protected by one or more of the protecting groups mentioned in process a). These protecting groups can be cleaved off by methods also described in process a).

Salts of the compounds of formula I can be prepared in a known manner. For example, salts of the compounds of formula I with acidic groups may be formed by reaction with metal compounds such as alkali metal salts of suitable organic acids, for example sodium 2-ethylhexanoic acid, organic alkali metal and alkaline earth metal compounds such as corresponding hydroxides, carbonates and bicarbonates, such as sodium or potassium hydroxide, carbonate or bicarbonate, with the corresponding calcium compounds or with ammonia or a suitable organic amine, preferably using a stoichiometric amount or a small excess of the salt-forming agent. Preferred acid addition salts of the compounds of formula (I) are obtained in a conventional manner, for example, with an organic acid or an inorganic acid or a suitable ion exchange salt. The inner salts of the compounds of formula I which contain acidic and basic salt-forming groups, for example free carboxy and free amino groups, can be formed, for example, by neutralizing salts such as acid addition salts to an isoelectric point, for example weak bases or contact with ion exchangers.

Salts can be converted to the free compounds in a conventional manner.

For example, metal salts and ammonium salts can be converted by treatment with acidic acid addition salts or acidic acid addition salts, for example, by treatment with suitable basic reagents or basic ion exchangers.

For example, converting one salt of a compound of formula I to another salt is accomplished by converting the salt to the free compound as described previously, followed by converting the free compound to another salt, as previously described, or directly converting one salt to another salt, e.g. conversion

106 by chromatography, for example by means of gel permeation chromatography, or from solutions with an excess of the counter ion necessary to form a new salt.

Stereoisomeric mixtures, as well as mixtures of diastereomers and / or enantiomers, such as racemic mixtures, can be separated into the corresponding isomers in a known manner by a suitable separation procedure. Thus, the diastereomeric mixtures can be separated into the individual diastereomers by crystallization, chromatography, solution resolution and the like. Racemates can be separated, for example, by reaction with optically active compounds, for example optically active acids or bases, by column chromatography of optically active compounds or by enzymatic methods, for example, one of the two enantiomers. This as at the level of the starting products, the compounds of formula I.

by the selective reaction only division can be carried out at the level itself

In a compound of formula I that can be prepared, an amino or carboxamide group can be substituted, esterified or amidated by a free carboxyl group or a carboxyl group present in reactive form, or optionally converted by an esterified or amidated carboxyl group to a free carboxyl group.

Substitution of a carboxamide group or a primary or secondary amino group, for example a di (lower alkyl) carbamoyl group or a mono- or dihydroxy (lower alkyl) carbamoyl group, in compounds of formula I in which the nitrogen atom is an amino group, to be reacted to the hydrogen atom is carried out, for example, by alkylation.

Suitable reagents for alkylating a carboxamide group in a compound of formula I are, for example, diazo compounds, for example diazomethane. The diazomethane may be decomposed in an inert solvent, the free methylene formed being reacted with the carboxamide group of the compound of formula I. The decomposition of the diazomethane is preferably carried out.

107 d z and catalytic, for example in the presence of a noble metal in finely divided form, for example copper, or a noble metal salt, for example copper (II) chloride or copper sulfate.

Alkylating agents are also disclosed in DOS 2,331,113. These are, for example, alkyl halides, sultonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, which can be reacted with the carboxyl group of a compound of formula I under the conditions set forth in said patent. file.

Other alkylating agents may be selected from the corresponding unsubstituted or substituted (lower alkyl) compounds which serve to introduce the substituted or unsubstituted lower alkyl radicals listed above for the R 1 radical of the N-substituted carbamic acid bearing an additional substituent X, where X is a leaving group The leaving group is in particular a leaving group selected from the group consisting of a hydroxy group esterified with a strong inorganic or organic acid, such as a hydroxy group esterified with a mineral acid such as hydrohalic acid such as hydrochloric, hydrobromic or hydroiodic acid, or a strong organic sultonic acid, in particular, for example, a halogen atom, such as a fluorine atom, substituted with (lower and 1 channel) sulfonic acid or an aromatic sulfonic acid, for example benzenesulfonic acid an optionally substituted lower alkyl group such as a methyl group, a halogen atom such as a bromine atom, and / or an anro group such as methanesulfonic acid, trimethanesulfonic acid or p-toluenesulfonic acid, and an acid-esterified hydroxy group hydrazoic.

Thus, for example, one of the compounds with the substituent X may be reacted, wherein X represents a leaving group having a high polarizability of the electron shell, for example bromine or iodine, in a polar aprotic solvent such as acetone, acetone, nitromethane,

108 children 1s 1 fοχ ide or children 1s 1 formam goes. These substitution reactions are optionally carried out at a reduced or elevated temperature, for example at a temperature of about -40 to about 100 ° C, preferably at a temperature of about -10 ° C to about 50 ° C, and optionally under an inert gas atmosphere, e.g. dusíkaaleboargónu.

In the esterification or amidation of a carboxy group in a compound of formula I, for example in the amidation of a free carboxy group of an amino acid, such as Glu or Asp, with ammonia, (lower alkyl amino or di (lower alkyl) amine), it is possible the desired free acid or the free acid can be converted into any of the above reactive derivatives and reacted with an alcohol, ammonia or a primary or secondary amine, or a free acid or reactive salt such as cesium salt can be reacted upon esterification Thus, for example, a carboxylic acid salt with a halide or sulfonic acid ester corresponding to the alcohol may be reacted, and the esterification of the carboxyl group may also be carried out using other conventional alkylating agents such as diazomethane, alkyl halides. , sulfonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, etc.

To convert an esterified or amidated carboxyl group to a free carboxyl group, one of the methods described above for cleavage of the carboxyl function may be used or, if desired, alkaline saponification under the usual reaction conditions set forth in Organikum, 17th ed., VEB Deutscher Verlag der Wissenschaften, Berlin 1988.

The free amino group present in the compound of formula (I) may be acylated, for example to introduce one of the radicals listed for R 1 in addition to a hydrogen atom. This acylation is carried out according to the methods already mentioned above in connection with method (a) or one of the methods mentioned above

109 for protecting groups or, for example, by one of the methods set forth in Organikum, 17th Ed., Deutscher Verl and g der Wissenschaften, Berlin (Ost) 1988.

In a compound of formula I wherein R 1 is an aminoacyl radical having a primary or secondary alpha amino group, the alpha amino group may be alkylated with a radical selected from the group consisting of lower alkyl, phenyl 1 (lower and 1 cy 1) o or a heterocyclyl (lower alkyl) group by reacting, for example, by an amine reduction reaction, an amino group on an amine acid or a new moiety (whose other groups not to be involved in the reaction are, if desired). (lower alkyl) aldehyde or ketone, phenyl (lower alkyl) and 1dehyde or ketone or heterocyclyl (lower alkyl) aldehyde or ketone, for example formaldehyde, heterocyclyl and Idehyd, for example furanaldehyde, such as turanate -2-aldehyde, pyridine aldehyde, such as pyridin-3-aldehyde, or imidazolylaldehyde, such as imidazol-4-ylaldehyde (optionally N-protected, for example trityl) by a cleavage which may be cleaved as described above for cleavage of this group from a compound of formula I, for example by catalytic hydrogenation, for example in the presence of a suitable heavy metal catalyst such as Raney nickel, at normal pressure or at pressures of 0.1 up to 10 MPa, preferably at a pressure of about 10 MPa, or by reduction with a complex borohydride, for example sodium cyanoborohydride.

In a compound of formula I in which R 1 is 2-halogen (lower alkanjoyl such as chloroacetyl), the halogen atom may be converted, if necessary, and in particular chlorine or bromine, by Finkelstein reaction in a polar aprotic solvent , in particular in a ketone such as acetone, by treating sodium iodide with the corresponding compound of formula I with 2-iodo (lower alkanjoyl, especially 2-iodoacetyl). 2-halogen (lower alkanjoyl, especially 2-iodoacetyl) can then be reacted with amino, (lower alkyl) amino or di (lower alkyl) amino (lower alkananol or with amino, (lower alkyl) or di (lower alkyl) amino (lower and lower alkyl) 1 alkoxy) (lower alkane) ol, preferably in the presence of bases such as carbonates or hydrogen carbonates, for example alkali metal carbonates or bicarbonates such as sodium or potassium carbonate, in the latter solvents or further (especially in the case of a 2-chloro- or 2-bromo (lower alkane) alkyl group) in the presence of the corresponding (optionally N-protected) alkali metal alkoxides amino- (lower alkylamino or di) (lower alkyl) amino (lower alkanol) or amino-, (lower alkyl) amino- or di (lower alkyl) amino (lower and 1-alkoxy) (lower alkanol), which can be prepared from the corresponding an alcohol, such as sodium or potassium, in a suitable halogen-free valine of the formula amino- or

I, d i (n is alkyl or alkyl) and amine - (n alkanjoy)

1 (lower alkanjoyl group xy / acetyl group in an aprotic solvent, converted to 1 by R 1 means amino-, (lower alkyl) lower alkyl) amino (lower alkoxy) -2- (lower than dimethylamino (lower alkoxyjacetyalkyl) amine lower alkoxy) no- / 2- (lower amino-, (lower or greater than)

- (lower and 1-alkoxy) ethoxy compounds whose substituents possess at least one residual hydroxy group which are free, the acylated functional groups can be prepared from the aforementioned meanings of the hydroxyl group and, in protected form, can or be purified.

of formula I, in which the contents are to be free

Said acylation may be carried out using acylating agents and any of the methods mentioned in methods a) to e) or the methods indicated for protecting groups or any of the methods disclosed in Organikum, 17th ed., VEB Deutscher Verlag der Wissenschaften, Berlin (Ost). ) 1,988.

Said esters can be converted using the aforementioned alkylating agents and under the same reaction conditions, for example, using diazomethane, and alkyl halides, sulfonic acid esters, Meerwe salts, 1-substituted 3-aryltriazenes, etc. .

1 1

The above reactions may be carried out under known reaction conditions, in the absence or usually in the presence of solvents or diluents, preferably solvents and diluents which are inert to the reagents used and which dissolve them, in the absence or presence of catalysts, condensation agents or neutralizing agents, depending on the nature of the reaction and / or the reactants at a reduced, normal or elevated temperature, for example at a temperature of about -80 ° C to about 200 ° C, preferably at a temperature of about -20 to about 150 ° C, for example at a temperature from ambient temperature to the reflux temperature, in the melt up to 220 ° C, at atmospheric pressure or in a sealed vessel, optionally under a pressure, for example at a pressure which is formed in the reaction mixture in a sealed tube under reaction conditions and / or under inert atmosphere, for example under argon or nitrogen. The reaction conditions specifically mentioned are always preferred.

Solvents and diluents are, for example, water, alcohols, for example lower alkanols, such as methanol, ethanol or propanol, diyls such as ethylene glycol, triols, such as glycerin, or aryl and alkali, such as phenol, acid amides, such as carboxylic amides acids such as dimethylformamide, diethyl acetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), or inorganic acid amides such as hexamethylphosphoric triamide , ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons such as halogenated alkanes, for example methylene chloride or chloroform, ketones such as acetone, nitriles such as acetonitrile, acid anhydrides such as acetic anhydride, esters such as ethyl acetate, biosulphides such as dimethylsulfoxides, nitrogen heterocycles such as paradine, hydrocarbons, e.g. lower alkanes, such as heptane or aro mint, such as benzene or toluene, or mixtures of these solvents, a suitable optimum solvent being selected for each of the above reactions.

Due to the close relationship between the compounds of formula I and their precursors in free form and in salt form,

The following compounds and intermediates are to be understood as meaning also the corresponding compounds The starting salts or the free compound contain one or more substances and among the products may be desirable, in protected form, the groups may be in a suitable protecting group if these are salt-forming groups, also occur when it is taking the corresponding protective moment to cleave. Protecting groups are mainly formed by protecting groups as defined above, and the cleavage of these protecting groups is carried out in particular in the manner described above.

These compounds, including their hydrate form or their crystals of Example 1 used for the crystallization of salts, may also be obtained in, for example, the invention. The invention relates to those processes which proceed at some stage as the remaining steps or are formed. starting from and in the form of the reactive intermediate of the process to substance according to the process according to the invention and used in a manner advantageously starting from those valued above

Pharmaceutical formulations of an embodiment of the compound obtained and for which a step of interrupting or the reaction conditions of the derivative or salt is carried out or the compound which is treated as described above is obtained as described below. In this case, the substances which lead to the poor are advantageous.

The invention is also to be referred to as active compounds).

relates to pharmaceutical compositions of formula I (these compounds will be

The compounds which can be used in pharmacology can, for example, be used for the manufacture of pharmaceutical preparations which contain an effective amount of the active compound together or in admixture with a significant amount of an inorganic or organic, solid or liquid pharmaceutically usable carrier.

1 3

The pharmaceutical compositions of the invention are those for enteral, such as nasal, beech, rectal or oral, or parenteral, intramuscular or intravenous administration to warm-blooded animals (humans and animals), which contain an effective dose of the pharmacologically active substance alone or together with a significant amount of a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, its body weight, age and individual condition, the individual pharmacokinetic properties, the disease to be treated and the route of administration.

The invention also relates to pharmaceutical compositions and methods for the treatment of diseases caused by retroviruses, for example AIDS, in particular when the disease is caused by HIV-1 or HIV-2, characterized in that it is a warm-blooded animal, e.g. for diseases, particularly AIDS, such treatment requires an antiretroviral effective amount of a compound of the invention of formula I. Dosages for administration to a warm-blooded animal, for example a human, having a body weight of about 70 kg range from about 3 mg to about 10 g, preferably from about 10 mg to about 4 g, for example about 25 mg to 20 g per person per day, the dose being divided into 1 to 5, in particular 1 to sub-doses, which may, for example, be of equal magnitude. A child usually receives half the adult dose.

Said pharmaceutical preparations contain about 1 to 95%, preferably about 20 to 90% of the active ingredient. The pharmaceutical compositions of the invention may be presented, for example, in unit dosage form, such as ampoules, vials, lace, dragees, tablets, or capsules.

The pharmaceutical preparations according to the invention are prepared in a known manner, for example by means of conventional solution, lyophilization, mixing, granulating or coating processes.

Preferably, solutions of the active ingredient are used and in addition

Also, suspensions or dispersions, and solutions, dispersions of worms may contain a substance, such as by use. These pharmaceuticals and / or can be stabilized, solubilizing or suspending, for example, in the case of itself effective, for example, man and / or buffers in conventional formulations, with carriers containing adjuvants, crosslinking and / or salts for the preparation or agents, and can be dissolved, a solution, a dispersion of a viscosity enhancer, cellulose, or gelatin immediately prior to sterilization of preservatives, or, in particular, isotonic aqueous, the lyophilized or together, it is possible to prepare the preparations with, for example, emulsifying regulation of the osmosis pressure in a known manner, lyophilizing suspensions may be coated with carboxymethyl polyvinylpyrrolidone such as carboxymethylcellulose, dextran, in oil containing as

Suspensions for injection purposes, semisynthetic, in particular, include liquid esters with a novel process, e.g. contain a component for synthetic or oils which contain a component to auric

2, in particular pentadecylic acid, other stearic acid, acidic acid, acidic acid or the corresponding unsaturated oleic acid is converted into acid. or dantic acids such as di-tert-butyl-4-hydroxytol / ene. The fatty acid alcohol has at most 6 monovalent b atoms but the glycol and the acids can be melted, cerintrioleate nu palatic, nu arachidic acid, such as elaidic, erucic acid, inulinitic acid, possibly vitamin E, for example. such as long chain chains such as myristic, margarobehenoic acid, or brasanedioxy acids, or polyvalent, such as monomethanol, ethanol, or alcohol, or

Such as pentanole glycerin.

for example, isopropyl palmitate, L and Br (Gattefossé, Paris), oils commonly used in vegetable oils. Examples of such fatty acids are C12-C22 fatty acids, tridecylic acids, acid acids, for example with the addition of beta-carotine or 3.5-beds of these carbon esters, and are composed of two or three propanol, their isomers, in particular said Ethyl oleate esters, isopropylmyrisM 2375 (polyoxyethylene glycol glyceride 812 (tri-1, 5-chain saturated fatty acids glyceride of 8 to 12 carbon atoms, company H u 1 s AG, Federal Republic of Germany), in particular vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and in particular peanut oil.

The preparation of injectables is carried out in a conventional manner under sterile conditions, as well as filling ampoules or medicaments and sealing them.

Pharmaceutical preparations for oral administration may be obtained by mixing the active ingredient with solid carriers, the resulting mixture optionally being granules, and, if desired or necessary, if desired or necessary, into tablets, dragees or capsule, or dispersion is prepared, preferably with phospholipids, which are then filled into a bottle and a bottle. In this context, it is also possible to incorporate the active substances in plastic carriers, which then release the active substance in a controlled manner or leave it in a controlled manner into the physiological environment.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or dibasic calcium phosphate, binders such as starch oils based on, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and / or, if desired, also disintegrating agents such as are the aforementioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, for example sodium alginate. The auxiliaries are, in particular, lubricants and glidants, for example silicic acid, talc, stearic acid or a salt thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable gastric-resistant coatings

116 juices, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or, in the preparation of gastric juice-resistant coatings, solutions of suitable cellulosic preparations, such as ethylcellulose phthalate or hydroxypropyl methyl phthalate phthalate. The capsules are gelatin retractable capsules as well as soft sealed gelatin capsules and a plasticizer such as glycerin or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally with stabilizers. suspended in suitable oily excipients such as fatty oils; paraffin oil or liquid polyethylene glycols, in which case stabilizers and / or anti-bacterial agents may also be added. Dyes or pigments may be added to the tablets, dragee coatings and capsule shells, for example to identify and distinguish different doses of the active ingredient.

Particularly preferred as pharmaceutical preparations are dispersed active agents stabilized by phosphoimide, suitable for oral administration and containing

a) f o s f o i d i d or several phospholipids of the general formula (A)

R - ^{2 - 2} rm

(A)

1 7 in which

Ra represents an acyl group having 10 to 20 carbon atoms and,

R b represents a hydrogen atom or an acyl group containing 10 to 20 carbon atoms,

R _a , R t 'and R' = hydrogen or C 1 -C 4 alkyl and n is an integer from 2 to 4

4.

(b) where appropriate. another phospholipid or several other phospholipids,

(c) the active substance; and

d) a pharmaceutically acceptable carrier liquid and optionally other excipients and / or preservatives.

The method for preparing this dispersion consists in the solution or suspension of components a) and c) or a), b) and c), preferably a) and b) in a weight ratio of 20: 1 to 1: 5, in particular in a weight ratio of 5: 1 up to 1: 1, converted to a dispersion by dilution with water, then the organic solvent is removed, for example by centrifugation, gel filtration, ultrafiltration or in particular dialysis, for example tangential dialysis, preferably against water, and the obtained dispersion is preferably after addition of excipients or preservatives. agents, optionally after adjusting the acceptable pH by the addition of pharmaceutically acceptable buffers such as phosphates or organic acids (alone or dissolved in water), e.g. acetic acid or citric acid, preferably after adjusting the pH between 3 and 6, e.g. pH 4-5; and if it does not yet contain the correct concentration of active substance, thicken, preferably to an active substance concentration of 2 to 30 mg / ml, in particular 10 to 20 mg / ml, the concentration being carried out by the methods mentioned above for the removal of the organic solvent, in particular by ultrafiltration, for example using a tangential dialysis apparatus and a filtration.

The dispersible and phospholipid-stabilized dispersion thus prepared is stable at ambient temperature for at least several hours, reproducible with respect to the mass fractions

Ingredients and toxicologically harmless and thus particularly suitable for oral administration to humans.

The order of magnitude of the obtained portions c in the dispersion is variable and ranges from about 1.0 x 10 ^with 1 x 10 ^-7 to about 2 x 10 ^?

The nomenclature of phospholipids follows the recommendations of (1977) Nomenclature of Lipids, chemical nomenclature (CBN).

up to about 1.0 x 10 ^-5 , especially from about and the numbering of carbon atoms in Eur. J. Biochem.79, 11-21

IUPAC-IUB Cornmission on Bio-nomenclature, stereospeci f i c,

In the phospholipid of formula (A), R a R b can be an acyl group having 10 to 20 carbon atoms, preferably a straight alkanoyl group having 10 to 20 carbon atoms with an even number of carbon atoms and a straight alkenoyl group having 10 to 20 carbon atoms. the number of carbon atoms.

A straight-chain alkanoyl group having 10 to 20 carbon atoms with an even number of carbon atoms in the meaning of the general substituents R a and R e is, for example, n-dodecanoyl, ntetradecanoyl, n-hexadecanoyl or n-ok tadecanoyl.

A straight-chain alkenoyl group containing from 10 to 20 carbon atoms with a double bond with an even number of carbon atoms in the meaning of the general substituents R a and R _e is, for example, 6-cis -, 6-trans-, 9- or 9-transdodecenoyl, -tetradecenoyl - a hexadecenoyl, -octadecenoyl or -icosoyl group, in particular a 9-cis-octadecenoyl (1-oloyl) group.

In the phospholipid of the general formula A n represents an integer from 2 to 4, preferably 2. The group of the formula - (C _n H 2 _n - represents a nero-branched or branched alkylene group, for example 1,1-ethylene, 1,1-, or 1 1,2-, 1,3- or 1,4-butylene, a 1,2-ethylene group, a 1,2-ethylene group or a 1,2-ethylene group, n = 2).

Phospholipids of formula (A) are, for example, naturally occurring hydrogen, R 1, R 2, R 3 or or and R c of the liver with acyl binders or brushes in which R _a , R b naturally occurring are methyl from soybeans, chicken eggs us R _f and R b, or _c and R d represent ECIT ny, in which the brush 1 for example, pyrimidin group, bovine brain, bovine same or different mixtures of phospholipids.

Synthetic, substantially pure phospholipids of the general formula A with different or identical acyl groups R a and R b are preferred.

The term synthetic phosphoipid (A) defines phospholipids, k. they have a uniform composition with respect to R a and R b. Such synthetic phospholipids are preferably the lecithins and cephalins defined below whose acyl groups R _A and R b have a defined structure and are derived from a defined fatty acid having a purity of greater than about 95%. R _A and R b can be the same or different and unsaturated or saturated. Preferably, Ra is a saturated group and is, for example, n-he, xadecanoyl, and Rb is an unsaturated group, and is, for example, a 9-cis-octadecenoyl group (= 1 eoyl).

The term naturally occurring phospholipids of formula (A) defines phospholipids which have no uniform composition with respect to Ra and Re. some natural phospholipids are also lecithins and cephalins whose acyl groups Ra and Rb are structurally undefined and are derived from naturally occurring fatty acid mixtures.

The term substantially pure phospholipid defines greater than 70% (w / w) purity of the phospholipid of formula A, which may be determined by a suitable method, for example, by paper chromatography.

120

Particularly preferred are synthetic, substantially pure phospholipids of formula A wherein Ra is a straight alkanoyl group having 10 to 20 carbon atoms with an even number of carbon atoms and Rb is a straight alkenoyl group having 10 to 20 carbon atoms with a double bond and an even number of atoms atoms. R ', R b and R _a are methyl, n is equal to the second

In a particularly preferred phospholipid of formula A, Ra is n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl, and R6 is 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis- hexadecenoyl, 9-cis-octadecenoyl or 9-cis-icosoyoyl. R _a , R b and R e = are methyl groups and n is 2.

A particularly preferred phospholipid of formula (A) is synthetically 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) 3-sn-phosphatidylcholine with a purity greater than 95%.

Particularly preferred naturally pure, substantially pure phospho [iota] i of formula (A) are lecithins (L-alpha-phosphatidyl choline) from soybeans or chicken eggs.

For the acyl radicals in both the phospholipids and the formulas of formula (A), the designations given below in respect of the corresponding acyl radicals in brackets are equally applicable:

9-cis-dodecenoyl (1 auroeoyl), 9-cis-tetradecenoyl (myristoeleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octydecenoyl (petroseolyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis -octadecenoyl (oleoyl), 9-trans-octadecenoyl (elaidoyl)

11-c is-octadecenoyl (vaccenoyl)

9-cis-icosoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl),

-12 1 n-hexadecanoyl (p and 1-methyl), n-octadecanoyl (s and t), n-ososanoyl (arachidoyl).

Other phospholipids are preferably phosphoric acid (3-sn-phosphatidic acid) with the aforementioned residues, such as phosphatides 1 serine and phosphatidyl ethanolamine.

The sparingly soluble active compounds can also be used in the form of the water-soluble, pharmaceutically acceptable salts as defined above.

In the carrier liquid (d), components (a), (b) and (ac) or (a) and (c) are contained as liposomes to such an extent that no solids or solid aggregates such as mice are recovered after several days to several weeks. with optional components, the pen 1 and 1 can be administered after optional filtration.

Pharmaceutically acceptable, non-toxic excipients, for example water-soluble excipients, which are suitable for providing isotonic conditions, for example ionic additives such as sodium chloride or non-ionic additives (structurants) such as rorbit, may be present in said carrier liquid d). mannitol or glucose, or water-soluble liposome dispersion stabilizers such as lactose, fructose or sucrose.

In addition to the water-soluble excipients, emulsifying agents, wetting agents or surfactants useful for liquid pharmaceutical formulations, in particular emulsifying agents such as oleic acid, non-ionic surfactants based on polyhydroxy fatty acids such as sorbitan monolaurate, sorbitan monooleate, sorbitan monooleate, sorbitan monooleate, sorbitan monooleate or sorbitan monopalmitate, sorbitan tristearate or sorbitan trioleate, polyoxyethylene adducts of polyhydroxy alcohol fatty acid esters, such as polyoxyethylene sorbitan monolaurate, -o a, -stearate, -pamitate, -tristearate, or -trio-1-stearate, polyethylene ether, polyethylene ester stearate, polyethylene glycol-200 stearate, especially ethylene oxide-propylene oxide block polymers of the Pluronic (Wyandotte Chem.Corp.) or Synperonic (ICI) type.

Preferred preservatives are, for example, antioxidants such as ascorbic acid or microbicides such as sorbic acid or benzoic acid.

In the following, the invention will be further elucidated by means of examples of specific embodiments thereof, which are illustrative only and are not intended to limit the scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Temperatures are given in degrees Celsius (° C). If no other temperature is indicated, the reaction is carried out at ambient temperature. The Rf values, which indicate the ratio of the starting material distance to the eluent face starting distance, are determined by thin layer chromatography using silica gel thin layer plates and the following eluent systems.

And ethyl acetate

B a 90: 10: 2 by volume mixture of methylene chloride, ethanol and triethylamine

C 1: 1 methylene chloride / tetrahydrofuran.

For example, the abbreviation R + - (A) means that the given value was determined in the elution system A.

All ratios of solvents and eluents to each other are by volume ratios.

123

Gradients used in high pressure liquid chromatography (H P L C):

I 20% and gradually az 100% a) v (b) during 35 minutes, II 20% and gradually up to 100% a) v (b) during 20 minutes. Eluent a): acetonitrile + 0.05 % THA. Eluent b): water + 0.05 about TFA. . Ko 1 she o size 250 x

4.6 mm is filled with reverse phase material consisting of C 18 Nucleosil (5 µm mean particle size, s c 1 and g c 1 covalently derivatized with octadecylsilanes, Macher u n N and g e 1, D ur e n, Federal Republic of Germany). Detection is performed by absorption in UV light at a wavelength of 215 nm. The retention time (t r e t) is given in minutes. The liquid flow rate is 1 ml / m in.

The following abbreviations have the following meanings:

Boe t-butoxycarbonyl

BOP benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate

DIPE diisopropyl ether

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

HOBt 1-hydroxybenzyl riazole

NMM N-methylmorpholine

TFA trifluoroacetic acid

THF tetrahydrofuran

Z - benzyloxycarbonyl.

Mass spectra values were determined either by conventional mass spectroscopy or by using fast atom ionization (Fast Atom Bombardment-FAB-MS). Mass data refers primarily to the unprotonated molecular ion (M) or to the protonated molecular ion (M + h) ⁺ .

The values of proton nuclear magnetic resonance spectroscopy are given in parts per million (ppm) which are. refer to tetramets 1 with i 1an as internal standard. In these spectra, the abbreviations have the following meanings:

24 s = s i ng 1 et, d - dub 1 et, t = tr i p 1 et, q = quartet, m = mu 11 i p 1et and dd - double doublet

Example 1

N-tert-Butyldecahydro-2- / 2 (R) -acetyloxy-4-phenyl-3 (S) - N - (2-quinolylcarbonyl) -L-asparaginyl (amino) butyl] - (4 and S, 8aS) isoquinolines n-3 (S) -carboxamide

Under a nitrogen atmosphere, to a solution of 81 mg (0.12 mmol) of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) - N - (2-quinolylcarbonyl) -L -asparaginyl (amino) butyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide in 2 ml of anhydrous THF and 50 µl _of 1 (0.36 mmol) triethylamine at ambient temperature add 2 DMAP crystals and 17 / U 1 (0.10 mmol) of acetic anhydride. After 18 hours, the reaction mixture is poured onto ice, then extracted with three portions of ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulphate and evaporated. Dissolution of the crude product in DIPE gives the desired compound.

Thin-layer chromatographs:

R p (A) = 0.44, t = tr _E 18.9 min.

FAB-MS: (M + H) @ + = 713

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CDsOD) delta 1.34 (s, (H ₃ C) ₃ C),

1.2-2.0 (m, ca. 13H),

2.08 (s, HACC).

2.2-2.44 (m, 2H),

2.6-2.8 (m, 5H);

2.95-3.13 (m, 2H),

4.4 3 (m, 1H), 3.0 (m, 1H), .89 (m, 1H),

125

7 .04 (t, J-7 H z, 2 H) 7. .24 (d, J = 7 H Z, 2 H) 7. 0.70 (m, 1H) _: 1 7 _: .85 (m, 1H) _: 1 8 _: 0.02 (d, J = 7 HZ, 1H) 8: 1.7 (m, 2H). 1 8. .47 (d, J = 7 H z, 1 H)

The starting materials were prepared as follows.

1a) N-tert-Butyl-decahydro-2- (2) (R) -hydroxy-4-phenyl-3 (S) - tert-butoxycarbonylamino / butyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide

1.105 g (4.195 mmol) of 2 (S) - / 1 (S) - (Boc-amino) -2-phenylethyl / oxirane (prepared by a procedure analogous to that described by BKHand, PJ Machin- Om, S.Redshaw, GJ Thomas in European Patent Application 0346847 (1989), using a tert-butoxycarbonyl group instead of a benzyloxycarbonyl protecting group, or Evans et al., J. Org. 46 1 5-4625 (1 985) and 1.18 g (4.95 mmol) of N-tert-butyldecahydro- (4aS, 8aS) -isoquinoline-3 (S) -carboxamide (prepared according to KEB Parkes, S.Redshaw, GJ Thomas, European Patent Application 0432694A2 (1990)) in 21 ml of ethanol is heated in a vial under nitrogen atmosphere at 90 ° C for 16 hours, chromatographed and flashed on a column using hexane / ethyl acetate in hexane. ratio of 5: 1 containing 2% triethylamine gave the title compound after evaporation for a third time - 18.1 min (FAB): (M + H) + = 502.

'H-nuclear magnetic resonance spectrum:

(200 MHz, CDsOD) delta values of 1, 1-2.23 (m, 14H),

1.26 and 1.33 (2s, 2 (H ₃ C) ₃ C),

2.57-2.70 (m, 2H), [delta] 3-2, 84 (rn, 1H), 93-3, 14 (rn, 2H),

3.73-3.90 (m, 2H).

126

7.1 7, 3 (ΓΠ, H C Ό r 'ο ι η).

1b) 1,1-tert-Butyldecahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) -aminobutyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide.HCl

0.6 g (1.2 mmol) of N-tert-butyldecahydro-2- [2 (R) -hydroxy-4-phenyl-3 (S) - (tert-butoxycarbonylamino) butyl] - (4aS, 8aS) -isoquinoline 11n -3- (S) -carboxamide is dissolved in 12 ml of dioxane under a nitrogen atmosphere, then 12 ml of 4N HCl in dioxane is added to this solution and the mixture is stirred for 2 hours at ambient temperature. Lyophilization gives the desired compound.

Ή-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CD100) delta values 1 3.7 (S, (H 3 C) 3 C) 1. , 2-1, 9 (m, 10H j, 1 _: 9-2.2 (m. 4H); 9 , 81 to 3.03 (m, 2HJ 3. , 14 to 3.27 (m, 2H) 3: 44 (m, 1 H),

4.0 7 (m, 1H),

4.5 3 (m, 1 H), 2 7 - 7, 4 3 (m, H C - ω m).

Alternative Synthesis Procedure: The title compound is obtained in free form (and not as the HCT salt) by dissolving 109 mg (0.217 mmol) of the compound of Example 1a) in 0.75 mL of concentrated formic acid, followed by stirring and After 16 hours at ambient temperature, formic acid was evaporated under high vacuum and the residue was partitioned between three portions of ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and brine, then dried over sodium sulphate and evaporated to give the title compound.

Ή-Nuclear Magnetic Resonance Spectrum:

(200 MHz, CD3OD) delta values among others

1.32 (s, 9H);

2.2 7 (d, 12H z, 1H),

2.37 (dd, l2Hz, 4 Hz, 1 H);

127.5? -2.7.8 (m, 3H), 2.99 (d, 12Hz, 1H), 3.1-3.4 (m, 2H), 6.88 (m, 1H) .

1c) N-tert-Butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) - [N-benzyloxycarbonyl-L-aspartyl] amino / butyl] - (4aS, 8aS) žochnolín-3 (S) carboxamide

0.624 g (1.35 mmol) of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) -amino / butyl] - (4aS, 8aS) isoquinolin-3 (S) - karboxam idu. HCl as a solution in 13 ml of 0.3N NMM in DMF and 2.24 ml (13 mmol) of N-ethyldiisopropylamine are reacted with 0.762 g (1.97 mmol) of Z-asparagine-p-nitrophenyl ester (Bachem, Bubendorf) , Switzerland) for 4 hours at ambient temperature. The reaction mixture was concentrated under high vacuum and the residue was partitioned between three portions of methylene chloride. Dissolving several times in a small amount of DMF and precipitating with ice-cold DIPE yields the title compound.

_e t tr = 15.7 min.

Mass Spectrum (FAB): (M + H) - 650.

d) N-tert-Butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) - (L asparaginyl) amino / butyl] - (4aS, 8aS) isoquinoline-3 (S) -carboxamide

0.69 g (1.06 mmol) of N-tert-butyl-decahydro-2- (2) (R) -hydroxy-4-phenyl-3 (S) - N-benzyloxycarbonyl-L-asparaginyl / amino / butyl The (4aS, 8aS) -isoquinoline-3 (S) -carboxamide dissolved in 20 ml of methanol was hydrogenated in the presence of 140 mg of 10% palladium on carbon at a hydrogen pressure of 1 bar and ambient temperature for 5 hours. Filtration of the catalyst and evaporation gave the title compound.

Ή-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDsOD) delta values of 1.33 (s, (H ₃ C) ₃ C),

1.2-2.24 (m, 15H), 2.45 (dd, J 1 = 15HZ, J ₂ = 5HZ, 1H), 2.55-2.80 (m, 3H),

3.02-3.14 (m, 2H),

128.5 4 (dd, J> = 8H z, J.2 = 5H z, 1 Η), 8 7 (m, 1 Η), 2 2 - 4, 3 2 (ιτι, 1 Η) ,, 1 - 7.34 (ii), Η (.η).

e) N-tert-Butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3- (S) - [N (2-quinolylcarbonyl) -L-asparagines 1 (amine)] Butyl 1 - (4 aS, 8 and S) isoquinoline-3 (S) -carboxamide

A solution of 246 mg (1.42 mmol) of quinic acid, 487 mg (0.945 mmol) of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) - // L -asparaginyl / amino / butyl / - (4aS, 8aS) quinoline-3 (S) carboxamide, 627 mg (1.42 mmol) BOP and 192 mg (1.42 mmol) H 0 BT sa Dissolve at ambient temperature in 7.5 mL of 0.3 M NMM in DMF and stir the resulting solution for 18 hours. The reaction mixture was then concentrated under high vacuum, and the residue was partitioned between 3 portions of methylene chloride, 2 portions of saturated sodium bicarbonate solution and brine. After drying the combined organic fractions over sodium sulfate, evaporation and chromatography of the residue on silica gel using an elution system consisting of: methylene chloride (ethanol) / acetic acid 90: 10: 1 ----> methylene chloride / ethanol / NHsaq 90: 10: 1 gives the title compound.

Thin-layer chromatographs:

Rf (B) = 0.50, t Rc = 16.0 min.

Mass spectrum (F A B): (M + H) + = 671.

H-Nuclear Magnetic Resonance Spectrum:

(300 MHz, CDsOD) delta values of 1.31 (s (Hs.C) aC),

1.1-2.4 (m, 14H);

2.6-2.9 (m, 5H);

3.04 (m, 2H), 3.92 (m, 1H), 4.23 (m, 1H), 9.22 (t, J = 7H2, 1H), 6.74 (t, J) = 7Hz, 1H), 6.91 (t, J = 8Hz, 2H), 7.19 (d, J = 8Hz, 2H),

129

7.69 (m, 1Η),

7.99 (t, J = 8Hz-1H), 14 (d, J = 9Hz, 1 1), 17 (d, J = 9Ηζ, 1Ηζ),

8.48 (d, J = 9 Hz, 1H).

Alternatively, the desired compound can also be prepared by (analogously to EP 0 432 695, Example 3, published June 19, 1991) a solution of N- (2-quinolylcarbonyl-M8M-L-asparticin and N-tert-butyldecahydro-2-). 2 (R) -hydroxy-4-phenyl-3 (S) aminobutyl] - (4aS, 8aS) isoquinoline-3 (S) -carboxamide (obtained as described in alternative method 1b)) in tetrahydrofuran was cooled to -10 ° C. C, to the cooled solution was added 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one (Fluka, Switzerland) and dicyclohexylcarbodiimide, and the mixture was stirred at the same temperature for 2 hours and then at 0 ° C. another 16 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was then washed with saturated sodium bicarbonate solution and brine, then evaporated and the residue purified by silica gel column chromatography eluting with 4% methanol in dichloromethane. The desired compound is then obtained from the corresponding eluate fractions.

Example 2

N-tert.butyl-decahydro-2- / 2 (R) - (furan-2-carbonyloxy) -4-phenyl-3 (S) - // N- (2-quinolylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide

To 40 mg (0.06 mmol) of N-tert-butyl-decahydro-2- [2- (R) -hydroxy-4-phenyl-3 (S) - [N- (2-quinolylcarbonyl) -L-asparaginyl] amino / butyl / - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide (Example 1e) is added a solution of 8.8 µl (0.06 mmol) of furan-2-carboxylic acid chloride, 0.5 mg of DMAP, 34 µL (0.2 mmol) of N-ethyl diisopropylamine in 5 mL of dioxane. After 2 days at ambient temperature, the reaction mixture was partitioned between 3 portions of ethyl acetate, saturated sodium bicarbonate solution and brine. After drying

Evaporation and chromatography on a silica gel column using a 5: 1 mixture of methylene chloride and tetrahydrofuran gave the title compound.

IRe = 19.0 min.

FAB-MS: (M + H) &lt; ^{+ &gt}; = 765.

Example 3

The following acyl derivatives of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) can also be prepared in a manner analogous to one of the above or the above-mentioned processes. - N- (2-quinolylcarbonyl) -L-aspartyl (amino / butyl) - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide:

3a) N-tert-Butyldecahydro-2- / 2 (R) -pivaloyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide,

3b) N-tert-Butyldecahydro-2- / 2 (R) - (N-methylaminoacetyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide,

3c) N-tert-Butyldecahydro-2- / 2 (R) - (N-benzyloxycarbonyl-N-methylaminoacetyloxy) 4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

d) N-tert-Butyldecahydro-2- / 2 (R) - (N-dimethylaminoacetyloxy) -

4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-aspartyl (amino) butyl (4aS, 8aS) -isoquinolin-3 (S) amide,

3e) N-tert-Butyldecahydro-2- / 2 (R) - (N-butyl-N-methylaminoacetyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

3f) N-tert-Butyldecahydro-2- / 2 (R) - (N-methyl-N-benzylaminoacetyloxy) 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L -asparaginyl / amine / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

(g) N-tert-butyldecahydro-2- / 2 (R) - (N-methyl-N-3-pyridylmethylaminoacetyloxy) -

4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

h) N-tert-Butyldecahydro-2- / 2 (R) - (3-pyridylcarbonyloxy) -

- phenylen-3 (S) - // N - (2-chloro-1-carboxylic acid) - L - a-p-phenylamino / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide or / a

3i) N-tert-Butyldecahydro-2- / 2 (R) - (4- (N-morpholinylmethyl) benzoyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide.

Example 4

The following acyl derivatives of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) can also be prepared in a manner analogous to one of the above-mentioned examples or the above-mentioned methods. - [N- (2-quinolylcarbonyl) -L-aspartyl] amino / butyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide:

4a) N-tert-Butyldecahydro-2- / 2 (R) -propionyl-4-phenyl-3 (S) - N - (2-quinoyl-carbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4b) N-tert-Butyldecahydro-2- / 2 (R) -butyryloxy-4-phenyl-3- (S) - N - (2-quinoylcarbonyl) -L-asparagines (amino) butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

4c) N-tert-Butyldecahydro-2- [2 (R) -methylpropionyloxy-4-phenyl-3 (S) - [N- (2-quinolinecarbonyl) -L-aspartyl] amino] buty1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

132

d) N-tert-Butyldecahydro-2- (2) (R) -pentanoyloxy-

4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartyl (amino) butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide .

e) N-tert-Butyldecahydro-2- (2) (R) -octanoyloxy-

4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxainide,

f) N-tert-butyldecahydro-2- (2) (R) -decanoyloxy-

4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

g) N-tert-Butyldecahydro-2- / 2 (R) -dodecanoyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

h) N-tert-Butyl-decahydro-2- / 2 (R) -palmitoyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -La sparginyl / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

4i) N-tert-Butyldecahydro-2- / 2 (R) - (3-carboxypropionyloxy) -

4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-aspartyl (amino) butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4j) N-tert-Butyldecahydro-2- / 2 (R) - (3-methoxypropionyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide,

k) N-tert-Butyldecahydro-2- / 2 (R) -benzyloxyacetyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide, 11-N-tert-butyldecahydro-2- / 2 (R) - [(S) -alpha-methoxy-alpha-phenylacetyloxy] 4-phenyl-3 (S) - // N- (2- quinoylcarbonyl) -L-asparaginyl (amino) butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

133

4m) N-tert-Butyldecahydro-2- / 2 (R) - / (R) -alpha-methoxy-alpha-phenylacetyloxy / 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) - L - asparagines 1 / amino / butyl 1 (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

n) N-tert-Butyldecahydro-2- / 2 (R) - [2- (2-methoxyethoxy) acetyloxy] 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L -asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4o) N-tert-Butyldecahydro-2- / 2 (R) - (n-butyloxyacetyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide,

4p) N-tert-Butyldecahydro-2- / 2 (R) - [2- (2- (2-methoxyethoxy) ethoxy) acetyloxy] -4-phenyl-3 (S) - N - (2-ch) 1-L-aspartic acid (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4q) N-tert-Butyldecahydro-2- / 2 (R) - (2-pyridylacetyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide,

r) N-tert-Butyldecahydro-2- [2 (R) - [3- (2-pyridyl) propionyloxy] -4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-asparaginyl]] amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

s) N-tert-Butyldecahydro-2- [2 (R) - [4-imidazolylcarbonyloxy] 4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-aspartyl] amino / butyl] ( 4 and S, 8aS) -isoquinoline-3 (S) -carboxamide,

4t) N-tert-Butyldecahydro-2- [2 (R) - [4-imidazolylacetyloxy] 4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-asparaginyl] amino (butyl) ( 4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

u) N-tert-Butyldecahydro-2- [2 (R) - [3- (4-imidazolyl) propionyloxy] 4-phenyl-3 (S) - [N- (2-quinolinecarbonyl)] - L-aspartyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

134

4v) N-tert-butyldecahydro-2- / 2 (R) -quinolin-2-ylcarbonyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4w) N-tert-Butyldecahydro-2- / 2 (R) -phenoxyacetyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparagines / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

(x) N-tert-butyldecahydro-2- / 2 (R) -pyridine-4-carbonyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

4y) N-tert-butyldecahydro-2- / 2 (R) -pyridine-2-carbonyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl (amino) butyl] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide.

Example 5

The following acyl derivatives of N-tert-butyldecahydro-2- / 2 (R) -hydroxy-4-phenyl-3 (S) can also be prepared in a manner analogous to one of the above or the above-mentioned processes. - [N- (2-quinolylcarbonyl) -L-asparaginyl (amine) butyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide:

5a) N-tert-Butyldecahydro-2- (2 (R) - (1-pyrazolylacetyloxy) 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartyl) amino / butyl 1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

5b) N-tert-Butyldecahydro-2- / 2 (R) -pyrazin-2-ylcarbonyloxy-4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartin (amino) butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

5d) N-tert-Butyldecahydro-2- / 2 (R) -aminoacetyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

135

5e) N-tert-Butyldecahydro-2- / 2 (R) - [(L) -pyrrolidine-2-carbonyloxy] 4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-asparaginyl] amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

(g) N-tert-butyldecahydro-2- / 2 (R) - N - (pyridin-2-ylmethyl) -N-methylaminoacetyloxy-

4-phenyl-3 (S) ~ // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

h) N-tert-Butyldecahydro-2- (2) (R) - (N, N- (4-dimethylaminobutyryl) oxy) -

4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartyl (amino) butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide .

5i) N-tert-Butyldecahydro-2- / 2 (R) -benzoyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline -3 (S) -carboxamide,

j) N-tert-Butyldecahydro-2- [2 (R) - (4-chloromethylbenzoyloxy)] -

4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide,

k) N-tert-Butyldecahydro-2- [2 (R) - [3- (N, N-trimethylaminopropyl) oxyacetyloxy] -

4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / benzyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide or

51) N-tert-Butyldecahydro-2- / 2 (R) - / 2- / 3- (N, N-dimethylaminopropyloxy) ethoxy / acetyloxy / 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) 1-L-asparaginyl / amino / butyl (4aS, 8aS) -isoquinoline-3 (S) -carboxamide.

Example 6

N-tert.butyl-decahydro-2- / 2 (R) -metoxyacetyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide

To a solution of 10 mg (0.0015 mmol) of N-tert-butyl decahydro-2

136/2 (R) -hydroxy-4-phenyl-3 (S) - N - (2-quinolylcarbonyl) -L-asparaginyl / amino / butyl / - (4aS, 8aS) -isoquinoline- 3 (S) -carboxamide (Example 1 e) in 0.24 ml of 5: 1 dioxane / pyridine (v / v) were added at 0 ° C with 4 / µl (0.046 mmol) of methoxyacetic acid chloride and 0.2 µl. mg (0.002 mmol) of DMAP. Since the starting material was shown to be high in the reaction mixture after 18 hours at ambient temperature, 35 _of µl pyridine and 35 _of µl of methoxyacetic acid chloride were added to the reaction mixture in two portions. When all starting material had been reacted by HPLC, the reaction mixture was partitioned between 3 portions of ethyl acetate, saturated sodium bicarbonate solution, water and brine, then the organic fraction was dried over sodium sulfate and evaporated. Digestion from hexane / diisopropyl ether in an ultrasonic chamber and standing at 0 ° C affords the pure title compound.

t r p p = 13.1 min.

FAB-MS: (M + H) &lt; ^{+ &gt}; = 743.

Example 7

N-tert.butyl-decahydro-2- / 2 (R) - (pyridin-2-carbonyloxy) 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4a S , 8aS) -izochino1ín-3 (S) -carboxamide

To a solution of 30 mg (0.24 mmol) of 2-picolinic acid (pyridine-2-carboxylic acid) in 1.6 mL of methylene chloride was added 20 µL (0.144 mmol) of nitrogen at 0 ° C. 1-chloro-N, N, 2-trimethyl-1-propenamine (B.Haveaux, AADekoker, M.Rens, ARSidani, J.Toy, L.Ghosez, M.Murakami, M.Yoshioka and W.Nagata, Organic Syntheses 59, 26 (1980)], and conversion to acid chloride was carried out at ambient temperature over 45 minutes. Then, 0.4 ml of pyridine, a catalytic amount of 4-dimethylaminopyridine and 40 mg (0.06 mmol) of N-tert-butyl decahydro-2- (2) (R) -hydroxy-4-phenyl-3 (S) are added. 1 H - N- (2-quinolylcarbonyl) -L-aspartin-1-amino-butyl-1- (4aS, 8aS) -quinazoline-3 (S) of the carboxamide (Example 1 e) and the resulting mixture is stirred at temperature

137 ambient for 18 hours. Since the presence of the starting material is still detected by high pressure liquid chromatography, 0.12 mmol of 2-picolinic acid chloride in 0.8 ml of methylene chloride (prepared as described above) is added and the mixture is added with ml of pyridine. After an additional 18 hours at ambient temperature, the reaction mixture was partitioned between 3 portions of methylene chloride, 2 portions of saturated sodium bicarbonate solution, water and brine. The organic phase is dried over sodium sulphate and evaporated. Chromatography on a silica gel column using a 1: 1 mixture of methylene chloride and THF and digestion with diisopropyl ether gave the pure title compound.

Thin layer chromatography:

R t (C) = 0.28, t _R t (II) = 13.2 min.

Mass spectrum (F A B): (M + H) + = 776.

Example 8

Gelatin solution

Sterilized aqueous solution of one of the compounds generally

formula I prepared in the examples 1 to 7, which in addition contains 20 % cyclodextrin, and sterile phenol - preserved gelatinous the solution is with heating and aseptic conditions mixes to such an extent that This gives 1.0 ml solution of the following composition: active substance 3 mg gelatin 150.0 mg phenol 4,7 mg distilled water with 20 % cyclodectrin 1.0 ml

Example 9

Dissolve a sterile dry substance for the injection of mg of one of the compounds of formula I prepared in the examples in 1 ml of an aqueous solution containing

138 mg mannitol and 20% cyclodextrin as solubilizing agent. This solution is then sterilized and filled under septic conditions into 2 ml ampoules in which it is deeply cooled and lyophilized. Immediately before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of saline. This solution is administered intramuscularly or intravenously. The formulation may also be filled into a bicameral injection ampule.

Example 10

Nasal spray

500 mg of finely divided powder (particle size less than 5.0 µm) of one of the compounds of formula (I) prepared in Examples 1 to 7 are suspended in a mixture of 3.5 ml of yog 1 in 812 and 0.08 g of benzyl alcohol . The suspension is then filled into a metering valve reservoir. 5.0 g of Freon 12 are then introduced under pressure into the reservoir via said metering valve. Shaking results in the dissolution of the freon in a mixture of Myglyol and benzyl alcohol. The reservoir contains about 100 sub-doses which are to be administered individually.

Example 11

Lacquer pills

The following ingredients are used in the manufacture of 10,000 tablets containing 100 mg of a compound of formula I:

Active substance Corn starch Colloidal silicic acid Magnesium stearate Stearic acid Sodium carboxymethyl starch Water

000 g

680 9 200 9 20 9 50 g 250 g

enough a. turnover quantity.

A mixture of one of the compounds of formula (I) prepared in Examples 1 to 7, wherein silica is treated with 250 g of maize in a wet sieve having a size of g of corn starch and colloidal acid with starch oil prepared from starch and 2.2 kg of demineralized water. the wet mass is then forced through a mm, then dried at the dryer temperature. Dried meat.

The mesh of a whirling sieve with a mesh size of 30 ° C for 30 minutes of granulated 1t is passed through a pre-screened sieve (mesh sieve 1 of corn starch, magnesium stearate, stearic acid in mm and blended mm) with a mixture of sodium carboxymethyl starch. slightly domed tablets.

Example 12

Dispersion for oral administration

625 mg of one of the compounds of formula I prepared in Examples 1-7 and 625 mg of POPC (1-palmitoyl-2-oleoylphosphatidylcholine n = 1-hexadecanoyl-2- (9-cis-octadecenoyl) -3- with phosphatidylcholine) are dissolved in 25 ml ethanol. The resulting solution is then diluted with ten times the amount of water. This is accomplished by dropping said ethanolic solution at ambient temperature at a rate of 10 ml / min to the present amount of water. Ethanol was then removed from the mixture by tangential dialysis (Cross Flow Filtration) against 1750 mL of water (system: Minitan, 700 cm-polyether sulfone membrane with a 100 k D separation threshold from Millipore (USA)). The mixture is then concentrated to an active compound content of 15 mg by ultrafiltration using the same system. After addition of 1.24 mg / ml citric acid and 1.24 mg / ml sodium hydrogen phosphate dihydrate to adjust the pH to 4.2 and 1 mg / ml sorbic acid as an anti-microbial preservative, the dispersion is again thickened to an active compound concentration of 15 mg / ml and filled into bottles having, for example, 20 ml. The particles of the dispersion have a diameter _of 0.1 to 2 microns. At 2 to 8 ° C, the dispersion is stable and suitable for administration for at least six months.

139

Example 13

Dispersion for oral administration 2

The dispersion was prepared in a manner analogous to that described in Example 12 except that 50 mg of POPC and 25 mg of the compound of formula I were used in the preparation of the ethanol solution.

Example 14

Dispersion for oral administration 3

The dispersion was prepared in a manner analogous to that described in Example 12 except that 25 mg of the compound of formula I and 125 mg of POPC were used in the preparation of the ethanol solution.

Example 15

Dispersion for oral administration

The preparation of this dispersion is carried out in a manner analogous to that described in Example 12 except that 50 mg of the compound of formula I and 50 mg of POPC are used in the preparation of the ethanol solution.

Example 16

The dispersion is prepared by a process analogous to that of Examples 12 to 15 except that a compound of formula I and soybean foafatildycholine or egg yolk phosphatidylcholine (purity 70-100) are used in the preparation of the ethanol solution instead of POPC. %). If desired, an antioxidant such as ascorbic acid is added at a concentration of 5 mg / ml.

Claims (23)

PATENT CLAIMS 1 y zine new, beta-diaminopropionic asymmetric carbon) L-amino acid, monoamide glutamine, ornithine, g-utamic acid, delta-hydroxylylamine, and alpha, in the absence of amino acids may have a D-pin configuration if one or two amino acids ( lower alkyl), or (D, present, N-alkylated is or or amino acid alanine, acidic acid, acidic acid, noreucine, phenylalanine, 4- carboxyphenylalanine, cyclohexylalanine aspartic acid, asparaminoaminoididine, arginine, 3-aminopropacic acid alpha, gamma-diaminobutyric acid, wherein (except for each of the aforementioned L), wherein a 1 phenylamino is unsubstituted or lower alkyl, phenyl or naphthylamino (lower and alkyl), phenyl 1 (lower alkyl), diphenylmethyl, trityl, furan 1 (lower alkyl), thienyl (lower alkyl) and / or 2-, 3- or 4-pyridyl (lower alkyl); and / or N-acylated with an unsubstituted or substituted lower alkanoyl group as mentioned above for the definition of R1, (lower and 1 alkoxy) carbonyl or phenyl (lower alkoxy) carbonyl, and pharmaceutically acceptable salts thereof. 1-Cionine, methionine, 4-chlorophenylalanine serine, phenylglycine, and 1 phtha-naphthalene, cyclohexylglycine, tryptophanamine 1,2,3,4-tetrahydro-indicated heterocyclic groups substituted by lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl (lower alkoxy), hydroxy (lower and lower alkyl) a halogen atom, a cyano group and / or a test group selected from naphthyl group and a fluorenyl group or trifluoromethyl group including an indanyl group, a group substituted with a group, and a phenyl indenyl aryl group, a halogen group (lower roxy) -group, kanjoyloxy, oxycarbonyl, alkyl, lower alkoxy carboxyl, these are the most unsubstituted alkyl, halogen, hydroxy, (lower and 1, lower alkyl) phenyl (lower and 1-alkoxy) 1ovou XII, carbamoyl, mono- or di (lower and alkyl) carbamoyl, mono- or di-hydroxy (lower alkyl) carbamoyl, halogen (lower alkyl), piperidinyl, piperazin-1-ylmethyl 4- (lower and 1-alkyl) piperazin-1-ylmethyl, 4- (lower alkane) oylpiperazin-1-ylmethyl, morpholinomethyl, cyano and 1α-carbones A 1-moiety selected from the group consisting of glycylbutyric acid, a thiomorpholomethyloalkyl or a bonded with an amino group, or an amino acid radical, alanine, 2-3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or 5-aminohexanoic acid, valine, norvaline, leucine, isoleucine, noreucine, serine, homoserine, threonine, methionine, cysteine, f enylalanine, tyrosine, 4-aminophenylalanine, 4-chlorophenylalaine, 4-carboxyphenylalanine, beta-phenylaserine, phenylglycine, and 1-naphthyl-1 and 1-anine, monoamido-cyclohexylglycine acid, asparagine, acid amine ammoniumic acid, lysic acid, delta-hydroxylysine alpha, gamma-dicide (except for the above (D, L), is present, is The N-alkylated tryptophan nomalone gututan-5-olefin is cyclohexylalanine, aspartic acid, and rhinin, 1,2,3 or or a lower (lower alkoxy) -2- (lower alkane carboxyl group, ( -phenyl (lower alkoxycarbonyl group, (lower and 1 alkyl carbamoyl hydroxy) (lower alkyl) carbamoyl, di bis / hydroxy (lower alkyl group containing 3 to 8 carbon atoms containing 4 to 8 carbon atoms, 5-dihydropyrrolyl group, fluorophenyl) , tetrahydrofuranyl group, imidazolyl group, pyrazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl indolyl group, isochi, benzofuranylpiperimidinyl, piperidino, morpholino S, S-dioxothiomorpholine 4-tetrahydroquinolyl The 1,2-dihydro- or 1,2-dihydropropyl unsubstituted or the group, pyrazo, tetrasyl, n, isonoyl, nyl, quinolyl, are quinolyl, Or a free di (lower alkane) oylamino group, such as an aryl (lower group or as alkane) oylamino group, the aryl moiety contains 6 to 14 carbon atoms and is unsubstituted or substituted with a lower hydroxy group , a lower alkoxy group, a carbamoyl group an alkyl group, a carboxy group or a famoyl group such as a (lower alkoxy) carbonylamino group such as an arylmethoxycarbonylamino group, wherein the 6-group contains a carbonyl nyl group and / or a free group, oyloxy- group or as (lower pi to. up to 14 carbon atoms, such as morpholinocarbonyl or as S, Sd hydroxy or phenyl (lower alkoxy) -alkyl, alkyl) oxycarbonyloxy-any aryl radical piperidyl-1-carbonyloxy, thiomorpholinooxothiomorpholinocarbone later than (lower chain is Compounds according to any one of claims 1 or 3, in which the octanoyl noyl group, or the substituted group, the decanoyl palmitoyl group is a lower alkanoyl group, a dodecan unsubstituted group, the substituents of which are one to three groups selected from the group consisting of hydroxy, lower alkoxy, (lower alkoxy) (lower and 1 alkoxy) -, (lower alkoxy) (lower alkoxy) (lower alkoxy) -, phenoxy, naphthoxy, phenyl and 1-alkoxy), (lower alkane) oyloxy, phenyl (lower alkane) oyloxy, amino-, (lower al) kyl) amino- or di (lower alkyl) amino (lower and 1 alkoxy) -2- (lower alkan) oyl group, XI amino, (lower alkyl) aminoalkoxy) (lower halogen atom> carbonyl group, alkyl amine noyoyl group, lower alkoxy group, carbamoyl group, (lower and alkylcarbamoyl group, acidyl / carbamoyl group, cyano group, cycloalkyl group, cycloalkenyl group nu, 2 pyrrolyl group, pyrrole group, pyrrole group, pyrrole group) 1-id imidazolidinyl lidinyl hydroxyloxazolyl tetrahydroisothiazolyl group, indolyl group, quinoyl group, benzimidazolyl group pyridyl group, piperazin-1-yl thiomorpholine group, 1-ogene (lower alkyl) carbamoyl alkyl) carbamoyl group such as lower alkoxy, carboxyl, phenyl, lower carbamoyl, monosubstituted, trifluoromethyl and / or nitro- an aryl group having from 6 to 14 carbon atoms and is unsubstituted or mono- or polysubstituted by lower alkyl, halogen (lower alkyl), halogen, hydroxy, lower alkoxy, (lower alkane) oxy, carboxyl, (lower alkyl) oxycarbonyl, phenyl (lower alkoxy) carbonyl, carbamoyl, mono- or di-hydroxy (lower alkyl) carbamoyl, halogen (lower and 1-yl) a heterocyclyl (lower alkyl) group in which the heterocyclyl radical has the meanings given above for the heterocyclyl radical forming the lower substituent an alkanoyl group, a cyano group and / or a nitro group, wherein at most one of the amino substituents of the carbonyl radical may be an aryl group, or further an amino acid radical bonded via an α 1 -carbonyl group selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or 5-aminohexanoic acid , valine, nor valine, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalanine, 4 chlorophenylalanine, 4-carboxyphenylalanine, beta-phenylserine, phenylglycine, and 1 phtha-naphthalene and cyclohexylglycine, tryptophan, aspartic acid, asparagine, am inomonic acid, am inomonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, d-hydroxy-lysine, ornithine, 3-aminopropanoic acid, 1α, 1-gamma-aminobutyric acid and 1α-β-di-amine inopropionic acid, with the exception of when it contains no asymmetric carbon) each of said amino acids may be in the form of D, L or (D, L), and 1? -amino group, if any, is unsubstituted or is N-alkylated one or two times by lower alkyl , amino (lower alkyl), phenyl- or naphthyl-amino (lower alkyl), phenyl (lower alkyl) wherein said group, diphenylmethyl, or / and heterocyclyl (lower) alkyl), the heterocyclic radical has a higher substituent The N-acylated and alkanoyl definition of R e for the hetrocyclyl alkanoyl group by unsubstituted or alkoxy) carbonyl is a phenyl group (lower side of the tri-radical meanings which the radical R 1 is already substituted for). The (lower alkoxy) carbonyl chain is a free group and / or substituted lower in the frame by a group and / or, carboxyl or occurs as a (lower alkyl) ester group, as an aryl ester group or as an aryl (lower alkyl) ester group a group in which the aryl group represents a phenyl group, a 4-nitrophenyl group, a naphthyl group, a fluorenyl group or a biphenylyl group such as a (lower and 1-yl) carbamoyl group such as a monoalkyl / carbamoyl or boxes (lower and 1-alkyl) a side chain carbamoyl that is not in position by a free group or occurs as a (lower and 1 alkyl) amino group, as (lower carbamoyl group, such as di (lower alkyl) - or di- / hydroxy (lower than mono- or di- / carboxy to amino-alpha, mono- or di-alkanoyl) amine a group such as an amino (lower and 1 channel) ylamino group such as an ar 1 (lower and 1 channel) amino group in which the aryl radical contains 6 to 14 carbon atoms and is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, carboxyl, carbamoyl or sulfamoyl, such as (lower alkoxy) carbonyloamino, such as arylmethoxycarbonylamino, in which the aryl radical contains 6 to 14 carbon atoms, such as piperidyl-1- kar bony group 1, VI as a morpholino-carbonyl group, as a thiomorpholino-carbonyl group, or as a S, S-dioxomorpholinocarbonyl group, and / or a side chain hydroxy group is free or occurs as a lower alkoxy group such as phenyl (lower) alkoxy, such as (lower and 1-cyano-oxy) or as (lower alkyl) oxycarbonyloxy, and salts thereof. The compounds according to claim 1 are unsubstituted of the general formula I in which the noyl group, the lower alkyinoyl one or including xy-group, pheny 1 (xy1 ovu (lower (lower and lower or lower or lower or lower or lower or lower)). alkenoyl by substituents selected from alkoxy, alkanoyloxy, halogen, carbo, phenyl, several hydroxy, naphthoxy, alkanjoyloxy, (lower alkoxycarbonyl, carbamoyl, hydroxy (lower and lower), and 1-alkoxycarbonyl alkylcarbamoyl, carbamoyl, di (lower alkylcarbamoyl), bis / hydroxy roxy (lower alkylcarbamoyl), carbamoyl wherein the nitrogen atom forms part of a 5- to 7-membered heterocyclic a ring which may still contain another heteroatom selected from the group consisting of is selected from methyl, ethyl, cyano, oxo, cycloalkyl, bicycloalkyl, tricycloalkyl, cycloalkenyl, bicycloalkenyl , a heterocyclyl group, which is a saturated, partially saturated or unsaturated ring, which exists as such or in a simple benzo, cyclopenta, cyclohexa- or cycloheptaanellated form containing from 5 to 7 ring atoms and at most four heteroatoms selected from the group consisting of nitrogen , a sulfur atom and / or an oxygen atom, preferably 1 or 2 of said heteroatoms, and which is unsubstituted or substituted by a lower alkyl group, a lower alkanoyl group, a hydroxy A lower alkoxy group, a phenyl ((lower alkoxy) group, a hydroxy (lower alkyl) group, a halogen atom, a cyano group and / or a trifluoromethyl group, an aryl group having 6 to 12 carbon atoms which is unsubstituted or one or more times substituted by lower alkyl, halogen (lower alkyl), halogen, hydroxy, lower alkoxy, (lower alkane) oyloxy, carboxyl, (lower and 1-yl) oxycarb bonyl, phenyl (lower, carbamoyl, monocarbamoyl, n, heterocyclyl (lower heterocyclyl and / or nitrocarbonyl, 2, aryl, substituted, or alkyl alkoxy) carbonyl, mono- or di (lower alkyl) carboxy or di-hydroxy (lower and halogen (lower alkyl) has a higher group, -halogen (n aryl (lower alkoxy) carbonyl containing 6 to 14 atoms, one or more times substituted by halogen, lower (lower alkyl), hydroxy, lower alkoxy, alkyl, as defined below (lower 1) of the cyano group; and 1 (alkoxy) alkoxy) carbonyl, in carbon and is a halogen atom having a lower (lower alkane) oyloxy, carboxyl, (lower alkyl) oxycarbonyl, (lower alkyl) oxycarbonyl, phenyl 1 (lower alkoxy) .y) carbonyl, carbamoyl, mono- or di (lower alkyl) carbamoyl, mono- or dihydroxy (lower alkyl) carbamoyl, and halo (lower alkyl), a heterocyclyl (lower alkyl) group in which the heterocyclyl radical has the meanings given above for the heterocyclyl group constituting the substituent of the lower alkanoyl, cyano and / or nitro group, further heterocyclic (lower alkoxy) carbonyl group, wherein the heterocyclyl moiety meanings which have already been mentioned above for a heterocyclyl group forming a substituent of lower alkanoyl group, an aminocarbonyl group, and m Anilinocarbonyl 1ový radical, in which The VIII amino acid carries 1 to 2 substituents independently selected from the group consisting of an unsubstituted lower alkyl group, including xy, phenyl (lower or substituted lower alkyl substituents, hydroxy, naphthoxy, and (1-alkanoyloxy) lower (lower, are selected from alkoxy, phenoalkane) oyloxy, halogen, carboxyl, (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, carbamoyl, a (lower and 1 alkyl) carbamoyl group, a hydroxy (lower alkyl) carbamoyl group, a di (lower and 1 alkyl) carbamoyl group, a bis / hydroxy (lower and 1 alkyl) / carbamoyl group, an oxo group and an aryl group containing atoms carbon which is substituted several times by a lower group of yano6 to 12 (lower alkyl), a lower alkoxy group, a carboxyl unsubstituted group or one al. or an alkyl group, a halogen atom, a halogen group, a hydroxy group, a (lower and 1 channel), a (lower and alkyl) oxyl carbonyl group, a phenyl (lower alkoxy) carbonyl group, a carbamoyl group, a mono- or di (lower and lower alkyl) 1) carbamoyl, mono- or di-hydroxy (lower and 1-alkyl) carbamoyl, halogen (lower alkyl), such as trifluoromethyl, cyano and / or nitro, az aryl (C až-C 14) group which is unsubstituted or mono- or poly-substituted by lower alkyl, halogen lower alkyl, halogen, hydroxy, lower alkoxy, (lower alkane) oyloxy, carboxyl, (lower alkyl) oxycarbonyl, phenyl (lower and 1 alkoxy) carbonyl, carbamoyl, mono or di (lower alkyl) carbamoyl, mono- or di- ydroxy (lower (lower alkyls which have been alkyl) carbamoyl, alkyl), heterocyclic (lower), wherein the heterocyclic radical has been previously mentioned for the heterocyclyl substituent of the lower alkanoyl group, cyano and / or nitro, wherein at most one of the haloalkyl groups is a radical. The IX substituents of the am inocarbonyl radical may be an aryl group, or further an alpha-carbonyl group linked to an amino acid radical selected from the group consisting of glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid , 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or 5-aminohexanoic acid, valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine, threonine, methionine, , phenylalanine, thyroline, 4-aminophenylsilane and 4-chlorophenylalanine, 4-carboxyphenylalanine, beta-phenylserine, phenylglycine, alpha-naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophan, aspartic acid, aspartic acid, aspartic acid, aspartic acid aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, delta-hydroxy1ysine, ornithine, 3-aminopropanoic acid, acid and 1 fa, gamma-diamine inomasic acid and alphabeta-diamine inopropionic acid, wherein (except in the absence of asymmetric carbon) each of said amino acids may be in the form of D, L or (D, L), alpha-amino in the case of that it is present is unsubstituted or mono- or double-alkylated with a lower alkyl group, an amino (lower alkyl) group, a phenyl- or naphthyl-amino (lower alkyl) group, a phenyl (lower alkyl) group, diphenylmethyl, triethyl and / or heterocyclyl (lower alkyl) in which the heterocyclyl radical has the meanings given above for the heterocyclyl group representing a lower alkanoyl substituent of R1 or / and N-acylated with one unsubstituted or substituted lower alkanoyl radical mentioned above in connection with the definition of R1, (lower alkoxy) carbonyl or phenyl (ni); a lower alkoxy) carbonyl group, the side chain carboxyl group is a free group or occurs as a (lower alkyl) ester group, an aryl ester group or an aryl (lower alkyl) ester group wherein the aryl group is a phenyl group, a 4-nitrophenyl group, naphthyl, fluorenyl or biphenylyl such as carbamoyl, such as (lower alkyl) carbamoyl, such as mono- or di (lower alkyl) carbamoyl, di / hydroxy (lower alkyl) / carbamoyl or di / carboxes (lower and 1alkyl) / carbamoyl, a chain that is not found in the po group or occurs as moalkyl) an amino group, such as a (lower than amino (lower and 1-channel) oyl) in which the monoamino side group Compounds of formula I wherein R 1 is an acyl group, and salts thereof. Compounds according to claim 1 of the general formula I, 1 '- 4151-95 (I) in which R 1 represents octanoyl, decanoyl, dodecanoyl, palmitoyl, unsubstituted or substituted lower alkanoyl, lower alkenoyl or lower alkyinoyl, wherein the substituents are one or more hydroxy groups selected from the group consisting of hydroxy; lower alkoxy, (lower alkoxy) (lower alkoxy), (lower alkoxy) (lower alkoxy) (lower alkoxy), phenoxy, naphthoxy, phenyl (lower alkoxy), 2-halo (lower alkanjoyl, amino-, (lower alkyl) amino- or di (lower alkyl) amino- (lower alkoxy) -2- (lower alkanjoyl, amino-, (lower alkyl) amino- or di ( lower alkyl is amino- (lower alkoxy) - (lower alkoxy) -2- (lower alkane) oyl, (lower alkane) oyloxy, phenyl (lower alkane) oyloxy, halogen, carboxyl, ( lower alkoxy) carbonyl, phenyl (lower and 1-alkoxy) carbonyl, carbamoyl, (lower and 1-alkyl) carbamoyl, hydroxy (lower and 1-alkyl) carbamoyl, di (lower alkyl) carbamoyl, a bis / hydroxy (lower alkyl) / carbamoyl group, a carbamoyl group of which the nitrogen is part of a 5- to 7-membered heterocyclic ring, which may still contain another heteroatom selected from oxygen, sulfur, atom a nitrogen atom and a nitrogen atom substituted by a lower alkyl group, and is methyl or ethyl, cyano, oxo, cycloalkyl, bicycloalkyl, tricycloalkyl, cycloalkenyl, bicycloalkenyl, heterocyclyl, which is saturated. a partially saturated or unsaturated ring which exists as such or in a simple benz-, cyclopenta-, cyclohexa- or cyclohepta-fused form containing from 5 to 7 ring atoms containing up to four heteroatoms selected from the group consisting of nitrogen, sulfur or (a) an oxygen atom which is unsubstituted or substituted by a lower alkyl group, a lower alkanoyl group, a hydroxy group, a lower alkoxy group, a phenyl (lower and 1-alkoxy) group, a hydroxyl (lower alkyl) group, a halogen atom, cyano- and / or a tri-fluoromethyl group, and an aryl group of 6 to 12 carbon atoms which is unsubstituted or mono- or polysubstituted by a lower alkyl group, such as a lower (lower alkyl) group, a halogen atom, a hydroxy- lower alkoxy, (lower alkane) oyloxy, carboxyl, (lower alkyl) oxycarbonyl another, phenyl (lower 1-alkoxy) carbonyl, carboyl, mono- or di- (lower alkyl) carbamoyl, mono or di-hydroxy (lower alkyl) carbamoyl, halogen (lower alkyl) heterocyclyl (lower alkyl) wherein the heterocyclyl radical has a III as defined above, by cyano and / or nitro, hereinafter (lower alkoxycarbonyl, 2-halogen (lower alkoxycarbonyl), aryl 1 (lower alkoxycarbonyl) in which the aryl radical contains 6 to 14 carbon atoms and is unsubstituted or one or multiple-substituted lower alkyl, halogen (lower alkyl, halogen, hydroxy, lower alkoxy, (lower alkanedoxy, carboxyl, (lower alkyl) oxycarbonyl, phenyl (lower alkoxycarbonyl, carbamoyl, mono) - or di- (lower and lower alkylcarbamoyl, mono- or dihydroxy (lower alkyl) carbamoyl, halogen (lower alkyl), heterocyclyl (lower alkyl) in which the heterocyclic radical has the meanings already mentioned as above for the heterocyclyl radical forming the lower alkano substituent heterocyclyl (a lower alkoxycarbonyl group in which the heterocyclyl radical has the meanings given above for the heterocyclyl radical forming a substituent of the lower alkanoyl group, furthermore an aminocarbonyl radical, an aminocarbonyl radical in which the amino group bears one to two substituents independently selected from the group consisting of unsubstituted lower alkyl or substituted lower alkyl, the substituents of which are selected from the group consisting of hydroxy, lower alkoxy, phenoxy, naphthoxy, (lower and 1-canoyloxy), phenyl (lower alkanjoyloxy, halogen, carboxyl, (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, carbamoyl , (lower and lower alkylcarbamoyl, hydroxy (lower and lower alkylcarbamoyl) u, di (lower and alkylcarbamoyl, bis / hydroxy (lower and alkylcarbamoyl), cyano, oxo and aryl of 6 to 12 carbon atoms which is unsubstituted or mono- or poly-substituted for example lower alkyl, halo (lower alkyl), atom IV of halogen, hydroxy, (lower alkane) oyloxy, (lower alkyl) oxycarbonyl and 1-alkoxy) carbonyl, mono- or di-lower or di-hydroxy (lower 3-aminopropanoic acid and alpha, beta-diaminopropionic acid, in the absence of asymmetric carbon) of amino acids, may have the configuration D, L, and 1 phamamino when the amino amide is substituted or not. alkyl phenyl- or, in the case of, or once or twice, amino (lower alkyl), naphthyl amino (lower alkyl), phenenyl (lower alkyl), diphenylmethyl, trityl, furanyl (lower alkyl), thienyl (lower alkyl), imidazoles (lower alkyl) or / and 2-, 3- or 4-pyridyl (lower alkyl) or / and N- acylated with one unsubstituted or substituted lower alkanoyl group, which has already been mentioned above in connection with the definition of R1, (lower alkoxy) carbonyl is tested by Or a phenyl (lower alkoxy) carbonyl group, and pharmaceutically acceptable salts thereof. 4-morpholinomethylbenzoyl, 4-thiomorpholinomethylbenzoyl, aminoacetyl, N- (lower alkyl) aminoacetyl is acetyl, N- (lower aminoacetyl, N- (nylaminoacetyl), (lower alkyl) aminoacetyl pyridyl) (lower alkyl) aminoacetyl dimethylamino) butyryl usable salts. nu, N, Nd i (lower alkyl) aminoalkyl) -N-phenyl (lower alkyl) lower alkyl) -N-benzyloxycarb N-imidazolyl (lower and alkyl) -N-N groups, nu, N- (lower and (1) -N-4- (N, N-pharmaceutical) Compounds according to claim 1 or 3 of the general formula I, in which R 1 represents an unsubstituted or substituted lower alkanoyl group, the substituents of which are composed of one of hydroxy, lower alkoxy, phenoxy, naphthoxy, (lower alkane) oyloxy, phenyl (lower alkane) ) oyloxy, halogen, carboxyl, (lower alkoxy) carbonyl, phenyl (lower alkoxy) carbonyl, carbamoyl, (lower alkyl) carbamoyl, hydroxy (lower alkyl) carbamoyl , di (lower alkyl) carbamoyl, bis / hydroxy (lower alkyl) / carbamoyl, cyano, oxo, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 4 to 3 carbon atoms, pyrrolyl, 2,5-dihydropyrrolyl, furyl, thienyl, tetrahydrofuranyl, pyrrolidinyl, imidazolyl, i mido-azidinyl, pyrazolyl, pyrazolidinyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, indolyl, isoquinolyl, isoquinolyl, isoquinolyl, isoquinolyl, isoquinolyl benzimidazolyl, benzofuranyl, pyridyl, pyrimidinyl, piperidinyl, piperazin-1-yl, morpholino, thiomorpholino, S, S-dioxothiomorpholino, 1,2 a dihydro- or 1,2,3,4-tetrahydroquinolyl or 1,2-dihydro- or 1,2,3,4-tetrahydroisoquinolyl group, said heterocyclic radicals being unsubstituted or substituted lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl (lower and 1-alkoxy), hydroxy (lower alkyl), atom gene, cyano and / or tri fluoromethyl, and aryl u XIV of a group comprising a phenyl indanyl group, an indenyl group wherein or more than one, the unsubstituted group is substituted by a lower alkyl halogen atom (lower hydroxy, n (lower alkyl) group, lower alkoxy group, carboxyl group, phenyl (lower carbamoyl, n, buy, alkyl) carbamoyl, monoalkyl) carbamoyl, hapidimidomethylmethylpiperazin-1-ylmethyl, 4- (lower alkyl) -, 4- (lower alkane) oylpimorpholinomethyl, cyano and / or 1-carbonyl group selected from 2-aminobutyric acid, 4-aminobutyric acid, 34-aminopentanoic acid, 53-aminohexanoic acid, 4-amino-5-aminohexanoic acid, valine, norvaline serine , homoserine, threonine, tyrosine, 4-aminophenylalabeta-phenyl groups at the choice of naphthyl group, and fluorenyl group, bold or one group pine, halogen, alkanoyloxy, alkyl) oxycarbonyl alkoxy) carbonyl mono- or di (lower or di-hydroxy (lower logene (lower alkyl) group, pine, piperazin-1-ylmethyl perazin-1) -methylmethyl, thiomorpholinomethyl or triple bonded radical including 3-aminobutyric, aminopentane, aminopentane, amopentane, hexane glycine via or Compounds according to claim 1 of the general formula I, in which R 1 represents octanoyl, decanoyl, dodecanoyl, palmitoyl, lower alkanoyl, hydroxy (lower alkan) oyl, (lower alkoxy) (lower alkan) oyl, (lower alkoxy) (lower and 1 alkoxy) (ni) (lower alkoxy) (lower alkoxy) (lower alkoxy) (lower alkane) oyl, phenoxy (lower alkane) oyl, phenyl 1 (lower alkoxy) (lower and 1 kan) o 1 an amino-, (lower and 1-alkyl) amine or di (lower alkyl) amino (lower alkoxy) -2- (lower alkan) oyl group, amino-, (lower alkyl) amino- or di ( lower alkyl) amino (lower alkoxy) (lower alkoxy) -2 (lower alkan) oyl, (lower alkan) oyloxy (lower alkan) oyl, carboxy (lower alkan) oyl, oxo (lower alkane) oyl 5-hydroxymethylfuran-2-ylcarbonyl, 2- or 3-pyrrolylcarbonyl, furylcarbonyl, thi enylcarbonyl, pyridyl (lower and 1-canolyl), quinolylcarbonyl, quinolylcarbonyl, 2-, 3- or 5-indolyl; carbonyl, pyrrolidinyl- (2- or 3-) carbonyl, 2-, 3 or 4-piperidinylcarbonyl, 1,2,3,4-tetrahydroquinolin-1-2-, -3- or -4-carbonyl, 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl, imidazolyl (lower alkane) -yl, pyrazolyl (lower alkane) oyl, morpholinocarbonyl, thiomorpholinocarbonyl, morpholinoacetyl moiety, thiomorpholinoacetyl, 4- (lower alkyl) -1-piperazinoacetyl, indolylacetyl, alkenyl, benzofuran (acetyl), benzofuran (acetyl), benzofurane (acetyl) which is unsubstituted on the phenyl residue or substituted one or more times by a lower alkyl group, a halogen (lower alkyl) group another, halogen, hydroxy, lower and 1-alkoxy, alkoxy, piperidinomethyl, piperazin-1-ylmethyl, 4- (lower and 1-alkyl) piperazin-1-ylmethyl, an morpholinomethyl group, a thiomorpholinomethyl group, a cyano group and / or an itro group, or an aliphatic amino acid radical bonded via an alpha-carbonyl group selected from the group consisting of alanine, valine, norvaline, leucine, 3-aminopropionic acid, 2-aminobutyric acid and 2-aminobutyric acid or amino acids selected from the group consisting of glycine, asparagine, glutarine, methionine, lysine, phenylalanine, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexic acid , 4-aminohexanoic acid and 5-aminohexanoic acid, each (except in the absence of asymmetric carbon) of which each amino acid may have a ciu D, L or (D, L), and 1 phenylamino, if present, is unsubstituted or N-alkylated once or twice by a lower alkyl (alkyl) group, 2-, 3 - or phenyl, phenyl (lower 4-pyridyl (lower and 1-yl)), imidazolyl (lower alkyl), or 2-, 3- or 4-pyridyl (lower) alkyl) such as 2-, 3- or 4-pyridylmethyl, and / or N-acylated (lower alkoxy) carbonyl or benzyloxycarbonyl, and pharmaceutically acceptable salts thereof. 7 group and their Compounds according to claim 1 of the general formula I, in which R1 represents a lower alkanoyl group, a hydroxy (lower and 1-chanoyl) group, a (lower alkoxy) (lower alkan) oyl group, a phenoxy (lower alkane) oyl group, 1 kan) oy loxy (lower alkane) oyl, oxo (lower alkane) oyl XVII, 5-hydroxymethylfuran-2-ylcarbonyl, 2-, or 3-pyrrolylcarbonyl, furylcarbonyl, for example 2-furyl carbonyl, thienylcarbonyl, pyridylcarbonyl, 2-, 3- or 5-indolylcarbonyl pyrrolidinyl-3-carbonyl, 2-, 3- or 4-piperidinylcarbonyl, 1,2 ', 3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3, 4-tetrahydroisoquinoyl-1-, -3- or -4-carbonyl, imidazolylcarbonyl, morpholino-carbonyl, thiomorpholino-carbonyl, morpholinoacetyl, thiomorpholinoacetyl, 4- (lower alkyl) -1-piperazinacetyl acetyl a benzofuranyl acetyl group, a phenyl (lower alkane) aryl group which is unsubstituted on the phenyl residue or substituted one or more times with a lower alkyl group, a halogen (lower and 1-yl) group, a halogen atom Ogene, hydroxy, lower alkoxy, piperidinomethyl, piperazin-1-ylmethyl, 4- (lower and 1-methyl) perazin-1-ylmethyl, morpholinomethyl, thiomorpholinomethyl, cyano and / or nitro- an aliphatic amino acid radical bound by an alpha-carbonyl group selected from the group consisting of α, n, valine, norvaline, leucine, 3-amino propionic acid, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, and isoleucine, or amino acids selected from the group consisting of glycine, asparagine, glutamine, methionine, lyin, prionine, lyin or proline. or phenylalanine, wherein (except in the absence of asymmetric carbon) each of said amino acids may have a D, L or (D, L) and the alpha-amino group, if present, is unsubstituted or one or two N-alkylated lower alkyl, phenyl (lower alkyl) and / or 2-, 3 or 4-pyridyl (lower alkyl) groups and / or N-acylated (lower alkoxy) carbonyl or phenyl XVIII (lower alkoxy) carbonyl, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the general formula I, in which R 1 represents an octanoyl group, a decanoyl group, a dodecyl group, a palladoyl group, a lower alkanoyl group, a (lower alkoxy) (lower alkane) -yl group, (lower and 1-alkoxy) (lower and 1-alkoxy) (n lower alkanoyl, (lower alkoxy) (lower alkoxy) (lower alkoxy) (lower alkan) oyl, phenoxy (lower alkan) oyl, phenyl (lower alkoxy) (lower alkan) oyl, amino-, (lower) alkyl) amino- or di (lower alkyl) amino (lower alkoxy) -2- (lower alkane) oyl, amino-, (lower alkyl) amine o- or di (lower alkyl) amino (lower alkoxy) (lower alkoxy) -2- (lower alkane) -yl, 2- (lower alkoxy) -2-phenyl-acetyl, furylcarbonyl, pyridyl 1 (lower alkane) -yl, quinolylcarbonyl, isoquinolylcarbonyl , pyrrolidinyl-2-carbonyl, imidazolyl (lower alkanjoyl, pyrazolyl (lower alkanilyl, phenyl (lower alkanjoyl, 4-chloromethylbenzoyl), Compounds according to claim 1 of the general formula I, in which R 1 is lower alkanoyl, furylcarbonyl, pyridylcarbonyl, phenyl 1 (lower alkanjoyl, 4-morpholinomethylbenzoyl, 4-thiomorpholinomethylbenzoyl, aminoacetyl, N (lower alkyl, aminoacetyl) alkyl) XIX is an aminoacetyl group, N- (lower and alkyl) N-phenyl (lower alkyl) aminoacetyl, N- (lower alkyl) -N-pyridyl (lower alkyl) aminoacetyl, or N-phenyl (lower alkoxy) carbonyl-N- (lower alkyl) aminoacetyl group, and pharmaceutically acceptable salts thereof. Compounds according to claim 1, in which R 1 is lower alkanoyl, (lower alkoxy) (lower alkanjoyl, pyridylcarbonyl or furylcarbonyl), and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the general formula I, in which R 1 is lower alkanoyl or furylcarbonyl, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the general formula I, in which R represents (lower and 1 alkoxy) (lower alkanjoy group or pyridylcarbonyl group), and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the general formula I, in which R 1 represents a lower alkanoyl group, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the formula I selected from the group consisting of N-tert.butyl-decahydro-2- / 2- (R) -pivaloyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) isoquinolin 3 (S) -carboxamide, N-tert-Butyldecahydro-2- (2) (R) - (N-methylaminoacetyloxy) -4-phenyl-3 (S - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl) (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide, XX N-tert.butyl-decahydro-2- / 2 (R) - (N-benzy1oxykarbonyl Nmetylaminoacetyloxy) feny1-3 4 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4a S , 8aS) -izochino1ín-3 (S) -carboxamide, Terc.but.yldekahydro N-2/2 (R) - (N-dimetylaminoacetyloxy) 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4a S , 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - (N-n-butyl-N-metylaminoacetyloxy) 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - (N-methyl-N-benzylaminoacetyloxy) 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) - (N-methyl-N-3-pyridylmethylaminoacetyloxy) 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L -asparaginyl / amine / butyl 1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) - (3-pyridylcarbonyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-aspartyl (amino) butyl] (4aS) , 8aS) -isoquinoline-3 (S) -carboxamide, N-1-tert-Butyldecahydro-2- / 2 (R) - (4- (N-morpholinylmethyl) benzoyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino (butyl) (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, and pharmaceutically acceptable salts thereof. Compounds according to claim 1 of the formula I selected from the group consisting of N-tert-Butyldecahydro-2- [2 (R) -propionyloxy-4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-aspartyl] amino (butyl)] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, XXI N-tert.butyl-decahydro-2- / 2 (R) -butyryloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginy1 / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -metylpropionyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -pentanoyloxy4-feny1-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -octanoyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl (4aS, 8aS) ) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -dekanoyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -dodekanoyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -palmitoyloxy-4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline- 3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - (3-carboxypropionyloxy) -4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - (3-metoxypropionyloxy) 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, XXII N-tert.butyl-decahydro-2- / 2 (R) -benzyloxyacety1cxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / (S) -alpha-methoxy-alpha-phenylacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino (butyl) - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- (2) (R) - [(R) -alpha-methoxy-alpha-phenylacetyloxy] 4-phenyl-3 (S) - [N- (2-quinolinecarbonyl)] -L-aspartyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / 2- (2-rnetoxyetoxy) acetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / n-butyloxyacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -N- (2- (2-methoxyethoxy) ethoxy) acetyloxy / 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) ) -L-asparaginyl / amino / butyl / (4aS, 8aS) - isoquinoline-3 (S) -carboxamide, N-tert-butyldecahydro-2- / 2 (R) - (2-pyridylacetyloxy) 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-aspartyl (amino) butyl] (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) - [3- (2-pyridyl) propionyloxy] 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -izochino1ín-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / 4-imidazolylcarbonyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, XXIII N-tert.butyl-decahydro-2- / 2 (R) - / 4-imidazolylacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / 3- (4-imidazolyl) propionyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -quinolin-2-ylcarbonyloxy-4-phenyl-3- (S) - N - (2-quinolinecarbonyl) -L-aspartyl / amine no / buty1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -fenoxyacetyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -pyridine-4-carbonyloxy-4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartyl / amine no / buty1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- / 2 (R) -pyridine-2-carbonyloxy-4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartyl / amine no / buty1 / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert-Butyldecahydro-2- (2) (R) - (1-pyrazolylacetyloxy) 4-phenyl-3 (S) - N - (2-quinolinecarbonyl) -L-aspartin / am iso -butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) pyrazine-2-ylkarbonyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -isoquinoline-3-karbonyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, XXIV N-tert-Butyldecahydro-2- [2 (R) -aminoacetyloxy-4-phenyl-3 (S) - [N- (2-quinoylcarbonyl) -L-aspartyl] amino (butyl)] (4aS, 8aS) -izochino1ín-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / (L) -pyrrolidin-2-carbonyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / biJtyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / N- (imidazolyl-4-methyl) -Nmetylaminoacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / N- (pyridin-2-ylmethyl) Nmetylaminoacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / N, N- (4-dimetylaminobutyryl) oxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbony1) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) -benzoyloxy4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / 4-chlórmetylbenzoyloxy / 4-feny1-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino / butyl / (4aS, 8aS ) -isoquinoline-3 (S) -carboxamide, N-tert.butyl-decahydro-2- / 2 (R) - / 3- (N, N-dimethylaminopropyl) oxyacetyloxy / 4-phenyl-3 (S) - // N- (2-chinoylkarbonyl) -L-asparaginyl / amino (butyl) (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, and N-tert-Butyldecahydro-2- / 2 (R) - / 2- / 3- (N, N-dimethylaminopropyloxy) -ethoxy / acetyloxy / 4-phenyl-3 (S) - N - (2-quinoylcarbonyl) 1-L-asparaginyl / amino / butyl / XXV (4aS, 8aS) -isoquinoline-3 (S) -carboxamide, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R 1 is acetyl, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R 1 is. a furan-2-ylcarbonyl group, and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R 1 is methoxyacetyl, and pharmaceutically acceptable salts thereof. A compound according to claim 1 of the general formula wherein R 1 represents a pyridin-2-ylcarbonyl group, and pharmaceutically acceptable salts thereof. A compound of formula I, or a salt thereof according to claims 1 to 19, for use in a method of therapeutic treatment of the human or animal body. Use of a compound according to any one of claims 1 to 19 in or a pharmaceutical salt thereof for the manufacture of pharmaceutical compositions for the treatment of AIDS. Pharmaceutical preparations, characterized in that they comprise a compound of the formula I according to any one of claims 1 to 19 or a pharmaceutically acceptable salt of such a compound with at least one salt-forming group together with a pharmaceutically acceptable carrier. A process for the preparation of a compound of formula I according to claim 1 and a salt of such compounds, characterized in that: 4; (a) from 1 to Formula II - XXVI - reacts with a carboxylic acid of general formula III R 1 - OH (III) wherein R 1 is as defined in claim 1, or a reactive derivative thereof, wherein the free functional groups in the starting materials of formula II and formula III not to be involved in the reaction are in protected form, if necessary, the protective groups present are subsequently cleaved, or b) amine-generalization of general formula IV i O (IV) XXVII wherein R 1 is as defined above, or a reactive derivative thereof is amidated with a carboxylic acid of formula V or a reactive derivative thereof, wherein the free functional groups in the starting compounds of formula IV which are not to be involved in the reaction are in protected form, the protective groups present are subsequently cleaved, or c) an amine compound of formula VI (VI) wherein R 1 is as defined above, or a reactive derivative thereof is amidated with a carboxylic acid of formula VII (VII) XXVIII or a reactive derivative thereof, wherein the free functional groups in the starting materials of formula VI and formula VII which are not to be involved in the reaction are, if necessary, in protected form, followed by cleavage of the protective groups present, followed optionally by a single salt-forming group converting a compound to a salt thereof, or to another salt obtained and / or converting a salt of formula I into at least the aforementioned process into a free isomeric mixture of compounds of formula I divides and / or converts according to the invention of the formula I into the invention according to the formula I