FI114634B - A process for the preparation of pharmacologically effective hydrazine derivatives - Google Patents

Abstract

The invention relates to compounds of the formula <IMAGE> in which R1 and R9 are, independently of one another, hydrogen, acyl, unsubstituted or substituted alkyl, alkenyl or alkynyl; heterocyclyl; sulpho, or sulphonyl which is substituted by unsubstituted or substituted alkyl, aryl, heterocyclyl, alkoxy, which is unsubstituted or substituted, or by aryloxy; sulphamoyl which is unsubstituted or substituted on the nitrogen; or phosphoryl which is substituted by one or two radicals selected independently of one another from unsubstituted or substituted alkyl, from unsubstituted or substituted cycloalkyl, from aryl, from hydroxyl, from unsubstituted or substituted alkoxy, from cycloalkoxy and from aryloxy, with the proviso that not more than one of the radicals R1 and R9 is hydrogen; and R2 and R8 are each, independently of one another, hydrogen or one of the radicals mentioned above for R1 and R9; or the pairs of substituents R1 and R2 or R8 and R9 can each, independently of one another, form together with the nitrogen atom to which they are bonded certain heterocyclic rings; R3 and R4 are, independently of one another, hydrogen, unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; or R3 and R4 together are unsubstituted or substituted alkylene, alkylidene or benzo-fused alkylene; R5 is hydroxyl; R6 is hydrogen; or R5 and R6 together are oxo; and R7 is unsubstituted or substituted alkyl or cycloalkyl; aryl; heterocyclyl; or unsubstituted or substituted alkenyl; as well as the salts of the said compounds where salt-forming groups are present, furthermore process for the preparation thereof, pharmaceutical products, the use as pharmaceutical composition or for the preparation of pharmaceutical products, as well as intermediates for the preparation of these compounds.

Description

114634

A process for the preparation of pharmacologically effective hydrazine derivatives

The invention relates to a process for preparing a new class of non-hydrolyzable analogs of peptides cleaved by aspartate proteases, namely hydrazine derivatives. Pharmaceutical preparations containing these peptide analogs can be used to treat diseases caused by viruses.

Acquired Immunodeficiency Syndrome (AIDS) is a fatal disease. This disease is spreading globally to an increasing extent, above all within specific risk groups, but also outside these risk groups. It is already affecting millions of people and its causal struggle is one of the most important goals of modern medicine. Up to now, retroviruses HIV-1 and HIV-2 (HIV is the "Human Immunodeficiency Virus") have been identified as the cause of the disease and have been molecularly characterized. In addition to the potential for alleviation of AIDS symptoms so far, and for predetermined pre-treatment, for therapy. in addition to preventive options, there is a particular mind; it is interesting to look for products that affect the viral * * «reproduction itself without damaging the patient's intact • · · cells and tissue.

i ··· In particular, compounds that · · · · · · · · · · · · · · · · · · · · · · · · Suppresses Biosynthesized Virus in Human Cells; . ; treatment of the protein moieties, and thus the proper integration of these moieties into complete infectious virions.

'"· The HIV-1 and HIV-2 genomes each have a region encoding a" gag protease ". This" gag protease "is responsible for the correct proteolytic cleavage of the 114634 2 precursor proteins derived from" Group Specific Antigens "(gag). This will release the structural proteins of the viral nucleus," Core ".

The "gag protease" itself is a portion of the precursor protein encoded by the polynomial portion of HIV-1 and HIV: 2, which also contains portions for reverse transcriptase and integration and is presumably also autoproteolytically cleaved.

"gag protease" cleaves HIV-1 or the like. P24 of the major core protein ("Major Core Protein") of HIV-2, particularly at the N-terminus of the proline residues, e.g., the Phe-Pro, Leu-Pro or Tyr-Pro bivalent groups. It is a protease having a catalytically active aspartate residue in an active center, the so-called aspartate protease.

If the effect of the "gag protease" could be suppressed, the virus would no longer have access to the proteins necessary for viral nucleation. This would restrict or even prevent the virus from multiplying. Thus, there is a need for "gag-'!" Protease inhibitors as antiviral agents against AIDS and other retroviral diseases.

• · «• *« f ·. '. Several "gag protease" inhibitors containing key groups that are not proteolytically cleavable peptide isosteres have already been synthesized. However, so far, despite the intense - * ;;; to provide human aspartate protease inhibitors suitable for the control of AIDS in a large number of infected individuals. This is primarily due to the Farmako dynamic problems. In addition, most of the hitherto known "gag protease" inhibitors have more than two asymmetric carbon atoms in said central moiety, necessitating relatively laborious stereo-specific syntheses or isomeric separations. The purpose of this patent application 114634 3 is therefore to provide a new class of viral aspartate protease inhibitors with a new central moiety. In addition, synthesis of this central moiety must be possible in a sterically simple manner. Still further, the central moieties have amino groups at each end such that, when selecting suitable substituents, structures analogous to, for example, retro-inversopeptides occur.

The compounds of the invention are of the formula | r7

I \ Λ I

"Τ '®« 3 ^ 4 |

Re, as well as salts of these compounds, in the presence of salt-forming groups in which R1, and R8 are independently hydrogen, lower alkanoyl, phenyl-lower alkanoyl, phenyl-lower alkanoyl, where the lower alkanoylamino, Lower alkanoyl, quinolyl lower alkanoyl, tetrazolyl; lower alkylkanoyl, N-morpholino or N-thiomorpholino: amino-lower alkanoyl substituted by carbonyl in amino nitrogen, halogen-lower alkanoyl containing up to 3 halogen atoms, 2- (N-morpholino-lower alkyl) ···, carbamoyl-lower (alkanoyl) -carbamoyl pyridyl lower alkylcarbamoyl) lower alkanoyl, 2 (R, S) - (N- (2-pyridyl *, '*; methyl) carbamoyl) -3-methylbutyryl, lower alkoxycarbonyl, phenyl lower alkoxycarbonyl, benzyl- cicarbonyl, tetrahydrofuranyl-lower alkoxycarbonyl, lower alkylsulfonyl, morpholinosulfonyl, thio-morpholinosulfonyl, N-pyridyl lower alkyl-N-lower alkylcarbamoyl, glycine aminoacid, In the (D), (L) or (D, L) form, wherein the α-amino group is unsubstituted or acylated by one of the other R 3 or R 8 residues mentioned above, provided that at most one of R 1 and R 8 represents hydrogen, R 2, R 4, R 8 and R 8 represent hydrogen, R 3 represents lower alkyl; sykloheksyylialempialkyyliä; or phenyl-lower alkyl which is unsubstituted or substituted with halogen, lower alkoxy or cyano, R 5 represents hydroxy, and

Ry means lower alkyl; sykloheksyylialempialkyyliä; or phenyl-lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy or cyano as last defined for R-j.

The term "lower ·" as used in the definition of groups or residues, e.g., lower alkyl, lower alkoxy, lower alkanoyl, etc., in the specification of this invention means that the groups or residues thus defined, unless otherwise expressly stated, include the highest. 7 and especially up to 4 C atoms.

Unless otherwise specified, the substituents are present at R 1, R 2 / R 3, R 4, R 7, R 8 and / or R 8 independently of one another: · independently one or more times, especially one to three times, e.g. once.

The residues R3 and R4 of the compounds of the formula I or ·; · ', respectively. R5 and R6 substituted carbon atoms may be present, as long as they are asymmetric, as well as any other asymmetric carbon atoms in the (R), (S) or (R, S) configuration. Thus, these compounds may exist as isomeric mixtures or pure isomers, in particular diastereomeric mixtures, enantiomeric pairs or pure enantiomers. Particularly preferred are compounds of formula I wherein the carbon atom substituted with R 3 or hydroxy R 5 has the (S) configuration and the other asymmetric carbon atoms that may be present are independently of the (R), (S) or (R, S) configuration.

In particular, the generic terms and designations used in the description of this invention have the following meanings, wherein arbitrary combinations or single residues can be used at various levels of definition of the above and the following:

For example, acyl R1 or Rg has up to 25, especially up to 19, C atoms and is primarily carboxylic acid, carbonic acid semi-ester, unsubstituted or N-substituted carbamic acid, unsubstituted or N-substituted oxalamide or unsubstituted *. ; or an acyl group of a substituted amino acid, whereby instead of the carbonyl groups of said acyl residues, thiocarbonyl groups are also possible. Preferably, only at most one of the residues R · ^ ;; or, Rg is acylated.

Preferred acyl groups R 1 and R 8 of the carboxylic acid are unsubstituted or substituted alkanoyl containing up to 19 carbon atoms, e.g. n-decanoyl, or especially lower alkanoyl such as formyl, acetyl, propionyl, butyryl or pivaloyl, 6 containing e.g. 3-7 carbon atoms and having a lower alkanoyl as defined above, e.g. cycloalkylcarbonyl, especially having a total of 4-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylcarbonyl, or 2-cyclohexyl or 2 -cyclopenylacetyl, as a cycloalkenyl lower alkanoyl, wherein the cycloalkenyl has e.g. 3-7 carbon atoms, such as cycloalkenylcarbonyl, especially having 4-8 carbon atoms, such as 1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl or 1-cyclohexadienylcarbonyl or -cyclohexadienylacetyl-lif as bicycloalkyl-lower alkanoyl with bicyclo Alkyl has e.g. 5-10 carbon atoms, e.g. bicycloalkylcarbonyl, especially having 8-11 carbon atoms, such as decahydronaphthyl-2-carbonyl, endo- or exo-norbornyl-2-carbonyl, bicyclo [2.2.2] oct. -2-ylcarbonyl or bicyclo [3.3.1] non-9-ylcarbonyl, further on bicyclohexyl, -heptyl, -octyl, nonyl or -decylacetyl, or · ... -3-propionyl such as bicyclo [3.1.0] hex-1, -2- or -3- * yl, bicyclo [4.1.0] hept-1 or -7-yl, bicyclo [2.2.1] -: hept-2 -yl such as endo or exo-norbornyl, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.0] oct-3-yl or bicyclo [3.3.1] non-9 -yl, further α- or β-decahydronaphthylacetyl, or -3-propionyl, »· →» * bicycloalkenylcarbonyl, especially having 8-12 carbon atoms such as 5-norbornen-2-ylcarbonyl or bicyclo- [ 2.2.2] octen-2-ylcarbonyl, in the form of a tricycloalkyl lower alkanoyl, wherein the tricycloalkyl contains e.g. 8-10 carbon atoms, e.g. tricycloalkylcarbonyl, in particular 8-11 a carbon atom such as 1-7-14634 or 2-adamantylcarbonyl, further tricyclo [5.2.1. 02'6] dec-8-yl or adamantyl, such as 1-adamantylacetyl, as aryl-lower alkanoyl, wherein aryl has 6 to 14 carbon atoms, such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, asenaphthyl or fluorenyl, and may be unsubstituted or especially substituted one to three times lower alkyl, e.g. methyl, ethyl or propyl, halogen lower alkyl, e.g. trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, e.g. methoxy, carbamoyl lower alk. N-lower alkyl-carbamoyl lower alkoxy or Ν, Ν-dialempkylcarbamoyl lower alkoxy, amino, mono- or dialempkylalkylamino, lower alkanoylamino, e.g. pivaloylamino, halogen, e.g. cicarbonyl, phenyl, naphthyl or fluorenyl lower alkoxycarbonyl such as benzyloxycarbonyl lower alkanoyl, sulfo, lower alkyl sulfonyl, e.g., methyl sulfonyl, phosphono, hydroxy lower alkyl, coke phosphoryl or dialempkalkoxy phosphoryl, * *: carbamoyl, mono- or dialempalkylcarbamoyl, or dialkylalkylaminosulfonyl; with nitro and / or cyano, wherein the phenyl may be present up to three times, e.g., diphenyl, dibenzyl ···. or triphenyl-lower alkanoyl such as diphenyl, dibenzyl or triphenylacetyl, and lower alkanoyl may be unsubstituted or substituted with e.g. lower alkyl, e.g. methyl, heterocyclyl, which is pyrrolyl, furyl, thienyl, imidazolyl, imidazolyl, , thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,? -carbolinyl, or benzanelated, cyclopenta, cyclohexa or cyclohepta-anellated 114634 8 derivatives of these residues, which may also be wholly or partially saturated, hydroxy, lower alkoxy, lower alkanoyloxy, e.g., acetoxy, propionyloxy, butyroxy, isobutyloxy or pivaloyloxy, acetoacetoxy, amino or benzyloxycarbonylamino-lower alkanoyloxy, e.g., 2-amino- or 2-amino- Icaryl-1-amino-2-methyl-ipropyloxy-11a, aryl-lower alkanoyloxy wherein aryl is n 6 to 10 carbon atoms, e.g., benzoyloxy, phenylacetyloxy, 1- or 2-naphthyloxy, lower alkoxycarbonyl oxides, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, , sec-butoxy. tert-butoxy. n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy. n-hexoxy, isohexoxy, or n-heptoxycarbonyloxy, mono- or dialempkyl-aminocarbonyloxy, e.g. ethylaminocarbonyloxy or diethylaminocarbonyloxy, aryloxycarbonyloxy wherein aryl contains 6-10 carbon atoms or e.g. or 2-naphthyloxycarbonyloxy, aryl lower alkoxycarbonyloxy wherein aryl contains 6 to 14 carbon atoms, especially phenyl lower alkoxycarbonyl oxides, e.g. benzyloxycarbonyloxy, further 1- '·· *' or 2-naphthylmethoxycarbonyloxy or . · Methoxycarbonyloxy, sulfonyloxy, lower alkyl, • · sulfisloxy, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptylsulfo, ···, yloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy, 1- or 2 -naphthylsulfonyloxy, '· carboxy, esterified carboxy having a lower alkoxycarbonyl, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy. tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy or n-heptoxycarbonyl, aryloxycarbonyl wherein aryl contains from 6 to 10 114634 g of carbon atoms, e.g. phenyloxycarbonyl or 1- or 2-naphthyloxycarbonyl, aryl lower alkoxycarbonyl wherein aryl contains 6-12 carbon atoms, e.g. -butyl sulfonyl, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, one or two lower alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl. tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, e.g. N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, lower alkoxycarbonyl-lower alkyl, e.g. carboxymethylcarbamoyl (glycinylcarbonyl) or tert-butoxycarbonylmethylcarbamoyl, dialempalkylamino-lower alkyl, e.g. lower alkyl, e.g., hydroxymethyl or hydroxyethyl, and dialempalkoxy-lower alkyl, e.g., 2- (2,2-dimethoxyethyl) or one of ethylene, trimethyl: * * ethylene, tetramethylene and pentamethylene, where *: the carbon atom may be replaced by nitrogen, oxygen, sulfur or sulfur substituted with v * 'oxygen, which may be unsaturated, such as piperidin-1-yl, ··· pyrazin-1-yl, piperazin-1-yl, pyrimidin-1-yl, , pyridazin-1-yl, morpholino, thiomorpholino, or, •, S, S-dioxothiomorpholinocarbonyl-substituted carbamoyl, sulfamoyl, phosphono, benzofuranyl, oxo and / or cyano and is straight or branched: Y ; nut, for example benzoyl, which is unsubstituted; · *; mono- or polysubstituted with lower alkyl, e.g., methyl, phenyl, halogen, e.g., fluorine or chlorine, hydroxy, lower alkoxy, e.g., methoxy and / or nitro, such as 4-chloro, 4-methoxy or 4 -nitrobenzoyl, naphthylcarbonyl such as α- or β-naphthylcarbonyl or 1,8-naphthalenedicarbonyl bonded through an amino group, indenylcarbonyl such as 1-, 2- or 3-indenylcarbonyl, indanylcarbonyl such as 1- or 2-carbonyl , phenanthrenylcarbonyl such as 9-phenanthrenylcarbonyl, phenylacetyl, α-naphthylacetyl, O-naphthylacetyl, lower alkylphenylacetyl such as 4-methylphenylacetyl, loweralkoxyphenylacetyl such as 4-methoxyphenyl, -phenyl) propionyl / diphenylacetyl, di- (4-methoxy-phenyl) -acetyl, triphenylacetyl, 2,2-dibenzylacetyl, in the phenyl moiety with one or more lower alkyl, e.g. with or above ethyl, hydroxy, lower alkoxy, e.g., nethoxy, amino, mono- or dialempkylamino, e.g. ethylamino or dimethylamino, halogen, e.g., fluorine or chlorine, carboxy, sulfo, carbamoyl, sulfamoyl and cyano and / or amino benzyl-substituted anilinophenylacetyl such as' 2- (o, o-dichloroanilino) -phenylacetyl or 2- (o, o- ... · dichloro-N-benzylanilino) -phenylacetyl, 3-a- or • 3 -? - naphthylpropionyl , 2-benzyl-3- (1-pyrazolyl) -propionyl, 3-phenyl- or 3-a-naphthyl-hydroxy-propionyl, 3-phenyl- or 3-a-naphthyl-2-lower alkoxy-propionyl, such as 3-phenyl or 3-α-naphthyl-2-neopentyloxy-propionyl, 3-phenyl or 3-α-naphthyl-2-lower alkanoyloxy-propionyl such as 3-phenyl-2-pivaloyloxy or -2 -acetoxy-propionyl, 2-benzyl- or 1- or 2-dimethyl-3- (N-methoxymethylamino) propionyl, 3-α-f? style-2-asetoa cetoxy-propionyl, 3-a-naphthyl-2-ethyl -?, aminocarbonyloxy-propionyl or 3-a-naphthyl-2- (2-amino- or 2-benzyloxycarbonylamino-2-methyl-propionyloxy) - propionyl, 3-phenyl- or 3-a-naphthyl-2-carboxymethylpropionyl, 3-phenyl- or 3-a-naphthyl-2-lower-4-alkoxycarbonyl-propionyl, such as 3-a-naphthyl-2 -ethoxycarbonyl-propionyl, 3-phenyl- or 3-α-naphthyl-2-benzyloxycarbonylmethylpropionyl, 2- (S) -benzyl-3-tert-butylsulfonylpropionyl, 3-phenyl-2-phosphono- or -phosphonomethylpropionyl, 3- phenyl-2-dimethoxyphosphoryl or -dimethoxyphosphorylmethylpropionyl, 3-phenyl-2-diethoxyphosphoryl or -dethoxyphosphorylmethyl-propionyl, 3-phenyl-2-ethoxy- or methoxy-hydroxyphosphoryl-propionyl, phenyl-lower, wherein the alexinpalkanoyl residue is substituted with a carbamoyl such as 2 (R, S) -carbamoyl 3-phenylpropionyl, 3-phenyl or 3-a-naphthyl-2-carbamoylpropionyl, 3-phenyl or 3-an aftyl-2-tert-butylcarbamoylpropionyl, 3-phenyl or 3-a-naphthyl-2- (2-dimethylaminoethyl) carbamoylpropionyl, 3-a-naphthyl-2- (carboxy or tert-butoxycarbonyl) methylcarbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (3-hydroxy-2-propyl) -carbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2- (2,2- dimethoxyethyl) -carbamoylpropionyl, 3-phenyl- or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) -carbamoyl-propionyl, 3-phenyl- or 3-anaphthyl-2-cyano-propionyl- 1, 3-phenyl or 3-α-naphthyl-2-cyanomethyl-propionyl, 3-phenyl or 3-α-naphthyl-2-acetonyl-propionyl, • · 4-hydroxyphenylbutyryl, 4-phenyl or 4-α-naphthyl-3-carboxy-butyryl, 4-phenyl or 4-α-naphthyl-3-benzyloxycarbonyl-butyryl, 2-benzyl or 2-α-naphthylmethyl-4-cyano-butyryl , 2-benzyl-4- (2-benzofluorophenyl) -4-oxobutyryl, 2-benzyl or 2-o-naphthylmethyl-5-dimethylamino-pentanoyl, 2-benzyl or, *, 2- a-naphthylmethyl-4-ok sopentanoyl, 2-benzyl or 1-i; 2-a-naphthylmethyl-4,4-dimethyl-3-oxo-pentanoyl, 2- '···' benzyl- or 2-a-naphthylmethyl-5-dimethylamino-4-oxo-V-sopentanoyl, and 2-benzyl - or 2a-naphthylmethyl-5, 5-dimethyl-4-oxo-hexanoyl, preferably phenylalklexnepalkanoyl such as phenylacetyl, or phenyl-lower alkanoyl wherein the lower alkanoyl residue is substituted with carbamoyl such as 2 (R, S) -carbamoyl. 3-phenylpropionyl, 12-114634 as phenyl lower alkenoyl, such as β-phenylacryloyl or β-phenylvinylacetyl, heterocyclyl lower alkanoyl, wherein lower alkanoyl is unsubstituted or substituted with aryl lower alkanoyl, or is unsubstituted or substituted as defined above, - or especially via a nitrogen atom and containing up to 3 other heteroatoms selected from oxygen, nitrogen, sulfur, selenium and sulfur attached to 1 or 2 oxygen atoms, said ring order the system may additionally be annealed with 1 or 2 phenyl or naphthyl residues, wherein the naphthyl may also be linked by condensation via two sides, or it may be annealed with 1 or 2 cycloalkyl residues, in particular cycloalkyl containing 5-7 ring atoms, and may be unsaturated or partially or fully saturated, e.g., thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, tetrazolyl, • pyridyl, pyrazinyl; , pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, N, quinazolinyl, cinnolyl, purinyl, pteridinyl,:: naphthyridinyl, 4H-quinolizinyl, 3,1-benzfuranyl, benz [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, O-carbolinyl, phenazinyl, phenanthridyl -, acridinyl, phenoxazinyl, phenothiazinyl, 1- aza-acenaphthenyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexa [d] pyrazolyl, cyc-, · lohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohex [ b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl,, v, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidyl, 2-imidazolinyl, 2, 3-dihydro-pyridyl, piperidyl, piperazinyl, 2,3,5,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-114634 13 dioxo-thiomorpholinyl, indolinyl, isoindolinyl, 4 , 5,6,7-tetrahydro-indolyl, 1,2,3,4-tetrahydro-quinolyl, 1,2,3,4-tetrahydro-isoquinolyl, chromanyl, thiocromonyl, 1,2,3,4- tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tetrahydro-1 H- 5,1-benzazepinyl or 5,6-dihydrophenanthridinyl-alexnpialkanoyl wherein said heterocyclyl radicals are unsubstituted or substituted by lower alkyl, e.g., methyl, phenyl , 1- or 2-naphthyl, phenyl-lower alkyl, e.g., benzyl, hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hydroxy-ethyl, lower-alkoxy-lower-alkyl, e.g., methoxymethyl or 2-methoxy-ethyl, phenoxy or naphthoxy-lower, alkyl. , 1- or 2-naphthoxymethyl, phenyl-lower alkoxy or naphthyl-lower alkoxy-lower alkyl, e.g. benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, e.g. -naphthyloxy-methyl, -2-ethyl or -2- (2,2-dimethylethyl), lower alkoxycarbonyloxy-lower alkyl, e.g., tert-butyloxycarbonyloxy-lower alkyl, phenyl, naphthyl- or fluorenyl-lower alkoxycarbonyloxy-lower alkyl, e.g. , amino-lower alkyl, e.g., aminomethyl, 2- [beta] -aminoethyl, or 2-aminopropyl, carboxy-lower alkyl, *. alkyl, e.g. carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, e.g. methoxy or 1-ethoxy, phenyl or naphthyl lower alkoxy, e.g. benzyloxy or 1- or 2-naphthyloxy, amino, lower alkylamino, e.g. or tert-butylamino, dialempkylamino, e.g., dimethyl or diethylamino, carboxy, lower alkoxycarbonyl, e.g., methoxy, isopropoxy, sec-butoxy, or 1,6,64,14 tert-butoxycarbonyl. phenyl or naphthyl-lower alkoxycarbonyl, e.g. benzyloxycarbonyl, halogen, e.g. fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, e.g. , phosphono, hydroxy-lower alkoxy-phosphoryl or dialkoxy-phosphoryl, e.g. lower alkylcarbamoyl e.g. pyrrolylcarbonyl, 4- or 5-methylpyrrole ylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, thienylcarbonyl such as 2-thienylcarbonyl, furylcarbonyl such as 2-furyl | alkylcarbonyl, pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, optionally lower alkyl such as methyl, phenylthi lower alkyl such as benzyl, lower alkoxy, · Such as methoxy, phenyl-lower alkoxy, such as benzylic solutions, or indolylcarbonyl substituted with halogen, such as chlorine, such as 2-, 3-, or 5-indolylcarbonyl, 1-methyl, 5-methyl, 5-methoxy- , 5-benzyloxy, ···, 5-chloro or 4,5-dimethylindolyl-2-carbonyl, 1-benzylindolyl-2- or -3-carbonyl, 4,5,6,7- tetrahydroindolyl-2-carbonyl, optionally hydroxy-substituted quinolyl lower alkanoyl, e.g. quinolylcarbonyl such as 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, optionally hydroxy-substituted isoquinolylcarbonyl, such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-114634 15-3-carbonyl, 2-quinoxa linylcarbonyl, 2- (3,1-benzofuranyl) carbonyl, benz [e] indolyl-2-carbonyl, β-carbolinyl-3-carbonyl, cyclohepta [b] pyrrolyl-5-carbonyl, 3-chromanylcarbonyl, 3 thiochromanylcarbonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinyl-carbonyl such as 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl such as 5-oxopyrrolidinyl-2-carbonyl, piperidylcarbonyl 2 -, 3-tax 4-piperidinylcarbonyl, pyrazinylcarbonyl such as pyrazin-1-ylcarbonyl, piperazinylcarbonyl such as piperazin-1-ylcarbonyl, morpholinyl-lower alkanoyl, e.g. such as thiomorpholinecarbonyl, S, S-dioxothiomorpholinylcarbonyl, such as S, S-dioxothiomorpholinocarbonyl, indolinylcarbonyl, such as 2-tax 3-indolinylcarbonyl, 1,2,3,4-tetrahydro-quinolylcarbonyl, such as 1,2,3,4-tetrahydroquinol yl-2-, -3- or -4-carbonyl, 1,2,3,4-tetrahydroisoquinolylcarbonyl such as 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl; -oxo-1,2,3,4-tetrahydroisoquinolyl-3-carbonyl, tetrazolyl lower alkanoyl such as 3- (tetrazol-1-yl) propionyl, or pyridyl lower alkanoyl, e.g. pyridyl acetyl such as 2-, 3- or 4-pyridylacetyl, especially morpholinocarbonyl, thiomorpholinocarbonyl, S, S-dioxo-thiomorpholinocarbonyl, pyridylacetyl, indolylacetyl, benzfuranylacetyl, 4-pyrrolidinylacetyl, 1-imidazolylacetyl, ylacetyl, 2-morpholino-2-isopropyl-1 'acetyl or 2- (S, 5-dioxothiomorpholino) 2-isopropylacetyl, especially morpholinocarbonyl, thiomorpholinocarbonyl, quinolin-2-ylcarbonyl, 3- (tetrazole) -lv, yl) -propionyl or 2- or 3-pyridylacetyl, as a heterocyclyl-lower alkenoyl wherein the heterocyclyl is especially pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl, or benzanellated, cyclopenta, cyclohexa or cyclohepta-anellated derivatives thereof, which may be wholly or partially , e.g., pyrrolidinyl-lower alkenoyl such as N-pyrrolidyl-acryloyl, hydroxy-lower alkanoyl such as 3-hydroxypropionyl or 2-hydroxy-3-methylpentanoyl, hydroxy-lower alkoxy-lower alkanoyl, such as 3-hydroxy-in-alkoxy-lower alkoxy, -styl or lower alkoxypropionyl such as methoxyacetyl, ethoxyacetyl or 3-methoxypropionyl, lower alkoxy lower alkoxy-lower alkanoyl such as 2-methoxymethoxy-3-methylpentanoyl, t * ... or 4-nitrophenoxyacetyl, »* ·» a »* *. *: naphthoxy-lower alkanoyl as α- or β-naphthoxyacetyl: * ·· lower alkanoyloxy lower alkanoyl, where lower alkanoyloxy means e.g. acetoxy, propionyloxy, *, butyroxy, isobutyloxy or pivaloyloxy such as aceto · · ·; · Oxoacetyl or 3-acetoxypropionyl, V: acetoacetoxy-lower alkanoyl such as 3-acetoacetoxy-propionyl, amino- or benzyloxycarbonylamino-lower alkanoyloxy-lower alkanoyl, e.g. l, such as -acetyl or -3-propionyl, as aryl lower alkanoyloxy lower alkanoyl wherein aryl contains 6-10 carbon atoms such as benzoyloxy, phenylacetyloxy or 1- or 2-naphthyloxy-lower alkanoyl, lower alkoxycarbonyloxy-lower alkanoyl, e.g. ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy. tert-butoxy. n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy. n-hexoxy-, isohexoxy- or n-heptoxycarbonyloxy-lower alkanoyl, such as -acetyl or -3-propionyl, mono- or dialempkyl-amino-carbonyloxy-lower alkanoyl, e.g. e.g. methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl. tert-butyl, n-pentyl, iso-pentyl, neopentyl, tert-pentyl, n-hexyl, iso-hexyl or n-heptylsulfonyloxy-lower alkanoyl such as -acetyl or -3-propionyl, phenylsulfonyloxy, 2 - or 4-toluenesulfonyloxy- or 1- or 2-naphthylsulfonyloxy-lower alkanoyl, aryl mercapto-lower alkanoyl wherein aryl contains 6 to 10 carbon atoms and in particular represents phenyl or naphthyl, e.g. at the N-position, such as 5-aminopentanoyl, as the lower alkanoylamino-lower alkanoyl, wherein the amino group .. does not exist at the α or β position of the lower alkanoyl residue, such as 5-amino-pentaoyl, lower alkoxycarbonylamino-lower alkanoyl, where or β- * / ·; ' in a position such as 5- (tert-butoxycarbonylamino) -pentanoyl: T; li, .phenyl lower alkoxycarbonylamino-lower alkanoyl,, ···. wherein the amino group is not present at the o or • / 8-position of the lower alkanoyl residue such as 5-benzyloxycarbonylaminopentanoyl * * · '' tli or 6-benzyloxycarbonylaminohexanoyl, »

* I

heterocyclyl-lower alkanoyl as defined above for heterocyclyl-lower alkanoyl, R 6 or R 8, especially N-morpholino- or N-thiomorpholinocarbonyl as amino-substituted amino-lower alkanoyl, e.g. such as N-morpholino or N-thiomorpho-Lino-carbonylaminoacetyl, as a halogen lower alkanoyl containing in particular up to 3 halogen atoms, e.g. α-haloacetyl such as α-fluoro, α-chloro, α-bromo, α-iodine -, α, α, α-trifluoro or α, α, α-trichloroacetyl, or halopropionyl such as β-chloro or β-bromopropionyl, as a carboxy lower alkanoyl, e.g. carboxyacetyl or β-carboxypropionyl, lower alkoxycarbonyl lower alkanoyl, e.g. lower alkoxycarbonylacetyl or lower alkoxycarbonylpropionyl such as methoxycarbonylacetyl, 3-methoxycarbonyl-propionyl, ethoxycarbonyl-acetyl, 3-ethoxycarbonyl-propionyl or 3-tert-butoxycarbonylpropionyl, lower alkylcarbonyl-halo-lower alkanoyl, such as 3-ethoxycarbonyl-2-difluoromethyl-propionyl, •, 12-halo-lower alkoxycarbonyl-lower alkanoyl, • * 1 • -chloro, 2-bromo, 2-iodo or 2,2,2-trichloroethoxycarbonylacetyl or -3-propionyl, II t phenyl or naphthyl lower alkyloxycarbonyl lower alkanoyl, e.g. benzyloxycarbonyl lower alkanoyl, ··· · Such as 3-benzyloxycarbonyl-2,2-dimethylpropionyl, · · · as a heterocyclyl-lower alkoxycarbonyl-lower alkanoyl, in which the heterocyclyl is especially pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridyl, pyridyl, , quinolyl, isoquinolyl, quinoxalinyl or O-carbolinyl, or a benzanated, cyclopenta, 114634 20 cyclohexa or cyclohepta-anellated derivative of these residues, wherein said residues may also be present fully or partially saturated, such as 4-pyridylmethoxycarbonylacetyl or -3-propionyl or 2-morpholinocarbonyloxy-4-methyl-pentanoyl, sulfonyl-lower alkanoyl such as 3-sulfonyl-propionyl, lower alkyl-sulfonyl-lower-alkanoyl, tert-butylsulfonylacetyl, arylsulfonyl lower alkanoyl wherein aryl contains in particular 6-10 carbon atoms, e.g. alkyylikarbamoyyliasetyyli metyylikarbamoyylialempi- or alkanoyl, such as metyylikarbamoyyliasetyyli, • 'dialempialkyylikarbamoyylialempialkanoyylinä, e.g. di- or dimethylcarbamoyl alempialkyylikarbamoyyliasetyyli • v · lower alkanoyl, such as dimetyylikarbamoyyliasetyyli i' hydroksialempialkyylikarbamoyyli- or di- (hydroksialempi- alkyl) carbamoyl-lower alkanoyl, such as hydroxymethyl. stylcarbamoyl or di- (hydroxymethyl) carbamoyl-acetyl or -propionyl; :: N-lower alkoxy lower alkoxy lower alkyl carbamoyl: ··· lower alkanoyl such as 2-isobutyl-3- (2- (2-methoxyethoxy) ethylaminocarbonyl) propionyl, 21 114634 carboxy lower alkyl carbamoyl or di- (carboxyl) lower lower alkanoyl such as carboxymethyl or di- (carboxymethyl) carbamoylacetyl or propionyl, ethylene, trimethylene, tetramethylene or penta-methylene, where the carbon atom may be substituted with one or two times substituted nitrogen, oxygen, sulfur or oxygen sulfur, nitrogen-substituted carbamoyl-lower alkanoyl, wherein the residue thus formed may also be wholly or partially unsaturated, e.g., piperidin-1, pyrazin-1-yl, piperazin-1-yl, pyrimidin-1-yl, pyridazin 1-yl, morpholino, thiomorpholino or S, S-dioxothiomorpholinocarbonyl lower alkanoyl such as morpholinocarbonylacetyl, 3- (morpholinocarbonyl) propionyl or 3- (morpholinocarbonyl) -2-i sobutyl-propionyl, N-heterocyclyl-lower alkyl-carbamoyl-lower-alkanoyl or N-lower-alkyl-N-heterocyclyl-lower alkyl-carbamoyl-lower alkanoyl, in which the heterocyclyl is especially pyrrolyl, furyl, thienyl, imidazol; racolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, γ-carbolinyl, or benz-, α-anellated, cyclopenta, cyclohexa- or cyclohepta-anel of these residues; a derivative which may also be wholly or partially saturated, morpholinyl and thiomorpholinyl, such as N-methyl-2- (N-2-pyridylmethyl) -carbamoylacetyl, 2- (N-morpholino-lower alkyl-carbamoyl)-lower- Canoyl such as 2 (R, S) - (N- (2-morpholinoethyl) -carbamoyl; · -1-methyl-butyryl, or 2- (N- (pyridyl lower alkyl) carbamoyl) lower alkanoyl such as ( 2 (R, S) - (N- (2-Pyridylmethyl) carbamoyl) -3-methyl) butyryl, as sulfamoyl lower alkanoyl such as 2-sulfamoylacetyl, 114634 22 N- (Phenyl or naphthyl lower alkyl) sulfamoyl lower- alkanoyl such as 3-benzylaminosulfonyl-2-isopropylpropionyl, on the nitrogen atom with ethylene, trimethyl, tetramethylene and pent amethylene, where the carbon atom may be replaced by nitrogen, lower alkyl such as methyl substituted nitrogen, oxygen, sulfur or oxygen as sulfur substituted by sulfamoyl lower alkanoyl, whereby the residue thus formed may also be wholly or partially unsaturated e.g. -, pyrazin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino or S, S -dioxothiomorpholinosulfonyl-lower alkanoyl such as 3- (4-methylpiperazinylsulfonyl) -2-isopropyl-propionyl or 3- (morpholinosulfonyl) -2-isopropyl-propionyl, oxo-lower alkanoyl such as acetoacetyl or propionyl-acetyl, cyano, or 3-cyanopropionyl or 2-, 3- or 4-cyanobutyryl. ·· as hydroxy-carboxy-lower alkanoyl such as 2-hydroxy-2V: carboxyacetyl or 2-hydroxy-3-carboxypropionyl, j. as α-naphthoxy-carboxy-lower alkanoyl such as 2-α-naphthoxy-4-carboxy-butyryl, 1-hydroxy-lower alkoxycarbonyl-lower alkanoyl, e.g.

hydroxy-lower alkoxycarbonyl-acetyl or -propionyl: or hydroxy-ethoxy or hydroxy-methoxy-carbonyl-lower alkanoyl such as 2-hydroxy-2-ethoxy or -methoxycarbonylacetyl or 2-hydroxy-3-ethoxy or - methoxycarbonyl-propionyl, 114634 23 as α-naphthoxy-lower alkoxycarbonyl-lower alkanoyl, e.g. α-naphthoxy-lower alkoxycarbonyl-acetyl, -propionyl or -butyryl or α-naphthoxy-ethoxycarbonyl | lower alkanoyl such as α-naphthoxy-ethoxycarbonyl-acetyl, 2-α-naphthoxy-3-ethoxycarbonyl-propionyl or 2-α-naphthoxy-4-tert-butoxycarbonyl-butyryl, α-naphthoxy-benzyloxycarbonyl-lower alkanoyl, such as -3-benzyloxycarbonyl-propionyl, esterified as hydroxy-lower alkoxycarbonyl-lower alkanoyl, wherein the hydroxy group is esterified with lower alkanoyl, e.g. , e.g., cyclohexylcarbonyl or 2-cyclohexyl or 2-cyclopentylacetyl, bicycloalkyl lower alkanoyl wherein bicycloalkyl contains e.g. 5-10, especially 6-9 carbon atoms such as; - bicyclohexyl, -heptyl, -octyl, - or -decylacetyl or -3-propionyl, e.g. bicyclo [3.1.0] hex-1-, -2- or -3-yl, bicyclo [4.1.0] hept-1 '··' or - 7 yl, bicyclo [2.2. 1] hept-2-yl such as endo or exo-norbornyl, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.0] oct-3-yl or bicyclo [3.3.1 ] non-9-yl, further i-α or β-decahydronaphthylacetyl or -3-propionyl, tricycloalkyl lower alkanoyl with tricycloalkyl. alkyl contains, for example, 8-10 carbon atoms, e.g., tricyclo '\ [5.2.1.O2 · 6] dec-8-yl or adamantyl such as 1-adamantylacetyl, with aryl lower alkanoyl wherein aryl contains 6-14 carbon atoms, e.g., phenyl, indenyl, ..., indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, which may be unsubstituted or substituted one to three times lower * 1 alkyl such as isopropyl, halogen lower alkyl such as trifluoromethyl, hydroxy, lower alkoxy, carbamoyl lower alkoxy, N-lower alkylcarbamoyl lower alkoxy or N, N-dialempalkylcarbamoyl, lower alkoxy, mono, chlorine or bromine, carboxy, lower alkoxycarbonyl, phenyl, naphthyl or fluorenyl lower alkoxycarbonyl, lower pialkanoyl, lower alkyl sulfonyl, e.g. methyl sulfonyl, with phosphono, hydroxy-lower alkoxy-phosphoryl or dialem-alkoxyphosphoryl, carbamoyl, mono- or dialem-alkyl-aminocarbamoyl, sulfamoyl, mono- or dial-alkyl-alkylsulfamoyl, nitro and / or cyano, further lower alkoxycarbonyl, e.g. as defined above, or phenyl or fluorenyl-lower alkoxycarbonyl, e.g., benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, such as α-acetoxy-α-methoxycarbonyl-acetyl, α-benzoyloxy, α- (1- or 2-naphthyloxy) -,? - (phenyl-2-acetyloxy),? - (1- or 2-naphthyl-2-acetyloxy),? - (4-methylphenyl-2-acetyloxy) -,? - (4 -methoxyphenyl-2-acetyloxy) - or α- (2- (o, o-dichlorophenyl) -2-acetyloxy) -α-methoxycarbonylacetyl, * · → as dihydroxycarboxy-lower alkanoyl, such as 2,3-dihydro-N * hydroxy-3-carboxy-propionyl, dihydroxy-lower alkoxycarbonyl-lower alkanoyl, etc. 2,3-Dihydroxy-3-ethoxy- or -methoxycarbonyl-pro * · »·. ···. pionyl, '· "· lower alkanoyl such as acetyl, propionyl or butyryl, lower alkoxycarbonyl, e.g. 114634 25 as alkoxycarbonyl-lower alkanoyl, e.g., dialempalkanoyloxy-lower alkoxy-propionyl, such as 2,3-diacetoxy-3-methoxycarbonyl-propionyl, α-naphthoxy-dialempalkylamino-lower alkanoyl, such as 2-α-naphthoxy- pentanoyl, α-naphthoxy-carbamoyl-lower alkanoyl such as 2-a-naphthoxy-4-carbamoyl-butyryl, α-naphthoxy-oxo-lower alkanoyl such as 2-a-naphthoxy-4-oxo-pentanoyl, α-naphthoxy -cyano lower alkanoyl such as α-naphthoxy-cyano-acetyl or 2-α-naphthoxy-4-cyanobutyryl, lower alkenoyl having 3 to 7 carbon atoms, especially 3 to 4 carbon atoms, wherein the lower alkenoyl may be unsubstituted or substituted with the same substituents as the lower alkanoyl, especially phenyl, hydroxy, lower alkoxy such as methoxy, phenyl lower alkoxy such as benzyloxy, lower alkanoyloxy such as acetoxy, lower alkanoylamino such as acetoxy, lower alkanoylamino, hydroxy, phenyl or naphthyl lower alkoxycarbonyl, such as benzyloxycarbonyloxy, carboxyl, lower alkoxycarbonyl, such as tert-butoxycarbonyl, phenyl or naphthyl lower alkoxycarbonyl, halo or monomer, halo, - or dialempalkylcarbamoyl such as acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, 3-phenylacryloyl, 3-phenylvinylacetyl or 5-phenyl-4-acetylaminopen-2-ylalkyl, cycloalkyl, in particular 3-7 carbon atoms, e.g. cyclohexylacryloyl, or 26-14634 as lower alkynyl having 3-7, especially 3 or 4 carbon atoms, e.g. propioloyl or 2- or 3-butinoyl.

Preferred acyl groups R 2 and R 8 of the carbonic acid semi-ester are lower alkoxycarbonyl, e.g. -, 2-iodo or 2,2,2-trichloroethoxycarbonyl, aryloxycarbonyl wherein the aryl contains 6-14 carbon atoms and is e.g. phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl or lower alkyl, e.g. methyl or tert-butyl. hydroxy, lower alkoxy, e.g., methoxy, ethoxy or tert-butoxy. phenyl mono- or polysubstituted by halogen, e.g. chlorine or bromine and / or nitro, such as phenyloxycarbonyl, aryl-lower alkoxycarbonyl, e.g. arylmethoxycarbonyl: aryl having 6 to 14 carbon atoms and being: for example, phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl, or lower alkyl, e.g., methyl or tert-butyl, hydroxy, lower alkoxy, e.g., ethoxy, ethoxy or tert-butoxy. phenyl substituted by mono- or polysubstituted by halogen, e.g., chlorine or bromine and / or nitro, e.g., phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, 4-methoxybenzyl-· · * * oxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenyl-lower alkoxycarbonyl such as diphenylmethoxycarbonyl,. : di- (4-methoxyphenyl) -methoxycarbonyl, trityloxycarbonyl or fluorenyl-lower alkoxycarbonyl, such as 9-fluorenylmethoxycarbonyl, particularly preferably benzyloxycarbonyl, 27-114634 heterocyclyl-lower alkoxycarbonyl, where heterocyclyl-ethyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl, or benzanellated, cyclopenta, cyclohexa or cyclohepta-anellated derivative of these residues, which may also be wholly or partially saturated and / or may be unsubstituted or substituted, especially with lower alkyl such as methyl such as 1-methylpyrrolidin-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, 2-tetrahydrofuranyl lower alkoxycarbonyl such as 2-tetrahydrofuranylmethoxycarbonyl, 1-methyl methoxycarbonyl or 2-morpholine o-ethoxycarbonyl, or 2-, 3-, or 4-pyridylmethoxycarbonyl, 2-trialempkylsilyl-lower alkoxycarbonyl, such as 2-trimethylsilyloxycarbonyl, or 2-triaryl-silyl-lower alkoxycarbonyl, wherein aryl, phenyl is 1- or 2-yl, or 1- or 2-yl; ethoxycarbonyl.

Preferred acyl groups of unsubstituted or substituted carbamic acid - and R 9 are, besides the already mentioned preferred acyl groups ^ and R 9 - carbamoyl or * ·

I I

/ t unsubstituted or substituted N-alkyl or N, N-dial- »· · '* alkylcarbamoyl having up to 12 carbon atoms in the alkyl group, especially unsubstituted or substituted' lower alkyl or dialem-alkylcarbamoyl such as methyl, ethyl, propyl -, tert -butyl, dimethyl, diethyl or di-n-propylcarbamoyl, wherein the substituents are phenyl, e.g. benzylcarbamoyl, N-phenyl lower alkyl-N-lower alkylcarbamoyl, such as 114634 28 N-benzyl-N -methylcarbamoyl, or dibenzylcarbamoyl, heterocyclyl, as defined for heterocyclyl-lower alkanoyl and Rg, and in particular thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pheridine yl, naphthyridinyl, 4H-quinolizinyl / 3,1-benzofuranyl, benz [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, 3-carbolinyl, phenazinyl, phenanthridyl, acridinyl, phenoxazinyl , phenothiazinyl, 1-aza-acenaphthenyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexa [d] pyrazolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5 , 6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxothio-morpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetra-'hydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2 , 3,4-Tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benz-. : oxazinyl, 3,4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-dihydro-phenanthridinyl, said residues being substituted. ·· *. unsubstituted or substituted by lower alkyl, e.g. methyl, phenyl, 1- or 2-naphthyl, phenyl lower alkyl, e.g. benzyl, hydroxy lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, lower alkoxy lower alkyl, e.g. 2-phenoxyethyl, 1- or 2-naphthoxymethyl, phenyl-lower alkoxy or naphthyl-lower alkoxy-lower alkyl, e.g. benzyloxy-lower alkyl, lower alkanoyloxy-lower. naphthyl-lower alkanoyloxy-lower alkyl, e.g. benzoyloxy, phenylacetyloxy or 1- or 2-naphthyloxy-methyl, -2-ethyl or -2- (2,2-dimethylethyl), lower alkoxycarbonyloxy-lower alkyl , e.g., tert-butyloxycarbonyloxy lower alkyl, phenyl, naphthyl or fluorenyl lower alkoxycarbonyloxy lower alkyl, e.g. 2-benz cyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, e.g. aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy-lower alkyl, e.g. or naphthyl-lower alkoxy, e.g., benzyloxy or 1- or 2-naphthylmethoxy, amino, lower alkylamino, e.g. methyl, ethyl or tert-butylamino, dialempalkylamino, e.g., dimethyl or diethylamino, carboxy, lower alkoxy, with methoxy, isopropoxy, sec-butoxy or tert-butoxycarbonyl. phenyl or naphthyl lower pialkoxycarbonyl, e.g. benzyloxycarbonyl, halogen, e.g. fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, e.g. acetyl or pivaloyl, lower alkyl: e.g., methyl or ethylsulfonyl, phospholone, hydroxy-lower alkoxyphosphoryl or dialkoxy-phosphoryl, e.g. dimethoxy or diethoxyphosphoryl, Mί <, ··, carbamoyl, mono- or dialempkylcarbamoyl, [· e.g. N-methylcarbamoyl butylearbamoyl

* I I

'Or', Ν, Ν-dimethylcarbamoyl, hydroxy or carboxy-lower alkylcarbamoyl, e.g., hydroxy or carboxymethylcarbamoyl or hydroxy or carboxyethylcarbamoyl, sulfamoyl, nitro, oxo and / or cyanol, such as 2-, 3- or 4-pyridyl, preferably N-heterocyclyl-lower alkyl-N-lower-alkyl-carbamoyl, e.g. N-pyridyl-lower-alkyl-N-lower-alkyl-carbamoyl, such as N- (2-, 3- or 4-pyridylmethyl) -N-methylcarbamoyl, or N-heterocyclyl-lower alkylcarbamoyl, e.g. 2- or 3-pyridyl-lower alkylaminocarbonyl such as 2- or 3-pyridylmethylaminocarbonyl, hydroxy, e.g. hydroxymethyl 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, N-dihydroxy-lower alkyl such as 2,3-dihydroxy-n-propyl or 2-hydroxy-2,2-dimethylethyl, lower alkoxy, especially lower alkoxy lower alkyl, e.g. methoxymethyl or 2-methoxyethyl, Alem-pialkanoyloxy, especially lower alkanoyloxy-lower alkyl, e.g. , aryloxy or aryloxy and hydroxy wherein the aryl has 6 to 14 carbon atoms such as phenyl, naphthyl or fluorenyl, especially aryloxy-lower alkyl or aryloxy-hydroxy-lower alkyl such as phenyloxymethyl, 2-phenyloxyethyl, 1- or 2-naphthyloxymethyl - or in 2-naphthyloxyethyl, or in 2-phenyl-2-hydroxyethyl, wherein the aryl is unsubstituted or substituted once or twice, for example, lower; methyl, ethyl, propyl, iso-

»* I

V: with propyl, butyl, sec-butyl or tert-butyl, hydroxy, lower alkoxy, e.g., nethoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy, carboxy, lower alkoxy, *> carbonyl, e.g. isopropoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl, or carbamoyl, lower alkyl or dialempalkylcarbamoyl;

And / or mono- or di- (hydroxy or carboxy-lower alkyl) carbamoyl and said substituents may exist at various ring positions, e.g., 4-methylphenyl oxides, 2,4,5-trimethylphenyloxy, 4-hydroxyphenyl-oxy, , 4-methoxyphenyloxy, 3,5-dimethoxyphenyloxy, 2-carboxyphenyloxy, 2-tert-butoxycarbonyl-phenyl-yloxy, 2- or 4-carbamoyl-phenyl-oxy, carbamoyl, carboxy-lower alkylcarbamoyl or hydroxy-allyl-carbamoyl, 4-carbamoyl, , 7-carbamoyl-n-heptyl, 2-hydroxyethylcarbamoyl-n-butyl or 4- (tris [hydroxymethyl] -methyl) -carbamoyl-n-butyl, further in amino, e.g. 2-aminoethyl or 3-aminopropyl , lower alkylamino, e.g., methyl or ethylaminomethyl, dialempalkylamino, e.g., dimethylaminomethyl, halogen, especially fluorine, chlorine or bromine, e.g., 2,2,2-trichloroethyl, sulfo, e.g. sulfomethyl or 4-sulfobutylamino, and -famoyl, e.g. in 2-sulfamoylethyl.

Preferred acyl groups of the unsubstituted or substituted N-substituted oxalamide and R 9 are oxamoyl or lower alkyl oxamoyl such as methyl or ethyl oxamoyl.

Preferred acyl groups of the unsubstituted or substituted amino acid R 1 and R 9 are formed by the amino acid residues of the α- or β- 'amino acid, especially the natural α-amino acid of L configuration, such as v, or the epimer of such amino acid, m.p. it has an unnatural '·· D configuration, or a mixture of D, L isomers thereof, of such an amino acid homologue, e.g., wherein the amino acid side chain is, elongated or truncated by one or two methylene; * · A substituted aromatic amino acid having an aromatic residue at the 3-position and / or where the methyl group is replaced with hydrogen; 6 to 14 carbon atoms, e.g., substituted phenylalanine or; phenylglycine wherein the phenyl substituent may be lower alkyl, e.g. methyl, hydroxy, lower alkoxy, e.g., methoxy, lower alkanoyloxy, e.g. acetoxy, amino, lower alkylamino, e.g. methylamino, dialempalkylamino, e.g. dimethylamino, lower dimethylamino, lower dimethylamino, acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. / or nitro and is present one or more times in the presence of benzanellated phenylalanine or phenylglycine such as α-naphthyl or hydrogenated phenylalanine or phenylglycine such as cyclohexylalanine or cyclohexylglycine.

These amino acids may be substituted in the free amino or hydroxy functions, particularly in the free amino function by any of the above acyl Rx, carboxylic acid, carbonic acid half-ester, unsubstituted or N-substituted carbamic acid or unsubstituted or unsubstituted or substituted N-substituted oxalamide alkyl, aryl-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl, sulfon, alkyl, aryl, aryl-lower alkyl, heterocyclyl-lower alkyl, alkoxy, aryloxy, aryl-lower alkoxy or hetero-cycloalkyl-substituted alkyl, '·. the phosphoryl substituted with Rj ^ or R9 is substituted with a cycloalkyl, cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, hydroxy, alkoxy, cycloalkyl-alkoxy, aryloxy and .. or with a residue mentioned as one of the protecting groups in the methods section.

114634 33

Particularly preferred is the glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (α-aminovaleric acid), leucine (H-Leu) bonded via the carboxy group of the amino acid. OH), isoleucine (H-Ile-OH), norleucine (α-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (α-amino-7-hydroxybutyric acid), threonine (H) -Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe- OH), Tyrosine (H-Tyr-OH), 4-Aminophenylalanine, 4-Chlorophenylalanine, 4-Carboxyphenylalanine, N-Phenylserine (5S-Hydroxyphenylalanine), Phenylglycine, α-Naphthylalanine (H-Nal-OH), Cyclohexane cyanoalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp- OH), Asparagine (H-Asn-OH), Aminomalonic acid, Aminomalonic acid monoamide, Glutamic acid (H-Glu-OH), Glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), δ-hydroxylysine, ornithine (α, δ-diaminovaleric acid), 3-aminopropanoic acid, ', a, 7-diaminobutyric acid and α, β-diaminopropionic acid, particularly preferably an aliphatic amino acid residue, which amino acid is alanine, alanine, leucine and isoleucine, or amino acid residue which is glycine, glutamic acid and aspartic acid , wherein (with the exception of glycine), each of the said amino acids may be present in D, L or (D, L), especially (except Val, which may also occur in (D) - ** or (D, L) ) form) in the L form, • the N- (α-amino group is unsubstituted or singly or twice) • N-alkylated, e.g. with a lower alkyl such as methyl or n-propyl, an amino lower alkyl such as 3-aminopropyl, phenyl - or a naphthylamino lower alkyl such as 3-phenylaminopropyl, or a lower alkyl such as methyl, with nitrogen-substituted piperazinyl or aryl lower alkyl such as 4-methylpiperazinylcarbonyl! 114634 34 limethyl, or is N-acylated e.g. with lower alkanoyl such as acetyl, aryl lower alkanoyl wherein aryl is phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and may be unsubstituted or especially mono- three times substituted with lower alkyl, e.g. methyl, ethyl or propyl, halogen lower alkyl, e.g. trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, e.g. methoxy, carbamoyl lower alkoxy, N-lower alkoxy, N-lower alkoxy, N-dialem-pialkylcarbamoyl-lower alkoxy, amino, mono- or dial-alkyl alkylamino, lower-alkanoylamino, e.g. pivaloyl-amino, halogen, e.g. -oxycarbonyl, lower alkanoyl, sulfo IIa, Alem-dialkylsulfonyl, e.g. methylsulfonyl, phospholol, hydroxy-lower alkoxy-phosphoryl or dialkylalkoxyphosphoryl, carbamoyl, mono- or dialkylalkylcarbamoyl, sulfamoyl, mono- or dialkylalkylaminosulfonyl, The '···' created phenyl can occur up to three times, e.g.

• 1 2 3 I

'Diphenyl, dibenzyl or triphenyl-lower alkanoyl-2' such as diphenyl, dibenzyl or triphenylacetyl, and the lower alkanoyl is unsubstituted or substituted with, e.g., lower alkyl, e.g. methyl, heterocyclyl, which is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazol , thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl ,; isoquinolyl, quinoxalinyl,? -carbolinyl, or a benzo, cyclopenta, cyclohexane or cycloheptane annealed derivative of these residues, which may also be wholly or partially saturated, hydroxy, lower alkoxy, lower alkanoyloxy, e.g. With acetoxy, propionyloxy, butyroxy, isobutyroxy or pivaloyl 714634 | Hydroxyacetoxy, amino or benzyloxycarbonylamino-lower alkanoyloxy, e.g. - or 2-naphthyloxy, lower alkoxycarbonyl, e.g. methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, npentoxy- , isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy or n-heptoxycarbonyloxy, mono- or dialempkylalkylaminocarbonyl, e.g. ethylaminocarbonyloxy or diethylaminocarbonyloxy, aryloxycarbonyloxy, , e.g., phenyloxycarbonyloxy or 1- or 2-naphthyloxycarbonyloxy, aryl lower alkoxycarbonyloxy wherein aryl contains 6 to 14 carbon atoms, especially phenyl lower alkoxycarbonyloxy, e.g. be oxyloxycarbonyloxy, further 1- or 2-naphthylmethoxycarbonyloxy, or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, lower alkylsulfonyloxy, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, tert-pentyl. n-hexyl, isohexyl: or n-heptylsulfonyloxy, or phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy, or 1- or 2-naphthylsulfonyloxy, carboxy, esterified carboxyl, e.g. lower alkoxycarbonyl, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, si, sec-butoxy. tert -butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxycarbonyl, aryloxycarbonyl ,; wherein aryl contains 6-10 carbon atoms, e.g., phenyloxycarbonyl or 1- or 2-naphthyloxycarbonyl, aryl lower alkoxycarbonyl wherein aryl contains 6-12 carbon atoms, e.g., benzyloxycarbonyl, 1- or 114634 36 2-naphthylmethyloxycarbonyl, or 9-fluorocarbonyl, lower alkanoyl, lower alkylsulfonyl, e.g. methyl or tert-butylsulfonyl.

hydroxy-lower alkoxyphosphoryl, and dial-lower alkoxyphosphoryl, carbamoyl, one or two lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. n-pentyl, isopentyl, neopentyl, tert-pentyl. with n-hexyl, isohexyl or n-heptyl, e.g. .

dialempalkylamino lower alkyl, e.g. 2-dimethylaminoethyl, arainocarboxy lower alkyl, e.g.

5-amino-5-carboxypentyl, hydroxy-lower alkyl, e.g., hydroxymethyl or hydroxyethyl, or di-lower alkoxy-lower alkyl, e.g., 2- (2,2-dimethoxy-, ethyl), or one ethylene, trimethylene,. tetramethylene or pentamethylene wherein the carbon atom ... may be replaced by nitrogen, oxygen, sulfur and once or twice substituted oxygen, sulfur and which may be unsaturated such as piperidino, pyrazin-1-yl, 1-yl, pyrimidin-1-yl, pyridazin-1-yl, v-morpholino, thiomorpholino or S, S-dioxothiomorpholinocarbonyl, substituted carbamoyl, sulfamoyl, ··· phosphono, benzofuranyl, oxo and / or cyano and is unbranched or branched, in particular aryl lower. canoyl wherein aryl contains 6 to 14 carbon atoms and; · Is unsubstituted or substituted e.g.

With a compound such as 2-benzyl-3-pivaloylpropionyl, or: with a lower alkylsulfonyl such as 2-benzyl-3-tert-? butylsulfonylpropionyl, with phenyl lower alkanoyl being particularly preferred, e.g. -, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl -, purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1-benzfuranyl, benz [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl, O-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl, phenothiazinyl, 1-aza-acenaphthenyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohex [ d] pyrazolyl, cyclohexa [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1, 4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3, 5,6-Tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxo-dioxioxynorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4 -tetrahydroquinolyl, 1,2,3,4-tetrahydroiso-, quinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H- 4,1-benzoxazinyl: 3,4-dihydro-3H-4,1-benzthiazinyl, 2,3,4,5-tet-; Rahydro-1H-5,1-benzazepinyl and 5,6-dihydrophenanthridi [not] vinyl-lower alkanoyl wherein said heterocyclyl radicals are unsubstituted or substituted by lower alkyl, e.g. methyl, phenyl, 1- or 2-naphthyl -

Alkyl, phenyl-lower alkyl, e.g., benzyl, hyd, hydroxy-lower alkyl, e.g., hydroxymethyl or 2-hyd-; / roxyethyl, lower alkoxy lower alkyl, e.g.

methoxymethyl or 2-methoxyethyl, phenoxy or; ; naphthoxy lower alkyl, e.g. 2-phenoxyethyl, 1- or: ··· 2-naphthoxyethyl, phenyl lower alkoxy or naphthyl lower alkoxy lower alkyl, e.g. benzyloxy lower alkyl, lower alkanoyloxy lower alkyl, e.g.

114634 38 with acetyloxymethyl, phenyl or naphthyl-lower alkanoyloxy-lower alkyl, e.g. benzoyloxy, phenylacetyloxy or 1- or 2-naphthyloxy-methyl, -2-ethyl or -2- (2,2-dimethylethyl): lower alkoxycarbonyloxy lower alkyl, e.g. tert-butyloxy lower alkyl, phenyl, naphthyl or fluorenyl lower alkoxycarbonyloxy lower alkyl, e.g. 2-benzyloxycarbonyloxyethyl or 9-fluorenylmethoxycarbonyloxy. , carboxy lower alkyl, e.g. carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, e.g. methoxy or ethoxy, phenyl or naphthyl lower alkoxy, e.g. benzyloxy or 1- or 2-naphthylmethoxy, amino, lower alkylamine, e.g. ethyl or tert-butylamino, dialempkylamino, e.g. dimethyl or diethylamino, carboxy, lower alkoxycarbonyl, e.g., methoxy, isopropoxy, sec-butoxy or tert-butoxycarbonyl, phenyl or naphthyl-lower alkoxycarbonyl. benzyloxycarbonyl, halogen, e.g.

fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, e.g. acetyl '' or pivaloyl, lower alkylsulfonyl, e.g. : ethyl or ethylsulfonyl, phosphono, hydroxy-lower alkoxy-phosphoryl or dialkoxy-phosphoryl, e.g.

dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or dialem-alkylcarbamoyl, e.g. N-methylcarbonyl ···. bamoyl, N-n-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy or carboxy-lower alkylcarba- '; moyl, e.g. hydroxy or carboxymethylcarbamoyl or hydroxy or carboxyethylcarbamoyl, sul; famoyl, nitro, oxo and / or cyano, e.g. pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl, 3,4-dihydroxypyrrolidinylcarbonyl, N-benzyloxycarbonyl-piperidin-4-ylcarbonyl, 1- 114634 39 methylpiperazin-4-ylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, S, S-dioxothiomorpholinocarbonyl, indol-2-ylcarbonyl, quinol-2-ylcarbonyl, pyridylacetyl, such as 2- or 3-dimethyl, imidazol-2-yl, -1-ylacetyl, morpholinylacetyl such as morpholinoacetyl, pyridylpropionyl such as 3- (2- or 3-pyridyl) propionyl, pyrrolidinylpropionyl such as 3- (4-pyrrolidinyl) propionyl, morpholinylpropionyl such as 3-morpholinyl, -solylpropionyl such as 3- (tetrazol-1-yl) -propionyl, heterocyclyl-lower alkenoyl, in which the heterocyclyl is especially pyrrolyl, furyl, thi enyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, δ-carbolinyl, or the benzanellated, cyclopentan, cyclohexane, or cycloheptaanated derivatives of these residues saturated or partially saturated, e.g., pyrrolidyl-lower alkenoyl, such as N-pyrrolidyl-acryloyl, halogen-lower alkanoyl containing up to 3 ha-halogen atoms, e.g., α-haloacetyl, such as α-fluoro, α-chloro, α- bromine, c * iodine, α, α, α-trifluoro-or α, α, α-trichloroacetyl, or halo-propionyl such as 3-chloro or 3-bromopropionyl, lower alkoxycarbonyl such as tert. -butoksikarbonvvlillä. aryl lower alkoxycarbonyl wherein aryl contains 6 to 14 carbon atoms and is e.g. phenyl, naphthyl or fluorenyl, e.g. thienyl, V: imidazolyl, pyrazolyl, oxazolyl, thiazolyl, • pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinyl, isoquinolyl, quinoxalinyl, O-carbolinyl, or benzanellated, cyclopenta, cyclohexane-114634 or cyclohexan-4-cyclohexyl which may also be wholly or partially saturated and unsubstituted or substituted in particular with lower alkyl such as methyl, e.g. 1-methylpyrrolidin-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, tetrahydrofuranyl-lower alkoxycarbonyl, with ylmethoxycarbonyl, 1-methyl-2 -piperidyl-methoxycarbonyl or 2-morpholino-ethoxycarbonyl, carboxyl-lower alkanoyl such as 3-carboxy-propionyl, 5-carboxypentanoyl or 6-carboxy-hexanoyl, lower-alkoxycarbonyl-oxy-carboxyl such as 5-methoxycarbonyl 3-hydroxy-n-propoxycarbonyl, amino-lower alkanoyl wherein the amino group is not in the lower or lower position of the lower alkanoyl residue, such as 5-aminopentanoyl, phenyl-lower alkoxycarbonylamino-lower alkanoyl, the amino group is not in the lower alkanoyl, such as 5-benzyloxycarbonylaminopentanoyl or 6-benzyloxycarbonylaminohexanoyl, in the amino nitrogen with heterocyclyl-lower alkanoyl, especially as defined above for heterocyclyl-lower alkanoyl, R ^ or R b tai, especially N-morphol • favorite alkanoyl, e.g.

v · 'N-morpholino or N-thiomorpholino-carbonylamino-lower alkanoyl such as N-morpholino or N-thiomorpholino-carbonyl ··ylamino-acetyl, · · ·, carbamoyl, phenyl-lower alkylaminocarbonyl,' · ' , N-dialempalkylamino-lower alkyl-N-lower alkylaminocarbonyl such as N- (2-dimethylamino) ethyl-N-methylaminocarbonyl, N-, dihydroxy lower alkyl-N-lower alkylaminocarbonyl such as N- (2,3-dihydroxy) -N -methylaminocarbonyl, N-heterocyclyl-lower alkyl-N-lower alkyl-114634 41 carbamoyl, in which the heterocyclyl is especially thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, iso-oxazolyl, thiazolyl, thiazolyl, thiazolyl, , pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl, naphthyridine yl, 4H-quinolizinyl / 3,1-benzfuranyl, benz [e] indolyl, 4,1-benzoxazinyl, 4,1-benzthiazinyl, carbazolyl,? -carbolinyl, phenazinyl, phenanthridyl- , acridyl, phenoxazinyl, phenothiazinyl, 1-aza-acenaphthenyl, cyclohexa [b] pyrrolyl, cyclohepta [b] pyrrolyl, cyclohexa [d] pyrazolyl, cyclohex [b] pyridyl, cyclohexa [b] pyrazinyl, cyclohexa [b] pyrimidinyl, cyclohexa [b] -1,4-oxazinyl, cyclohexa [b] -1,4-thiazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S, S-dioxo-thiomorpholinyl, indolinyl- , isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl, thiochromanyl, 1, 2,3,4-Tetrahydro-3,1-benzdiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-N-benzothiazinyl, 2,3 , 4.5 -tetrahydro-1H-5,1-benzazepinyl or 5,6-dihydrophenanthridinyl wherein said residues are unsubstituted or substituted with lower alkyl, e.g. methyl, phenyl, 1- or 2-naphthyl;

Benzyl, hydroxy lower alkyl, e.g. hydroxymethyl or 2-hydroxyethyl, lower alkoxy lower alkyl, e.g., methoxymethyl or 2-methoxyethyl, phenoxy or naphthoxy lower alkyl, e.g. - or 2-naphthoxymethyl, phenyl-lower alkoxy or naphthyl-lower alkoxy-lower alkyl, e.g. benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, e.g.

114634 42 with acetyloxymethyl, phenyl or naphthyl-lower alkanoyloxy-lower alkyl, e.g. benzoyloxy, phenylacetyloxy or 1- or 2-naphthyloxy-methyl, -2-ethyl or -2- (2,2-dimethylethyl): 11a, lower alkoxy-carbonyloxy-lower alkyl, e.g., tert-butyloxy-carbonyloxy-lower alkyl, phenyl, naphthyl or fluorenyl-lower alkoxycarbonyloxy-lower alkyl, e.g. aminoethyl or 2-amino-propyl, carboxy-lower alkyl, e.g., carboxymethyl or 2-carboxyethyl, hydroxy, lower-alkoxy, e.g., nethoxy or ethoxy, phenyl or naphthyl-lower alkoxy, e.g., benzyloxy, or 1- or 2-naphthylmethoxy, amino, lower alkylamino, e.g. methyl, ethyl or tert-butylamino. dialem-alkylalkylamino, e.g. dimethyl or diethylamino, carboxy, lower alkoxycarbonyl, e.g. methoxy, isopropoxy, sec-butoxy or tert-butoxycarbonyl, phenyl or naphthyl lower alkoxycarbonyl, e.g.

. benzyloxycarbonyl, halogen, e.g. fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower alkanoyl, e.g. acetyl or pivaloyl, lower alkylsulfonyl, e.g. , e.g., dimethoxy- or diethoxyphosphoryl, carbamoyl, mono- or dial-alkylcarbamoyl, e.g. N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, hydroxy or carboxy-lower alkylcarbamoyl. carboxymethylcarbamoyl or hydroxy or carboxyethylcarbamoyl, sulfamoyl, nitro, oxo and / or cyano, in particular pyridyl such as 2-, 3- or 4-pyridyl, e.g. 2- or 3-pyridyl-lower alkylaminocarbonyl such as 2 - or 3-pyridylmethylaminocarbonyl, N-2, N-3 or N-4-pyridyl-lower alkyl-N-lower alkylaminocarbonyl such as N-2-, N-3 or N-4-pyridylmethyl-N-methylaminocarbonyl, heterocyclyl-lower alkyl-carbamoyl-lower-alkanoyl, as defined above for heterocyclyl-lower-alkyl-carbamoyl-lower-alkanoyl, e.g.

2- (N-morpholino-lower alkyl-carbamoyl)-lower-alkanoyl such as 2 (R, S) - (N- (2-morpholino-ethyl) -carbamoyl-3-methyl-butyryl, or 2- (N- (pyridyl-lower alkyl) -carbamoyl) lower alkanoyl such as (2 (R, S) - (N- (2-pyridylmethyl) carbamoyl) -3-methyl) butyryl, sulfonyl, lower alkylsulfonyl such as methyl or ethylsulfonyl, arylsulfonyl wherein aryl contains 6- 10 carbon atoms and is e.g. phenyl or naphthyl and is unsubstituted or especially substituted by lower alkyl such as methyl or lower alkoxy such as n-ethoxy such as p-toluenesulfonyl, heterocyclylsulfonyl, in particular pyrrolyl, furyl, thienyl, -I 1, oxazolyl, thiazolyl, pyridyl, pyrazinyl, t * ;; pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxyl: salinyl, β-carbolinyl, or benzanelated, cyclopenta-, cyclohexa- or cyclohepta-anellated derivatives of these residues which may also be wholly or partially saturated, morpholinyl or thiomorpholinyl ', ** and may be unsubstituted or especially substituted by lower alkyl such as methyl, such as morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, * 4-methylpiperazinyl (4-methylpiperazinyl) is absent as a substituent in preferred embodiments), sulfamoyl or heterocyclyl-lower alkyl, where heterocyclyl has the last meaning, and / or lower alkyl-substituted sulfamoyl, such as N , e.g., as a lower alkyl ester group such as methoxycarbonyl or tert-butoxycarbonyl. as an aryl ester group or an aryl lower alkyl ester group, wherein aryl represents phenyl, 4-nitrophenyl, naphthyl or biphenyl, e.g. 4-nitrophenyloxycarbonyl, benzyloxycarbonyl, -, mono- or di- (hydroxy lower alkyl) carbamoyl such as hydroxymethylcarbamoyl or di- (hydroxymethyl) carbamoyl, or mono- or di- (carboxy lower alkyl) carbamoyl such as carboxymethylcarbamoyl or di- (carboxymethyl) as a carbamoyl group, the side chain amino group is present in an alkylated form, e.g. , aryl-lower-time, noylamino a wherein aryl contains 6 to 14 carbon atoms, * <'e.g. as phenyl, naphthyl or fluorenyl, and is unsubstituted or lower alkyl, hydroxy, lower *; substituted with coke, carboxy, carbamoyl or sulfamoyl, such as 4-hydroxyphenylbutyryl, lower alkoxycarbonylamino such as tert-butoxycarbonylamino, arylmethoxycarbonylamino, where aryl contains 6-14 carbon atoms, such as benzamoyl, carbamoyl, or benzamoyl, piperidyl-1-carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, carbonyl or S, S-dioxothiomorpholinocarbonyl and / or *; the side chain hydroxy group exists in an etherified or esterified form, e.g., a lower alkoxy such as methoxy or tert-butoxy. aryl lower alkoxy such as benzyl 114634 45 oxy, lower alkanoyloxy such as acetoxy, or lower alkyloxycarbonyloxy group, e.g. tert-butyloxycarbonyloxy group.

Particularly preferred are the acyl groups R 4 and R 8 of the unsubstituted or substituted amino acid phenylalanine, N- (benzyloxycarbonyl) phenylalanine, N- (2 (R, S) -benzyl-3-pivaloyl-propionyl) -phenylalanine, N- (9-fluorenylmethoxycarbonyl) -phenylalanine, tyrosine, N-propyltyrosine, tyrosine-O-methyl ether, N- (3-amino-3,3-dimethylpropionyl) -tyrosine-O-methyl ether, N- (2 (S) ) -Benzyl-3-tert-butylsulfonylpropionyl) -Tyrosine-O-tert-butyl ether, N- (9-fluorenylmethoxycarbonyl) -Tyrosine-O-methyl ether, N- (9-fluorenylmethoxycarbonyl) -Tyrosine-O-tert -butvvlieetteri. N-morpholinocarbonylglycine, N- (N- (2-, 3- or 4-pyridyl) methyl-N-methylaminocarbonyl) glycine, valine, N- (3-phenylaminopropyl) valine, N- (4-methylpiperazinylcarbonylmethyl) valine, N-, ··. (trifluoroacetyl) -valine, N-phenylacetyl-valine, N → 4. acetylvaline, N- (3-phenylpropionyl) valine, N- ... (2 (R, S) - or - (2S) -benzyl-3-pivaloyl-propionyl) -valine. N- (2-Carbamoyl-3-phenyl-ophthyl) -valine, N-. * (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -v- line, N- (2 (R, S) -carbamoyl-3-phenyl-propionyl) -valine, N- (2-, 3- or 4-pyridylcarbonyl) -valine, N- (1-imidazolylacetyl) -valine , N- (2- or 3-pyridylacetyl) valine, N- (morpholinoacetyl) valine, N- (3- (2- * * or 3-pyridyl) propionyl) valine, N - (3- (4-Pyrrolidine, 1,1'-yl) -propionyl) -valine, N- (3- (morpholino) -propionyl) -line, N- (N-benzyloxycarbonylpiperidin-4-yl). · · · · Carbonyl) -valine, N-tetrahydrofurylmethoxycarbonyl-valine, N-3- (tetrazol-1-yl) -propionyl-valine, N-(indol-2-ylcarbonyl) -valine, N- ( quinoline-2-carbonyl) -valine, N- (1-methylpiperazin-4-ylcarbonyl) -valine, N- (3,4-dihydroxypyrrolidinylcarbonyl) -valyl-114634 46 li, N-methoxycarbonyl-valine, N-isobutoxycarbonyl -valine, N-tert-butoxycarbonyl-valine, N-ben cyloxycarbonylvaline, N- (2-furylmethoxycarbonyl) valine, N- (1-methylpyrrolidin-2-ylmethoxycarbonyl) valine, N- (1-methyl-2-piperidylmethoxycarbonyl) valine, N- (1 -methyl-3-piperidylmethoxycarbonyl) -valine, N- (2- (morpholino) ethoxycarbonyl) -valine, N- (3-carboxypropionyl) -valine, N- (5-carboxypentanoyl) -valine, N- (6 -carboxyhexanoyl) -valine, N- (5-methoxycarbonyl lipentanoyl) -valine, N- (6-methoxycarbonylhexanoyl) -valine, N- (3-aminopropionyl) -valine, N- (4-aminobutyryl) - valine, N- (5-benzyloxycarbonylamino-pentanoyl) -valine, N- (6-benzyloxycarbonylamino-hexanoyl) -valine, N- (morpholinocarbonyl) -valine, N- (thiomorpholinocarbonyl) -valine, N- (S, S-dioxothiomorph) -nocarbonyl) -valine, N- (N-benzylaminocarbonyl) -valine, N- (N-2-pyridylmethyl-N-methylmethylaminocarbonyl) -valine, N- (N-3-pyridylmethylaminocarbonyl) -valine, N- (N -2-pyridylmethylaminocarbonyl) -vinine, N-mor fo-Lino-carbonylamino-acetyl-valine, N- (2-pyrrolidyl-acryloyl) -valine, N-methylsulfonyl-valine, N-morpholinosulfonyl-valine, N- (p-toluenesulfonyl) -valine, N- (4- methylpiperazinylsulfonyl) -valine, N- (N- (2-pyridylmethyl) -N-methylsulfamoyl) -valine, N- (N-2-pyridylmethyl-N-methylaminocarbonyl) -valine, N- ( 3. · Aminopropyl) -leucine, N-acetylleucine, N- (3-aminopropionyl) -leucine, N- (2 (R, S) - or N- (2S) -benzyl-3: pivaloyl-propionyl) -leucine, N- (2 (S) -Benzyl-3-; tert -butylsulfonylpropionyl) -leucine, N- (2-, 3-, or 1,4-pyridylcarbonyl) -leucine, N- (4-thiomorpholinocarbo-) nyyl) -leucine, N- (4- (S, S-dioxothiomorpholino) carbonyl) -; · leucine, N- (4-aminobutyryl) -leucine, N- (3-hydroxy-n-: propoxycarbonyl) -leucine , N- (benzyloxycarbonyl) -, * leucine, N- (N- (2-dimethylamino) ethyl) -N-methylaminocarbonyl) -leucine, N- (N- (2,3-dihydroxy-n-propyl) ) -N-methylaminocarbonyl) -leucine, N-acetylisoleucine, 114634 47 N-propionylisoleucine, N- (benzyloxycarbonyl) isoleucine, N- (2 (R, S) -benzyl-3-pivaloylpropionyl) -li) -norleucine, N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -norleucine, N- (tert-butoxycarbonyl) -norleucine, N- (tert-butoxycarbonyl) serine, N- ( benzyloxycarbonyl) serine, N-acetyl ser ine-O-methyl-ether. N- (Benzyloxycarbonyl) -Serine-O-Methyl Ether, N- (2 (R, S) -Benzyl-3-pivaloyl-propionyl) -Serine, N-Benzyloxycarbonyl-Glutamic Acid, Asparagine, N-Benzyloxycarbonyl-Asparagine , quinoline-2-carbonyl-asparagine and N- (morpholinocarbonyl) -paragine, the amino acid residues in particular in the (L) or (D, L) form, and in the case of valine also in the (D) form.

Unsubstituted or substituted alkyl R 1 or R 8 contains an alkyl radical of 1 to 20, in particular up to 10 carbon atoms, branched or unbranched, may contain a heteroatom instead of a methylene group which is thia, aza or Selana and is e.g. methyl, isopropyl, n-butyl, isobutyl, sec-butyl.

* ·. tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl or n-Decyl. Particularly lower alkyl is e.g.

: · 'Methyl, ethyl, n-propyl, isopropyl, n-butyl, *. isobutyl, sec-butyl, tert-butyl, n-pentyl, isopenyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, unsubstituted or substituted.

«F I

As substituents on substituted alkyl, in particular substituted lower alkyl, the residues mentioned in R 3a to R 9 of lower alkanoyl are suitable.

Substituted lower alkyl is especially cycloalkyl lower alkyl wherein cycloalkyl contains from 3 to 7 carbon atoms and lower alkyl has the meaning as defined above, e.g., cycloalkylmethyl or -ethyl, especially having from 4 to 13 carbon atoms, e.g., cyclopropyl, -, cyclopentyl or cyclohexyl lower alkyl such as methyl or ethyl, cycloalkenyl lower alkyl, e.g. cycloalkenylmethyl wherein cycloalkyl contains in particular 4-8 carbon atoms such as 1-cyclohexenylmethyl, 1,4-cyclohexadienylmethyl, or 1-cyclohexenylmethyl, 4-cyclohexadienyl-ethyl, bicycloalkyl-lower alkyl wherein the bicycloalkyl contains e.g. 5-10 carbon atoms, e.g. bicycloalkylmethyl or ethyl, especially those having 8-11 carbon atoms such as decahydronaphthyl-2-methyl, endo- or exo-norbornyl -2-methyl, bicyclo [2.2.2] oct-2-ylmethyl or bi-cyclo [3.3.1] non-9-ylmethyl, furthermore bicyclohexyl, -heptyl, -octyl, - nonyl or decyl ethyl or -3-propyl, e.g. bicyclo [3.1.0] hex-1-, -2- or -3-yl-bicyclo [4.1.0] hept-1 or - 7-yl, bicyclo [2.2.1] -i. hept-2-yl, e.g. endo or exo-norbornyl, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.0] oct-3-yl or bicyclo; · '[3.3. l] non-9-yl, further α- or β-decahydronaphthyl-ethyl or -3-propyl, v-1-tricycloalkylalkyl, wherein the tricycloalkyl contains e.g. 8-10 carbon atoms, e.g. tricycloalkylmethyl or ethyl, especially such, having from 8 to 11 carbon atoms such as 1- or 2-adamantylmethyl, further tricyclo [5.2.1.02/6] dec-8-yl or adamantyl such as 1-adamantyl; t; ! ; aryl-lower alkyl, in particular •; j-aryl contains from 6 to 14 carbon atoms, such as phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl which may be unsubstituted or substituted one to three times especially with lower alkyl, e.g. methyl, ethyl or ethyl. , halo-lower alkyl such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, e.g. la, e.g. pivaloylamino, halogen, e.g. carbamoyl, mono- or dialempalkylcarbamoyl, sulfamoyl, mono- or dialempalkylsulfamoyl, nitro and / or cyano, wherein the phenyl may be present up to three times, such as diphenyl, dibenzyl or triphenyl-lower alkyl, e.g. diphenyl, dibenzyl- -2-ethyl, and - wherein lower alkyl is unsubstituted or substituted. e.g. lower alkyl such as methyl, heterocyclyl; pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, O-carbolinyl, or benzanellated of these residues, cyclopenta, cyclohexa or cyclohepta *: anellated derivative, which may also be wholly or partially saturated, with hydroxy, lower alkanols, *, lower alkanoyloxy such as Acetoxy, propionyloxy, butyroxy, isobutyloxy or pivaloyloxy; • solutions, acetoacetoxy, amino or benzyloxycarbonyl: -onyloxy-lower alkanoyloxy such as 2-amino or; j 2-benzyloxycarbonylamino-2-methylpropionyloxy, aryl lower alkanoyloxy wherein aryl contains 6 to 10 carbon atoms, as in benzoyloxy, phenylacetyl;

J

solutions, 1- or 2-naphthyloxy, lower alkoxycarbonyl, raised, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, isohexoxy or n-heptoxycarbonyloxy, mono- or dialempkyl-aminocarbonyloxy such as ethylaminocarbonyloxy or diethylaminocarbonyloxy, aryl 6 to 10 carbon atoms, e.g., phenyloxycarbonyloxy or 1- or 2-naphthyloxycarbonyloxy, aryl lower alkoxycarbonyloxy wherein aryl contains 6 to 12 carbon atoms, especially phenyl lower alkoxycarbonyloxy, e.g. , sulfonyloxy, Alem-dialkylsulfonyloxy, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptylsulfonyloxy, phenylsulfonyloxy, 2- or. 4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy, amino, mono- or di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, such as N-methoxy-N-methylamino, mono- or di- (phenyl- or naphthyl) -I palkyl) amino such as benzylamino, lower alkoxy, * 'noylamino such as pivaloylamino, carboxy, esterified carboxy having lower alkoxycarbonyl, *; * e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-bu - toxic, isobutoxy, sec-butoxy. tert-butoxy, n-pen -. *, toxic, isopentoxy, neopentoxy, tert-pentoxy, n-; ; hexoxy, isohexoxy or n-heptoxycarbonyl, aryloxycarbonyl wherein aryl contains 6-10 carbon atoms, e.g. phenyloxycarbonyl or 1- or 2-naphthyl: oxycarbonyl, aryl lower alkoxycarbonyl wherein aryl contains 6-12 carbon atoms, e.g. benzyloxycarbonyl, 1- or 2-naphthylmethyloxycarbonyl 51 or 9-fluorenylmethoxycarbonyl, lower alkanoyl such as pivaloyl or acetyl, lower alkyl sulfonyl such as tert-butylsulfonyl. hydroxy-lower alkoxyphosphoryl and dial-lower alkoxyphosphoryl, carbamoyl, one or two lower alkyls such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl. tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl such as N-methylcarbamoyl, Nn-butylcarbamoyl or N, N-dimethylcarbamoyl, carboxy-allyl lower alkyl, e.g. carboxymethylcarbamoyl (glycinylcarbonyl) or tert-butoxycarbonylmethylcarbamoyl, dialempkylamino-loweralkyl, e.g. 2-dimethylaminoethyl, aminocarboxy-loweralkyl, e.g. -alkoxy-lower alkyl, e.g., 2- (2,2-dimethoxyethyl) or one ethylene, trimethylene, tetramethylene or pentamethylene, where the carbon atom may be replaced by nitrogen, oxygen, sulfur or sulfur substituted one or two times with oxygen and which may be unsaturated, e.g. piperidino, pyrazine-1- yl, piperazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino or S, S-dioxothiomorpholino-carbonyl, substituted carbamoyl, sulfamoyl, · Phosphono, benzfuranyl, oxo (not bonded to the carbon atom attached to the residue, or an amino nitrogen containing R 9) and / or cyano and • straight or branched, particularly phenyl ·· 'lower alkyl such as benzyl at the benzyl residue V: unsubstituted or mono- or polysubstituted; lower alkyl, e.g., methyl, phenyl, hydroxy, lower alkoxy, e.g. methoxy, halogen, e.g. chlorine, nitro and / or cyano, such as 4-methoxy-4-fluoro-, 4- chloro, 4-nitro or 4-cyano-benzyl, naphthylmethyl such as α- or β-naphthylmethyl, indenylmethyl e.g. 1-, 2- or 3-indenylmethyl, indanylmethyl such as 1- or 2- indanylmethyl, or phenanthrenylmethyl such as 9-phenanthrenylmethyl, 2-phenylethyl, 2-α-naphthylethyl, 2-β-naphthylethyl, 2-lower alkylphenyl ethyl such as 2- (4-methylphenyl) ethyl, 2-lower alkoxyphenylethyl such as 2- (4-methoxyphenyl) ethyl, 2,2-diphenylethyl, 2,2-di- (4-methoxyphenyl) ethyl, 2,2,2-triphenylethyl, 2,2-dibenzylethyl, with two phenyl lower alkoxycarbonyl such as benzyloxycarbonyl, or phenyl-lower alkyl substituted at the 2- and p-position by lower alkanoylamino such as pivaloylamino such as 2, p-dibenzyloxycarbonylamino-phenylethyl i or 2-pivaloylamino-p-benzyloxycarbonylamino-non-phenylethyl, 2, p-diaminophenylethyl, 3-phenylethyl, 3- (p-hydroxyphenyl) propyl, 3-a- or 3-trans-naphthylpropyl, 2-benzyl-3- (1-pyrazolyl) -propyl, 3-phenyl or 3-α-naphthyl-2-hydroxypropyl, 3-phenyl or 3-α-naphthyl-2-lower alkoxypropyl, such as 3-phenyl-2-yl or 3-a-naphthyl-2-neopentyloxy-propyl, 3-phenyl, -li- or 3-a-naphthyl-2-lower alkanoyloxy-propyl, such as; ten 3-phenyl-2-pivaloyloxy or -2-acetoxypropyl, * 2-benzyl or 1- or 2-naphthyl-3- (N-methoxy-N-methyl '*: amino) -propyl, 3-phenyl or 3-naphthyl-2-dimethyl-1'-aminomethyl-propyl, 3-a-naphthyl-2-pivaloyloxy or -2-acetoxy-propyl. 3-a-naphthyl-2-acetoacetoxy-propyl; *, 3-a-naphthyl-2-ethylaminocarbonyloxy-propyl or N, 3-a-naphthyl-2 - ((2-amino- or 2- benzyloxycarbonyl, amino) -2-methylpropionyloxy) -propyl, 3-phenyl or; - 3-α-naphthyl-2-carboxymethylpropyl, 3-phenyl or • 3-α-naphthyl-2-lower alkoxycarbonylpropyl, such as 3-α-naphthyl-2-ethoxycarbonyl-propyl, 3-phenyl or β-α-naphthyl-2-benzyloxycarbonylmethyl-propyl, 2- (S) -benzyl-3-tert-butylsulfonyl-propyl, 3- phenyl-2-phosphono- or phosphonomethyl-propyl, 3-phenyl-114634 53 2-dimethoxyphosphoryl or -dimethoxyphosphorylmethyl-propyl, 3-phenyl-2-diethoxyphosphoryl or -dethoxy-phosphorylmethyl-propyl, 3-phenyl- 2-ethoxy- or methoxy-hydroxyphosphoryl-propyl, 3-phenyl- or 3-α-naphthyl-2-carbamoyl-propyl, 3-phenyl or 3-α-naphthyl-2-tert-butylcarbamoyl-propyl. 3-Phenyl taxa 3-a-naphthyl-2- (2-dimethylaminoethyl) -carbamoyl-propyl, 3-a-naphthyl-2- ( carboxy tax tert-butoxycarbonyl) methyl carbamoyl propyl, 3-phenyl tax 3-a-naphthyl-2- (3-hydroxy-2-propyl) carbamoyl propyl, 3-phenyl or 3-a-naphthyl 2- (2,2-Dimethoxyethyl) carbamoylpropyl, 3-phenyl or 3-α-naphthyl-2- (5-amino-5-carboxypentyl) carbamoylpropyl, 3-phenyl tax 3-a -naphthyl-2-cyano-propyl, 3-phenyl-tax 3-a-naphthyl-2-cyano-methyl-propyl, 3-phenyl-tax 3-a-naphthyl-2-acetonyl-1-propyl, 4 -hydroxy-phenyl-butyl, 4-phenyl-tax 4-a-naphthylox-3-carboxy-butyl, 4-phenyl-tax 4-or-naphthyl-3-benzyloxycarbonyl-butyl, 2-benzyl-4- (2-benzofuranyl) -4-oxobutyl, 2-benzyl tax 2-a-naphthylmethyl-4-cyano-butyl, 2-benzyl tax 2-a-naphthylmethyl-5-dimethylaminopentyl, 2-benzyl tax 2- a-naphthylmethyl-4-oxo-pentyl, 2-benzyltax-2-a-naphthylmethyl-4,4-dimethyl-3-oxo-pentyl, 2-benzyltax-2-a-naphthylmethyl-5-dimethylamino- 4-oxo-pentyl tax 2-benzyl-tax 2-or-naphthylmethyl-5.5 -dimethyl-4-oxo-hexyl, especially phenyl-lower alkyl such as benzyl, 2-phenylethyl tax 3-phenylpropyl, 4-hydroxy-benzoxyl, 1-tax 2-naphthylmethyl tax 1-tax 2-naphthyl -2-ethyl, especially the last-defined phenyl -. *. lower alkyl, heterocyclyl lower alkyl containing in particular heterocyclyl lower alkanoyl and unsubstituted or unsubstituted heteroaryl substituent, wherein R A nitrogen atom containing R 9), e.g. methyl, 2-ethyl or 3-propyl bonded to an unsubstituted or lower alkyl or phenyl substituted pyrrolyl such as 2- or 3-pyrrolyl, 4- or 5-methylpyrrolyl, or - or 5-phenylpyrrolyl, thienyl such as 2-thienyl, furyl such as 2-furyl, pyrazolyl such as 1-pyrazolyl, tetrazolyl such as tetrazol-1-yl, pyridyl such as 2-, 3- or 4-pyridyl -alkyl, unsubstituted or lower alkyl, e.g. methyl, phenyl-lower alkyl, e.g. benzyl, lower alk indolyl such as 2-, 3- or 5-indolyl, 1-methyl-, 2-methyl-, 5-methoxy-, such as nethoxy, phenyl-lower alkoxy, e.g. benzyloxy, or halogen, e.g. , 5-benzyloxy, 5-chloro or 4,5-dimethylindol-2-yl, 1-benzylindol-2-yl or -3-yl, 4,5,6,7-tetrahydroindole- 2-yl, cyclohepta [b] pyrrol-5-yl, unsubstituted or hydroxy-substituted quinolyl such as 2-,

i I.

: 3- or 4-quinolyl or 4-hydroxyquinol-2-yl, unsubstituted or hydroxy substituted isoquinolyl such as 1-, 3- or 4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3 yl, 2-quinoxalinyl, 3,1-benzofuran-2-yl, benz [e] indol-2-yl, 5-carbolin-3-yl, * 3-chromanyl, 3-thiochromanyl, 3-pyrrolidinyl, hydroxypyrrolidinyl such as 3- or 4-hydroxypyrrolidin-2-yl, oxopyrrolidinyl such as 5-oxopyrrolidin-2-yl, piperidinyl such as 2-, 3- or 4-piperidinyl, morpholinyl such as 2- or 3-morpholinyl, thiomorpholinyl such as 2- or 3-thiomorpholinyl, S, S-dioxothiomorpholinyl such as S, S-dioxothiomorpholin-2-or -3-yl, indolinyl such as 2- or 3-indolinyl, 1 , 2,3,4-tetrahydroquinolinyl such as 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl, 1,2,3,4-tetrahydroisoquinolinyl such as 1,2 , 3,4-tetrahydroisoquinol-1-, -2- 114634 55 or -3-yl, or 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl, or s to 4-pyrrolidinylmethyl or 1-imidazolylmethyl, hydroxy lower alkyl such as 3-hydroxypropyl or 2-hydroxy-3-methylphenyl, lower alkoxy lower alkyl, e.g. lower alkoxyethyl or lower alkoxypropyl such as 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxyethyl, , lower alkoxy-lower alkoxy-lower alkyl such as 2-methoxy-methoxy-3-methyl-pentyl, phenoxy-lower alkyl or nitrophenoxy-lower alkyl such as phenoxymethyl, phenoxyethyl or 4-nitrophenoxymethyl, naphthoxy-lower alkyl, e.g. ; oxyethyl or lower alkanoyloxypropyl such as acetoxyethyl or 3-acetoxypropyl, '' acetoacetoxy lower alkyl, tt ·, · aryl mercapto lower alkyl, wherein aryl contains 6-10 carbon atoms, e.g. phenyl or naphthyl such as phenylmercaptomethyl, amino lower alkyl, e.g. 5-amino-pentyl, :: mono- or dial-alkylamino-lower alkyl, such as dimethylamino-ethyl or 2-dimethylamino-2-isopropylethyl, phenyl or naphthylamino-lower alkyl, such as 3-phenylaminopropyl, 114634 56-lower alkanoylamino-lower, -nopentyl, lower alkyl such as methyl, piperazinylcarbonyl lower alkyl such as 4-methylpiperazinylcarbonylmethyl, lower alkoxycarbonylamino lower alkyl, such as 5-tert-butoxycarbonylamino) -pentyl, or 3-ethyl, 5- (benzyloxycarbonylamino) pentyl , aminocarbonylamino-lower alkyl such as aminocarbonylamino-ethyl, N-phenyl-lower alkyl-N-lower alkylaminocarbonyl-amino-lower alkyl, e.g. 2-isobutyl-3- (N-benzyl-N-methylaminocarbonylamino) propyl, halo. haloethyl such as 2-fluoro, 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroethyl, trifluoro-lower alkyl such as: trifluoromethyl, or halopropyl, such as 3-chloro or 3-bromopropyl, carboxy-lower alkyl, e.g. carboxyethyl or 3-carboxy-cipropyl, lower alkoxycarbonyl-lower alkyl, e.g. lower alkoxycarbonylethyl or lower alkoxycarbonylpropyl, ku-; ten methoxycarbonylethyl, 3-methoxycarbonylpropyl, ethoxycarbonylethyl or 3-ethoxycarbonylpropyl, 2-halo-lower alkoxycarbonyl-lower alkyl such as 2-chloro, 2-bromo, 2-iodo or 2,2,2-trichloroethoxycarbonyl-2-chloro 3-propyl, 114634 57 phenyl or naphthyl-lower alkyloxycarbonyl-lower alkyl, e.g. thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl or a benzanellated, cyclopenta, cyclohexa or cyclohepta-anellated derivative of these residues, wherein said residues may also be present in whole or in part, e.g. -pyridylmethyloxycarbonyl-2-ethyl or -3-propyl or 2-morpholinocarbon bonyloxy-4-methyl-pentyl, lower alkylsulfonyl lower alkyl such as 2-ethylsulfonyl or 2-tert-butylsulfonylmethyl.

arylsulfonyl lower alkyl wherein aryl contains from 6 to 10 carbon atoms, e.g. phenyl or naphthyl, such as. phenylsulfonylmethyl, 'karbamoyylialempialkyyli, such as carbamoylethyl or 3-: carbamoylpropyl, T I, «alempialkyylikarbamoyylialempialkyyli, for example, lower alkyl." likarbamoyylietyyli or metyylikarbamoyylialempialkyyli,: such as 2-methylcarbamoylethyl, dialempialkyylikarbamoyylialempialkyyli, e.g., 2-di-alkyylikarbamoyylietyyli or dimetyylikarbamoyylialempial- :: molecule. such as 2-dimethylcarbamoyl-ethyl, hydroxy-lower alkyl-carbamoyl or di- (hydroxy-lower-alkyl) -carbamoyl-alerapalkyl, such as 2-hydroxymethyl-114634 58 -carbamoyl or di- (hydroxymethyl) -carbamoyl-2-ethyl or -3-propyl, N -emphyloxyl -emphyl; lower alkyl such as 2-isobutyl-3- (2- (2-methoxyethoxy) -ethylaminocarbonyl) -propyl, carboxy-lower alkyl-carbamoyl or di- (carboxy-lower alkyl) -carbamoyl-lower alkyl such as carboxymethyl or di- (carboxymethyl) carbamoyl-2 -ethyl or -3-propyl / ethylene, trimethylene, tetr amethylene or penta-methylene, where the carbon atom may be replaced by nitrogen, oxygen, sulfur or sulfur substituted once or twice with oxygen, the carbamoyl-lower alkyl substituted by nitrogen, whereby the residue thus formed may also be wholly or partially unsaturated, e.g. pyrazin-1-yl, piperazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino or S, 5-dioxothiomorpholino-carbonyl lower alkyl such as 2-morpholinocarbonyl -ethyl, 3- (morpholinocarbonyl) -propyl or 3- (morpholinocarbonyl) -2-isobutyl-propyl, N, N-lower alkyl-N-heterocyclyl-lower alkylcarbamoyl-lower alkyl, wherein the heterocyclyl is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazo

Mi-. lyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, tI, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-tttcarbolinyl, or the benzanellated, cyclo [penta-, cyclohexa-, or cyclohepta-anellated derivative of these residues which may also be wholly or partially saturated, such as 2- (N-2-pyridylmethyl) -N-methylcarbamoyl-ethyl, 59! 114634 sulfamoyl lower alkyl such as 2-sulfamoylethyl, N- (phenyl or naphthyl lower alkyl) sulfamoyl lower alkyl such as 3-benzylaminosulfonyl-2-isopropylpropyl or on a nitrogen atom with ethylene, trimethylene, tetramethylenethyl, sulfamoyl lower alkyl substituted with lower alkyl such as methyl substituted nitrogen, oxygen, sulfur or oxygen, wherein the residue thus formed may also be wholly or partially unsaturated, e.g. piperidino, pyrazin-1-yl, piperazine 1-yl, 4-methylpiperazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino, or S, S-dioxothiomorpholinosulfonyl lower alkyl such as 3- ( 4-methylpiperazinylsulfonyl) -2-isopropyl-propyl or 3- (4-morpholinylsulfonyl) -2-isopropyl-propyl, oxo-lower alkyl (wherein the oxo does not exist on the carbon atom bonded to a nitrogen atom containing R 1 or R 8) such as 3-oxo-n-butyl or 3-oxo-n-pentyl, 4 V cyano-lower alkanoyl such as cyanomethyl, 2-cyanoethyl, 2- or 3-cyano -n-propyl or 2-, 3- or 4-cyano-n-butyl / hydroxy-carboxy-lower alkyl such as 2-hydroxy-2-carb, / -boxoxy-ethyl or 2-hydroxy-3-carboxypropyl, α-naphthoxy-carboxy-lower alkyl such as 2-α-naphthoxy-4-carboxy-n-butyl, hydroxy-lower alkoxycarbonyl-lower alkyl, e.g. 2-hydroxy-2-lower alkoxycarbonyl-ethyl or -propyl 60 114634 or hydroxy-ethoxy- or hydroxy-methoxy-carbonyl-lower alkyl, such as 2-hydroxy-2-ethoxy- or methoxy-carbonyl-ethyl or 2-hydroxy-3-ethoxy- or methoxycarbonyl-propyl, and α-naphthoxy-; lower alkoxycarbonyl lower alkyl, e.g., α-naphthoxy-lower alkoxycarbonyl-2-ethyl, -2-propyl or -2-butyryl, or α-naphthoxyethoxycarbonyl-lower alkyl such as α-naphthoxy-ethoxycarbonyl-2-ethyl, 2-or-naphthoxy-3-ethyl propyne l1 or 2-α-naphthoxy-4-tert-butoxycarbonylbutyl, α-naphthoxy-benzyloxycarbonyl-lower alkyl, such as 2-α-naphthoxy-3-benzyloxycarbonyl-propyl, esterified with hydroxy-lower alkoxycarbonyl-lower alkyl, where hydroxy is lower, e.g. acetyl, propionyl or pivaloyl, cycloalkyl lower alkanoyl wherein cycloalkyl contains 3 to 7 carbon atoms and lower alkanoyl has the last meaning, e.g. wherein the bicycloalkyl contains * e.g. 5-10, in particular 6-9 carbon atoms, such as bicyclohexyl, -heptyl, -octyl, nonyl or -decyl- N -acetyl or -3-propionyl, e.g. bicyclo [3.1.0] hex-1-, -2- or -3-yl, bicyclo [4.1.0] hept-1 or ·· -7-yl, bicyclo [2.2. 1] hept-2-yl, e.g. endo or exo-norbornyl, bicyclo [3.2.1] oct-2-yl, bicyclo [3.3.0] oct-3-yl or bicyclo [ 3.3.l] non-9-yl, further ar or S-decahydronaphthylacetyl or -3-propionyl, tricycloalkyl lower alkanoyl wherein the tricycloalkyl contains e.g. 8-10 carbon atoms, e.g. tricyclo: [5.2. 1.02,6] dec-8-yl or adamantyl such as 1-adamantylacetyl, aryl-lower alkanoyl wherein aryl contains 6-14 carbon atoms, e.g. phenyl, indenyl, indyl, naphthyl, anthryl , phenanthryl, acenaphthyl or fluorenyl, which may be unsubstituted or mono- to triple with lower alkyl, hydroxy, lower alkoxy, carbamoyl lower alkoxy, N-lower alkyl carbamoyl lower alkoxy or N, N-dialempalkylcarbamoyl, lower alkyl, hydroxy, such as fluorine, chlorine or bromine, carboxy, lower alkoxycarbonyl, phenyl, naphthyl or fluorenyl lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, e.g. , as defined above, or phenyl or fluorenyl-lower alkoxycarbonyl, e.g., benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, such as 2-acetoxy-2-methoxycarbonyl-ethyl, 2-benzoyloxy, 2- (1- or 2- naphthyloxy), 2- (phenyl-2-acetyloxy) 2- (1- or 2-naphthyl-2-acetyloxy) 2- (4-methylphenyl-2-acetyloxy), 2- (4-methoxyphenyl-2) -acetyloxy) or 2- (2- :, (o, o-dichlorophenyl) -2-acetyloxy) -2-methoxycarbonylethyl or -3-propyl; dihydroxy-carboxy-lower alkyl such as 2,3-dihydroxy-3-carboxy-propyl ;;; dihydroxy-lower alkoxycarbonyl-lower alkyl such as * 2,3-dihydroxy-3-ethoxy- or methoxycarbonyl-propyl, lower alkanoyl such as acetyl, propionyl or butyryl, lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, fluorine, lower alkyloxycarbonyl such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; -propyl, α-naphthoxy-dialempalkylamino-lower alkyl such as 2-a-naphthoxy-5-dimethylamino-pentyl, α-naphthoxy-carbamoyl-lower alkyl such as 2-a-naphthoxy-4-carbamoyl-butyl, α-naphthoxy-oxo lower alkyl (wherein the oxo does not exist on the carbon atom attached to the nitrogen atom containing the radical or Rg) such as 2-α-naphthoxy-4-oxo-pentyl, or α-naphthoxy lower alkyl such as 2-a-naphthoxy-cyano-ethyl or 2-a-naphthoxy-4-cyanobutyl.

Particularly preferred is lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

Alkyl-substituted sulfonyl R 6 and R 8 include: an unsubstituted or substituted alkyl radical, especially mentioned in connection with R 4 and R 8, and is especially lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or tert-butyl li, t 114634 63 Sulfonyl substituted with aryl lower alkyl, containing, for example, the unsubstituted or substituted radical mentioned above with respect to the aryl lower alkyl R 1, R 2, R 8 3a r 9, and is particularly benzyl, 4-chloro, 4-methoxy or 4-nitrobenzyl; methylmethyl, e.g., α- or β-naphthylmethyl, 2-phenylethyl, 2-α-naphthylethyl, 2- (β-naphthylethyl), 2- (4-methylphenyl) ethyl, 2- (4-methyl -toxyphenyl) ethyl, 3-phenylpropyl, 3- (p-hydroxyphenyl) propyl, 2,2-diphenylethyl or 2,2-di- (4-methoxyphenyl) ethylsulfonyl, or sulfonyl substituted with heterocyclyl lower alkyl containing, for example, heterocyclyl lower alkyl R1f R 2, R 8 and R 8 are taken together with said unsubstituted or substituted radical and are in particular 2- or 3-pyrrolyl, 2-thienyl, 2-furyl, 1-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-indolyl, (1-methyl, 2-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dira-indole-2 -yl) -, (1-benzylindol-2-yl or -3-yl) -, 4,5,6,7-tetrahydroindol-2-yl, (2-, 3- or 4-carbonyl) • Nylyl or 4-hydroxyquinol-2-yl) -, (1-, 3- or 4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl) -, 3-pyrrolidinyl-; , (3- or 4-hydroxypyrrolidin-2-yl) -, 5-oxopyrrolidin-2-yl, (2- or 3-morpholinyl), (2- or: 3-thiomorpholinyl) -, (S, S-Dioxothiomorpholin-2- or -3-yl) -f- (2- or 3-indolinyl) -, (1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl) or (1,2,3,4-tetrahydroisoquinol-1, -2- or -3-yl) methylsulfonyl.

Aryl-substituted sulfonyl R 4 and R 8 include in particular the unsubstituted or substituted aryl radical of the aryl lower alkanoyl R 4 Da R 8 and is in particular unsubstituted or lower or mono- or phenyl substituted with lower alkyl such as phenyl or 1- or 2-naphthylsulfonyl such as phenyl , 2-or 4-toluenesulfonyl or 1- or 2-naphthylsulfonyl.

114634 64

Heterocyclyl-substituted sulfonyl R and especially include heterocyclyl, which is pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinolyl, quinoline, benzanellated, cyclopenta-, cyclohexa, or cyclohepta-anellated derivatives, which may also be wholly or partially saturated, morpholinyl or thiomorpholinyl, and which may be unsubstituted or substituted especially with lower alkyl such as methyl such as morpholinosulfonyl, thio- , 4-methylpiperazinylsulfonyl or piperazinosulfonyl. In particularly preferred embodiments of the invention, heterocyclylsulfonyl may also be absent as a substituent.

Preferably, only maximally each of R-1 and R9 is defined for acyl, sulfone, substituted sulfone, phosphonone or substituted phosphoryl by said radicals, while in each case the other radical is selected from the other substituents mentioned.

:: Unsubstituted or substituted alkyl R3 or R7 is also: *; , lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl ;;; cyclohexyl-lower alkyl such as -methyl or -ethyl such as cyclohexylmethyl, phenyl-lower alkyl which is unsubstituted or substituted by halogen such as fluorine or chlorine, lower alkoxyl such as methoxy or cyano such as benzyl, 2-phenylethyl, 3-phenylpropyl , 4-fluoro, 4-cyano or 4-methoxybenzyl, particularly preferably lower phenyl alkyl as defined above.

114634 65

The salts of the compounds of the formula I are in particular acid addition salts, salts with bases and, where several salt-forming groups are present, optionally also mixed salts or internal salts.

Salts are preferably pharmaceutically acceptable non-toxic salts of the compounds of formula I.

Such salts are formed, for example, from compounds of formula I containing one acidic group, e.g. a carboxy, sulfo or one or two hydroxy groups substituted by one or two hydroxy groups, and are, for example, salts thereof with suitable bases, such as non-toxic, metal salts of Group Ia, Ib, Ha and Hb metals of the Periodic Table of the Elements, preferably suitable alkali metal, e.g. lithium, sodium or potassium salts, or alkaline earth metal, e.g. magnesium or calcium salts, further zinc salts or ammonium salts, also salts formed with organic amines, such as optionally hydroxy substituted mono-, di- or trialkylamines, in particular mono-, di- or trialkylalkylamines, or quaternary ammonium compounds, e.g. -methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris- (2-hydroxy) lower alkyl amines such as mono-, bis- or tris- (2-hydroxyethyl) -amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) -methylamine, N, N-dialempalkyl-N- ( hydroxy lower alkyl) amines such as N, N-dimethyl-N- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -amine, N-methyl-D-glucamine or quaternary ammonium -! ' : with salts such as tetrabutylammonium salts. In formula I, a basic group, e.g., an amino group, contains:. These compounds may form acid addition salts, for example, inorganic acids, e.g., a hydrohalic acid such as hydrochloric, sulfuric or phosphoric acid, or li; organic carboxylic, sulfonic, sulfonic or phosphoric acids or N-substituted sulfamic acids such as ': e.g. acetic acid, propionic acid, glycolic acid, succinic acid': maleic acid, hydroxamic , gluco ', nic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxy-114634 67 benzoic acid, niconic acid, embonic acid the aforesaid amino acids, especially glutamic acid and aspartic acid, and methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (to form cyclamates) or other acidic or with organic compounds such as ascorbic acid. Compounds of formula I containing acidic and basic groups may also form internal salts.

Pharmaceutically unsuitable salts may also be used for isolation and purification.

The compounds of this invention have inhibitory activity against viral aspartate proteases, in particular gag protease inhibitory activity. Primarily, they inhibit the activity of HIV-1 and HIV-2 gag protease in concentrations of 10 ° to 10 mol / l in the following assays and: therefore, they can be used as agents caused by these or viral retroviruses. diseases such as e.g.

iv against AIDS.

•.

The ability of the compounds of formula I to inhibit the proteolytic activity of e.g. HIV-1 protease can be demonstrated, for example, according to the method described in J. Hansen et al., The EMBO Journal 7, 1785-1791 (1988). The inhibition of gag protease activity against the substrate, which is a fusion protein expressed from gag precursor protein and MS-2, is then measured. The substrate and its cleavage products are separated by polyacrylamide di-gel electrophoresis and visualized by immunoblotting with monoclonal antibodies against MS-2.

114634 68

In an even simpler assay that provides accurate quantitative data, a synthetic peptide corresponding to the cleavage site of the gag precursor protein is used as a substrate for gag protease. This substrate and its cleavage products can be measured by high performance liquid chromatography (HPLC).

For example, recombinant HIV-1 protease [preparation: Bil-Lich, S., et al., J. Biol. Chem. 263 (34), 17905-17908 (1990)], a synthetic chromophoric peptide, e.g. .

This substrate and its cleavage products can be measured by high performance liquid chromatography (HLPC).

To this end, the inhibitor of formula I to be tested is dissolved in dimethylsulfoxide; the enzyme assay is performed by adding appropriate dilutions of the inhibitor in 20 mM O-morpholinoethane sulfonic acid (MES) pH 6.0 to an assay mixture of 67.2 μΜ of the above chromophore peptide in 0.3 M sodium acetate , In 0.1 M NaCl,; pH 7.4, or 122 μΜ of the above icosapeptide in 20 mM MES buffer pH 6.0. The size of the batches is 100 μΐ. The reaction was initiated: 'j. by adding 2 μ 2 in the first case, 10 μΐ in the second case HIV-I protease and stopping in the first case by adding 100 μΐ 0.3 M HClO4 after 15 minutes, in the second case by adding 10 μΐ O after one hour incubation at 37 ° C, 3 M; HCl04 added. The sample is centrifuged for 5 minutes at 10,000: x g and quantitated in 100 μΙιεΒΛ (aliquot of chromophore Λ peptide) or equivalent. At 20 μΐ. (batch of icosapeptide) after application of the resulting supernatant to 125 x 4.6 mm Nucleosil * 018-5µ-ΗΡΕ0-ργΓν ^ 11β (Macherey & Nagel,

After elution), with the Peak height 114634 69 of the cleavage product at 280 (batch of chromophore peptide) or at 215 nm (batch of icosapeptide), gradient: 100% E1 -> 50%

E1 / 50% E1.2 (E1: 75% acetonitrile, 90% H2O, 0.1% trifluoroacetic acid (TFA); E1.2: 75% acetonitrile, 25% H2O, 0.08 % TFA) over 15 minutes, flow rate 1 ral / min.

Thus, in particular n is obtained for the compounds of the formula I.

ΙΟ "" IC50 values of 8 to 10 "9 M, especially about 10" to 7 ~ 10 ~ 8 M (IC50 = concentration that decreases HIV-1 protease activity in the absence of inhibitor). %: in).

In another test, it may be demonstrated that the compounds of this invention protect cells that are normally infected by HIV from such infection, or at least slow down such infection. The human T-cell-Leu chemistry cell line MT-2 [Science 229: 563 (1985)], which is highly sensitive to the cytopathogenic effect of HIV, is then incubated with HIV alone or with HIV in the presence of the compounds of the invention and after a few days, the viability of the cells so treated is evaluated.

: 'To this end, MT-2 cells are maintained in RPMI 1640 medium ;;; (Gibco, Switzerland; RPMI 1640 contains amino acid mixture without L-Gln) supplemented with 10% heat-inactivated fetal calf serum, L-glutamine, He-, · *, washed (2- [4- (2- hydroxyethyl) -1-piperazino] -ethane-1 T sulfonic acid) and standard antibiotics at 37 ° C in humidified air containing 5% CO 2. 50 μΐ of each of the test compounds in question in culture medium and 100 μΐ of v, HIV-1 in culture medium (800 TCID50 / ml) (TCID50 = Tissue 'Culture Infectious Dose 50 = dose infecting 10% of MT-2 cells) is added 4 x 103 exponentially growing MT-2 cells in 50 µl culture medium per well in 114634 70 9 6-well xaecrotiter plates. The aliquots of cells in the second microtiter plate containing cells and test compound receive 100 μ 100 of medium without virus. Incubate for 4 days and then reverse transcriptase (RT) activity is assayed in 10 µl of cell supernatant. RT activity is determined in a mixture of 50 mM Tris (α, α, α-tris (hydroxymethyl) methylamine, ultra pur, Merck, Federal Republic of Germany), pH 7.8, 75 mM KCl, 2 mM dithiothreitol , 5 mM MgCl 2, 0.05% Nonidet P-40 (detergent; Sigma, Switzerland), 50 µg / ml Polyadenylic Acid (Pharmacia, Sweden), 1.6 µg / µl dT (12-18) ( Sigma, Switzerland).

The mixture is filtered through a 0.45 μm Acrodisc filter (Gellman Science Inc, Ann Arbor) and stored at -20 ° C. To the aliquots of this solution is added 0.1% (v / v) [alpha-32P] dTTP to obtain 10 µ <3ί / ιη1: η of radioactivity. Transfer 10 μΐ of culture supernatant to a new 96-well microtiter plate and add 30 μΐ of said RT cocktail. After mixing, the plate is incubated for 1.5-3 hours at 37 ° C. 5 μΐ of this reaction mixture is transferred to Whatman DE81 paper (Whatman). The dried filters are washed 3 times for 5 minutes with 300 mM NaCl / 25 mM trisodium citrate and 1 time with 95% ethanol and dried.

t t I

• airborne again. Evaluation by Matrix Packard: '; 96well (Packard). The ED90 values are calculated and determined: '·; the lowest concentration of the test compound in question, which decreases the RT activity by 90% compared to untreated batches of cells, is determined. la. RT activity is then a measure of HIV-1 proliferation.

\ ·. The ED90 values of the compounds of the invention are then n.

10 "5 - 10" 8 M, especially about 5 x 10 "7 - 5 x 10" 8 M

The following groups of compounds of formula I can be used meaningfully, e.g., to replace more general definitions with more specific definitions, or to add or exclude definitions from other groups.

Particularly preferred are also the compounds of formula I as well as the pharmacologically useful salts of these compounds wherein lower alkoxycarbonyl, phenyl lower alkoxycarbonyl, a monovalent moiety bonded via a carboxy group of an aliphatic amino acid, aliphatic amino, , thiomorpholinyl-lower alkanoyl, S, S-dioxothiomorpholinyl-lower alkanoyl, pyridyl-lower alkanoyl, lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl acylated as defined above, with D, In the L form, especially in the L form, R 2 represents hydrogen, R 3 represents phenyl-lower alkyl, R 4 represents: -; is hydrogen, R5 is hydroxy, R6 is hydrogen, j. Ry denotes lower alkyl, cyclohexyl lower alkyl or phenyl lower alkyl, R8 denotes hydrogen and Rg denotes any of the radicals mentioned for R · ^ and denotes the radical the asymmetric carbon atoms containing R3 and R5 appear in the S configuration.

; Preference is given to compounds of the formula I and the pharmacologically usable salts of these compounds, wherein R 1 represents tert-butoxycarbonyl, benzyloxycarbonyl, a monovalent group bonded via an amino acid intermediate via a carboxy group, or phenylamino, bonded via a carboxy group of alanine acylated with morpholinocarbonyl, thiomorpholinocarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, R 2 represents hydrogen, R 3 represents benzyl, R 6 represents hydrogen, R 5 represents hydroxy, R 6 represents hydrogen, R 6 represents hydrogen, R 6 represents hydrogen, denotes hydrogen and R 9 denotes any of the residues mentioned for R 1 and the asymmetric carbon atoms containing R 3 and R 5 exist in the S configuration.

Particularly preferred are the compounds of formula I and the salts of such salt-forming compounds wherein R1 and R9 are independently hydrogen, lower alkanoyl such as acetyl, phenyl lower alkanoyl such as phenylacetyl, phenyl-lower alkanoyl wherein a carbamoyl such as 2 (R, S) -carbamoyl-3-phenylpropionyl, a morpholino-lower alkanoyl such as morpholino-carbonyl, a thiomorpholino-lower alkanoyl such as thiomorpholylcarbonyl, pyridyl-lower alkanoyl such as 2-, 3- or 4-ethyl, quinolyl-lower alkanoyl such as quinoline-2-carbonyl, tetrazolyl-lower alkanoyl such as 3-tetrazol-1-yl-propionyl, N-morpholyl: N- or N-thiomorpholinocarbonyl substituted amino-lower alkanoyl in amino-amino. or N-thiomorpholino-carbonylamino-lower alkanoyl such as N-morpholino or N-thiomorpholino-carbonyl liaminoacetyl,,, halo-lower alkanoyl containing up to three halogen atoms, such as trifluoroacetyl, 2- (N-morpholino-lower alkyl-carbamoyl)-lower alkanoyl, such as 2 (R, S) - (N- (2-morpholino-ethyl) -carbamoyl -3-methyl-butyryl, 2- (N-pyridyl-lower alkyl-carbamoyl)-lower-alkanoyl such as 2 (R, S) - (N- (2-pyridylmethyl) -carbamoyl) -3-methyl-butyryl, lower-alkoxycarbonyl such as methoxy, isobutoxy or tert-lower alkoxycarbonyl, 114634 73 phenyl lower alkoxycarbonyl such as benzyloxycarbonyl, tetrahydrofuranyl lower alkoxycarbonyl, such as 2 (R, S) -tetrahydrofuranyl-methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methoxycarbonyl, methyl-2 , thiomorpholinosulfonyl, N-pyridyl-lower-alkyl-N-lower-alkylcarbamoyl, or an acyl residue of an amino acid consisting of glycine, alanine, valine, leucine, isoleucine, glutamic acid or asparagine (D), (L) - or (D, L) - form, in which the α-amino group is unsubstituted or acylated by one of the other radicals R 1 or R 2 mentioned hereinbefore, N-morpholinocarbonyl glycine, N- (N- (2- , 3- or 4-pyridyl) methyl-N-methylaminocarbonyl) glycine, valine, N- (trifluoroacetyl) valine, N-phenylacetylvaline, N- (2- or 3-pyridyl) acetylvaline, N- acetylvaline, N- (2-carbamoyl-3-phenyl-propionyl) -valine, N- (2 (R, S) -carbamoyl-3-phenyl-propionyl) -valine, N- (2- or 3-pyridylacetyl) -valine, N-2-tetrahydrofurylmethoxy-carbonyl-valine, N- (3- (tetrazol-1-yl) -propionyl) -valine, N- (2-quinolin-2-yl) -carbonyl) -valine, N-methoxycarbonyl-valine, N-isobutoxycarbonyl-valine, N-tert-butoxycarbonyl-valine, N-benzyloxycarbonyl-valine, N- (morpholino-; · Carbonyl) -valine, N- (thiomorpholinocarbonyl) -valine, ·, N- (S, S-dioxothiomorpholinocarbonyl) -valine, N- (N-2-; pyridylmethyl-N-methylaminocarbonyl) -valine, N-morpholino -carbonylamino-acetyl-valine, N-methylsulfonyl-valine, morpholinosulfonyl-valine, N-acetyl-isoleucine, N-propionyl-isoleucine, N- (benzyloxycarbonyl) -isoleucine, N-benzyloxycarbonyl-1-glutamic acid , asparagine, N-benzyloxycarbonyl-1-asparagine, quinoline-2-carbonyl-asparagine, in which the amino acid residues are present, in particular in the (L) or (D, L) form, with valine also in the (D) form, provided that one of the radicals R 4 and R 8 represents hydrogen, 114634 74 1 * 2 / R 4 / R 8 and R 8 represent hydrogen,

R 1 represents lower alkyl such as n-butyl or isobutyl, cyclohexyl lower alkyl such as cyclohexylmethyl, or phenyl lower alkyl which is unsubstituted or substituted by halogen such as fluorine, Alem-alkoxy such as methoxy or cyano, fluorobenzyl or 4-cyanobenzyl, R 5 represents hydroxy, and R 7 represents lower alkyl, cyclohexyl lower alkyl or phenyl lower alkyl which is unsubstituted or substituted by halogen such as fluorine, lower alkoxy such as methoxy or cyano as last defined by more preferably wherein R 1 and / or R 8 do not represent morpholinosulfonyl or thiomorpholinosulfonyl.

Above all, the compounds mentioned in the examples and their salts are preferred.

The compounds of formula I and the salts of the compounds having at least one salt-forming group are prepared in% according to methods known per se, e.g. a) A hydrazine derivative of the formula? - («)« 8: wherein the residues have the meanings given above are attached to an epoxide of the formula 1 143434 75 ϊ2 «β r-nO <j (IV) r3X Xr4 wherein the residues have the above mentioned meanings wherein the free functional groups except for the reactive groups exist in potentially protected form and cleavage of any protecting groups present; or b) for the preparation of compounds of formula I wherein and R 9 represents acyl, sulfo, unsubstituted or substituted alkyl, aryl, heterocyclyl, which is unsubstituted or substituted, or aryloxy-substituted sulfonyl, sulfamoyl, which is unsubstituted or substituted in nitrogen, mu and the other residues have the meanings given in the formula

* I

* · * A · * "'R- I R7

'' R, R. I

; (V) ::: <x i; : Re 114634 76, wherein the residues have the meanings given above, are condensed with the

Rg-OH (VI) or a reactive acid derivative thereof, wherein Rg has the above meanings, wherein the free functional groups except for the groups involved in the reaction exist in a protected form and optionally deprotect any protecting groups; or c) for the preparation of compounds of formula R 1 and R 8 represent acyl, sulfo, unsubstituted or substituted alkyl, aryl, heterocyclyl, alkoxy, unsubstituted or substituted, or aryloxy-substituted sulfonyl, or sulfamoyl, which is unsubstituted or substituted in nitrogen, and the like. meanings of the formula • »r * · I»

• * i * I

ί FL

;; * f R '(vn, iR3X X 1 JR®, wherein the residues have the meanings indicated above, is condensed with an acid of formula 114634 77 R 1 -OH (Vili) or reactive acid derivatives thereof, wherein R 1 ^ is above wherein the free functional groups, except for the groups involved in the reaction, exist in potentially protected form and cleave any protecting groups present; or d) for the preparation of compounds of formula I wherein R 1 and R 8 represent two similar residues, acyl, sulfo, unsubstituted or substituted; alkyl, aryl, heterocyclyl, alkoxy, which is unsubstituted or substituted, or aryl-oxy-substituted sulfonyl, sulfamoyl, which is unsubstituted or substituted at nitrogen, and the other moieties have the meanings given in the formula t · • · • * * » l · * r7 '^> <C'Vn ^ h (K) ·: · <X | a diamino compound according to r8: · wherein the residues have the meanings given above: are condensed with an acid or reactive acid thereof suitable for attachment of the identical residues Rx and R9, wherein the residues R1g and Rg have the meanings given above, except the free functional groups or (e) for the preparation of a compound of formula I wherein, instead of R 7, R 7 "which represents unsubstituted or substituted alkyl or cycloalkyl, has the formula 1 '; i2

<X I

8 °

wherein R7 'is hydrogen and the other residues have the meanings indicated, R7' is substituted by substitution of formula XII

With a compound of R7 "-X (XII) wherein X is a leaving group and R7" represents an unsubstituted or substituted alkyl or cycloalkyl wherein the free functional groups are C1-6. - '* in a protected form and cleavage of any protecting groups present; or • * * t * • · (f) in a compound of the formula I in which the substituents have the meanings given above, provided that the In the compound of formula I, at least one functional group is protected, deprotected, and if desired, a compound of formula I obtained according to one of the above processes a) to f) is converted into its salt or the resulting salt is converted free compound 1 4634 79 or another salt and / or separating any resulting isomeric mixtures and / or converting the compound of the formula I according to the invention into another compound of the formula I according to the invention.

The above methods are explained in more detail below:

Method a) (Addition of amine to epoxide):

Depending on the meaning of the radical Ry, the amino group involved in the reaction of the hydrazine derivatives of formula III preferably contains at least one free hydrogen atom, but may also be itself derivatized to increase the reactivity of the hydrazine derivative.

In particular, the epoxide of the formula IV has a structure which preferably permits the addition of the main position of the hydrazine derivative.

The reactive functional groups of the starting materials, in particular the carboxy, amino, hydroxy, mercapto and sulpho groups, may be protected by conventional protecting groups conventionally used for peptide compounds, but also for cephalosporins. in the synthesis of rinses and penicillins and nucleic acid derivatives [and sugars. These protecting groups may already exist in the precursors and should protect the functional groups in question against unwanted side reactions such as · · acylations, etherifications, esterifications, oxidations, solubilities, etc. In certain cases, protecting groups may additionally provide a selective, for example stereoselective, course of reactions. A characteristic of protecting groups is that they are readily cleaved, i. without unwanted side reactions, for example solvolytically, by means of reduction, photolytically or also enzymatically, e.g. also by physiologist 11463480 under these conditions. However, residues analogous to protecting groups may also be present in the residues. Compounds of formula I containing protected functional groups may have better metabolic stability or otherwise improved intrinsic properties than corresponding free functional group compounds. The protecting groups are referred to in the narrower sense above and below when the residues in question are no longer present in the final materials.

The protection of functional groups by such protecting groups, the protecting groups themselves and their cleavage reactions are described, for example, in standard works such as J.F.W.

McOmie, "Protective Groups in Organic Chemistry", Plenum Press London and New York 1973, Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, "The Peptides", Volume 3 (E. Gross and J. Meienhofer, Eds.), Academic Press, London and New York 1981, "Methoden der. orga-nischen Chemie ", Houben-Weyl, 4th Edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Je-scheit, "Aminosäuren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974.

•> • * *

The carboxy group is protected, e.g., as an ester group, which can be selectively cleaved under mild conditions.

In the esterified form, the protected carboxy group is esterified · · - primarily by a lower alkyl group which is preferably branched at the 1-position of the lower alkyl group or substituted at the 1- or 2-position of the lower alkyl group by suitable substituents.

The protected carboxy group esterified with a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

1 1 4634 81 i

A protected carboxy group esterified with a lower alkyl group branched at the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, e.g., tert-butoxycarbonyl.

A protected carboxy group which is esterified with a lower alkyl group substituted at the 1- or 2-position of the lower alkyl group with suitable substituents is, for example, an arylmethoxycarbonyl having one or two aryl residues wherein aryl is unsubstituted or e.g. lower alkyl such as tert-butyl, lower alkoxy, e.g., nethoxy, hydroxy, halogen, e.g., chlorine and / or nitro, mono-, di- or trisubstituted phenyl, e.g., benzyloxycarbonyl, benzyloxycarbonyl, substituted with said substituents, e.g. or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted with said substituents, e.g. di- (4-methoxyphenyl) -methoxycarbonyl, further carboxy esterified with a lower alkyl group, wherein the lower alkyl group is substituted with 1, lower alkoxy-lower alkoxycarbonyl, e.g., methoxy; ,. cimetethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxy, *: - ethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl, e.g. such as bromo-substituted benzoyl, e.g.

phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxy. carbonyl or 2-iodoethoxycarbonyl, as well as 2- (trisubstituted silyl) lower alkoxycarbonyl wherein the substituents independently of each other are optionally substituted with, for example, lower alkyl, lower alkoxy, aryl, halogen and / or nitro-aliphatic? , a cycloaliphatic or aromatic hydrocarbon residue, for example lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl optionally substituted as above, e.g. n-butylmethylsilyl) ethoxycarbonyl, or 2-triarylsilyl ethoxycarbonyl such as triphenylsilyl ethoxycarbonyl.

The carboxy group may also be protected as an organic silyloxycarbonyl group. An organic silyloxycarbonyl group is, for example, a trialempkylsilyloxycarbonyl group, e.g. trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be substituted with two lower alkyl groups, e.g., a methyl group and an amino group or carboxy group of another molecule of formula I. Compounds containing such protecting groups may be prepared, for example, using dimethylchlorosilane as the silylating agent.

The protected carboxy group is especially tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl. benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.

The protected amino group may exist in the form of a protected amino protecting group, e.g. in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alkyl-1-enylamino or silylamino group, or an azido group.

In the corresponding acylamino group, acyl is, for example, an organic carboxylic acid having up to 18 carbon atoms, in particular lower alkanecarboxylic acid optionally substituted with, for example, halogen or aryl, or acetic acid benzoic acid or optionally substituted with halo, lower alkoxy or Such acyl groups include, for example, lower alkanoyl such as formyl, acetyl, propionyl or pivaloyl, halogen lower alkanoyl, e.g. 2-haloacetyl such as 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2, 2,2-trichloroacetyl, optionally substituted, for example, by halogen, lower alkoxy or nitro, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, especially at the 1-position or 2-position of the lower alkyl residue; substituted lower alkoxycarbonyl, e.g., tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl, having one, two or three aryl radicals optionally represented by, e.g., lower alkyl, especially tert-lower alkyl, such as tert-butoxy, lower , hydroxy, halogen such as chlorine and / or nitro, mono- or polysubstituted phenyl, e.g. benzyloxycarbonyl, 4-nitro benzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl wherein aroyl; the group denotes in particular optionally substituted benzoyl, e.g., halogen, * '* · such as bromine, e.g., phenacyl: oxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g.

2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl * or 2-iodoethoxycarbonyl, 2- (trisubstituted silyl) lower alkoxycarbonyl, e.g. lower alkoxycarbonyl such as 2-trimethylsilyl ethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl; butyl, or triarylsilyl-lower alkoxycarbonyl, e.g., 2-triphenylsilyl-ethoxycarbonyl.

»· ·

In the arylmethylamino group, e.g., mono-, '* di- or especially triarylmethylamino, aryl radicals are especially optionally substituted phenyl radicals.

Such groups include, for example, benzyl, diphenylmethyl or especially tritylamino.

In the etherified mercaptoamino group, the mercapto moiety is primarily present as a substituted arylthio or aryl-lower alkylthio, whereby aryl is optionally, e.g., lower alkyl such as methyl or tert-butyl, lower alkoxy such as nethoxy, halogen such as chlorine and / or nitro; 4-nitrophenylthio.

In the 2-acyl-lower alk-1-enyl residue useful as an amino protecting group, acyl is e.g. lower alkanecarboxylic acid, optionally e.g. lower alkyl such as methyl or tert-butyl. the corresponding residue of a benzoic acid substituted with a lower alkoxy such as methoxy, a halogen such as chlorine and / or nitro, or in particular a carbonic acid semi-ester such as a carbonic acid lower alkyl ester. Corresponding protecting groups are primarily 1-lower alkanoyl-lower alk-1-en-2-yl, e.g. 1-lower alkanoyl-prop-1-en-2-yl such as 1-acetyl-prop-1-en-2 -yl, or lower alkoxycarbonyl-lower alk-1-en-2-yl, e.g.

: lower alkoxycarbonyl-prop-1-en-2-yl such as 1-ethoxy. carbonyl-prop-l-en-2-yl.

• 4 1

For example, the silylamino group is trialempkylsilyl- *? * an amino group, e.g. trimethylsilylamino or tert-dimethylsilylamino. The silicon atom of the silylamino group may also be substituted with only two lower alkyl groups, ·,, e.g., a methyl group and an amino group or carboxy group of another molecule of formula I. Compounds containing such protecting groups may be prepared using, for example, the corresponding chlorosilanes, such as dimethyl a-chlorosilane, as a silylating agent.

I t

The amino group may also be protected by conversion to a protonated form; the corresponding anions are primarily anions of strong inorganic acids such as sulfuric acid, phosphoric acid or hydrohalic acids, e.g. chlorine or bromine anion, or organic sulfonic acids such as p-toluenesulfonic acid.

Preferred amino protecting groups are lower alkoxycarbonyl, phenyl lower alkoxycarbonyl, fluorenyl lower alkoxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl or lower alkoxycarbonyl-lower alkyl-1-en-2-yl.

The hydroxy group may be protected, for example, by an acyl group, e.g., a lower alkanoyl substituted with a halogen such as chlorine, such as 2,2-dichloroacetyl, or, in particular, by an acyl radical mentioned in connection with protected amino groups of the carbonic acid half ester. A preferred hydroxy protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. The hydroxy group may be further protected with a trialempkylsilyl, e.g., trimethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl, a readily cleaving ether, *, alkyl group such as tert-lower. alkyl, e.g. tert-butyl, oxa or thia aliphatic or cycloaliphatic, especially 2-oxa or 2- ».

; a thia-aliphatic or cycloaliphatic hydrocarbon star. with tea, for example 1-lower alkoxy-lower alkyl or 1- 'lower-alkylthio-lower alkyl such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl-1 * -methylthioethyl or 1-ethylthioethyl, or 2-' ... or 2-thiacycloalkyl having 5 to 7 ring yields such as 2-tetrahydrofuryl or 2-tetrahydropyranyl

• or a corresponding thia analog, and 1-phenylalmalkyl such as benzyl, diphenylmethyl or trityl, wherein the phenyl moieties may be substituted, for example, by halogen, e.g. chlorine, lower alkoxy, e.g. or nitro.

114634 86

The two hydroxyl and amino groups present in the molecule, especially adjacent, or adjacent hydroxy and amino groups, may be protected, for example, by divalent protecting groups, in particular optionally substituted by one or two lower alkyl radicals or by oxy-substituted, e.g. such as isopropylidene, cycloalkylidene such as cyclohexylidene, carbonyl group or benzylidene.

In particular, the mercapto group, such as in cysteine, may be protected by S-alkylation with optionally substituted alkyl residues, silylation, thioacetal formation, S-acylation, or formation of asymmetric disulfide groups. Preferred mercapto-protecting groups are, for example, benzyl optionally substituted on a phenyl radical, e.g., with a nethoxy or nitro, such as 4-methoxybenzyl, optionally substituted on a phenyl radical, e.g., ethoxy, such as di- (4-methoxyphenyl) methyl, triphenylmethyl, pyridylmethyl, pyridylmethyl, , tetrahydropyranyl, acylaminomethyl such as acetamidomethyl, iso-butyrylacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkyl, in particular lower alkylaminocarbonyl such as ethylaminocarbonyl, and Alem-pialkylthio, such as. it * 'S-sulfo.

The sulfur group may be protected, for example, with lower alkyl, e.g., methyl or ethyl, phenyl or sulfonam. . as an imidazolid.

The "protecting group", for example the carboxy protecting group, also refers to the polymeric 114634 87 polymeric carrier, which is suitable for e.g. Merrifield synthesis, in an easily cleavable functional group, such as a carboxy group. Such a suitable polymeric carrier is, for example, copolymerization with divinylbenzene of a weakly crosslinked polystyrene resin containing a bridge linkage suitable for reversible bonding.

The coupling of the compounds of the formula III to the epoxides of the formula IV is advantageously carried out under the conventional reaction conditions used to attach the nucleophiles to the epoxides.

The coupling takes place in particular in aqueous solution and / or in the presence of polar solvents such as alcohols, e.g. methanol, ethanol or ethylene glycol, ethers such as dioxane, amides such as dimethylformamide, or phenols such as phenol, also under anhydrous conditions such as in toluene, or in benzene / water emulsions, optionally in the presence of acidic or basic catalysts, e.g. bases such as sodium hydroxide, or hydrazine-solid phase catalysts such as; in the presence of aluminum oxide, in ethers, e.g. diethyl ether, generally at temperatures between about 0 ° C and the reflux temperature of the corresponding reaction mixture, particularly 20 °,. At 130 ° C, possibly with reflux, at elevated *. 'at pressure, e.g. in a bomb, where the boiling point i> *' may also be exceeded, and / or in an atmosphere of an inert gas such as nitrogen or argon, whereby each individual compound of formula III and IV may be present in an excess, e.g. 1: 1 to 100, especially in a molar ratio of 1: 1 to 1:10, especially 1: 1 to 1: 3.

* · •%

The protected groups may be liberated, if appropriate, according to the methods set forth in process f) (cleavage of protecting groups).

114634 88

Method b) (Amide bond formation)

In the starting materials of formulas V and VI, the functional groups are independently protected with the protecting groups shown in method a) except for those groups which must undergo the reaction or which do not react under the reaction conditions.

The compounds of formula VI contain a free carboxy, sulfo or phosphoryl group or a reactive acid derivative thereof, e.g., derived activated esters or reactive anhydrides, further reactive cyclic amides. Reactive acid derivatives may also be formed in situ.

The activated esters of the compounds of formula VI which contain the main carboxy group include, in particular, at the carbon atom of the esterifying moiety, unsaturated esters, e.g., vinyl ester types such as vinyl esters (obtainable, for example, by re-esterification with vinyl acetate, ester); carbamoyl esters (obtainable, e.g., by treatment with • the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl • «* ·. esters (obtainable, e.g., by treating the corresponding acid * with lower alkoxyacetylene; ethoxyacetylene method), '' or amidino-type esters, such as Ν, Ν'-disubstituted amidinoesters (obtainable, e.g., by treating the corresponding. with an imide, e.g. Ν, dis'-dicyclohexylcarbodiimide; carbodiimide: method), or Ν, Ν-disubstituted amidinoesters (available, for example, by treatment of the corresponding acid with N, N-disubstituted cyanamide; cyanamide method), suitable * · 'aryl esters, in particular phenyl esters suitably substituted by electron withdrawing substituents (obtainable e.g. by treatment of the corresponding acid with an appropriate I 114634 89 phenol, e.g. 4-nitrophenol, 4-methylsulfonylphenol, 2,4, 5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol in the presence of a condensing agent such as Ν, Ν'-dicyclohexylcarbodiimide method of activated aryl esters), cyanomethyl esters (obtainable e.g. by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl ester method), thioesters, especially optionally e.g. nitro-substituted phenylthioesters (obtainable e.g. by treatment of the corresponding acid with optionally nitro-substituted thiophenols, inter alia by the anhydride or carbodiimide method), or especially amino or amido esters (obtainable, e.g., by treating the corresponding acid with an N-hydroxyamino or, respectively, N-hydroxyamido compound, e.g. N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-nor -borne-2,3-dicarboxylic acid imide, 1-hydroxybenz-triazole, or 3-hydroxy-3,4-dihydro-1,2,3-benzstriazin-4-one, e.g. according to the anhydride or carbodiimide method ; method of activated N-hydroxyesters). Internal esters may also be used, e.g.

γ-lactone.

* »* *» T. The anhydrides of acids can be symmetric to these acids.

* I

or anhydrides of inorganic acids, e.g. anhydrides of inorganic acids, such as acid halides, especially acid chlorides (obtainable, e.g., by treatment of the corresponding acid with? - = · thionyl chloride, phosphorus pentachloride, phosgene ,,, * or oxalyl chloride); azides (obtainable, e.g., from the corresponding acid ester via the corresponding # * hydrazide and treatment with nitric acid; azide method), anhydrides formed with carbonic half-esters, e.g., carbonic acid lower alkyl esters (e.g. - 114634 90 alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline; O-alkyl carbonic acid mixed anhydrides method), or anhydrides formed with dihalogenated, especially dichlorinated phosphoric acid (obtainable e.g. other f anhydrides formed with osphoric acid derivatives (e.g. those which can be obtained with phenyl-N-phenylphosphoramide amidochloridate or by reacting alkylphosphoric acid amides in the presence of sulfonic acid anhydrides and / or racemization-reducing additions such as N-hydroxybenz anhydrides formed such as mixed anhydrides with organic carboxylic acids (obtainable e.g. by treatment of the corresponding acid with an optionally substituted lower alkane or phenyl-lower alkane carboxylic acid halide, e.g. phenylacetic acid, pivalic acid or trifluoroacetic acid); . anhydrides formed with organic sulfonic acids: (obtainable, e.g., by treatment of a salt of the corresponding acid, such as an alkali metal salt with a suitable organic sulfonic acid, such as a lower alkane or aryl,; e.g., methane or p-toluene acid chloride; anhydrides method) and symmetric anhydrides (obtainable e.g. by condensation of the corresponding acid in the presence of carbodiimide or 1-diethylaminopropine; symmetrical anhydrides method).

Suitable cyclic amides are in particular the amides which are ··. formed with five-membered aromatic diazazoles, such as amides formed with imidazoles, e.g. imidazole (obtainable e.g. by treatment with the corresponding acid Ν, Ν'-carbonyldiimidazole; imidazole method) or pyrazole, e.g. , 5-dimethylpyrazole 114634 91

With III (obtainable, e.g., via acid hydrazide by treatment with acetylacetone; pyrazolid method).

As mentioned, the carboxylic acid derivatives used as the acylating agent can also be formed in situ.

Thus, for example, Ν, Ν'-disubstituted amide noesters can be formed in situ by reacting a mixture of the starting compound of formula V and the acid used as the acylating agent with a suitable N, N'-disubstituted carbodiimide, e.g. Ν, Ν'-cyclohexylcarbodiimide. in the presence of an imide. Further, amino or amido esters of the acids used as the acylating agent can be formed in the presence of an acylating starting material of formula V by reacting a mixture of the corresponding acid starting amino acids with Ν, Ν'-di-substituted carbodiimide, e.g. Ν, Ν'-dicyclohexyl carbodiimide and N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxysuccinimide, optionally in the presence of a suitable base, e.g. 4-dimethylaminopyridine. Further activation can be accomplished in situ by reacting N, N, N ', N'-tetraalkyluronium compounds such as O-benzthiazol-1-yl-Ν, Ν, Ν', Ν'-tetramethyluronium hexafluorophosphate, O- (1,2-dihydro-2-oxo-1-pyridyl) -N, N, N ', N'-tetramethyluronium tetra, fluoroborate or O- (3,4-dihydro-4-oxo) -1,2,3-benz- (triazolin-3-yl) -N, N, N ', N'-tetramethyluronium tetra-1'-fluoroborate. Finally, the formula I or VII according to Formula VI or VII | carboxylic acids, phosphoric anhydride can be formed in situ in such a way that alkyylifosforihappoamidi, such as hexamethylphosphoric triamide is reacted with a sul-acid anhydride, such as 4-tolueenisulfonihappoanhydri-chloride in the presence of hexamethylphosphoric triamide salt, such as tetrafluoroborate, for example. natriumtetrafluoriboraa-, ·, with tin or another derivative thereof, such as benzotriazol with 1-yloxy-tris- (dimethylamino) -phosphonium hexafluoride, especially in the presence of a racemization-reducing additive such as N-hydroxybenzo-triazole.

114634 92

Similarly, many of the reaction types described above for the carboxylic acids of Formula VI can also be performed for compounds of Formula III containing a sulfonyl or phosphoryl group in the predominant position when condensing compounds of Formula V into sulfonamides.

Thus, for example, activated sulfonic acid poesters, e.g. the corresponding, especially nitro-substituted aryl esters, such as phenyl esters, can be used, whereby an alkali metal amide, e.g. an alkali metal aryl amide, or a nitrogen-containing potassium pyrrole dia.

Further, reactive anhydrides such as optionally corresponding symmetric (can be prepared, e.g.

> I

e.g., by reaction of the corresponding sulfonic acids with inorganic acid chlorides, e.g. thionyl chloride, phosphorus pentachloride), organic carboxylic acids (obtainable e.g. by treatment of a sulfonic acid halide with a carboxylic acid salt such as the alkali salt). said sulfonic acid mixed anhydrides method), or azides (obtainable [e.g. from the corresponding sulfonic acid chloride and sodium azide or through the corresponding hydrazide and treatment with nitric acid according to the above azide method).

93 1 1 4634

The amino group involved in the reaction of the compounds of formula V contains, in particular, at least one reactive hydrogen atom, especially when the carboxy, sulfonyl or phosphoryl group reacting with it is present in a reactive form; but it may also be self-derivatized, e.g. by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite. The derivative of such a compound having an amino group is also e.g. a carbamic acid halide or an isocyanate, wherein the amino group involved in the reaction is substituted with a halocarbonyl e.g. chlorocarbonyl or the like, converted to an isocyanate group containing only the compounds of formula I on the nitrogen atom of the amide group formed by the reaction.

"If the compound of formula V is simply substituted on an amino group with lower alkyl or aryl lower; 1, the corresponding urea compound is also a reactive derivative. For example, when heating eximolar amounts of this urea compound and the formula. The free carboxy-containing compound of formula VI or VIII gives the corresponding compounds of formula I.

;;; The condensation to form the amide bond may be carried out in a manner known per se, for example, in the standard 114634 94, such as "Houben-Weyl, Methoden der Organic Chemie", 4th Edition, Part 15/11 (1974), Part IX (1955), Part E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" (E.

Gross and J. Meienhofer, Eds., Volumes 1 and 2, Academic Press, London and New York, 1970/1980, or M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, Berlin 1984.

The condensation of the free carboxylic acid with the corresponding amine can be carried out, in particular, in the presence of a conventional condensing agent or using carboxylic acid anhydrides or carboxylic acid halides such as chlorides, or activated carboxylic acid esters such as p-nitrophenyl esters. Conventional condensing agents include, for example, carbodiimides, for example diethyl, dipropropyl, N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide or, in particular, dicyclohexylcarbodiimide, further suitable carbonyl compounds, for example, carbonylimidazole. , 1,2-oxazolium compounds, e.g., 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-. methyl isoxazolium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N, N, N ', N'-tetraalkyluronium compounds such as O-benzo-triazol-1 -yl N, N, N ', N'-tetramethyluronium hex: safluorophosphate, further activated phosphoric acid derivatives', e.g., diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoroamidochloride 2-oxo-3-oxazolidinyl) -phosphinic acid chloride or 1-benzthiazolyloxy-tris (dimethylamino) -phosphonium hexafluorophosphate.

If desired, an organic base, in particular a tertiary amine, e.g. trialempkylamine having large residues, e.g. ethyldiisopropylamine, or triethylamine and / or a heterocyclic base, e.g. 4-dimethylaminopyridine or especially N-methylmorpholine, is added.

95114624

The condensation of activated esters, reactive anhydrides, or reactive cyclic amides with the corresponding amines is conveniently carried out in the presence of an organic base, e.g., simple trialemphylalkylamines, e.g., triethylamine or tributylamine, or one of the above organic bases. If desired, a further condensing agent, as disclosed in connection with the free carboxylic acids, is additionally used.

The condensation of acid anhydrides with amines can take place, for example, in the presence of inorganic carbonates, e.g., ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (if desired together with sulfate).

Carboxylic acid chlorides, for example chloro-carbonic acid derivatives formed from an acid of formula VI, or sulfonic acid chlorides are condensed with the corresponding amines, especially in the presence of an organic amine, e.g. the above-mentioned trialempalkylamines or heterocyclic bases, optionally in the presence of hydrogen sulfate.

The condensation is carried out especially in an inert, aprotic solvent, especially in an anhydrous solvent or solvent mixture, for example, in a carboxylic acid amide, e.g. e.g. tetrahydrofuran, ester, e.g. acetic acid ethyl ester, or nitrile, e.g. acetonitrile or a mixture thereof, optionally at reduced temperature or at elevated temperature, e.g., -4 ° C to about 0 ° C.

In the temperature range of + 100 ° C, in particular from about -10 ° C to about + 50 ° C, when arylsulfone esters are also used, for example ca.

+ 100 ° C to + 200 ° C, and optionally under an inert gas such as nitrogen or argon.

114634 96

Aqueous, e.g. alcoholic, e.g., ethanol, and aromatic solvents, e.g., benzene or toluene, are also possible. In the presence of alcoholic hydroxides, acetone may also optionally be added as a base.

The condensation can also be carried out according to the prior art as solid phase synthesis by R. Merrifield and described, for example, in An-gew. Chem. 97, 801-812 (1985), Naturwissenschaften 71.

252-258 (1984) or R. A. Houghten, Proc. Natl. Acad.

Sci. USA 82, 5131-5135 (1985).

Depending on the starting compounds used, the residues R 1 and R 8 may be obtainable in the compounds of formula I, identical or different.

The protected groups may be liberated, if appropriate, according to the methods described in method f) (cleavage of protecting groups).

»; Method c) (Amide bond formation)

In the starting materials of formulas VII and VIII, functional groups except those which must participate in the reaction or which do not react in the reaction. · Is protected independently of one another by one of the protecting groups set out in Method a).

*; The process is fully equivalent to that described in process b) when compounds of formula VII and compounds of formula VI are used in place of the compounds of formula V; * the compounds of formula VIII are used and in Y, R 4, in place of R 8, binds to the compounds of formula VII ·; ·· in place of the compounds of formula V.

Depending on the starting compounds used, the residues R 1 and R 8 may be obtainable in the compounds of formula I, identical or different.

114634 97

The deprotection of the protected groups may be effected according to the methods described in process f) (cleavage of protecting groups).

Method d) (Amide bond formation)

In the starting materials of formula IX and in the acid or reactive derivatives thereof which are suitable for the coupling of identical residues to R 9, the functional groups which are not to be reacted or which do not react under the reaction conditions are independently protected by one of the protecting groups shown in process a).

The formula for the acid suitable for the attachment of the identical residues R 1 to R 8 is in particular VI or VIII.

Preferably, the starting compounds of formula IX, optionally protected by protecting groups, are those compounds of formula II, which are explained below in the section on starting compounds.

•. The process corresponds exactly to that mentioned in process b), in which

instead of compounds of formula V, formula IX is used

• *.

and compounds of formula VI are used instead of compounds of formula VI.

The protected groups may be liberated in accordance with the procedures described in method f) (cleavage of protecting groups).

Method e) (Alkylation of a secondary nitrogen atom) In functional compounds of formula I 'and reactive derivatives thereof, in the starting materials of formula I' and the R7M moiety, the functional groups which are unreacted or unreacted 114634 98 are independently protected with one of the protecting groups represented in process a).

In particular, the leaving group X is a nucleofugic leaving group which is esterified with a strong inorganic or organic acid hydroxy such as a mineral acid such as hydrochloric acid such as hydrochloric, hydrobromic or iodic acid, or a strong organic sulfonic acid such as e.g. such as fluorine-substituted lower alkanesulfonic acid or aromatic sulfonic acid, e.g. optionally lower alkyl such as methyl, halogen such as bromine and / or nitro substituted benzenesulfonic acid, e.g. hydroxy.

Substitution may take place under conditions of first or second order nucleophilic substitution.

For example, a compound of formula XII wherein X represents a leaving group having a high polarity of the electron sheath, e.g. iodine, may be used in a polar aprotic solvent, e.g. acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide. The reaction may also be carried out in water mixed with any solvent which may be solubilizing: · an organic solvent such as ethanol, tetrahydrofuran or acetone. The substitution reaction is optionally carried out at a reduced or elevated temperature, e.g., from about -40 ° C to about 100 ° C, in particular from about -10 ° to about 50 ° C. and possibly an inert gas, e.g.

: Y: under nitrogen or argon.

The deprotection of the protected groups may be effected according to the methods described in process f) (cleavage of protecting groups).

114634 99 f j

Method f) (Removal of protecting groups)

The cleavage of protecting groups which are not part of the desired final product of formula I, e.g. carboxy, amino, hydroxy, mercapto and / or sulfo protecting groups, is carried out in a known manner, e.g. by solvolysis, in particular hydrolysis, alcoholysis or acidolysis. , or by reduction, in particular by hydrogenation or reduction chemically, and by photolysis, possibly stepwise or simultaneously, whereby enzymatic methods may also be used. Cleavage of protecting groups is described, for example, in the standard works previously mentioned in the chapter "Protecting groups".

Thus, for example, a protected carboxy, e.g. or trifluoroacetic acid, optionally adding a nucleophilic compound such as phenol or anisole. · Lower alkoxycarbonyl · can also be liberated with bases, hydroxides, e.g. alkali metal hydroxides such as NaOH or KOH. Optionally substituted benzyloxycarbonyl can be liberated, e.g., by hydrogenation, m.p. with hydrogen in the presence of a metal hydrogenation catalyst such as palladium catalyst. Further, a suitably substituted benzyloxycarbonyl such as 4-nitrobenzyl-oxy-carbonyl can also be converted to the free carboxy by reduction, e.g., by treatment with an alkali metal such as sodium dithionite, or a reducing metal such as zinc, or a reducing metal salt such as With a -II salt, e.g. chromium II chloride, a conventional hydrogen donor which can produce 100 to 114634 hydrogen with a metal such as an acid, preferably a suitable carboxylic acid such as optionally a hydroxy substituted lower alkanoic acid, e.g. acetic acid, in the presence of formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chloro-mandelic acid or tartaric acid, or alcohol or thiol, with the addition of water preferably. By treatment with a reducing metal or metal salt as described above, the 2-halo-lower alkoxycarbonyl (optionally after conversion of the 2-bromo-lower alkoxycarbonyl group to the corresponding 2-iodo-lower alkoxycarbonyl group) or the aroylmethoxycarbonyl can also be converted. The aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic reagent, especially a salt-forming reagent such as sodium thiophenolate or sodium iodide. 2- (trisubstituted silyl) lower alkoxycarbonyl such as 2-trialempalkylsilyl lower alkoxycarbonyl can also be converted to the free carboxy by treatment with a fluoride anion-producing hydrofluoric acid salt such as alkali metal fluoride, e.g. or an organic quaternary base fluoride such as tetra-lower alkylammonium fluoride or trialempkylaryl lower alkylammonium fluoride, e.g. .

Carboxy protected as an organic silyloxycarbonyl, such as trialempkyl, ', lisilyloxycarbonyl, e.g. trimethylsilyloxycarbonyl, may be liberated solvolytically, e.g. by treatment with water, alcohol or acid, or additionally with fluorine: ··· dilla as above. The esterified carboxy may also be released enzymatically, for example by esterases or suitable peptidases, e.g., esterified arginine or lysine such as lysine methyl ester by trypsin.

The protected amino group is liberated in a manner known per se and depending on the type of protecting group, in particular by solvolysis or reduction. Lower alkoxycarbonylamino such as tert-butoxycarbonylamino may be cleaved with acids, e.g. mineral acids, e.g., halogen hydrogen, such as hydrochloric or hydrobromic acid, or sulfuric or phosphoric acid, especially hydrochloric acid, or strong organic acids, such as trihaloacetic acid, e.g. in the presence of formic acid in polar solvents such as water or ethers, especially cyclic ethers such as dioxane, the 2-halo-lower alkoxycarbonylamino (optionally after converting the 2-bromo-lower alkoxycarbonylamino group into a 2-bromoalkoxy) , aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino may be cleaved e.g. by treatment with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. The aroylmethoxycarbonylamino can also be cleaved by treatment with a nucleophilic reagent, especially a salt-forming reagent such as sodium thiophenolate, and a 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. Optionally substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2- (tri-substituted silyl) lower alkoxycarbonylamino such as: 2-trialempkylsilyl lower alkoxycarbonylamino may be liberated by treatment with a suitable acid, e.g.

; . formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino e.g. by hydrogenation, m.p. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst such as platinum or palladium catalyst, optionally substituted triarylmethylamino or formylamino e.g. by treatment with an acid such as a mineral acid, e.g. hydrochloric acid, ethanolic acid, e.g. or trifluoroacetic acid, optionally in the presence of water, and the silylamino protected amino group, e.g., by hydrolysis or alcoholysis. The amino group protected with 2-haloacetyl, e.g. bases such as alkali metal hydroxide or carbonates such as Na 2 CO 3 or K 2 CO 3 in polar solvents, e.g. alcohols such as methanol at temperatures of 0 to 100 ° C, especially 40 to 80 ° C. An amino group protected with a 2- (trisubstituted silyl) lower alkoxycarbonyl such as 2-trialempialkylsilyl lower alkoxycarbonyl can also be converted to the free amino group by treatment with a fluoride anion producing salt of hydrofluoric acid as described above for the correspondingly protected carboxy group release. Likewise, silyl directly attached to a heteroatom such as nitrogen, such as trimethylsilyl, can be cleaved by fluoride ions.

The protected amino in the form of an azido group is converted to the free ·· amino, e.g. in the presence of an acid such as acetic acid. The catalytic hydrogenation is carried out, in particular, in an inert solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or also in water or in a mixture of water and an organic solvent such as alcohol or dioxane at about 20 ° to 25 ° C or also under cooling or heating.

The hydroxy or mercapto group protected by a suitable acyl group, a trial lower alkylsilyl group, or an optionally substituted 1-phenyl lower alkyl, is liberated in a manner similar to that of the correspondingly protected amino group.

The hydroxy or counter protected mercapto group protected by 2,2-dichloroacetyl is liberated e.g. by basic hydrolysis, hydroxy or counter protected by a tert-lower alkyl or 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon residue, e.g. mineral acid or a strong carboxylic acid, e.g. trifluoroacetic acid. Pyridyldiphenylmethyl-protected mercapto can be liberated e.g. with mercuric II salts at pH 2-6 or by zinc / acetic acid or by electrolytic reduction, by reaction with acetamido-methyl or iso-butyrylamidomethyl e.g. by reaction with mercury II salts At pH 2-6, 2-chloroacetamidomethyl with e.g. 1-piperidinothiocarboxamide, S-ethylthio, S-tert-butyl lithio and S-sulfo e.g. by thiolysis with thiophenols, thioglycolic acid, sodium thiophenolate or 1,4-dithiothreitol . Two hydroxy, hydroxy or adjacent amino and hydroxy groups such as; which is protected together with a divalent protecting group, especially * lower alkyl, once or twice substituted with a methylene group such as lower alkylene, e.g. isopropylidene, cycloalkylidene, e.g. cyclohexylidene, or benzylidene; release by acidic solvolysis, especially in the presence of mineral * · «...” acid or strong organic acid. The lower alkyl alkylsilyl group is likewise cleaved by acid oxidation, e.g. with mineral acid, especially hydrofluoric acid, or: ·: with strong carboxylic acid. The 2-halo-lower alkoxycarbonyl is removed by the above-mentioned reducing agents, e.g., a reducing metal such as zinc, reducing metal salts such as chromium II salts, or sulfur compounds, for example sodium dithionite or especially sodium sulfide.

The sulfur group protected as the sulfonic acid ester or sulfonamide is released, for example, by acidic hydrolysis, e.g. in the presence of a mineral acid, or particularly by basic hydrolysis, e.g., by an alkali metal hydroxide or an alkali metal carbonate, for example sodium carbonate.

In the presence of multiple protected functional groups, protecting groups may be selected so that more than one such group can be cleaved simultaneously, for example, by an acidolytic reaction such as by treatment with trifluoroacetic acid, or by hydrogen and a hydrogenation catalyst such as palladium on carbon. On the other hand, the groups may also be selected such that they cannot be cleaved simultaneously but in the desired order to give the corresponding intermediates.

Additional method steps

In the additional process steps, if desired, the functional groups of the starting compounds which are not required to participate in the reaction may be present in unprotected or protected form, for example with one or more of the protecting groups set forth in process a) above. The protecting groups may remain in the final products or they may. may be partially or partially cleaved according to one of the methods described in method f).

* ·:; : At least one salt of the formula I; · *; salts of the group containing compounds may be prepared in a manner known per se. Thus, salts of acidic groups of formula I can be formed, e.g., by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g., sodium salt of 2-ethylhexanoic acid, organic alkali or alkaline earth metal oxide compounds, , carbonates or hydrogencarbonates such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, corresponding calcium compounds or ammonia or a suitable organic amine, in particular stoichiometric amounts or only a small amount of a salt-forming substance.

The acid addition salts of the compounds of the formula I are obtained by conventional means, e.g., by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I with acidic and basic salts, e.g., free carboxy group and free amino group, can be formed, e.g., by neutralizing salts, such as acid addition salts, with isoelectric point, e.g., by weak bases or by ion exchange.

> ·

The salts can be converted in the conventional manner into the free compounds, the metal and ammonium salts, for example by treatment with suitable acids, the acid addition salts, for example, by treatment with suitable basic substances.

v * Stereoisomeric mixtures, i.e. mixtures of diastereomers and / or enantiomers, such as racemic mixtures; * can be separated into the corresponding isomers by methods well known in the art. Thus diastereo-. the mixtures of the mer can be separated into individual diastereomers by fractional crystallization, chromatography, solvent distribution, etc.

k. The racemates can be separated from each other by converting the optical antipodes into diastereomers, e.g. · A club to react with optically active compounds, e.g.

with optically active acids or bases, by chromatography on optically active compounds on the column materials 114634 106 or by enzymatic methods, e.g. by reacting only one of the enantiomers selectively. This separation can occur both at the degree of one of the starting products or in the compounds of formula I itself.

In the individual chiral centers of the compound of formula I, the configuration can be inversely reversed. For example, the configuration of asymmetric carbon atoms having nucleophilic substituents such as amino or hydroxy may be reversed by second-order nucleophilic substitution, optionally after conversion of the bound nucleophilic substituents to a suitable nucleofugic leaving group, and reacting with the original containing carbon atoms, such as the R5 carbon atom of formula I, can be reversed by oxidation and reduction of compounds of formula I.

The hydroxy R5 and hydrogen Rg residues present in the compound of formula I can be oxidized to the oxo group, in particular oxidizing agents which selectively convert the hydroxy group to the keto group, for example chromic acid or its derivatives such as pyridinium: chromate or tert-butyl chromate. dichromate / sulfuric acid, sulfur trioxide in the presence of heterocyclic bases such as pyridine / SO 3, further nitric acid, pyrrole. lucite or selenium dioxide, or dimethyl sulfoxide, in the presence of oxalyl chloride, in water, aqueous> ·; or in organic solvents such as halogenated solvents, e.g. 114634107, particularly at -10-50 ° C, for example as disclosed in European Patent Application EP-A-0 236 734.

On the other hand, in the compounds of formula I thus obtained, wherein R 5 and R 8 together form an oxo group, the oxo group can be reduced to a hydroxy group. Suitable reducing agents for the oxo group in the compound of formula I are reducing agents which selectively reduce the isolated keto group under the reaction conditions of the process or faster than the amide groups present in the compounds of formula I.

Suitable borohydrides such as alkali metal borohydrides, especially sodium borohydride, lithium borohydride or sodium cyanoborohydride, furthermore zinc borohydride, or suitable aluminum hydrides such as alkali metal lower alkoxide aluminum hydrides, are mentioned.

The reduction may also be carried out with hydrogen on suitable heavy metal catalysts, e.g. Raney nickel or platinum; in the presence of sodium or palladium catalysts, for example platinum or palladium on activated carbon, or Meerwein-Ponn-Dorf-Verley by means of aluminum alkanates, in particular Aluminum-2-propanolate or ethanolate.

The reduction may be carried out, in particular, in stoichiometric amounts of the reducing agent or in a substantially dimensioned excess of I in an inert solvent at temperatures between -80 ° C and the boiling point of the solvent, e.g. -20 ° to + 100 ° C. under nitrogen or argon. Excess reducing agent is necessary especially when it also reacts with protons of a solvent, e.g. a protic solvent.

When using sodium borohydride, polar protic solvents, e.g. methanol, ethanol or isopropanol, are suitable, while other reducing agents are polar, aprotic solvents, e.g. tetrahydrofuran.

In the compound of formula I wherein and Rg do not contain reactive aryl radicals or do not contain highly reactive aryl radicals, the aryl radical present in Ry and / or the residue, especially the phenyl radical, may be hydrogenated, for example by catalytic hydrogenation, particularly in the presence of heavy metal oxides such as rhodium / platinum , e.g. Nishimura catalyst, especially in a polar solvent such as alcohol, e.g. methanol or ethanol at temperatures of 0 to 80 ° C, especially 10 to 40 ° C and hydrogen pressure of 1 to 10 atmospheres, especially at about normal pressure.

In the resulting compound of Formula I, the amino or carboxamido group may be substituted, in free or reactive form, the carboxy group esterified or amidated, or the esterified or amidated carboxy group converted to a free; ; to the main carboxy group.

· Substitution of a carboxamide group or another primary or secondary amino group, for example residues; for the attachment of Rj or Rg of unsubstituted or substituted alkyl, alkenyl or alkynyl, aryl-lower alkyl, carbon-linked heterocyclyl, or heterocyclyl-lower alkyl to compounds of formula I wherein one or more of the following: by alkylation.

Suitable agents for the alkylation of the carboxamide group in the compound of formula I include, for example, diazo compounds, e.g.

: diazomethane. The diazomethane can be decomposed in an inert solvent, whereby the free methylene formed reacts with the carboxamide group of the compound of formula I. The decomposition of the di-azomethane is particularly catalytic, e.g. in the presence of a fine noble metal, e.g. copper, or a noble metal salt, e.g. copper (X) chloride or copper (II) sulfate.

Alkylating agents are also disclosed in German Application Publication 2,331,133, e.g., alkyl halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-aryl-triazenes which can be reacted with the carboxamide group of formula I in the reaction conditions disclosed therein. .

Other alkylating agents are those of the formula Ηχ-Χ (X) R2-X (XI)

Compounds of Rg-X (XIII) and R9-X (XIV): wherein X represents a leaving group and 'other residues have the meanings given for acyl, substituent, or unsubstituted or substituted sulfo, phosphono or except for substituted phosphoryl as above. In particular, the leaving group is a nucleofugic leaving group such as a strong inorganic hydroxy esterified with an inorganic or organic acid, such as a mineral acid such as hydrochloric acid such as hydrochloric, hydrobromic or iodic acid, or a strong organic sulfonic acid such as e.g. a lower alkane sulfonic acid or an aromatic sulfonic acid, e.g. optionally lower alkyl such as methyl, halogen such as bromine and / or nitro substituted benzenesulfonic acid, e.g. methanesulfonic, trimethanesulfonic esterified with hydroxy.

114634 110 i

The reaction may be carried out under conditions of first or second order nucleophilic substitution.

For example, a compound of formula VIII-XIII wherein X represents a leaving group having a high polarity of the electron sheath, e.g. iodine, in a polar aprotic solvent, e.g. acetone, acetonitrile, nitromethane, dimethylsulfoxide or dimethylformamide can be used. The reaction may also be carried out in water to which an organic solvent, such as ethanol, tetrahydrofuran or acetone, has been added as a possible solubilizer. The substitution reaction is optionally carried out at a reduced or elevated temperature, e.g., from about -40 ° C to about 100 ° C, especially from about -10 ° C.

In a temperature range of 50 ° C and optionally under an inert gas such as nitrogen or argon.

For the esterification or amidation of a carboxy group in a compound of formula I, if desired, the free acid may be used or the free acid may be converted into one of the above derivatives and reacted with an alcohol, ammonia, primary or secondary amine, or a free acid or salt, The cesium salt may be reacted with a reactive derivative of the alcohol. For example, the cesium salt of a carboxylic acid may be reacted with an alcohol-equivalent halide or sulfonic acid ester. The esterification of the carboxy group may also be effected by others ;; conventional alkylating agents, e.g. diazomethane; · * alkyl halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, etc.

To convert the esterified or amidated carboxy group to the free carboxy group, one of the methods described for cleavage of the carboxy protecting groups or 114634111 may be employed if desired by alkaline saponification according to the conventional conditions, e.g., published in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaft

In the compound of formula I, the esterified carboxy group may be converted to an optionally substituted carboxamide group by aminolysis with ammonia or a primary or secondary amine. Aminolysis may take place according to the conventional reaction conditions for such reactions, e.g., Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1976.

The free amino group present in the compound of formula I may be acylated, for example, to attach an acyl, sulfo, substituted sulfonyl, phosphono or substituted phosphoryl radical of any of the radicals R 1 - or R 9. The acylation is carried out in accordance with one of the methods described for methods b), c) or d) for condensation or protecting groups or, for example, according to one of the methods described in Organangikum, 17th ed.

: Available in a compound of formula I wherein the substituents have the meanings indicated and have at least one free hydroxy group and the other functional groups exist in protected form, the free hydroxy group may be acylated or etherified.

Acylation can be accomplished with acylating reagents of any one; according to methods b) to d), disclosed for protecting groups or disclosed in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.

114634 112

The etherification can be carried out with the above alkylating agents and under the same reaction conditions, e.g. diazomethane, alkyl halides, sulfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazines, etc.

In the resulting compound of formula I, the working group can be formed by oxidation to a sulfinyl or sulfonyl group, a sulfoxide corresponding to the sulfide, or a sulfone.

Oxidation to a sulfonyl group or sulfone can be carried out with most conventional oxidizing agents. Particularly preferred are oxidizing agents which selectively oxidize the thio group or sulfide sulfur in the presence of other functional groups, e.g. amino or hydroxy groups, of the compound of the formula I in question, for example aromatic or aliphatic -poa, permic acid or trifluoro-peracetic acid. Oxidation with peroxycarboxylic acids takes place in the same manner; in conventional solvents suitable for this purpose, for example chlorohydrocarbons, e.g. methylene chloride or chloroform, ethers such as diethyl ether, l-esters such as acetic ester and the like at temperatures between -78 ° C and room temperature, e.g. -20 ° C to + 10 ° C: at about 0 ° C. Peroxycarboxylic acid may also be formed in situ, e.g. with hydrogen peroxide in acetic acid or formic acid optionally containing acetic anhydride, e.g. with 30% or 90% hydrogen peroxide in acetic acid / acetic anhydride. Other peroxo compounds are also suitable, for example potassium peroxomonosulfate in a lower alkanol / water mixture, e.g. methanol / water or ethanol / water, or in aqueous acetic acid at -70 ° to + 30 ° C, e.g. -20 ° C. and room temperature, further 114634 l of sodium metaperiodate in methanol or methanol / water mixtures at 0 ° to 50 ° C, e.g. at about room temperature. Using stoichiometric amounts of said oxidizing agents, the corresponding sulfinic acids or the corresponding sulfoxides can also be obtained. Suitable for this purpose are, for example, sodium periodate in methanol or methanol-water mixtures at temperatures between -15 ° C and room temperature, e.g. about 0 ° C, m-chloroperbenzoic acid in methylene chloride, chloroform or acetic ester -78 ° to 10 °. At temperatures between -30 ° C and 0 ° C, further tert-butyl butyl chloride in lower alkanols, e.g. methanol, or hydrogen peroxide in acetone or acetic acid at about 0 ° C, or the aforementioned potassium peroxomonosulfate at low temperatures.

If desired, the corresponding thio compound or the corresponding sulfide may be formed by reduction of the sulfonyl group or sulfone residue in the resulting compound of formula I, for example with diisobutylaluminum hydride in ether or tetrahydrofuran.

· Available in a compound of formula I having a sulfinyl group, this group can be reduced to a working group.

Preferred are selective reducing agents which leave other functional groups of the compound of formula I unchanged, e.g., the amide function. Examples of such selective reducing agents include il-dichloroborane, which is preferably used in tetrahydrofuran or dimethoxyethane at temperatures from -30 ° C to + 10 ° C, triphenylphosphine in boiling carbon tetrachloride, trichlorosiloxylisopropylsulfonic acid, e.g., water-methanol, water-ethanol or also water-tetrahydrofuran at temperatures between -10 ° C and + 50 ° C, further in the presence of sodium borohydride cobalt (II) - 114634 114 chloride or also hydrogen in the presence of catalytic amounts of palladium, e.g. in boiling ethanol.

The protecting groups or suitable residues or Rg, i.e. those denoting acyl, sulfo, substituted sulfo, phosphono or substituted phosphoryl may be cleaved by any of the processes mentioned in process f), in particular by hydrolysis, for example bases such as alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide, or acids , such as in the presence of organic acids or mineral acids, e.g., halogen hydrogen, such as hydrogen chloride. The hydrolysis takes place under conventional conditions, for example in aqueous solution or in anhydrous solvents, especially in ethers such as dioxane at temperatures between -50 ° C and the reflux temperature of the corresponding reaction mixtures, e.g. 0 ° to 50 ° C, especially in a protective gas such as argon or nitrogen.

All of the above process steps may be carried out under known reaction conditions, especially those mentioned above, conventionally in the presence of solvents or diluents, in particular those which are inert to and used in the reagents used, or, in their absence, catalysts, in the presence or absence of substances, e.g. ion exchangers, such as cation exchangers, e.g., in the H + form, depending on the reaction and / or the substances involved in the reaction at a reduced, normal, or elevated temperature, e.g.

: Temperature of 190 ° C, especially about -80 ° C to about 150 ° C, in a room range, e.g. -80 to 60 ° C, at room temperature, -20 to 40 ° C or at the boiling point of the solvent used, at atmospheric pressure or in a closed vessel, optionally under pressure and / or under an inert atmosphere, e.g. under argon or nitrogen.

115 114634

All of the starting and intermediate compounds may have salts, provided that salt-forming groups are present. Salts can also be present when such compounds are reacted, as long as this does not interfere with the reaction.

The isomeric mixtures present in each of the reaction steps may be separated into individual isomers, e.g., diastereomers or enantiomers, or arbitrary mixtures of isomers, e.g., racemates or diastereomeric mixtures, for example according to the methods described in "Additional Process Steps".

In certain cases, for example, hydrogenation, it is possible to obtain stereoselective reactions so that, for example, individual isomers can be more readily obtained.

Solvents which may be selected for the particular reaction are, for example, water, esters such as lower alkyl lower alkanoates, e.g. acetic acid diethyl esters, ethers such as aliphatic ethers, e.g. diethyl ether, or cyclic ethers, e.g.

:: tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols such as methanol,. ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halocarbons such as methylene chloride, acid. amides such as dimethylformamide, bases such as heterocyclic nitrogen bases, e.g. pyridine, carboxylic acid; · 'anhydrides such as lower alkanoic anhydrides, e.g.

acetic anhydride, cyclic, linear or branched hydrocarbons such as cyclohexane, hexane or isopentane, or mixtures of these solvents, e.g. aqueous solutions, unless otherwise stated in the specification. Such solvent mixtures can also be used to carry out the final steps, for example, by chromatography or partitioning.

114634 116

The invention also relates to those embodiments of the process wherein, at some point in the process, the intermediate compound is obtained and the missing process steps are carried out or the starting material is formed under reaction conditions or used in the form of a derivative or salt. and deal with the situation in situ. The starting materials are in particular those which lead to the compounds described above as being advantageous, in particular highly preferred, primarily preferred, and / or very preferred.

Pharmaceutical preparations

The pharmacologically useful compounds of the formula I can be used, e.g., for the preparation of pharmaceutical preparations containing the active ingredient in admixture or in admixture with an inorganic or organic, solid or liquid pharmaceutical; significant amounts of pharmaceutically acceptable carriers; : with quantity.

* ·

Pharmaceutical composition (preparation) / which may be administered to warm blood, especially human ;;;; for treating or preventing a disease which responds to a retroviral protease, in particular a retroviral aspartate protease such as HIV-1 or HIV-II gag protease, e.g., treating or preventing a retroviral disease such as AIDS, comprising inhibiting a retroviral protease. an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

114634 117 Such pharmaceutical preparations are intended for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous use in warm blood (humans and animals), and contain an effective dose of a pharmacologically active agent, alone or in combination with a pharmaceutically with. The dosage of the active ingredient depends on the type, weight, age and individual condition of the warm-blooded animal, the individual pharmacokinetic conditions, the disease being treated and the mode of administration.

A method for treating diseases caused by viruses, particularly retroviruses, e.g. AIDS, by administering a therapeutically effective amount of the compounds of formula I according to the invention, especially to a warm-blooded, e.g., human, who needs such treatment for any of said diseases, particularly AIDS. For warm-blooded, e.g., 70 kg, human subjects, the dosage amounts are from about 3 mg to about 3 g, particularly about 10 mg to about 1.5 g, e.g., about 300 mg to about 1000 mg / person / day preferably in 1-3 divided doses which may be e.g. Usually: children are given half the adult dose.

> I

. . The pharmaceutical preparations contain from about 1% to about 95%, in particular from about 20% to about 90% of the active ingredient. The formulations of the invention may be, e.g., in unit dosage form such as ampoules, vials, suppositories, in the form of tablets, tablets or capsules.

Such pharmaceutical preparations are prepared in a manner known per se, e.g. by conventional dissolving, lyophilizing, mixing, granulating or granulating techniques.

114634 118

Solutions of the active ingredient are preferably used, in addition to suspensions, in particular aqueous isotonic solutions or suspensions, which may be prepared before use, e.g. in the case of lyophilized preparations containing the active ingredient alone or in combination with a carrier, e.g. mannitol. The pharmaceutical preparations may be sterilized and / or contain adjuvants, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubilizers, salts for adjusting the osmotic pressure and / or buffers, and are prepared in a manner known per se, e.g. solubilization or lyophilization methods. Said solutions or suspensions may contain viscosity enhancing agents such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

suspensions in oil contain, as an oil component, conventional vegetable, synthetic or semi-synthetic oils for injection purposes. Such include in particular liquid fatty acid esters containing as the acid component a long chain fatty acid of 8 to 22, in particular 12 to 22 carbon atoms, such as lauric acid, f ': tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, palmitic acid , behenic acid or similar unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassic acid or linoleic acid, optionally! with the addition of antioxidants such as vitamin E, j-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters: contains up to 6 carbon atoms and is monovalent or monovalent, e.g. mono-, di- or tri-alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol their isomer, but above all glycol or glycerol. Thus, as fatty acid esters, for example, 1 9 9464634 are for example: ethyl oleate, isopropyl myristate, iso-propyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol tririoleate, manufactured by Gattefosse, Paris), "Miglyol 812" , Germany), but especially vegetable oils, such as tree wool seed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and above all peanut oil.

The preparation of the injectables is carried out in the usual manner under sterile conditions, as well as filling into ampoules or vials and closing the containers.

Pharmaceutical preparations for oral use may be obtained by combining the active ingredient with solid carriers, optionally granulating the resulting mixture, and treating the mixture as tablets, granules or capsules, if desired or after addition of suitable excipients. In this case, it can also be treated with a plastic carrier that dispenses the active ingredients or allows them to diffuse.

: Suitable carriers are in particular excipients such as blind lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch paste, e.g.

Corn, wheat, rice or potato starch, gelatin; tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, furthermore, a carboxymethyl starch moiety, a cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are, in the first place, flow regulators and lubricants,? silicic acid, talc, stearic acid or its salts such as magnesium or calcium stearate and / or polyethylene glycol. The granulators are provided with suitable, possibly gastric-resistant coatings. concentrated sugar solutions, optionally containing acacia, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or lyophilized sodium hydroxide formulations suitable for the preparation of gastric Capsules include plug-in capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. with excipients such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers.

In soft capsules, the active ingredient is preferably dissolved or suspended in suitable excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, with the possible addition of stabilizers and / or antibacterial agents. In tablets: or in granules or capsule shells may be added,. dyes or pigments, e.g. to identify or label various doses of the active ingredient.

; Starting Materials Λ Preferably starting materials are used and the reaction conditions are selected so as to obtain the initially preferred compounds.

114634 121

In the preparation of all starting materials, the free functional groups which are not to be involved in the particular reaction may exist in unprotected or protected forms, for example protected by the protecting groups mentioned above in process a). These protecting groups may be liberated at appropriate times by the reactions set forth in process f).

The starting materials of process a) are known or can be prepared, if novel, according to methods known per se, e.g. from hydrazine or derivatives thereof, of the appropriate amino acids or analogs thereof, for example having one or two of said side chains R 3 and R4, compounds of formula IV.

Compounds of formula III are obtained, for example, from compounds of formula H2N-NH-R1; 1 (XV) '* wherein R11 represents hydrogen or an amino protecting group as described above in process b), in particular tert-lower alkoxycarbonyl such as tert-butoxycarbonyl; aryl-lower alkoxycarbonyl; , · Such as benzyloxycarbonyl or 9-fluorenylmethoxy; carbonyl, or any of the above acylamino protecting groups, so that to form a compound of formula I wherein R7 is substituted with R7 "which represents unsubstituted or substituted alkyl or cycloalkyl, the alkyl of formula R7" The compound of formula XII as described above in method e) or the R7 residue is coupled by reacting the appropriate carbonyl compounds with the free amino group of the compound of formula VIII or its acylated derivatives and subsequently reducing the resulting hydrazone to form the formula ί 1 22 114634 Hydrazine derivatives of R7-NH-NH-R11; (XVI) wherein the residues in each of the compounds mentioned above have the meanings indicated above and the functional groups of the reactive reagents which are not required to be reacted are optionally protected, optionally cleavable by protecting group R11; if it does not correspond to any of Rg and Rg of the compounds of formula I and / or other protecting groups and Rg and Rg except hydrogen are reacted by condensing under the conditions mentioned in process b) above with an acid of formula VI or R8-OH (XVII) wherein Rg has the meanings indicated, or by alkylating a compound of formula XIII or XVI as defined above, or both, under the conditions mentioned in the additional process steps.

Carbonyl compounds used for the preparation of compounds of formula XVI which are suitable for attachment of R 7 are aldehydes and ketones with reactive carbonyl V; the group is part of R7, after reaction with compounds of formula XV and subsequent reduction, in particular aldehydes suitable for the attachment of lower alkyl, cyclohexyl lower alkyl or phenyl lower alkyl.

t

The reaction of the carbonyl compounds with the compounds of formula XVI to give the corresponding hydrazones takes place in the reaction of the carbonyl compounds and amines under conventional conditions; ratios, especially in polar organic solvents, e.g. ethers such as tetrahydrofuran or diethyl ether, alcohols such as methanol or ethanol, carboxylic acid amides such as dimethylformamide, or esters such as acetic acid, ethyl ether, further in the presence or absence of acidic catalysts, e.g.

The reduction of the resulting hydrazones is preferably effected by hydrogenation in the presence of a suitable catalyst. Suitable hydrogenation catalysts are metals such as nickel, iron, cobalt or ruthenium, or precious metals, or oxides thereof, such as palladium or rhodium or equivalent, their oxides, optionally e.g. on a suitable support such as or as framework catalysts such as Raney nickel. Solvents commonly used for catalytic hydrogenation include, for example, water, alcohols such as methanol or ethanol, esters such as ethyl acetate, ethers such as dioxane, chlorocarbons such as dichloromethane, carboxylic acid amides; such as dimethylformamide, or carboxylic acids such as glacial acetic acid, or mixtures of these solvents. Hydrogenation occurs; At temperatures of from 10 ° to 250 ° C, particularly from room temperature to 100 ° C, and pressures of from 1 to 200 bar, in particular from 1 to 10 bar, in conventional equipment.

Particularly preferred for the preparation of compounds of formula XV are reaction conditions similar to those described in J. Chem. Soc. Perkin I, 1712 (1975).

; The compounds of formula IV are obtained, for example, by reduction of formula 114634 124j

Riö “NH .COOH

X cxvni) wherein R 10 represents hydrogen or an amino protecting group mentioned in process a), in particular tert-lower alkoxycarbonyl such as tert-butoxycarbonyl, aryl lower alkoxycarbonyl such as benzyloxycarbonyl or 9-fluorenylmethoxyacetic acid or 9-fluorenylmethoxy R 3 and R 4 have the meanings indicated for the compounds of formula I, in particular of formula

Rflj - NH COOH

(XVin A) * 3 wherein the residues have the meanings indicated

, Rtf-NH CHO

X (xix): i RT «4 aldehydes in which the residues have the meanings indicated, especially the formula

. ··. R, O ~ NH CHO

(XIXa)

• i K

·. *. aldehydes having the meanings indicated (obtainable, for example, from compounds of formula XVIII A), by reacting these aldehydes with a ylide compound, in particular a sulfide ylide compound, of formula 1 25 114634 j R * rNH ^ <vJ (XX) in which the residues have the meanings indicated, especially the formula

B

RtirN, l | (XXA) to R3 compounds (obtainable, for example, from compounds of formula XIXA) in which the residues have the meanings indicated, optionally cleavage of the protecting group R1; L if it does not correspond to any of Rg or Rg of the compounds of formula I and acylation VIII or the acids of formula R2-OH (XXI) wherein the residues have the meanings indicated under the conditions described in process b): and / or the amino group of the resulting compound by reacting the compounds of formula X or XI nucleofugic; ; : Removes residual groups with residual meanings under additional conditions in the method.

Reduction of the amino acids of formula XVIII or XVIII A to the corresponding aldehydes XIX or XIX A is effected, for example, by reduction to the corresponding alcohols and oxidation to v then the said aldehydes.

The reduction to alcohols is effected, for example, by hydrogenation of the acid halides or other activated carboxylic acid derivatives mentioned in process b) under hydrogenation conditions of the hydrazones obtained from the compounds of formula XVI, or with complex hydrides such as sodium borohydride. Subsequent oxidation of the resulting alcohols is possible, for example, under conditions where the compounds of formula I wherein R5 represents hydroxy and Rg represents hydrogen are oxidized to compounds wherein Rg and R6 together represent oxo as described in the additional process steps or by oxidation of the hydroxy group with sulfoxide, such as dimethylsulfoxide in the presence of a hydroxy group activating reagent such as a carboxylic acid chloride e.g. oxalyl chloride in an inert solvent e.g. halogenated hydrocarbon such as dichloromethane and / or an acyclic or cyclic ether such as -78 ° C -80 °. -50 ° C.

It is also possible to directly reduce the amino acids to aldehydes, for example by hydrogenation in the presence of a partially poisoned palladium catalyst or by reduction of the corresponding amino acid esters, e.g. li-1: thium tri- (tert-butoxyc) aluminum hydride or, in particular, diisobutylaluminum hydride in apolar solvents, e.g. hydrocarbons or aromatic solvents such as toluene at -100 to 0 ° C, especially -70 to -3 ° C. And subsequently reacting with the corresponding sero-carbazones, e.g. with the corresponding acid salts of semicarbazones such as semicarbazide hydrochloride in aqueous solvent systems such as alcohol / water, e.g. ethanol / water at -20 to 60 ° C, especially 10 ° C. At -30 ° C and reacting the resulting semicarbazone with a reactive aldehyde, e.g. formaldehyde, in an inert solvent, for example a polar organic 1 27 114634! in a solvent such as a carboxylic acid amide such as dimethylformamide at -30 to 60 ° C, particularly at 0 to 30 ° C and then with an acid such as a strong mineral acid such as halogen in aqueous solution, optionally in the presence of the solvent used above At temperatures of 50 ° C, particularly -10 to 30 ° C. The corresponding esters are obtained by reacting the amino acids with the corresponding carboxylic acids, for example ethanol, by condensation under the conditions used in method b), for example by reaction with inorganic acid halides such as thionyl chloride in organic solvent mixtures such as aromatic and alcoholic solvents, e.g. At temperatures of from 50 to 50 ° C, in particular from -10 to 20 ° C.

The preparation of the compounds of formulas XIX and XIX A is particularly preferably carried out under conditions analogous to those described in J. Org. Chem. 47, 3016 (1982) or J. Org.

Chem. 43, 3624 (1978).

Sulfur ylide suitable for the reaction of compounds of formula XIX or XIX A with epoxides of formula XX or XX A is, for example, dialkylsulfonium methylide, e.g. dimethylsulfonium methylide, alkyl- or phenyl-dialkylaminosulfoxonium methylide, e.g. dimethylaminosulfoxonium methylide, or dialkylsulfoxonium methylide, e.g. dimethyl or di-. etyylisulfoksoniummetylidi.

The sulfur ylide compound in question is conveniently prepared in situ from the corresponding sulfonium or counter, sulfoxonium salt and base, e.g., sodium borohydride in a dipolar aprotic solvent, e.g.

'*, dimethylsulfoxide, or ether, e.g., tetrahydrofuran or 1,2-dimethoxyethane, and then reacted with the compounds of formula XIX or XIXA. The reaction is normally carried out at room temperature with cooling, e.g. to -20 ° C or with slight warming, e.g. to 40 ° C. Simultaneously formed sulfide, sulfinamide or counter, sulfoxide is removed during subsequent aqueous final steps.

The reaction with sulfur ylide is particularly preferred in J. Org. Chem. 50, 4615 (1985).

The compound of formula XX (especially XXA) can also be obtained from a compound of formula XIX (especially XIXA) as defined above by reacting it with a trialem-alkylalkylsilylmethyl-Grignard compound prepared e.g. from the corresponding halogenomethyl silicate such as chloromethyl trimethylsilane in an inert solvent e.g. ether such as dioxane or diethyl ether at 0 to 50 ° C, e.g. at room temperature to about 40 ° C, then removing the silyl residue and by forming a double bond, e.g., by means of a Lewis acid such as BF3, preferably also cleaving the amino protecting group R10 which is present; in an inert solvent, e.g. an ether such as diethyl ether, or a halogen hydrocarbon such as dichloromethane. in Denmark, or a mixture thereof, at temperatures between -50 ° C and reflux temperature, especially 0 - 30 ° C, by re-acylation if necessary !!! at the same time the amino protecting group as R10 as defined above and the double bond obtained by oxidation to oxirane, especially with percarboxylic acid, e.g. m-chloroperbenzoic acid: in an inert solvent, e.g. halogenated hydrocarbon such as dichloromethane, -20 ° C: n and the reflux temperature of the mixture, e.g.

At 10-30 ° C.

114634 129

The starting materials of processes b), c) and d) are known or, if novel, can be prepared according to methods known per se, e.g., the compound of formula V may be obtained from the appropriate hydrazine derivatives of formula III wherein R 8 is hydrogen and the appropriate meanings for the compounds of formula V, and the appropriate epoxides of the formula IV wherein the residues have the meanings indicated for the compounds of formula V (method b), the compound of formula VII may be obtained from the appropriate hydrazine derivatives of formula III and the appropriate epoxides of the formula IV in which R 4 represents hydrogen and the other residues have the meanings indicated for the compounds of formula VII (method c), and the compound of formula IX may be obtained from the corresponding hydrazine derivatives of formula III the compounds have the meanings indicated for the compounds of formula IX (method d), and the appropriate epoxides of the formula IV wherein R 4 represents hydrogen and the other residues have the meanings indicated for the compounds of formula IX (method d), optionally employing protecting groups and: they.

Compounds of formula 1 'wherein the substituents have the meanings given above may be prepared, for example. formula III '

B

j H% ^ R9 (ΠΓ)

i I.

wherein the residues have the meanings indicated for compounds of formula I as depicted in process b), by reacting a compound of formula IV with a compound of formula 114634 130, wherein the non-reactive functional groups are protected as provided therein; can be released after the reaction.

Particularly for method d), the compounds of formula | Starting compounds of OH ^ 7 where R3 represents unsubstituted or substituted alkyl or cycloalkyl, aryl, heterocyclyl or unsubstituted or substituted alkenyl, and R7 represents unsubstituted or substituted acyl or cycloalkyl, aryl or cycloalkyl, substituted alkenyl, as well as salts of said compounds, if any salt-forming groups are present, which are intermediates of the invention.

These may be protected at one or both amino groups, so that when two amino protecting groups are present, these may be identical or different.

: The amino protecting groups used are, for example, the amino protecting groups shown in Method a) above. In the context of the compounds of formula II, the aforementioned R3 and R7 residues have the meanings given above for the compounds of the formula I in the definition of R3 and R7.

»I 'I

Particularly preferred are those compounds of formula II, v, and salts of these compounds, if a salt is present. forming groups wherein R3 represents cyclohexyl-lower alkyl, phenyl-lower alkyl or p-fluorophenyl-lower alkyl and R? denotes lower alkyl, cyclohexyl-114634 131 lower alkyl, phenyl lower alkyl, p-cyanophenyl lower alkyl or p-fluorophenyl lower alkyl.

Particularly preferred are the compounds of formula II as well as the salts of these compounds in the presence of salt-forming groups wherein R 3 represents phenyl-lower alkyl and R 3 ??? denotes lower alkyl, cyclohexyl-lower alkyl or phenyl-lower alkyl.

Preference is given to compounds of formula II as well as salts of these compounds, provided that salt-forming groups are present in which R3 represents cyclohexylmethyl, benzyl or p-fluorobenzyl and R3 is hydrogen. denotes n-butyl, isobutyl, cyclohexylmethyl, benzyl, p-fluorobenzyl or p-cyanobenzyl.

Particularly preferred are the compounds of formula II and the salts thereof, in the presence of salt-forming groups wherein R 3 represents benzyl and Ry represents isobutyl, cyclohexylmethyl or benzyl.

»♦

Above all, the compounds of formula: II mentioned in the examples are preferred.

t

Compounds of the formula II in which the substituents have the meanings indicated, or salts thereof, in the presence of salt-forming groups, are prepared, for example, by incorporation of a compound of formula * Ry-NH-NH-R 13 (XVI) f! «T 132 114634« o

RfrN1 ^ ^ Cg (XXA) r3, an amino protecting group and, if desired, a compound of formula II obtained according to Method A above, having at least one salt-forming group, is converted into a salt thereof or the resulting salt is converted into the free compound; into another salt and / or separating the resulting isomeric mixture and / or cleaving the protecting groups present in the compound of formula II and / or converting the compound of formula II obtained according to the invention into another compound of formula II according to the invention.

The preparation and conversion of salts, separation of isomeric mixtures, cleavage of protecting groups and conversion of compounds of formula II are carried out according to the methods set forth above for compounds of formula I.

Particularly preferred is the preparation of the starting compounds of formula II: · where the substituents have the meanings indicated, by cleavage of protecting groups of the compound of formula II; those in which one or both amino groups are protected by amino protecting groups, particularly under the conditions described above for the hydrolysis of the compounds of formula I as set forth in the additional process steps.

»T | Methods for incorporating compounds of formula XVI into compounds of formula XXA are set forth above in process a) for the preparation of compounds of formula I.

The protected compounds of formula I are prepared, for example, by one of the processes disclosed hereafter, in particular compounds of formula III and IV, wherein the functional groups of these compounds are protected by the protecting groups set forth in process a).

The acids of formulas VI, VIII, XVII and XXI and the compounds of formula X, XI, XII, XIII, XIV and XV containing nucleofugic groups are known or, if new, can be prepared according to methods known per se.

The following examples illustrate the invention without, however, limiting it in any way.

Temperatures are presented in degrees Celsius (° C). Unless indicated, the reaction proceeds at room temperature. The Rf values, which represent the ratio of the range of the substance in question to the range of the propellant front, are determined by thin-layer silica gel thin-layer chromatography (DC) in the following solvent systems:. · DC Propellant Systems: »'A chloroform / methanol / water / acetic acid 75: 27: 5: 0.5: B chloroform / methanol / water / acetic acid 90: 10: 1: 0.5 C chloroform / methanol / water / acetic acid 85:13; 1.5: 0.5 D chloroform / methanol 8: 1; · E chloroform / methanol 95: 5, F hexane / acetic acid ethyl ester 2: 1 G methylene chloride / diethyl ether / methanol 20: 20: 1 H methylene chloride / diethyl ether 1 : 1 L toluene / acetic acid ethyl ester 2: 1 K chloroform / methanol 5: 1 J methylene chloride / diethyl ether 5: 1 L hexane / acetic acid ethyl ester 4: 1 34 344634 M hexane / acetic acid ethyl ester 5: 1 N hexane / acetic acid 1: methylene chloride / ethanol / NH3vesip. 90: 10: 1Q methylene chloride / diethyl ether 10: 1R hexane / acetic acid ethyl ester 3: 1S methylene chloride / diethyl ether 20: 1T chloroform / methanol 30: 1U chloroform / methanol 15: 1V methylene chloride / diethyl ether / hexane 1: 3 W methylene chloride / diethyl ether 20: 1 X methylene chloride / methanol 40: 1 Y toluene / acetic acid ethyl ester 4: 1

For example, the abbreviation "Rf (A)" means that the Rf values are determined in the solvent system A. The ratio of solvents to each other is always expressed in volume.

HPLC gradients: I: 20% to 100% acetonitrile / 0.05% trifluoroacetic acid in water / 0.05% trifluoroacetic acid over 35 minutes, II: 0% to 40% acetonitrile / 0.05% trifluoroacetic acid in water / 0.05% trifluoroacetic acid for 30 minutes, III: 20% to 60% acetonitrile / 0.05% trifluoroacetic acid in water / 0.05% trifluoroacetic acid for 60 minutes, '. IV: 10% to 50% acetonitrile / 0.05% trifluoroacetic acid in water / 0.05% trifluoroacetic acid for 60 minutes.

Column (250 x 4.6 mm) filled with "Reversed Phase" material with C18-Nucleosil (5 μτη average grain size, Silica-gel covalently derivatized with octadecylsilanes, Maciroy & Nagel, Diiren, BRD). 1 35 1 1 4634? At 215 nm Retention times (tRe?) Are expressed in minutes Run speed 1 ml / min.

For the designation of propulsion systems, the same abbreviations are used for flash chromatography (Flash-Chromatography) and medium-pressure chromatography.

Other abbreviations used have the following meanings: abs. absolute (indicates that the solvent is anhydrous), atm. physical atmospheres (pressure unit) - 1 atm equals 1.013 bar,

Boc tert-butoxycarbonyl, BOP benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, DIPE diisopropyl ether, DMF dimethylformamide, DMSO dimethyl sulfoxide, ether diethyl ether, HB 1-yl-Ν, Ν, Ν ', N'-tetramethyl-uronium hexafluorophosphate, • HOBt 1-hydroxy-benzstriazole, HV high vacuum, • min minutes ,; MS mass spectroscopy, NMM N-methylmorpholine, brine saturated sodium chloride solution, TFA trifluoroacetic acid, Z benzyloxycarbonyl.

Mass spectroscopic measurement values are obtained either by conventional ·, ·, MS or by the MFast-Atom-BombardmentM (FAB-MS) method. The mass values in the former case apply to the non-protonated molecular ion (M) + or the protonated molecular ion (M + H) +.

114634 136

Proton nuclear resonance spectroscopy (1 H-NMR) values are reported in parts per million relative to the tetramethylsilane used as internal constant. s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, lev. = wide.

The IR spectra are expressed in cm -1, with the solvent in question in parentheses. Where indicated, s denotes the intensity of the band in question, m denotes medium magnitude and w denotes the low intensity.

The residue designated as - [PheNNPhe] denotes a divalent group of 3 (S) -amino-4-phenyl-1- (N-benzylhydrazino) butan-2 (S) -ol and has the formula oh -NH f |

VVHN

I ^ NH-

Cr 'The residue designated as - [Phe ^ Cha] represents the bivalent group of 3 (S) -amino-4-phenyl-1- (N-cyclohexylmethylhydrazino) -butan-2 (S) -ol and has the formula 114634 137 '..- 0

-NH I I

Or The residue designated as - [PheNNLeu] denotes a divalent group of 3 (S) -amino-4-phenyl-1- (N-isobutylhydrazino) -butan-2 (S) -ol and has the formula:

OH

f I

VW

: A residue designated as - [PheNNNle] represents a bivalent group of 3 (S) -amino-4-phenyl-1- (Nn-butylhydrazino) butan-2 (S) -ol and has the formula 1338 1 4634 OH - *

nholC

5 ^ NH- cy The residue designated as - [Phe ^ ip -F) Phe] denotes 3 (S) -amino-4-phenyl-1- (N- (p-fluorophenylmethyl) -hydrazino) -butan-2 ( S) -ol is a divalent group and has the formula oh 'Λ'1--; &

'I

; The residue designated as - [(pF) Phe (f) -F) -Phe] represents 3 (S) -amino-4- (p-fluorophenyl) -1- (N- (p-fluorophenylmethyl) hydrazino ) -butan-2 (S) -ol divalent group and has the formula 1 39 114634! = ^ ΝΗ- .JCr1 The residue designated - * [PheNN (p-CN) Phe] denotes 3 (S) -amino-4-phenyl-1- (N- (p-cyanophenylmethyl) -hydrazino) -butane A divalent group of -2 (S) -ol and has the formula

rrCT

l & The residue designated as - [ChaNNLeu] denotes 3 (S) -amino-

t I

Is a divalent group of 4-cyclohexyl-1- (N-isobutyl-hydrazino) -butan-2 (S) -ol and has the formula »· *» • »1 40 114634 OH

-NH [I

= XH-

CR1

Conventional abbreviations in peptide chemistry are used to designate bivalent groups of native α-amino acids. However, in this case, the amino acids to the right of the groups - [PheNNPhe], - [Phe ^ Cha], - [Phe ^ Leu], - [Phe ^ Nle], - [Phe ^ ip-F) Phe], - [ (pF) PheNN (pF) Phe], - [PheNN (p-CN) Phe], or - [Cha ^ Leu], unlike a conventional peptide sequence having an amino residue on the left and a carboxy end on the right, the carboxy group on the left is shown the arrow («-) which symbolizes the reversal of the bond, the configuration of the α-carbon atom: is shown, if known, by preceding (L) or '> (D) -. In the phenolic hydroxy group containing the R: etherified tyrosine groups are designated Tyr (OR).

f Nle represents the group of norleucine.

Example 1: Boc- [PheNNPhe] -Boc

A solution of 300 mg (1.14 mmol) of (2R) - [1 '(S) -Boc- *; * * amino-2'-phenylethyl] oxirane [J. Org. Chem., 50, 4615 (1985)] and 253 mg (1.14 mmol) of tert-butyl 3-benzylcarbazate [J. Chem. Soc., Perkin I, 1712 (1975)] in 4 ml of methanol is heated under reflux for 12 hours. After the reaction mixture has cooled to 0 ° C, much of the title compound precipitates. The mother liquor is evaporated and the residue is dissolved in a small amount of methylene chloride. 141 114634 hexane is added dropwise, whereupon the remaining title compound precipitates as a white precipitate. FAB-MS: (M + H) + = 486, t Ref (I) = 26.8 min, Rf (E) = 0.70.

Example 2; Z- (L) -Val- [PheNNPhe] - ((L) -Val-Z) 191 mg (0.76 mmol) of Z- (L) -valine, 336 mg (0.76 x mol) B0P: and 103 mg (0.76 mmol) of HOBt are dissolved in 5 ml of a 0.3M solution of NMM in DMF, then after 10 minutes 100 mg (0.25 mmol) of H- [PheNNPhe] -H are added. * 3HCl and stirred for 2 hours at room temperature under nitrogen. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution. The organic phases are filtered through a pad, evaporated and the residue is purified by chromatography on silica gel with methylene chloride / ether (1: 1). The product-containing fractions are lyophilized from dioxane to give the title compound as a white solid. FAB-MS: (M + H) + = 752, t Ref (I) = 27.8 min, Rf (E) = 0.45.

The starting material is prepared as follows: i a) H-TPheNNPhe1-H3HCl

A solution of 280 mg (0.58 mmol) of Boc-iPhe ^ Phe] -Boc from Example 1 in 10 ml of 4N hydrogen chloride in dioxane is stirred for 2 hours at room temperature under nitrogen and then lyophilized. Lyophilization · from dioxane / tert-butanol. to give ot-; pig compound as a flocculent solid. FAB-MS: (M + H) + = 286, t Ret (II) = 23.1 min, R f (C) = 0.17.

114634 142

Example 3: Boc- (L) -Val- [PheNNPhe] - ((L) -Val-Boc)

As in Example 2, the title compound is obtained from 50 mg (0.13 mmol) of H- [PheNNPhe] -H * 3HCl, 83 mg (0.83 mmol) of Boc- (L) -valine, 168 mg (0 , 38 mmol) of BOP, 51 mg (0.38 mmol) of HOBt and 2.5 mL of 0.3MMM in DMF on silica gel with chloroform / methanol (95: 5) and lyophilization from dioxane after. FAB-MS: (M + H) + = 684, t Ret (I) = 27.4 min, R f (E) = 0.38.

Example 4: Boc- [PheNNCha] -Boc

The title compound is obtained according to Example 1 from 231 mg (0.88 mmol) of (2R, 3S) -1- [3-Boc-amino-2-phenylethyl] oxiran and 200 mg (0.88 mmol) of tert butyl 3-cyclohexylmethyl carbazate as a white precipitate from hexane. FAB-MS: (M + H) + = 492, t Ret (I) = 30.4 min, R f (E) = 0.78.

The starting material is prepared as follows: a) tert-Butyl-3-s-cyclohexyl-methyl-carbazate 10.2 g (45.1 mmol) of t-butylhexylcarbaldehyde-tert-butoxycarbonylhydrazone dissolved in 400 ml of methanol are hydrogenated with 5% platinum. in the presence of carbon (5.1 g) at room temperature and 4 atm of hydrogen.

At the end of the reaction, the mixture is filtered off from the catalyst and the filtrate is evaporated. The residue is dissolved in methylene chloride and washed with water. After evaporation of the organic phase, the title compound is obtained as a colorless resin. ^ H NMR

(200 MHz, CDCl 3): 6.1 (s, lev, 1H), 3.9 (s, lev, 1H),? 2.65 (d, 2H), 1.8 - 0.75 (m, UH), 1.45 (s, 9H), t Ret (I) = 32.0 min, R f (E) = 0.75 .

114634 143 (b) SvkloheksvyTicarbaldehyde-tert-butoxycarbonylhydrohydrate

A solution of 10.8 g (81.2 mmol) of tert-butyl glycarbazate and 10.1 g (90 mmol) of cyclohexylcarbaldehyde in 400 ml of ethanol is heated under reflux for 2 hours. Half of the solvent is then distilled off and the title compound is mixed by addition of water.

It is still directly used in step a).

Example 5: H- (L) -Vai- [PheNNPhe] * - ((L) -Vai) -H »3HCl

A solution of 40 mg (0.06 mmol) of Boc- (L) -Vai [Phe ^ Phe] - ((L) -Vai) -Boc of Example 3 in 4 ml of 4N hydrogen chloride in dioxane is stirred for 1 hour. at room temperature. It is then diluted with dioxane and, after lyophilization, the title compound is obtained as the hydrochloride. FAB-MS: (M + H) + = 484, t Ret (II) = 25.8 min, R f (A) = 0.45.

Example 6: N-Thiomorpholinocarbonyl- (L) -Val- [PheNNPhe] - (N-Thiomorpholinocarbonyl- (L) -Vai) r: To a solution of 20 mg (0.03 mmol) in Example 5: lane H- (L) -Val- [PheNNPhe] - ((L) -Val) -H »3HCl in 0.5 ml; ; DMF, add 35 μΐ (0.25 mmol) triethylamine and 16 mg (0.1 mmol) (4-thiomorpholinylcarbonyl) chloride sequentially at room temperature and stir for 1 hour at room temperature. The reaction mixture is diluted with chloroform and washed with saturated sodium bicarbonate. solution. The organic phase is filtered through a pad, evaporated and the residue chromatographed on silica gel with a gradient of chloroform / methanol (15: 1 to 8: 1). The product fractions are evaporated and precipitated with methylene chloride / DIPE. After lyophilization from dioxane, they afford the title compound as a fluffy solid. FAB-MS: (M + H) + = 742, t Ret (I) = 21.6 min, R f (D) = 0.54.

The starting material is prepared as follows: a) (4-Thiomorpholine / carbonyl) chloride

To a solution of 85 ml (165 mmol) of 20% phosgene in toluene is added dropwise at 0 ° C a solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene and the white suspension is stirred for 1 hour at room temperature. . Excess phosgene is displaced by passing nitrogen, the suspension is filtered and the filtrate is evaporated. The title compound is obtained as a yellow oil. IR (CH 2 Cl 2, cm -1): 1735, 1450, 1440, 1405, 1370, 1290, 1180.

Example 7: N-Morpholinocarbonyl- (L) -Va 1 - [PheNNPhe] <- (N-Morpholinocarbonyl- (L) -Vai)

To a solution of 100 mg (0.25 mmol) of H- [PheNNPhe] -H * 3HCl of Example 2a, 163 mg (0.76 mmol) of N-morpholinocarbonyl (L) -valine and 288 mg (0, 76 mmol) HBTU in 2 mL DMF, add 210 μΐ (1.52 mmol) triethylamine and stir at room temperature for 16 hours under nitrogen. The reaction mixture is evaporated: completely, the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is filtered through a pad, evaporated and chromatographed on silica gel with methylene chloride / methanol (15: 1). The title compound is precipitated from methylene chloride / hexane and is obtained after lyophilization from dioxane / tert-butanol as a fluffy solid. FAB-V. MS: (M + H) + = 710, t Ret (I) = 16.3 min, R f (E) = 0.16.

The starting material is prepared as follows: 114634 145 a) N-Morpholinocarbonyl (L) -valine 2.7 g (8.4 mmol) of N-morpholinocarbonyl- (L) -valine benzyl ester are dissolved in 75 ml of glacial acetic acid and 10% in Hydrate. palladium-on-charcoal (500 mg) under 1 atm of hydrogen at room temperature for 3 hours. The catalyst is filtered off and the solvent is evaporated to give the title compound as a colorless oil. 1 H-NMR (300 MHz, CD 3 OD): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H), 0.95 ( 2d, 6H).

b) N-Morpholinocarbonyl (L-valine-benzyl ester)

To a solution of 4 g (10.5 mmol) of (L) -valine-benzyl ester-4-toluenesulfonate in 56 mL of methylene chloride is added 0.8 mL (8.1 mmol) of (morpholinocarbonyl) chloride [preparation: J. Med. Chem. 31, 2277 (1988)] and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine and stirred for 24 hours at room temperature. The reaction mixture is diluted with glacial acetic acid and washed successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic phase is dried over sodium sulfate and evaporated. Chromatograph on: silica gel with ethyl acetate to give the N-morpho-: linocarbonyl- (L) -valine-benzyl ester as a colorless oil. The ester is used immediately in step a).

Example 8: Phenylacetyl- (L) -Val- [PheNNPhe] - (N-Phenylacetyl- (L) -Vai)

I

*> * · According to Example 7, 100 mg (0.25 mmol) of H- [Phe ^ NPhe] -He 3 HCl of Example 2a, 143 mg (0.61 mmol) of phenylacetyl (L) valine [preparation: Mem. Tokyo

Univ. Agric. 20, 51 (1978)], 230 mg (0.61 mmol) of HBTU and 200 µl (1.42 mmol) of triethylamine give the title compound methylene chloride / ether / methanol 114634 146 (20: 20: 1). after chromatographic purification and lyophilization from dioxane / tert-butanol. FAB-MS: (M + H) + = 720, t Ret (I) = 23.7 min, R f (G) = 0.21.

Example 9: N- (3-Pyridylacetyl) - (L) -Val- [PheNNPhe] - (N- (3-Pyridylacetyl) - (L) -Vai)

According to Example 7, 100 mg (0.25 mmol) of H- [PheNNPhe] -H? 3HCl of Example 2a, 576 mg (1.52 mmol) of HBTU, 358 mg (1.52 mmol) N- (3-pyridylacetyl) - (L) -valine and 316 µl (2.3 mmol) of triethylamine give the title compound by chromatography on chloroform / methanol (5: 1) and dioxane / tert. after lyophilization from butanol as a white solid. FAB-MS: (M + H) + = 722, t Ret (II) = 27.9 min, R f (A) = 0.71.

The starting material is prepared as follows: a) N- (3-pyridylacetyl) - (L) -valine 3.4 g of N- (3-pyridylacetyl) - (L) -valine tert-butyl ester are dissolved in 20 ml of trifluoroacetic acid / methylene -: chloride (1: 1) and stirred at room temperature for 16 hours. The reaction solution is completely evaporated and the residue is di-gerated with DIPE. The title compound is obtained as a white, amorphous solid. 1 H-NMR (200 MHz, CD 3 OD): 8.9-8.6 (m, broad, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H). ), 3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6H).

b) N - (3-pyridylmethyl) -? - valine tert-butyl ester ... To a solution of 3.36 g (16 mmol) of (L) -valine tert. butyl ester »HCl, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17 ml (14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml of DMF are added dropwise 114634 147 0 At 4.2 ° C 4.2 ml triethylamine. The reaction mixture is stirred for 48 hours at room temperature, then diluted with methylene chloride and washed with 10% citric acid and saturated sodium bicarbonate solution. The organic phase is filtered through a pad to give, after evaporation of the solvent, an N- (3-pyridylacetyl) - (L) -valine tert-butyl ester which is used immediately in step a).

Example 10: Boc- (L) -Va 1 - [Phe ^ Cha] <- ((L) -Val) -Boc

According to Example 7, from 500 mg (1.25 mmol) of H- [PheNNCha] -ΗΗΗΗΗ, 1.08 g (4.98 mmol) of Boc- (L) -valine, 1.89 g: (4.98 mmol) of HBTU and 1.39 mL (9.96 mmol) of triethylamine give the title compound, after chromatographic purification with methylene chloride / ether (1: 1) and lyophilization from dioxane, as a fluffy solid. FAB-MS: (M + H) + = 690, t Ret (I) = 29.3 min, R f (H) = 0.48.

The starting material is prepared as follows: a) H-Phe ^ Cha 1 -H * 3HCl 1.10 g (2.2 mmol) of Boc-fPhe ^ Cha] - according to Example 4 is dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred 3 hours at room temperature. After lyophilization of the reaction solution, the title compound is obtained as the hydrochloride. FAB-MS: (M + H) + = 292, t Ret (II) = 27.3 min.

Example 11: Z- (L) -Val-CPhe (Cha) * (L) -Val) -Z

According to Example 2, 50 mg (0.12 mmol) of H- (PheNIiCha] -H * 3HCl of Example 10a, 94 mg (0.37 mmol) of Z- (L) -valine, 165 mg (0.37 mmol) B0P, 51114634 148 mg (0.37 mmol) HOBt and 2.5 mL 0.3M NMM in DMF give the title compound on silica gel with methylene chloride / ether (1: 1). after chromatographic purification and lyophilization from dioxane FAB-MS: (H + H) + = 758, t Ret (I) = 29.1 min, R f (H) = 0.55.

Example 12: Boc- [Phe ^ Leu] -Boc

According to Example 1, starting from 1.0 g (3.8 mmol) of (2R) - [1 '(S) -Boc-amino-2'-phenylethyl] oxirane and 715 mg (3.8 mmol) of tertiary butyl 3-isobutylcarbazate [preparation: J. Chem. Soc., Perkin I, 1712 (1975)] gives the title compound as a precipitate from hexane. FAB-MS: (M + H) + = 452, t Ret (I) = 27.2 min, R f (I) = 0.55.

Example 13: Z- (L) -Val- [PheNNLeu] - ((L) -Val) -Z

According to Example 2, starting from 60 mg (0.17 mmol) of H- [PheNNLeu] -He3HCl, 125 mg (0.50 mmol) of Z- (L) -valine, 221 mg (0.50) mmol) of B0P, 67 mg (0.50 mmol) of HOBt and 3.3 mL of 0.3 M NMM in DMF gives the title compound on silica gel with methylene chloride / ether (1: 1) purification and | after lyophilization from dioxane. FAB-MS: (M + H) + = 718, t Ret (I) = 26.8 min, R f (H) = 0.38.

According to Example 10a, 1.21 g (2.48 mmol) of Example 12Boc-fPhe ^ LeuJ-Boc gives the title compound FAB-MS: (M + H) + = 252, t Ret (II) = 20.9 min.

Rf (K) = 0.23.

! 114634 149

Example 14: H- (L) -Val-CPhe ^ Chaj-i (L) -Vai) -H -3HCl

According to Example 10a, 6.32 mg (0.91 mmol) of the Boc - (L) - Val - [PheNNCha] * - ((L) - Val) - Boc of Example 10 are obtained after lyophilization to give the title compound as the hydrochloride. FAB-MS: (M + H) + = 490, t Ret (II) = 29.4 min, R f (K) = 0.23.

Example 15: N- (3-Pyridylacetyl) - (L) -Val-fPhe ^ Leu] * - (N- (3-Pyridylacetyl) - (L) -Vai)

According to Example 9, from 90 mg (0.25 mmol) of Example 13a) H- [PheNNLeu] -He3HCl, 358 mg (1.52 mmol) of N- (3-pyridylacetyl) - (L) -valine, 576 mg HBTU (1.52 mmol) and triethylamine (316 µl) (2.5 mmol) give the title compound after chromatographic purification with methylene chloride / methanol (15: 1) and lyophilization from dioxane / tert-butanol / water. FAB-MS: (M + H) + = 688, t Ret (IV) = 15.5 min, R f (D) = 0.37.

Example 16: N-Trifluoroacetyl-fPhe ^ ip-FJPheJ-Boc

A solution of 4.0 g (15.4 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2'-phenylethyl] oxirane and 3.89 g (16.2 mmol) of tert -butyl-3- (p-fluorophenylmethyl) carbazate in 35 ml of methanol, is heated for about 20 hours in a bomb at 80 ° C. The reaction mixture is evaporated, the residue is dissolved in a small amount of dichloromethane and the title compound is precipitated with hexane (refrigerator).

Further product is obtained by column chromatography (SiO2, methylene chloride / ether 95: 7), DC Rf (J) = 0.57, tRe ^ (I) = 24.3 ': min, FAB-MS: (M + H) + = 500.

The starting materials are prepared as follows: 150 114634 a) 24.7 g (1.02 moles) of N-3 fsi - (Boc-aminol-2 (R. S -hydroxy-4-phenyl-1-trimethylsilyl) butane are introduced under N2 magnesium in 100 ml of abs. ether and a small amount of iodine is added over 35 minutes, while 132.5 ml (0.95 mole) of chloromethyltrimethylsilane and 300 ml of ether are added thereto, maintaining the temperature in an ice bath at 38 ° C. 1.5 hours at room temperature, cool to -60 ° C and then add a slurry of 48.6 g (0.195 mol) of N-Boc-phenylalaninal [Preparation: DJ Kempf, J. Org. Chem. 51, 3921 (1986)] in 1.1 L of ether The reaction mixture is warmed to room temperature for 90 minutes and then stirred for a further 90 minutes at this temperature, then poured into 2 L of ice water and 1.5 L of 10% The separated aqueous phase is extracted with ca. Wash twice with 500 ml of ether All the ether extracts are washed with 500 ml of 10% citric acid and twice with brine. It is dried over sodium sulfate and then evaporated in vacuo and the title compound obtained is used without further purification. DC Rf (L) = 0.6; FAB-MS: (M + H) + = 338.

b) 1-phenyl-3-butene-2S (S) -amine

To a solution of 18.8 g (0.055 mol) of 3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4-phenyl-1-trimethylsilyl-butane in 420 ml of methylene chloride is added At 5 ° C for 10 minutes, · 35.6 ml (0.28 mol) of approximately 48% solution of boron trifluoride in ether. The reaction mixture is then stirred for 16 hours at room temperature, cooled to 10 ° C and 276 ml of 4 N 'sodium hydroxide solution are added over 20 minutes. The aqueous phase is separated and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts are washed with brine and dried over sodium sulfate. The title compound is still used without further purification. DC Rf (C) = * 0.15; XR (methylene chloride) (cm -1): 3370, 3020, 2920, 1640, 1605.

c) N-Trifluoroacetyl-1-phenyl-3-butene-2S (S) -amine to 11.9 g (81 mmol) of 1-phenyl-3-butene-2 (S) -amine dissolved in 210 mL of methylene chloride and 70 ml of pyridine, 17.0 ml (121 mmol) of trifluoroacetic anhydride are added dropwise at 0 ° C. The mixture is stirred for 0.5 h at 0 ° C and then extracted twice with diluted HCl, water and brine. The aqueous phases are washed twice more with methylene chloride, dried over sodium sulfate and evaporated: DC Rf (M) = 0.4.

d) 2 f R 1 -F 'S 5 -Trifluoroacetylamino-2H-phenethyl-11-oxirane

To a solution of 14.5 g (60 mmol) of N-trifluoroacetyl-1-phenyl-3-butene-2 (S) -amine in 600 mL of chloroform is added 54.28 g (314 mmol) of m-chloroperbenzoic acid and stir for 24 hours at room temperature. The reaction mixture is washed twice with 10% sodium sulfite solution, twice with saturated sodium carbonate solution, water and brine. The aqueous phases are extracted; . 2 more times with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated to give the title compound which is used without additional; purification in the following step: DC Rf (N) = 0.6.

·: E) p-Fluorophenylcarbaldehyde-tert-butoxycarbonyl-1-dihydrazone According to Example 4b) 32 g (242 mmol) of tert-butyl carbazate and 30 g (242 mmol) of p-fluorobenzaldehyde are reacted in 300 ml of ethanol 80. At 3 ° C for 114634152 to give the title compound which crystallizes upon cooling and dilution with water: DC Rf (N) = 0.48, t Ret (I) = 19.4 min.

f) Tert-butyl-3-fp-fluorophenylmethyl) carbazate

According to Example 4a) 55 g (231 mmol) of p-fluorophenyl-1-carboxyldehyde-tert-butoxycarbonyl-1-hydrazone are hydrogenated in 500 ml of THF to give the title compound of palladium carbon (5%, 5.5 g): 1 H-NMR (200 MHz, CD 3 OD): 7.35 (dd, 8 and 6 Hz, 2H), 7.05 (t, 8 Hz, 2H), 3.9 (s, 2H), 1, 45 (s, 9H).

Example 17: N-Morpholinocarbonyl- (L) -Val-CPhe (ip-F) -Phe] -Boc

A mixture of 185 mg (0.80 mmol) of N-morpholinocarbonyl-L (L) -valine (preparation, see Example 7a), 270 mg (0.67 mmol) of H- [PheNN (pF) Phe] - Boc, 311 mg (0.70 mmol) B0P and 95 mg (0.70 mmol) HOBT are dissolved in 6.8 mL NMM / DMF 0.3 M at room temperature and stirred for 5 hours. at room temperature. The reaction mixture is evaporated under high vacuum and the residue partitioned between 4 portions of methylene chloride, 2 portions of 1 M sodium carbonate solution, water and brine. The combined organic phases dried over sodium sulfate are evaporated and purified by column chromatography (SiO 2, acetic acid ethyl ester): DC R f (O) = 0.38, t R e. (I) = 21.8 min, FAB-MS: (M + H) + = 616.

· The starting material is prepared as follows: a) H-TPhe1 * 1 * fn-FlPhel-Boc * »at 70 ° C in a solution of 0.3 g (0.6 mmol) of N-trifluoroacetyl [PheNN (pF) Phe] -Boc (preparation, see Example 16) in 50 ml of methanol is added dropwise to N 2 - at - 114634 153

In the biosphere, 15 ml of a 1M aqueous potassium carbonate solution and stirred for 25 hours at this temperature. The reaction mixture is evaporated under high vacuum, methylene chloride is added to the residue and washed twice with water and brine.

The aqueous phases are extracted twice with methylene chloride, the organic phases are dried over sodium sulfate and evaporated. The crude product is used without further purification in the following step: tRe ^. (I) = 16.2 min.

Example 18: N-Morpholinocarbonyl- (L) -Val- [PheN ^ (p-F) -Phe] - ((L) -Vai) -Z

To a solution of 86 mg (0.34 mmol) of Z- (L) -Val and 160 mg (0.31 mmol) of N-morpholinocarbonyl- (L) -Val- [Phennfp-FJPheJ-1] 2, In 7 mL of NMM / CH 3 CN 0.25 M (0.25 M NMM in CH 3 CN), 129 mg (0.34 mmol) of HBTU is added. Allow to stand for 4 hours at room temperature, then evaporate and partition the residue between 3 portions of methylene chloride, 2 portions of saturated sodium bicarbonate solution and brine. Drying of the organic phases with sodium sulfate and evaporation gives the title compound obtained after digestion from methylene chloride / ether (lii): DC Rf (P) = 0.4, tRet (I) = 22.4 min, FAB- MS: (M + H) <+> = 749.

• The starting material is prepared as follows:

a) N-Morpholinocarbonyl-fL) -Val-rPhe ^ fp-F) Phel-H

.. 210 mg (0.34 mmol) of N-morpholinocarbonyl- (L) -Val-I [PheNN (pF) Phe] -Boc (Example 17) dissolved in> 105 ml of formic acid are mixed For 4 hours at room temperature. It is then evaporated, the residue is taken up in methylene chloride and the solution is washed with saturated sodium bicarbonate solution and brine. The aqueous phases are extracted with 2 portions of methylene chloride, the organic phases 154-114634 are dried over sodium sulfate and evaporated to give the title compound which is used without further purification in the following step: t R e E (I) = 12.9.

Example 19: N-Morpholinocarbonyl- (L) -Vai- [PheNN (p-F) -Phe] - ((L) -Vai) -H

Under normal pressure, 160 mg (0.21 mmol) of N-morpholinocarbonyl- (L) -Val- [PheNN (pF) Phe] - ((L) -Vai) -Z (Example 18) in 6 mL of ethanol is hydrogenated mg of palladium carbon (10%). Filtration through Celite * (diatomaceous earth, filter aid, manufactured by Fluka, Buchs, Switzerland), evaporated and lyophilized from dioxane to give the title compound: tRet (hydrochloride, I) = 13.4 min, FAB-MS: (M + H) ) + = 615.

Example 20: N-Morpholinocarbonyl- (L) -Val- [PheNN (p-F) -Phe] * - ((L) -Val) * - (N-Morpholinocarbonyl-Gly)

To a solution of 26.9 mg (0.143 mmol) of N-morpholino-carbonyl glycine and 80 mg (0.130 mmol) of N-morpholino-carbonyl (L) -Val- [PheNN (pF) Phe] - (( L) -Vai) -H in 1.1 'ml of 0.25 M NMM / CH 3 CN, add 54 mg (0.143 mmol) of HBTU and stir for 16 hours at room temperature. The mixture is evaporated and the residue partitioned between 3 portions of ethyl acetate, water, 2 portions of a saturated sodium bicarbonate solution, water and brine. The organic phases are dried over sodium sulfate and evaporated to give the title compound which is dissolved in a small amount of DMF and precipitated with DIPE to prepare pure: tRet (I) = 15.1 min, FAB-MS: (M + H) + = 785.

The starting material is prepared as follows: 155 114634 a) N-Morpholinocarbonyl glycine benzyl ester

According to Example 7 b), 7.69 g (22.8 mmol) of glycine benzyl ester 4-toluenesulfonate and 2.8 g (19 mmol) of (morpholinocarbonyl) chloride are reacted in 118 mL of methylene chloride and 9 mL (53 mmol) ) N-ethyldiisopropylamine for 18 hours. After extraction with methylene chloride and digestion with hexane, the title compound is prepared in pure form: t Ret (1) = 11/6 min.

b) N-morpholinocarbonyl-glycine

According to Example 7a, 4.8 g (18.3 mmol) of N-morpholinecarbonyl glycine benzyl ester is hydrogenated in 100 ml of acetic acid ethyl ester with 1 g of palladium carbon (10%) to give the title compound: 1 H-NMR (300 MHz, CDCl 3): 3.88 (s, 2H), 3.64 (s, 4H), 3.50 (s, 2H), 3.35 (s, 4H).

Example 21: Z- (L) -Val- [PheNN (pF) Phe] -Boc> ·: A solution of 335 mg (1.33 mmol) of Z- (L) -Val and 448 mg (1, 11 mmol) H- [PheNN (pF) Phe] -Boc (preparation: see Example 17a) in 9.4 mL of NMM / CH 3 CN 0.25 M (0.25 M; NMM in CH 3 CN) ), 463 mg (1.22 mmol) of HBTU are added.

After stirring for 16 hours at room temperature, the residue is partitioned between 3 portions of methylene chloride, 2 portions of a saturated sodium bicarbonate solution and brine. *

Iillä. The organic phases are dried over sodium sulfate and evaporated to give the title compound, which is purified by column chromatography (SiO2, hexane / acetic acid ethyl ester 4: 1 → 1: 1): t Ret (I) = 26.6 min .; FAB-MS: (M + H) + = 637.

t * i 114634 156

Example 22: Z- (L) -Val-CPhe ^ ip-FJPhe] * ^ (L) -Vai) -Boc

According to Example 18, 165 mg (0.76 mmol) of Boc- (L) -Val and 371 mg (0.69 mmol) of Z- (L) -Val- [PheNN (pF) Phe] -H in 6 ml. NMM / CH 3 CN 0.25 M is reacted with HBTU (289 mg, 0.76 mmol) to give the title compound which can be crystallized directly from the reaction solution and filtered: t Ret (I) = 27.2 min, FAB-MS: ( M + H) + = 736.

The starting material is prepared as follows:

a) Z-III-Val-rPheNNfp-F) Phel-H

According to Example 18 a), 440 mg (0.69 mmol) of Z- (L) -Val- [PheNN (pF) Phe] -Boc is deprotected with 212 ml of formic acid to give the title compound: tRe ^ (I) = 17.8 min.

Example 23: Z- (L) -Val- [Phe ^ ip -F) Phe] - ((L) -Val) -H

According to Example 18 a) 250 mg (0.34 mmol) of Z- (L) -Val- [PheNN (pF) Phe] - ((L) -Vai) -Boc (Example 22) are deprotected in 50 ml: Formic acid 11a to the title compound: t Ret (I) = 18.0 min, FAB-MS: (M + H) + = 636.

. Example 24: Z- (L) -Val- [PheNN (pF) Phe] - ((L) -Val) - (N-mor-, .beta.-folinocarbonyl-Gly), according to Example 22, 32 mg ( 0.17 mmol) N-morpholino ;;; carbonyl glycine (Example 20 b) and 99 mg (0.16 mmol) of Z- (L) -Val- [PheNN (pF) Phe) <- ((L) -Val) -H is reacted in 1.3 ml of NMM / CH 3 CN with 0.25 M HBTU (65 mg, 0.17 mmol) to give the title compound which crystallizes directly from the reaction solution: t Ret (I) = 21.1 min. , FAB-MS: '* (M + H) + = 806.

114634 157

Example 25: z- (L) -Asn- [PheNN (p-F) Phe] -Boc

To a solution of 2.09 g (5.2 mmol) of H- [PheNN (pF) -Phe] -Boc (preparation, see Example 17a) in 68 mL of DMF and 2.7 mL (16 mmol) ) N-ethyldiisopropylamine, 3.0 g (7.8 mmol) of Z- (L) -aspartagine p-nitrophenyl ester (Bachem, Bubendorf / Switzerland) are added. After stirring for 16 hours at room temperature, evaporate under high vacuum, take up the residue in a large amount of methylene chloride (poorly soluble) and wash with 2 portions of 5% potassium carbonate solution. The aqueous phases are extracted twice more with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is dissolved in a small amount of methanol and precipitated by addition of toluene at -20 ° C to give the title compound: t Ret (I) = 21.2 min.

Example 26: H- (L) -Asn- [PheNN (p-F) Phe] -Boc

According to Example 19), 0.40 g (0.61 mmol) of Z- (L) -Asn- [PheNN (pF) Phe] -Boc is hydrogenated in 20 ml of methanol to give the title compound: t Ret (I) = 14.9 min. .

:. Example 27r Quinoline-2-carbonyl- (L) -Asn- [PheNN (p-F) -. · Phe] -Boc

According to Example 17, 134 mg (0.78 mmol) of quinoline-2-carboxylic acid (Fluka, Buchs / Switzerland) are reacted in 4 mL of NMM / DMF 0.3 M BOP (344 mg, 0.78 mmol), HOBT (105 mg) , 0.78 mmol) and H- (L) -Asn- [PheNN (pF) Phe] -Boc (268 mg, 0.52 mmol). Since H- (L) -Asn- [PheNN (p-F) Phe] -Bocr is still present after stirring for 16 hours at room temperature according to HPLC, an additional 299 mg of BOP, 70 mg of '' HOBT, 89 mg of quinaldic acid and 113 μΐ of NMM are added. After 16 hours, evaporate and partition the residue between 3 portions of methylene chloride 114634 158, 2 portions of saturated sodium bicarbonate solution and brine. The combined organic phases are dried over sodium sulfate and evaporated. The crude product is dissolved in a small amount of DMF, precipitated with DIPE 2 and cooled to -20 ° C to give the title compound: t Ret (I) = 22.8 min .; FAB-MS: (M + H) + = 673.

Example 28: Z- (L) -Asn- [PheNN (p-F) Phe] <- ((L) -Va1) -Z

88 mg (0.35 mmol) of Z- (L) -Val in 3.8 mL of NMM / DMF 0.3 M are activated with 153 mg (0.35 mmol) of BOP and 47 mg (0.35 mmol) ) HOBT and after 15 minutes add 144 mg (0.23 mmol) of Z- (L) -Asn- [PheNN (pF) Phe] -H 2 HCl. After stirring for 14 hours at room temperature, the reaction mixture is evaporated, the residue is dissolved in 2 ml of methanol and partitioned between 3 portions of methylene chloride and 2 portions of 1 M sodium carbonate solution, the organic phases are dried over sodium sulfate and evaporated. The crude product is redissolved in a small amount of DHF and precipitated with DIPE 2 to give the title compound: t Ret (I) = 22.2 min, FAB-MS: (M + H) + = 785.

:; The starting material is prepared as follows: a) Zm -Asn-rPheNNfp-F1Phel-H * 2HCl under N2 to a solution of 150 mg (0.23 mmol) of Z- (L) -Asn- [PheNN (p-F) Phe ] -Boc (Example 25) in 1 mL of dioxane, add 2 mL of HCl / dioxane 4N (Fluka,. · Buchs / Switzerland). After stirring for 1.5 hours at room temperature, the reaction mixture is lyophilized and the lyophilisate is immediately reacted further.

159 114634

Example 29: Trifluoroacetyl- [PheNN (p-F) Phe] * - ((L) -Vai) -Z

According to Example 17), 239 mg (0.95 mmol) of Z- (L) -Val is reacted in 10.5 mL of NMM / DMF with 0.3 M BOP (421 mg, 0.95 mmol), HOBT (129 mg, 0.95 mmol) and N-trifluoroacetyl- [PheNN (pF) Phe] -H (0.3 g, 0.63 mmol) for 15 hours. Column chromatography (SiO 2, methylene chloride / ether 10: 1) and precipitation from DMF with DIPE affords the title compound: DC Rf (Q) = 0.15, t Ret (I) = 25.9 min; FAB-MS: (M + H) + = 633.

The starting material is prepared as follows:

a) N-Trifluoroacetyl-rPhe ^ fp-FlPhel-H

At 0 ° C, to 0.20 g (0.40 mmol) of N-trifluoroacetyl [Phe ^ fp-FJPheJ-Boc (preparation, see Example 16) in 5 ml of methylene chloride is added 5 ml of trifluoroacetic acid . After stirring for 4 hours at 0 ° C and for 2 hours at room temperature, the reaction mixture is evaporated. Lyophilization of the residue from dioxane gives the title compound which is reacted further without purification: t Ret (I) = 14.7 min.

_ '[Example 30: Z- (L) -Asn- [Phe ^ Phe] -Boc • »t

According to Example 25, 167 mg (0.34 mmol) of H- · ·· [PheNNPhe] -Boc are reacted in 3.6 mL of DMF · ··· * and 0.18 mL (1 mmol) ) N-ethyldiisopropylamine with Z- (L) -aspartagine p-nitrophenyl ester (0.20 g, 0.52 mmol) to give the title compound as pure after column chromatography (SiO 2, acetic acid ethyl ester): DC Rf (O) = 0.19; t Ret (I) = 20.9 min.

The starting material is prepared as follows:

»I

114634 160 a) N-Trifluoroacetyl-rPheNNPhe1-Boc

According to Example 16, 1.82 g (7.0 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2'-phenylethyl] oxirane (Example 16 d) and 1.58 g ( 7.1 mmol) tert-butyl 3-benzyl carbazate [J. Chem., Perkin I, 1712 (1975)] is reacted with 15 ml of methanol in a bomb tube to give the title compound which is isolated by flash chromatography (SiO 2, methylene chloride / ether 50: 1): DC R f (J) = 0.38; t Ret (I) = 24.5 min.

b) H-rPhe ^ Phel-Boc

According to Example 17a), 258 mg (0.53 mmol) of N-trifluoroacetyl- [PheNNPhe] -Boc are reacted in 60 ml of methanol with 1 M potassium carbonate solution (10.7 ml) to give the title compound.

Example 31: Z- (L) -Val- [(p-F) Phe (p-F) Phe] -Boc

According to Example 21) 18 mg (0.070 mmol) of Z- (L) -Val and 27 mg (0.064 mmol) of H - [(pF) PheNN (pF) Phe] -: Boc are reacted with 0.6 ml: in NMM / CH 3 CN 0.25 M

; ; HBTU (26.6 mg, 0.070 mmol) as the title compound. : which is purified by dissolving in a small amount of methylene. ·, Chloride and precipitation by DIPE: FAB-MS: (M + H) + = 655.

, The starting material is prepared as follows: '·· * a) N-Boc-β-fluorophenylalanine) '20 g (109 mmol) of p-fluorophenylalanine (Fluka, Buchs, Switzerland) are reacted in 0.4 L of dioxane / water [( UI) with Boc anhydride (35.5 g, 163 mmol) and potassium carbonate (150 g, 1.09 mmol). After 4 hours, the reaction mixture is acidified with citric acid solution and 114634161 is extracted with 3 portions of acetic acid ethyl ester. The organic phases are washed with 10% citric acid, water and brine, dried over sodium sulfate and evaporated. The residue is dissolved in a small amount of methylene chloride and crystallized by the addition of hexane to give the title compound: t Ret (I) = 16.9 min.

b) N-Boc-β-fluorophenylalaninol) at 5 ° to -10 ° C to a solution of 17.9 (63 mmol) of N-Boc- (p-fluorophenylalanine) in 73 ml abs. THF, add 9.66 mL (69 mmol) of triethylamine and then add a solution of 9.05 mL (69 mmol) of chloroformic acid isobutyl ester in 44 mL of abs.

THF. The mixture is stirred for 0.5 hours at room temperature and then the precipitate formed is suction filtered. The filtrate is added dropwise with cooling to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. Stir for 4 hours at room temperature, acidify with 10% citric acid, partially evaporate the THF in a rotary evaporator and partition the residue between 3 portions of acetic acid ethyl ester, 2 portions of 2 N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution. The sodium sulfate dried and evaporated organic phases yield the title compound after being dissolved in a small amount of methylene chloride and crystallized by the addition of hexane: DC Rf (N) = 0.36, t Ret (I) = 16.8 min .; 1 H-NMR (200 MHz, CD 3 OD): 7.24 (dd, δ and 5 ;; H 2, 2H), 6.98 (t, 8 Hz, 2H), 3.73 (m, 1H), 3.47 (d, 5

Hz, 2H), 2.88 (dd, 13 and 6Hz, 1H), 2.62 (dd, 13 and 8Hz, 1H), 1.36 (s, 9H).

c) N-Boc-β-Fluorophenylmethylalanine) To a solution of 4.0 ml (46.8 mmol) of oxalyl chloride in 44 ml of methyl 114634 162 lene chloride cooled to -60 ° C is added dropwise 4.44 ml ( 62.4 mmol) of DMSO dissolved in 76 ml of methylene chloride. After stirring for 15 minutes, 8.4 g (31.2 mmol) of N-Boc- (p-fluorophenylalaninol) in 185 ml of methylene chloride / THF 1: 1 (-> precipitation) are added to the clear reaction solution. and stir for 25 minutes. 17.3 ml (124.8 mmol) of triethylamine dissolved in 38 ml of methylene chloride are then added. After stirring for 30 minutes, 278 ml of 20% potassium hydrogen sulfate solution and then 220 ml of hexane are added dropwise. Allow to warm to room temperature, separate the aqueous phase and extract with 2 portions of ether. The organic phases are washed with saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated to give the title compound which is used without further purification in the following step: 1 H-NMR (200 MHz, CDCl 3): 9.63 (s, 1H) 6.9-7.2 (2m, 4H), 5.04 (m, 1H), 4.42 (m, 1H), 3.10 (m, 2H), 1.43 (s, 9 H).

"D) N-3 (S) - (Boc-amino) -2 (R S) -hydroxy-4-trans-fluorophenyl) - ': 1-trimethylsilyl-butane

According to Example 16 a), 1.63 g (67 mmol) of magnesium in 33 ml abs. the ether is reacted with chloromethyl trimethylsilane (8.3 mL, 60 mmol) to form a Grignard compound which is reacted with N-Boc (p-fluorophenylalaninal) (13 mmol), extracted with p flash chromatography (S1O2, hexane / acetic acid ethyl ester 5: 1 → 4: 1) to give the dia- / stereoisomeric mixture of the title compounds: DC Rf (L) = 0.32; t Ret (I) = 24.9 min (22;%) / 25.5 min (78%); FAB-MS: (M + H) + = 356.

114634 163 e) 1- (p-Fluorophenyl) -3-butene-2 (S) -amine

According to Example 16 b), 1.1 g (3.1 mmol) of N-3 (S) - (Boc-amino) -2 (R, S) -hydroxy-4- (p-fluorophenyl) -1-trimethylsilyl butane in 22 ml of methylene chloride and 1.9 ml (15.5 mmol) of approximately 48% solution of boron trifluoride in ether are reacted to give the title compound: 1 H-NMR (300 MHz, CDCl 3): 7.2-7.10 and 7.05 - 6.9 (2m, 2H in each case), 5.9 - 5.8 (m, 1H), 5.2 - 5.0 (m, 2H), 3.57 (m, 1 H), 2.79 (dd, 12 and 6 Hz, 1H), 2.62 (dd, 12 and 8 Hz, 1H), 1.7 (Sb, 2H).

f) N-Trifluoroacetyl-1- (p-fluorophenyl) -3-butene-2 (Siamine)

According to Example 16c, 364 mg (2.2 mmol) of 1- (p-fluorophenyl) -3-butene-2 (S) -amine in 1.8 ml of methylene chloride and 5.4 ml of pyridine are reacted with with trifluoroacetic anhydride (460 μΐ, 3.3 mmol) to give the title compound, prepared after digestion in hexane pure: DC Rf (F) = 0.58; MS (M) &lt; + &gt; = 261.

:; g) 2 (R 1 - ΓΙ 'F) -Trifluoroacetylaminol-2' - (p-fluorophenylmethyl) -1-oxirane

According to Example 16 d) 359 mg (1.37 mmol) of N-trifluoroacetyl-1- (p-fluorophenyl) -3-butene-2 (S) -amine in 9 ml of chloroform are oxidized with 1.18 g ( 6.87 mmol) m-chloroperbenzoic acid to give the title compound: DC Rf (R) = 0.45.

h) N-Trifluoroacetyl-r (p-F1 Phe ^ fp-F) Phel-Boc 'Example 16) 415 mg (1.49 mmol) 2 (R) - [1'- (S) - ( trifluoroacetylamino) -2 '- (p-fluorophenyl) ethyl] -164.14634 oxirane and 377 mg (1.57 mmol) of tert-butyl 3- (p-fluorophenylmethyl) carbazate are reacted in 9 x methanol to give the title compound: DC Rf (S) = 0.53; FAB-MS: (M + H) + = 518; 1 H-NMR (300 MHz, CD 3 OD): 7.4-7.3 and 7.3-7.2 (2m, 2H each), 7.05-6.9 (m, 4H), 4.23 (m, 1H), 3.90-3.65 (m, 3H), 3.03-2.78 and 2.74-2.60 (2m, 2H each), 1.30 (s, 9 H).

i) H-Γ (p-FlPheNN (P-F) PheΊ-Boc

According to Example 17a), 285 mg (0.55 mmol) of N-trifluoroacetyl - [(pF) PheNN (pF) Phe] -Boc is reacted in 45 mL of methanol with 1 M potassium carbonate solution (14 mL) to give the title compound: tRet ( X) = 16.4 min.

Example 32: Z- (L) -Val - [(p-F) PheNN (p-F) Phe] -H

According to Example 18a, 215 mg (0.33 mmol) of Z- (L) -Val - [(pF) PheNN (pF) Phe] -Boc is deprotected with 100 ml of formic acid to give the title compound: FAB-MS: (M) + H) + = 555.

Example 33: Z- (L) -Val - [(pF) PheNN (pF) Phe] - * - (N- (N- (2-Pyridylmethyl) -N-methylaminocarbonyl) - (L) -Al ) According to [Example 18), 23.6 mg (0.089 mmol) of N- (N- (2-pyridylmethyl) -N-methylaminocarbonyl) - (L) -valine (preparation: see EP 402646 A1, 19). December 1990) and 45 mg ;;; (0.081 mmol) of Z- (L) -Val - [(p-FJPhe ^ ip-FJPhej-H2) is reacted with HBTU (33.8 mg, 0.089 mmol) in 0.76 mL NMM / CH 3 CN with 0.25 M as the title compound "and recrystallized with DMF / DIPE: DC R f (O) = 0.39; FAB-MS: (M + H) + = 802.

165 114634

Example 34: Z- (L) -Vai - [(p-F) PheNN (p-F) Phe] - (N- (2 (R, S) -Carbamoyl-3-phenyl-propionyl) - (L) -Va)

According to Example 18, 26.0 mg (0.089 mmol) of N- (2- (R, S) -carbamoyl-3-phenylpropionyl) - (L) -valine [preparation: Synth., Struct., Funet., Proc. Am. Pept.

Symp., 7th, 85 (1981)] and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe ^ fp-F) Phe] -H (Example 32) is reacted with HBTU. (33.8 mg, 0.089 mmol) in 0.76 mL of NMM / CH 3 CN to the 0.25 M title compound and recrystallized with DMF / DIPE: R f (P) = 0.64; FAB-MS: (M + H) + = 829.

Example 35: Acetyl-Val- [Phe ^ Phe) * - (N-Acetyl-Val)

According to Example 7, 100 mg (0.25 mmol) of H-fPhe ^ Phej-H ^ SHCl according to Example 2a, 121 mg (0.76 mmol) of N-acetyl- (L) -valine, 288 mg (0.76 mmol) of HBTU and 0.211 mL (1.52 mmol) of triethylamine in DMF gives the title compound after lyophilization from dioxane. FAB-MS: (M + H) + = 568; t Ret (I) = ** 15.0 min, Rf (B) = 0.46.

Example 36: Z- (D) -Vai- [Phe * ^ Phe] * - ((D) -Vai) -Z

According to Example 2, 50 mg (0.123 mmol) of H- [PheNNPhe] -H * 3HCl of Example 2a, 95 mg (0.38 mmol) of Z- (D) -valine, 168 mg (0.38 mmol) of BOP, 51 mg (0.38 mmol) of HOBt and 2.35 mL of 0.3 M NMM • * · DMF yields the title compound from dioxane after lyophilization. FAB-MS: (M + H) + = 752; tRet (I) =. ; 26.4 min, Rf (H) = 0.21.

»I · *» - · »114634 166

Example 37: Quinoline-2-carbonyl-Val- [PheNNPhe] * - (N-quinoline-2-carbonyl-Val) 145 mg (0.53 mmol) of N- (quinoline-2-carbonyl) - (L) -val line, 235 mg (0.53 mmol) of BOPt and 72 mg (0.53 mmol) of HOBt are dissolved in 3.5 mL of a 0.3M solution of NMM in DMF, 70 mg (0, 18 mmol) of H-fPhe ^ PheJ-H ^ HCl (Example 2a) and stirred for 5 hours at room temperature under nitrogen.

The reaction mixture is evaporated, the residue is dissolved in methylene chloride and washed twice with saturated sodium bicarbonate solution, once with 10% citric acid and once again with saturated sodium bicarbonate solution. The organic phases are filtered through a pad, evaporated and the residue is mixed twice with methylene chloride / methanol by addition of DIPE. Lyophilization from dioxane yields the title compound as a white solid (as a mixture of two diastereomers separated by HPLC).

FAB-MS: (M + H) + = 794, t Ret (A) = 29.1 and 29.3 min, R f (B) = 0.81.

i ·: a) N- (quinoline-2-carbonyl) -FL) -valine

4 I

A solution of 2.5 g (14.5 mmol) of (L) -valyl-tert-butyl ester and 2.5 g (14.5 mmol) of quinoline-2-carboxylic acid; of acylic acid in 100 ml of methylene chloride / THF (10: 1), 3.28 g (15.9 mmol) of N, N-dicyclohexylcarbodiimide and 2.0 ml (14.5 mmol) of triethylamine are added and mixed with Allow to stand for 18 hours at room temperature. The reaction mixture is cooled to -18 ° C and filtered off from urine. The filtrate is evaporated, the residue is dissolved in methylene chloride and washed each time with saturated sodium bicarbonate solution and water. The organic phases are filtered through a pad, evaporated and chromatographed on silica gel with hexane / acetic acid ethyl ether (2: 1) to give the N- (quinoline-2-carbonyl) - 167114634 fL) -valyvinyl tert-butyl ester. . 2.59 g (12.2 mmol) of this compound are allowed to stand at room temperature in methylene chloride / TFA (1: 1) for 4.5 hours. After evaporation, the residue is purified by chromatography on silica gel with hexane / acetic acid ethyl ester (2: 1). The product-containing fractions are evaporated, redissolved in methylene chloride and converted by washing with 1N sodium hydroxide and 1N hydrochloric acid to give the title compound hydrochloride. 1 H-NMR (200 MHz, CD 3 OD): 1.05 and 1.07 (2d, J = 6Hz, 6H), 2.40 (m, 1H), 4.65 (m, 1H), 7.70 ( m, 1H), 7.85 (m, 1H), 8.00 (dxd, 1H), 8.20 (m, 2H), 8.48 (d, 1H).

Example 38: Acetyl (L) -Val- [PheNNCha] - (N-Acetyl) - (L) -Vai)

According to Example 37, 160 mg (0.40 mmol) of Example 10a H- [Phe ^ Cha] -H? 3HCl, 190 mg (1.19 mmol) of N-acetyl- (L) -valine, 525 mg (1.19 mmol) BOP, 160 mg (1.19 mmol) H0Bt and 7.9 mL 0.3M NMM in DMF give the title compound after precipitation chloroform / methanol by DIPE and lyophilized: dioxane. FAB-MS: (M + H) + = 574, t Ret (I) = 18.1 min,

Rf (B) = 0.30.

»• Example 39: N- (3-pyridylacetyl) - (L) -Val- [PheNNCha] -, (N- (3-pyridylacetyl) - (L) -Vai) * 3HCl

According to Example 7, 100 mg (0.25 mmol) of H- [PheNNCha] -H? 3HCl of Example 10a, 358 mg (1.52 mmol) of N- (2-pyridylacetyl) - (L) in Example 9a. ) valine, 576 mg (1.52 mmol) of HBTU and 0.316 mL (2.28 mmol) of triethylamine in DMF give the title compound after chromatography on silica gel with methylene chloride / methanol (15: 1) and lyophilized product-containing fractions of dioxane. FAB-MS: (M + H) + = 728, t Ret (I) = 11.3 min, R f (U) = 0.21.

• '\ 114634 168

Example 40: Acetyl-Ile-fPheNNCha] - (for N-acetyl)

According to Example 37, 160 mg (0.40 mmol) of H- [PheNNCha] -H? 3HCl of Example 10a, 206 mg (1.19 mmol) of N-acetyl- (L) -isoleucine, from 525 mg (1). , 19 mmol) of BOP, 160 mg (1.19 mmol) of HOBt and 7.9 mL of 0.3M NMM in DMF give the title compound after precipitation from methylene chloride / methanol by addition of DIPEs and lyophilized dioxane / tert. butanol (mixture of 2 diastereomers separated by HPLC). FAB-MS: (M + H) + = 602, t Ret (I) = 20.4 and 20.7 min, R f (D) = 0.33.

Example 41: Thiomorpholinocarbonyl (L) -Vai- [PheNNCha] - (N-Thiomorpholinocarbonyl- (L) -Vai)

According to Example 6, starting from 70 mg (0.12 mmol) of the H- (L) -Val-fPhe (ChaJ-iN-iL ·) -Vai) -He3HCl of Example 14, 58 mg (0, 35 mmol) of Example 6a (4-thiomorpholininylcarbonyl) chloride and 0.127 mL of triethylamine in 2 mL of OHF gives the title compound after purification by chromatography on silica gel with methylene chloride / methanol (95: 5). and lyophilized; product-containing fractions of dioxane. FAB-MS: (M + H) + = 748, tRet (1) = 24 ', min Rf (B) = 0.70.

] Example 42: Z- (L) -Glu- [Phe ^ p -F) Phe] <* - ((L) -Glu) -Z

A solution of 130 mg (0.14 mmol) of Z- (L) -Glu (O-tert-butyl) - [PheNN (pF) Phe] <- ((L) -Glu (O-tert-butyl) ) -Z (fGlufO-tert-butyl) denotes a group esterified with a tert-butyl residue on the carboxy group of glutamic acid]. In 8 ml of methylene chloride / TFA (1: 1), stir for 3 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is precipitated from methylene chloride by addition of DIPE. The title compound is obtained after lyophilization from dioxane / tert-butanol. FAB-MS: (M + H) + = 830, t Ret (I) = 16.9 min, R f (B) = 0.32.

114634 1,69

a) Z-fL) -GlufO-tert-butyl) -TPheNNfp-F) Phel «-f fLl -GluiO-tert-butyl)) - Z

According to Example 37, 100 mg (0.24 mmol) of H- [Phe ^ Cp-F) Phe] -H * 3HCl, 245 mg (0.73 mmol) of Z- (L) -glutamic acid tert butyl ester, 321 mg (0.73 mmol) of BOP, 98 mg (0.73 mmol) of HOBt and 4.8 mL of 0.3M NMM in DMF give the title compound on silica gel with methylene chloride / ether (1: 1) after chromatographic purification. t Ret (I) = 30.2 min, R f (H) = 0.17.

b) H-rPheNNfp-Fi Phel-H * 3HCl

According to Example 2a, starting from 1.77 g (3.51 mmol) of Boc- [PheNN (p-F) Phe] -Boc, the title compound is obtained after lyophilization. FAB-MS: (M + H) + = 304, Rf (K) = 0.19.

c) Boc-fPhe ** 1 * (p-F) Phe 1 -Boc

According to Example 1, starting from 2.0 g (7.60 mmol) of (2R) - [1 '(S) -Boc-amino-2'-phenylethyl] oxirane and 2.17 g (9.04 mmol) tert -butyl 3- (4-fluorophenylmethyl) carbazate (Example 16f) is obtained by the title compound; diste on silica gel after chromatographic purification with hexane / acetic acid ethyl ester (2: 1).

FAB-MS: (M + H) + = 504, t Ret (I) = 26.2 min, R f (F) = 0.26.

Example 43: N- (2-Pyridylmethyl) -N-methylaminocarbonyl- (L) -Vai- [Phe ^ fp-F) Phe) · * - (N- (N- (2-Pyridylmethyl) -N) -methylaminocarbonyl- (L) -Va)

According to Example 37, from 70 mg (0.17 mmol) of H-iPhe ^ fp-FJPhe-HCl-HCl of Example 42b, 135 mg (0.51 mmol) of N- (N- (2-pyridylmethyl) - N-methylaminocarbonyl) - (L) - 114634 170 valines (Prepared EP 0 402 646 A1, December 19, 1990), 225 mg (0.51 mmol) of BOP, 69 mg (0 , 51 mmol) HOBt and 3.4 ml 0.3M NMM in DMF give the title compound after silica gel chromatography with methylene chloride / methanol (15: 1) and lyophilization of the product-containing fractions from dioxane. FAB-MS: (M + H) + = 798, t Ret (IV) = 35 min, R f (U) = 0.21.

Example 44: N- (3- (Tetrazol-1-yl) -propionyl) -Val- [PheNN (p-F) Phe] * - (N- (3- (Tetrazol-1-yl) -propionyl) -Va)

According to Example 37, 100 mg (0.24 mmol) of H- [Phe ^ fp-FJPhej-H ^ HCl (from Example 42b), 146 mg (0.61 mmol) of N- (3- (tetrazole) 1-yl) -propionyl) - (L) -valine, 268 mg (0.61 mmol) BOP, 82 mg (0.61 mmol) H0Bt and 4 mL 0.3M NMM In DHF, the title compound is obtained after precipitation from methylene chloride by addition of DIPE and lyophilization from dioxane (4 diastereomers separable by HPLC). FAB-MS: (M + H) + = 750, t Ret (III) = 30.8, 31.4, 32.4 and 32.8 min, R f (K) - 0.5.

Example 44a: N- (3- (Tetrazol-1-yl) -propionyl) - (L) -valine; Y; According to Example 9b, starting from 4 g (16.4 mmol) of (L) -valine benzyl ester * HCl, 2.1 g (14.9 mmol) of 3- (tetrazol-1-yl) -propionic acid (preparation: US 4,794,109 A, December 27, 1988), 2.4 ml of cyanophosphonic acid diethyl ester and 4.4 ml of triethylamine in DMF are obtained on silica gel with methylene chloride / methano-Y (30: 1). after chromatographic purification, N- (3- (tetrazol-1-yl) -propionyl) - (L) -valine *. benzyl. 2.66 g (8.03 mmol) of this compound are hydrogenated in methanol / water (9: 1) in the presence of 10% palladium on carbon (530 mg) under 1 atm of hydrogen to give a meta- 114634171! precipitation from noli / DIPE affords the title compound. 1 H NMR (200 MHz, CD 3 OD): 0.9 (d, J = 7Hz, 6H), 2.1 (m, 1H), 2.95 (m, 2H), 4.29 (d, J = 6 Hz, 1H), 4.78 (m, 2H), 9.15 (s, 1H).

Example 45; Z- (L) -Val- [PheNN (p-F) Phe] - ((L) -Vai) -Z

According to Example 37, from 100 mg (0.24 mmol) of H- [PheNN (pF) Phe] -H? 3HCl (from Example 42b), 182 mg (0.38 mmol) of Z- (L) -valine, 321 mg (0.73 mmol) of BOP, 98 mg (0.73 mmol) of HOBt, and 4.8 mL of 0.3M NMM in DMF give the title compound after precipitation from methylene chloride by addition of DIPE and lyophilized from dioxane. FAB-MS: (M + H) + = 770, t Ret (I) = 26.3 min, R f (H) = 0.25.

Example 46: Acetyl-Val-fPhe ^ ip-F) Phe] - (N-Acetyl-Val)

According to Example 37, 80 mg (0.19 mmol) of H- [PheNN (pF) Phe] -H * 3HCl (from Example 42b), 124 mg * (0.78 mmol) of N-acetyl- (L ) -valine, 344 mg (0.78 mmol) B0P, 105 mg (0.76 mmol) H0Bt and 4.5 mL 0.3M NMM in DMF give the title compound. ; · Double precipitated from methylene chloride / methanol by addition of DIPE and lyophilized from dioxane / tert-butanol. FAB-MS: (M + H) <+> = 586, tRe <+>. (I) = 15.8, min, Rf (E) = 0.32.

; · 'Example 47: Acetyl-Val-CPhe ^ ip-CN) Phe] <- (N-acetyl)

According to Example 37, 80 mg of (0.19 mmol) H- [PheNN (p-CN) Phe] -H * 3HCl, 124 mg (0.78 mmol) of N-acetyl- (L) -valine, 344 mg of ( 0.78 mmol) of BOP,

105 mg (0.78 mmol) of HOBt and 4.5 ml of 0.3M

114634 172 NMM in DMF gives the title compound after precipitation from methylene chloride / methanol by addition of DIPE and lyophilization from dioxane 2 as a mixture of diastereoisomers by HPLC. FAB-MS: (M + H) + = 593. (I) = 14.4 and 14.6 min, Rf (D) = 0.39.

a) H-rPheNN (o-CNIPhel-H * 3HCl)

According to Example 2a, starting from 2.69 g (5.27 mmol) of Boc- [Phe ^ N (p-CN) Phe] -Boc, the title compound is obtained after lyophilization. FAB-MS: (M + H) + = 311, Rf (K) = 0.16.

b) Boc-rPhe ^ fp-CNlPhel-Boc

According to Example 1, starting from 2.0 g (7.60 mmol) of (2R) - [1 '(S) -Boc-amino-2'-phenylethyl] oxirane and 1.87 g (7.6 mmol) tert-butyl 3- (4-cyanophenylmethyl) carbazate is obtained after crystallization of the title compound from methanol / DIPE. FAB-MS: (M + H) + =] 511, t Ret (I) = 25 min, R f (Y) = 0.19.

c) Tert-butyl-3- (bisphenylmethyl) carbazate: * According to Example 4b, 10 g (76.3 mmol) of 4-cyanobenzyl; aldehyde and 10 g (76.3 mmol) of tert-butylcarbazate are reacted in ethanol. 4-Cyanophenylcarbaldehyde-di-tert-butoxycarbonylhydrazone 11.1 g of this compound are hydrogenated in 150 ml of THF with 10% palladium on carbon.

* I

; In the presence of 2 g of hydrogen under 2 atm of hydrogen, the title compound is obtained. 1 H-NMR (200 MHz, CDCl 3): 7.65 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H), 6.08 (s, lev, 1H), 4.3V, (s, lev, 1H), 4.02 (s, 2H), 1.45 (s, 9H).

114634 173

Example 48: Z- (L) -Val- (PheNN (p-CN) Phe] - ((L) -Val) -Z

According to Example 37, from 70 mg (0.17 mmol) of H- [Phe ^ ip-CNJPhel-H 2 HCl (from Example 47a), 125 mg (0.5 mmol) of Z- (L) -valine, from 221 mg (0 , 5 mmol) of BOP, 68 mg (0.5 mmol) of HOBt and 3.33 ml of 0.3M NMM in DMF give the title compound after precipitation from methylene chloride by addition of hexane and lyophilization from dioxane. FAB-MS: (M + H) + = 777, t Ref (I) = 25.3 min, Rf (D) = 0.69.

Example 49: Z- (L) -Ile- [Phe * ^ Leu] - ((L) -Ile) -Z

According to Example 37, 70 mg (0.19 mmol) of H- [PheNNLeu] -He3HCl (from Example 13a), 154 mg (0.58 mmol) of Z- (L) -isoleucine, 257 mg (0.58 mmol) of BOP , 79 mg (0.58 mmol) of HOBt and 3.88 ml of 0.3M NMM in DMF give the title compound after chromatography on silica gel with methylene chloride / ether (3 µl) and precipitated product-containing fractions from methylene chloride / DIPE. FAB-MSr (M + H) + = 746, t Ret (I) = 28.2 min, R f (H) = 0.39.

Example 50r Isobutoxycarbonyl (L) -Val- [PheNNLeu] «- (N -fisobutoxycarbonyl (L) -Vai) •

According to Example 37, 70 mg (0.19 mmol) of H-, [PheNNLeu] -H 13 HCl (Example 13a), 130 mg (0.58 ;; mmol) of N- (isobutoxycarbonyl) - (L) -valine, 256 mgrsta t: · (0.58 mmol) BOP, 78 mg (0.58 mmol) HOBt and / ·: 3.9 mL of 0.3M NMM in DMF gives the title compound; : after chromatography on silica gel with methylene · [. nichloride / ether (1: 1) and lyophilized product-containing fractions of dioxane. FAB-MSr (M + H) + = 650, t Ret (I) = 26.4 min, R f (H) = 0.38.

114634 174 a) N- (Isobutoxycarbonyl) - (ΙΛ-valine

To a solution of 10 g (85.3 mmol) of (L) -valine in 100 mL of 2N sodium hydroxide is added 11.2 mL (85.3 mmol) of isobutyl chloroformate and stirred at room temperature for 18 hours. The reaction solution is washed with methylene chloride, acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic extracts are washed with brine, filtered through a pad, after evaporation to give the title compound as a colorless resin.

1 H-NMR (200 MHz, CD 3 OD): 0.95 (m, 12H), 1.9 (m, 1H), 2.15 (m, 1H), 3.85 (d, J = 7Hz, 2H). ), 4.05 (d, broad, 1H).

Example 51: N- (3- (Tetrazol-1-yl) -propionyl) - (L) -Val- [PheNliLeu] <- (N-3- (Tetrazol-1-yl) -propionyl (L) )

According to Example 37, 150 mg (0.42 mmol) of H- [Phe-Leu] -H 2 HCl (from Example 13a), 251 mg (1.04 mmol) of N- (3- (tetrazol-1-yl) propionyl) - (L) -valine (from Example 44a), 460 mg (1.04 mmol) of B0P, 140 mg (1.04 mmol) of HOBt and 6.9 mL of 0.3M N-methyl- limorpholine in DMF affords the title compound after precipitation from methylene chloride / DIPE and lyophilized from dioxane / tert-butanol / water FAB-MS: (M + H) + = 689, t Ret (1) = 14'7 min., Rf (K) = 0.36.

Example 52: Acetyl-Val-Phe (Leu-N - (N-acetyl-Val)

According to Example 37, 70 mg (0.19 mmol) of H- [Phe-Leu] -H 2 HCl (from Example 13a), 184 mg (1.16 mmol) of N-acetyl- (L) -valine, 512 mg. (1.16 mmol) BOP, 156 mg (1.16 mmol) HOBt and 7.8 mL 0.3M NMM in DMF give the title compound after precipitation from methylene chloride / methanol by addition of DIPE and lyophilized dioxane / tert-butanol / of water 114634 175 (2 diastereomers separable by HPLC).

FAB-MS: (M + H) + -534, t Ret (I) = 14.7 and 15.1 min, R f (D) = 0.35.

Example 53: Boc- (L) -Val- [PheNNLeu] - ((L) -Val) -Boc

According to Example 7, 300 mg (0.83 mmol) of H- [Phe ^ Leu] -H ^ HCl (from Example 13a), 722 mg (3.33 mmol) of Boc- (L) -valine, 1.262 g (3.33 mmol) of HBTU and 0.927 mL (6.66 mmol) of triethylamine in DMF give the title compound after purification by chromatography on silica gel with methylene chloride / ether (1: 1), precipitated product-containing fractions and lyophilized. FAB-MS: (M + H) + = 650, t Ret (I) = 26.3 min, R f (H) = 0.64.

Example 54: H- (L) -Val-CPhe ^ LeuJ (* · ^ (L) -Vai) -H * 3HCl

According to Example 5, 396 mg (0.61 mmol) of Boc - (L) - Val - [PheNNLeu] - ((L) - Val) - Boc (from Example 53) and 10 ml of 4N hydrogen chloride in dioxane are obtained. after lyophilization of the reaction solution, the title compound. FAB-MS: (M + H) + = 450, t Ret (II) = 24.1 min, R f (K) = 0.25.

Example 55: N-Thiomorpholinocarbonyl- (L) -Val- [PheNNLeu] -: -; (N-tiomorfolinokarbonyyli- (L) -Vai)

According to Example 6, starting from 100 mg (0.16 mmol) of H- (L) -Val- [PheNNLeu) <- (L) -Val-H * 3HCl, from 78.5 mg (0, 47 mmol) of (4-thiomorpholinylcarbonyl) chloride (pre-I from 6a) and 0.172 ml of triethylamine in DMF gives the title compound as an amorphous solid after purification by chromatography on silica gel with methylene chloride / methanol (95%). , precipitated product-containing fractions from methylene chloride / hexane and lyophilized from dioxane. FAB-MS: (M + H) + = 708, t Ret (I) = 21.4 min, R f (E) = 0.45.

114634 176

Example 56; 2 (R, S) -tetrahydrofuryl-methoxycarbonyl- (L) -Val- [ChaNNLeu] - (N-2 (R, S) -tetrahydrofuryl-methoxycarbonyl- (L) -Va)

According to Example 37, 80 mg (0.22 mmol) of H- [Cha-Leu] -H 2 HCl, 160 mg (0.65 mmol) of N- (2 (R, S) -tetrahydrofuryl-methoxycarbonyl) - ( L) -valine, 289 mg (0.65 mmol) of B0P, 88 mg (0.65 mmol) of HOBt and 4.35 mL of 0.3M NMM in DMF give the title compound after purification by chromatography on silica gel with ethyl acetate and lyophilization of the product-containing fractions from dioxane. FAB-MS: (M + H) + = 712, t Ret (I) = 22.4 min, R f (E) = 0.21.

a) H-ΓCha ^ Leu 1 -H »3HC1

According to Example 5, 150 mg (0.33 mmol) of Boc- [ChaNNLeu] -Boc and 10 ml of 4N hydrogen chloride in dioxane give 100 mg (83%) of the title compound after lyophilization of the reaction solution. Rf (K) = 0.26.

* b) Boc- Γ Cha ^ Leul -Boc

A solution of 200 mg (0.24 mmol) of Boc-fPhe ^ Leu] - Boc (Example 12) in 15 mL of methanol is hydrogenated; Nishimura catalyst (10 mg, Rh (III) and Pt (IV) oxide monohydrate, Degussa) at 1 atm of hydrogen for 4 hours. Filter off the catalyst, evaporate the solvent completely, and crystallize from methylene chloride / hexane to give the title compound. t Ret (D ': 26.7 min, R f (V) = 0.21.

114634 177 c) N- (2 (R, S) -tetrahydrofurylmethoxycarbonyl) - (L) -valine

According to Example 50a, 7 g (60 mmol) of (L) -valine and 9.8 g (60 mmol) of 2 (R, S) -tetrahydrofurylmethyl chloroformate [Heterocycles 27, 1155 (1988)] in 100 ml 2N sodium hydroxide and 30 ml of dioxane are obtained as a mixture of the diastereomer of the title compound 2. tRet ™ = 23.5 and 23.8 min.

Example 57: Z-Val-CPhe (Leu) -N-S-itetrazol-1-yl) -propionyl) -Al)

According to Example 37, from 100 mg (0.21 mmol) of Z- (L) -Val- [PheNNLeu] -H, 75 mg (1.31 mmol) of N- (3- (tetrazol-1) -yl) -propionyl) - (L) -valine (from Example 44a), 137 mg (0.31 mmol) of B0P, 42 mg (0.31 mmol) of HOBt and 2 ml of 0.3M NMM in DMF gives the title compound after precipitation from methylene chloride / hexane and lyophilized from dioxane / tert-butanol (2 diastereomers separable by HPLC). FAB-MS: (M + H) + = 708, t Ret (I) = 21.1 and 21.1 min, R f (D) = 0.45.

: a) Z-ΠΛ-Val-rPheNNLeul-H

A solution of 250 mg (0.43 mmol) of Z- (L) -Val- [PheNNLeu] -Boc in 5 ml of formic acid is stirred for 7.5 hours at room temperature. Thereafter, no starting material (tRe ^) can be detected in the HPLC analysis.

(I) = 27.5 min.) And the reaction solution is evaporated. Residue: Dissolve in chloroform and wash with saturated sodium bicarbonate solution. The chloroform phase is filtered through v / v and provides the crude title compound after evaporation of the solvent. t Ret (I) = 16.7 min, R f (K) = 0.21.

114634 178 b) Z-iL) -Val-rPheNNLeu1-Boc

According to Example 37, 230 mg (0.653 mmol) of H- [PheNNLeu] -Boc, 247 mg (0.98 mmol) of Z- (L) -valine, 434 mg (0.98 mmol) of BOP , 133 mg (0.98 mmol) HOBt and 6.5 ml 0.3M NMM in DMF give the title compound after precipitation from methylene chloride / methanol by addition of DIPE. FAB-MS: (M + H) + = 585, t Ret (I) = 27.5 min, R f (C) = 0.71.

c) H-Γ PheNNLeu1-Boc

According to Example 17a, starting from 1.27 g (2.84 mmol) of N-trifluoroacetyl-fhe-Leul-Bocr and 24 ml of 1N aqueous sodium carbonate solution in 90 ml of methanol, the title compound is precipitated from methylene chloride by addition of DIPE. : s. t Ret (I) = 14.9 min, R f (K) = 0.38.

d) N-Trifluoroacetyl-rPhe ^ Leul-Boc - »

According to Example 16, starting from 3 g (11.57 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2,1-phenylethyl] oxirane (from Example 16d) and 2.3 g. of (12.15 mmol) tert-butyl 3-isobutyl carbazate [preparation:; J. Chem. Soc. Perkin I, 1712 (1975)] gives the title compound after purification by chromatography on silica gel with methylene chloride / ether (20: 1). t Ret (I) = 24.7 min, R f (W) = 0.36.

* *. ·; Example 58: Acetyl-Val- [PheNNLeu] - (N - (2 (R, S) -carbamoyl-3-phenyl-propionyl) -Va)

According to Example 37, 140 mg (0.3 mmol) of acetyl- (L) -Val- [PheNNLeu] -H? 2HCl, 132 mg (0.45 mmol) of N- (2 (R, S) -carbamoyl-3-phenyl-propionyl) - (L) -valine 114634179 it [preparation: Synth., Struct., Funet., Proc. Am. Pept.

Symp., 7th, 85 (1981)], 199 mg (0.45 mmol) of BOP, 61 mg (0.45 mmol) of HOBt and 3.5 ml of 0.3M NMM in DMF then affords the title compound after being mixed with methylene chloride / DIPE and lyophilized from dioxane (2 diastereomers separable by HPLC). FAB-MS: (M + H) + = 667, t Ret (I) = 17.9 and 18.4 min, R f (D) = 0.33.

a) Acetyl-Val-rPhe ^ Leul -H + 2HCl

According to Example 2a, starting from 230 mg (0.46 mmol) of acetyl- (L) -Val- [PheNNLeu] -Boc, the title compound is obtained after lyophilization. t Ret (I) = 10.5 min, R f (D) = 0.38.

b) Acetyl-Val-ΓPheNNLeu1-Boc

According to Example 37, 250 mg (0.71 mmol) of H- [Phe ^ Leu] -Boc (from Example 57c), 170 mg (1.07 mmol) of N-acetyl- (L) -valine, 471. mg (1.07 mol) of BOP, 144 mg (1.07 mmol) of HOBt and 7.1 ml of 0.3M NMM in DMF give the title compound after precipitation from methylene chloride by addition of DIPE and lyophilized from dioxane . FAB-MS: (M + H) + = 493, t Ret (I) = 20.5 min, R f (D) = 0.59.

Example 59: N-Morpholinocarbonyl- (L) -Vai- [PheNNLeu] <- (N- (3- (tetrazol-1-yl) -propionyl) -Vai)

According to Example 37, from 100 mg (0.19 mmol) of N-morpholinocarbonyl- (L) -Val- [PheNNLeu] -H * 2HCl, 67 mg (0.38 mmol) of N- (3- (tetrazole) -1-yl) -propionyl- (L) -valine (from Example 44a), 124 mg (0.28 mmol) of BOP, 38 mg (0.28 mmol) of HOBt and 2.1 ml of 0.3M NMM in DMF gives the title compound after precipitation from methylene chloride by addition of DIPE and> 114634,101 lyophilized from dioxane (2 diastereoisomers separated by HPLC) FAB-MS: (M + H) + = 687, tRe = (I) = 15.2 and 15, 4 min, Rf (D) = 0.25.

a) N-Morpholinocarbonyl- (L) -Val-TPhe ^ LeuT-H + 2HCl

Starting from 279 mg (0.49 mmol) of N-morpholinocarbonyl (L) -Va 1- [PheNNLeu] -Boc according to Example 2a, the title compound is obtained after lyophilization. FAB-MS: (M + H) + = 464, t Ret (II) = 30.3 min, R f (D) = 0.46.

b) N-Morpholinocarbonyl- (L) -Val-TPhe ^ LeuI -Boc

According to Example 37, 250 mg (0.71 mmol) of H- [PheNNLeu] -Boc (from Example 57c), 265 mg (1.07 mmol) of N-morpholinocarbonyl (L) -valine (from Example 7a). 471 mg (1.07 mmol) BOP, 144 mg (1.07 mmol) H0Bt and 7.1 mL 0.3M NMM in DMF give the title compound after is precipitated from methylene chloride / hexane and lyophilized from dioxane. FAB-MS: (M + H) + = 564, t Ret (I) = 21.5 min, R f (K) = 0.69.

Example 60: N-Trifluoroacetyl- [PheNNLeu] * - (N- (2 (R, S) -: Carbamoyl-3-Phenyl-Propionyl) - (L) -Val)

According to Example 37, 136 mg (0.32 mmol) of N-trifluoroacetyl- [PheNNLeu] -He2HCl, 142 mg (0.49 mmol) of N- (2 (R, S) -carbamoyl-3). -phenyl-propionyl) - (L) -valine [preparation: Synth., Struct., Funet., Proc. Am.

Pept. Symp., 7 * · * 1, 85 (1981)], 215 mg (0.49 mmol): BOP, 66 mg (0.49 mmol) H0Bt and 3.5 mL 0.3M NMM in DMF gives the title compound after purification by chromatography on silica gel with chloroform / methanol (15: 1), precipitated product-containing fractions from methylene chloride / DIPE and lyophilized dioxane / tert-butanol ( 2 diastereomers (HPLC) (181-114634 f). FAB-MS: (M + H) + = 622, t Ret (I) = 21.6 and 22.0 min, R f (K) = 0.26.

a) N-Trifluoroacetyl-rPheNNLeu1-H * 2HCl

According to Example 2a, starting from 300 mg (0.67 mmol) of N-trifluoroacetyl-tPhe ^ Leu] -Boc (from Example 57d), the title compound is obtained after lyophilization. Rf (W) <0.1.

Example 61: Z- (L) -Val- [PheNNNle] * - (N- (2 (R, S) - (N- (2-Morpholinoethyl) carbamoyl) -3-methyl) butyryl)

According to Example 37, from 100 mg (0.17 mmol) of Z- (L) -Val- [PheNNNle] -H 2 HCl, 69 mg (0.27 mmol) of 2 (R, S) - (N - (2-morpholinoethyl) carbamoyl) -3-methylbutyric acid (isopropylmalonic acid N- (2-morpholinoethyl) monoamide), 119 mg (0.27 mmol) B0P, 36 mg (0.27 mmol) mmol) of H 2 Bt and 2.1 mL of 0.3M NMM in DMF gives the title compound after precipitation from methylene chloride / DIPE and lyophilized from dioxane (2 diastereomers separable by HPLC). FAB-MS: (M + H) + = 725, t Ref (I) = 17.2 and 17.6 min, Rf (D) = 0.56.

.] a) Z- m -Vai- ΓPheNNNle 1 -Η · 2Η01

According to Example 2a, starting from 310 mg (0.53 mmoles) of Z- (L) -Val- [Phe ^ Nle] -Boc, the title compound is obtained after lyophilization. t Ret (I) = 16.4 min, R f (U) =: * 0.25.

»·» «B) Z- ^ LI-Val-rPhe ^ Nlel-Boc

According to Example 37, 250 mg (0.71 mmol) of H- [Phe ^ NleJ-Boc, 268 mg (1.07 mmol) of Z- (L) -valine, 472 mg (1 (07 mmol) of B0P, 144 mg (1.07

> I

114634 (182 mmol) HOBt and 7.1 mL of 0.3M NMM in DMF give the title compound after chromatography on silica gel with methylene chloride / methanol (40: 1) and precipitated product-containing fractions methylene chloride / DIPE: from. t Ret (I) = 25.6 min, R f (X) = 0.17.

c) H-rPhe ^ Nlel-Boc

According to Example 17a, starting from 830 mg (1.85 mmol) of N-trifluoroacetyl- [PheNNNle] -Boc gives the title compound after precipitation from methylene chloride / DIPE. t Ret (I) = 15.4 min, R f (K) = 0.54.

d) N-trifluoroacetyl-liPhe ^ Nle 1 -Boc

According to Example 16, starting from 1 g (3.86 mmol) of 2 (R) - [1 '(S) - (trifluoroacetylamino) -2'-phenylethyl] oxirane (from Example 16d) and 720 mg (3.86 mmol) of tert-butyl-3-butyl-carbazate is obtained after purification by chromatography on silica gel with methylene chloride / ether (20: 1). t Ret: (I) = 25.3 min, Rf (Q) = 0.43.

e) tert-butyl 3-butyl carbazate

According to Example 4b, 18.0 g (136.2 mmol) of tert-butyl carbazate and 12.3 mL (136.2 mmol) of n-bu-. The corresponding tert-butoxycarbonylhydrazone (25 g, 99%) is obtained as a crude product, which is hydrogenated according to Example 4a in the presence of 5% platinum carbon (10 g) and 4 atm of hydrogen. Chromatographic purification of the crude product on silica gel hexane / acetic acid ethyl ester (1: 1) to give the title compound Rf (N) = 0.44.1H NMR (200 MHz, CD3OD): 0.92 (t, J = 7Hz, 3H), 1.43 (s, 9H), 1.30-1.50 (m, 4H), 2.75 (t, J = 7Hz, 2H).

114634 1 83 f) 2 TR (S) - N - (2-morpholinoethyl) carbamoyl) -3-methylbutyric acid

According to Example 9b, starting from 7 g (43.7 mmol) of racemic isopropylmalonic acid monomethyl ester [Chem. Ber. 119, 1196 (1986)], 6.3 ml (48.1 mmol) of aminoethyl morpholine, 6.6 ml (43.7 mmol) of cyano-phosphonic acid diethyl ester and 12.8 ml (91 (8 mmol) triethylamine in DMF yields 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methylbutyric acid methyl ester (isopropylmalonic acid-N-morpholinoethylamide methyl ester). This is stirred for 5 hours at room temperature in a mixture of 28 ml of 2N sodium hydroxide and 28 ml of dioxane, acidified with 2N hydrochloric acid and completely evaporated. The residue is digested with ethanol, filtered, and after evaporation of the filtrate, the title compound is obtained. 1 H-NMR (200 MHz, CD 3 OD): 0.95 and 1.00 (2d, J = 7H, 6H), 2.25 (m, 4H), 2.70 (m, 6H), 2.75 (d, J = 8Hz, 1H), 3.45 (m, 2H), 3.75 (m, 4H).

Example 62: Z- (L) -Val- [PheNNNle] «- (N- (3- (Tetrazol-1-yl) -propionyl) -Vai)»

According to Example 37, 100 mg (0.18 mmol) of Z- (L) -Val- [PheNNNle] -H 2 HCl (from Example 61a), 65 mg (0.27 mmol) of N- (3- (tetrazol-1-yl) -propionyl) - (L) -valine (from Example 44a), 119 mg (0.27 mmol) of BOP, 36 mg (0.27 mmol) of HOBt and 2.1 ml of 0.3M N-methylmorpholine in DMF gives the title compound after precipitation from methylene chloride / DIPE and: lyophilized from dioxane / tert-butanol (2 diastereomers by HPLC). FAB-MS: (M + H) <+> = 708, tRe <+>. (I) = ·, 20.3 and 20.6 min, Rf (D) = 0.43.

114634 1 84 i

Example 63: Z- (L) -Val- [PheNNNle] ** - (N- (2 (R / S) - (N- (2-Pyridylmethyl) carbamoyl) -3-methyl) -butyryl) ( -dibenz-sulfonate)

According to Example 37, from 95 mg (0.17 mmol) of Z- (L) - [PheNNNle) -H * 2HCl (from Example 61a), 60 mg (0.26 mmol) of (R, S) -isopropylmalonic acid -N- (2-picolyl) -monamide, 113 mg (0.26 mmol) of B0P, 35 mg (0.26 mmol) of HOBt and 2.0 ml of 0.3M NMM in DMF give the title compound as the free amine after chromatography on silica gel with methylene chloride / methanol (15: 1). This is dissolved in methylene chloride, 2 equivalents of benzenesulfonic acid are added and precipitated by addition of DIPE. Lyophilization on the tert-butano list yields the dibenzenesulfonate salt (2 diastereomers by HPLC separation). FAB-MS: (M + H) + = 703, t Ret (1) = 17.7 and 18.0 min, R f (D) = 0.54.

a) Isopropyl 1 Imalonic acid N- (2-picolyl) monoamide

To a solution of 15 g (93.6 mmol) of isopropylmalonic acid monomethyl ester [Preparation: Chem. Ber. 119, 1196 (1986)] in 150 mL of THF, 10.6 mL (103 mmol) of N-methylmorpholine are added followed by dropwise addition of 13.5 mL of I (103 mmol) of isobutyl chloroformate. After 30 minutes, 15.3 ml (150 mmol) of 2-picolylamine are added and the resulting suspension is stirred for 2 hours. The reaction mixture is diluted with methylene chloride, washed with 1N sodium hydroxide and water, the organic phase is filtered through a pad and evaporated. Crystallization of the residue affords isopropylmalonic acid N- (2-picolylamide) methyl ester which is hydrolyzed as in Example 61f in 2N sodium hydroxide and dioxane to give the title compound. t Ret (II) = 16.0 min.

114634 185

Example 64; Z- (L) -Val- [PheNN (p-F) Phe) - (N- (3- (tetrazol-1-yl) -propionyl) - (L) -Vai) (benzenesulfonate)

According to Example 37, from 100 mg (0.16 mmol) of Z- (L) -Val- [PheNN (pF) Phe] -H (from Example 22a), 59 mg (0.25 mmol) of N- (3- (tetrazol-1-yl) -propionyl) - (L) -valine (from Example 44a), 109 mg (0.25 mmol) of BOP, 33 mg (0.25 mmol) of HOBt and 1.9. ml of 0.3M N-methylmorpholine in DMF gives the title compound as the free amine after precipitation from methylene chloride / DIPE. This is dissolved in methylene chloride / methanol, added with 1 equivalent of benzenesulfonic acid and precipitated by the addition of hexane. Lyophilization from tert-butanol yields the title compound as the benzenesulfonate salt. FAB-MS: (M + H) + = 760, t Ret (I) = 21.6 min, R f (B) = 0.49.

Example 65; Methylsulfonyl-CPhe Phej ^ ^ -fn-fenyyliase-methyl- (L) -Vai)

According to Example 7, 132 mg (0.28 'mmol) of methylsulfonyl- [PheNNPhe] -H * 2HCl, 197 mg, · (0.84 mmol) of N-phenylacetyl- (L) -valine [Preparation:

Mem. Tokyo Univ. Agric. 20, 51 (1978)), 317 mg (0.84 mmol) of HBTU and 0.23 mL (1.67 mmol) of triethylamine in DMF are precipitated from methanol by addition of ether to give the title compound. FAB-MS: (M + H) + = 581, t Ret (I) = 20.2 min, R f (B) = 0.64.

a) Methylsulfonyl-TPheNNPhe1-H * 2HC1 * * * ♦ t · • '' According to Example 2a, starting from 130 mg (0.28 mmol) of methylsulfonyl-fPhe ^ PheJ-Bocr, the title compound is obtained after lyophilization. FAB-MS: (M + H) + = 364, t Ret (II) = 28.5 min, R f (K) = 0.56.

1 86 1 U634 b) Methylsulfonyl-rPheNNPhe1-Boc

According to Example 16a, starting from 1.1 g (4.56 mmol) of 2 (R) - [1 '(S) - (methylsulfonylamino) -2'-phenylethyl] oxirane and 1.11 g (5, 02 mmol) tert-butyl-3-benzylcarbazate [preparation: J. Chem. Soc.

Perkin I, 1712 (1975)] gives the title compound as a diastereomeric mixture in a ratio of 4: 1. Crystallization from methylene chloride / hexane improves the 2S diastereomer to 10: 1. FAB-MS: (M + H) + = 464, t Ret (I) = 21.3 min, R f (N) = 0.26.

c) 2 (R) -Γ (1S) - (methylsulfonylamino) -2H-phenylmethyl-oxirane

To a solution of 1 g (6.8 mmol) of 1-phenyl-3-butene-2 (S) -amine of Example 16b in 10 mL of methylene chloride is added 2.36 g (13.6 mmol) at 0 ° C. methanesulfonic anhydride and 1.88 ml (13.6 mmol) of triethylamine and stir for 1 hour. The reaction mixture is washed with water and saturated sodium bicarbonate solution, the organic phase is filtered through a pad and evaporated to give 2 (S) -methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of this crude product is dissolved in 30 ml of methylene chloride, 3.05 g (17.7 mmol) of 4-chloroperbenzoic acid are added at room temperature and stirred for 18 hours. The reaction solution is washed 5 times with 10% aqueous sodium sulphite solution, filtered through a pad and evaporated completely. According to 1H NMR, the crude product contains both (2R) and (2S) epimers in a ratio of 4: 1. 1 H-NMR (200: MHz, CD 3 OD): 2.30 and 2.52 (2s, together 3H), 2.6-3.2 (m, 5H), 3.55 (m, 1H), δ , 32 (m, 5H).

187 π 4634

Example 66; Methoxycarbonyl- (L) -Val-fPhe LeuJ ^ ^ -in-Me-toksikarbonyyli- (L) -Vai)

According to Example 37, 200 mg (0.55 mmol) of H- [Phe-Leuj-H 2 -CH 2 Cl (from Example 13a), 291 mg (1.66 mmol) of N-methoxycarbonyl (L) -valine [Preparation:

Chem. Lett. 705 (1980)], 735 mg (1.66 mmol) of BOP, 225 mg (1.66 mmol) of HOBt, and 11 mL of 0.3H NMM in DMF then afford the title compound, after precipitation from methylene chloride / DXPE and lyophilized from dioxane. FAB-MS: (M + H) + = 566, t Ret (I) = 18.6 min, R f (U) = 0.33.

Example 67: Methoxycarbonyl- (L) -Val-fPhe ^ ip-FJPhe] - * - (N-Methoxycarbonyl- (L) -Vai)

According to Example 37, 200 mg (0.48 mmol) of H- [PheNN (pF) Phe] -H? 3HCl (from Example 42b), 255 mg (1.45 mmol) of N-methoxycarbonyl (L). valine [preparation: Chem. Lett. 705 (1980)], 643 mg (1.45 mmol) of "BOP, 196 mg (1.45 mmol) of H 0Bt, and 9.7 mL * 0.3M NMM in DMF: yields the title compound after precipitation from methylene chloride / DIPE and lyophilized from dioxane FAB-MS: (M + H) + = 618, t Ret (I) = 19.5 min.

Rf (U) = 0.22.

Example 68: Methoxycarbonyl (L) -Val-iPhe (fp-CN) Phe] - (N-methoxycarbonyl (L) -Vai) t

According to Example 37, 200 mg (0.48 mmol) of H- [Phe ^ ip-CNJPheJ-H ^ SHCl (from Example 47a), 250 mg ,,, (1.43 mmol) of N-methoxycarbonyl- (L ) -valine [preparation: Chem. Lett. 705 (1980)], 631 mg (1.43 mmol) of B0P, 193 mg (1.43 mmol) of HOBt and 9.5 mL of 0.3M NMM in DMF are obtained. the title compound after chromatography on silica gel 114634 188 with methylene chloride / methanol (15: 1) and lyophilized product-containing fractions from dioxane. FAB-MS: (M + H) + = 625, t Ret (1) = 18 min ·, R f (u) = 0.31.

Example 69: Z- (L) -Val - [(pF) Phe ^ fp-F) Phe] - (N- (2 (R, S) - (N- (2-Morpholinoethyl) carbamoyl) -3- methyl) -butyryl)

According to Example 18, 23.0 mg (0.089 mmol) of 2 (R, S) - (N- (2-morpholinoethyl) carbamoyl) -3-methylbutyric acid (Example 61f) and 45 mg (0.081 mmol) of Z- (L ) -Val - [(pF) -PheNN (pF) Phe] -H (Example 32) is reacted with HBTU (33.8 mg, 0.089 mmol) in 0.76 mL of NMM / -CH 3 CN, 25 M to the title compound and reprecipitate with DMF / DIPE. DC Rf (P) = 0.42, FAB-MS: (M + H) + = 795.

Example 70: Z- (L) -Val - [(pF) PheNN (pF) Phe] - (N- (2 (R, S) - (N- (2-Pyridylmethyl) carbamoyl) -3-methyl) -butyryyli)

According to Example 18, 21.0 mg (0.089 mmol) of racemic isopropylmalonic acid N- (2-picolyl) amide (Example 63a) and 45 mg (0.081 mmol) of Z- (L) -Val - [(pF) Phe fp- 'F) Phe] -H (Example 32) is reacted with HBTU (33.8 mg, 0.089 mmol) in 0.76 mL of NMM / CH 3 CN *: 0.25 M to the title compound and precipitated again, | DMF / DIPE. DC Rf (P) = 0.52, FAB-MS: (M + H) + = 773.

> 1

Example 71 *> ·

According to one of the above methods, the following compounds can be prepared: a) Z- (L) -Val - [(pF) PheNN (pF) Phe] - * - ((L) -Val) - * - (N -morpholino-, carbonyl-Gly), b) N-morpholinocarbonyl- (L) -Val - [(pF) PheNN (pF) Phe] - ((L) -Val) <- (N-morpholinocarbonyl-Gly) , c) N- (Quinoline-2-carbonyl) - (L) -Asn- [PheNN (pF) Phe] * -? 114634 1 89 ((L) -Vai) -Z, d) N- (morpholinosulfonyl) - (L) -Val- [PheNNLeu] - (N- (morpholinosulfonyl) - (L) -Vai.

Example 72: Gelatin solution

A sterile filtered solution containing 20% of cyclodextrins as the Foaming Agent and the active ingredient of any of the compounds of formula I shown in the Examples above, is stirred under aseptic conditions with a sterile gelatin solution containing phenol as a preservative, so that 1.0 ml of solution contains : active substance 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water containing 20% cyclodextrins as a solubilizer in 1.0 ml

Example 73: Sterile powder for injection 5 mg of one of the compounds of formula I shown in the above examples is dissolved as active ingredient 1; ml of an aqueous solution of 20 mg of mannitol and 20% of cyclodextrins as solubilizer. The solution is sterile filtered and aseptically filled into 2 ml ampoules, frozen and lyophilized. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological saline. The solution is used; intramuscularly or intravenously. This product can also be filled in dual-chamber injection ampoules.

114634 190

Example 74: Nasal Spray

A mixture of 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol is suspended in the active ingredient 500 mg of a finely divided powder (<5.0 μτα) of any of the compounds of the formula I shown above.

This suspension is filled into a container fitted with a metering valve. The container is filled through a valve with 5.0 g Freon 12 * under pressure. By shaking, "Freon1 · is dissolved in Myglyol Benzyl Alcohol Mixture. This spray can contains about 100 single doses that can be used individually.

Example 75: Lacquer Tablets For the preparation of 10,000 tablets containing 100 mg of active ingredient, the following ingredients are used: 1000 g of corn starch 680 g of colloidal silicic acid 200 g of magnesium stearate 20 g of stearic acid 50 g of sodium carboxymethyl starch 250 g of water quantum satis

A mixture of the compound of the formula I as shown in the examples above with the active ingredient, 50 ;;; g of corn starch and colloidal silicic acid are treated to a moist mass with a starch liter containing 250 g of corn starch and 2.2 kg of demineralized water. The pulp is squeezed through a 3 mesh screen and dried at 45 ° C for 30 minutes in a fluid bed dryer. The dried granulate is squeezed through a 1 mm mesh sieve, mixed with the previously screened mixture (1 mm sieve) containing 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch, and slightly compressed into a tablet.

Claims (3)

An analogous process for the preparation of a pharmaceutically acceptable hydrazine derivative of the formula R 5 FL 1 <r 3 r 4 I n and pharmaceutically acceptable salts of this compound, where salt-forming groups are present wherein R 4 and R 8 independently of each other are hydrogen, lower , fenyylialempialkanoyyliä, wherein the lower-_ alkanoyl radical is substituted by carbamoyl, morpholino-lower alkanoyl, tiomorfolinoalempialkanoyyliä, pyridyl-lialempialkanoyyliä, kinolyylialempialkanoyyliä, tetrazol-lyylialempialkanoyyliä, n-morpholino or n-thiomorpholino-carbonyl amino nitrogen substituted aminoalempialka-noyyliä, halogeenialempialkanoyyliä containing up to 3 halogen atom, 2- (N-morpholino-lower alkyl-carbamoyl)-lower-alkanoyl, 2- (N-pyridyl-lower alkyl-carbamoyl)-lower-alkanoyl, 2 (R, S) - (N- (2-pyridyl-methyl) -carbamoyl) - 3-methylbutyryl, Alem pialkoksi-; carbonyl, phenyl-lower alkoxycarbonyl, benzyloxycarbonyl, tetrahydrofuranyl-lower alkoxycarbonyl, lower alkylsulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, carboxylic acid, N-pyridyl-lower alkyl, alanine, valine, leucine, isoleucine, glutamic acid or asparagine in the (D), (L) - ·,> or (D, L) form, wherein the α-amino group is unsubstituted or acylated by any of the above R • or R 8, provided that at most one of R 1 and R 8 represent hydrogen, R 2, R 4, R 8 and R 8 represent hydrogen, R 93 represents lower alkyl; sykloheksyylialempialkyyliä; or phenyl-lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy or cyano, R 5 represents hydroxy, and R 7 represents lower alkyl; sykloheksyylialempialkyyliä; or phenyl-lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy or cyano as last defined for R 3, characterized in that a) the formula? 'hk-n-'r. (ΠΙ) a hydrazine derivative of formula R. wherein the residues have the meanings indicated above, is attached to an epoxide of formula (iv) wherein the residues have the meanings above, wherein the free functional groups except for the reaction groups exist in potentially protected form; or b) for the preparation of compounds of the formula I in which R 1 and R 9 represent acyl, sulfo, unsubstituted, or substituted alkyl, aryl, heterocyclyl, alkoxy, unsubstituted or substituted, or aryloxy-substituted sulfonyl , or sulfamoyl, unsubstituted or substituted in nitrogen, and the other residues have the meanings indicated, an amino compound of the formula (V) 1 94 114634 1 · 2 R 7 - R 1 R 3 R 4 I Re, wherein the residues have the meanings given above , condensing with an acid of formula R9-OH (VI) or with reactive acid derivatives wherein Rg has the above meanings, wherein the free functional groups except for the groups involved in the reaction are optionally in protected form and any protecting groups are cleaved, or c) for the preparation of compounds of formula I wherein R3 and R8 are acyl, unsubstituted or substituted alkyl, aryl, heterocyclyl, alkoxy, unsubstituted or substituted, or aryloxy-substituted sulfonyl, or sulfamoyl, which is unsubstituted or substituted in nitrogen, and the other residues have the meanings indicated, formula. The amino compound of formula I: wherein the residues have the meanings given above are condensed with an acid of the formula RL-OH (VIII) 1925114634 or reactive acid derivatives thereof, wherein the residual R or thionic groups, except for the groups involved in the reaction, optionally in protected form and cleavage of any protecting groups, or d) for the preparation of compounds of formula I wherein R 4 and R 8 represent two similar residues, acyl, sulfo, unsubstituted or substituted alkyl, aryl; heterocyclyl, alkoxy-1a which is unsubstituted or substituted, or aryloxy-substituted sulfonyl, or sulfamoyl which is unsubstituted or substituted in nitrogen, and the other residues have the meanings indicated, a diamino compound of the formula R wherein the residues have the meanings indicated above: condensate an acid or reactive acid suitable for attachment of the identical residues R 1 and R 8. with derivatives wherein R ^^ and Rg are above. meanings wherein the free functional groups, except for the groups involved in the reaction, occur in potentially protected form and cleave any protecting groups present, or * · ·. .. · (e) for the preparation of a compound of formula I wherein R7 ", which is a substituent, an unsubstituted or substituted alkyl or cycloalkyl, is substituted for R7, having the formula 1 '1 96 114634? 2 R.I RS R6 In a compound of formula I7 * 3 R <I Re, wherein R7 'is hydrogen and the other residues have the meanings given, the residue R7 "is substituted by a compound of formula XII R7" -X (XII) wherein X is a leaving group and R7 "is unsubstituted or substituted alkyl; or. cycloalkyl wherein the free functional groups except for the reaction groups are optionally in protected form and any protecting groups are cleaved; or f) in a compound of formula I wherein the substituents have the meanings given above, provided that the compound of formula I At least one functional group is protected by protecting groups, the protecting groups present are cleaved; and, if desired, converting a compound of formula I having at least one salt-forming group according to one of the above processes a) to f) into a salt thereof or converting the resulting salt into a free compound or another salt and / or separating the resulting isomeric mixtures and / or converting a compound of formula I according to the invention into another compound of formula I according to the invention. A process for the preparation of a compound of formula I according to claim 1 and a pharmacologically useful salt of this compound, wherein and Rg are each a monovalent moiety acylated by a benzyloxycarbonyl amino acid (L) -valine via a carboxy group, R 2 and R 8 represent hydrogen, R 8 represents benzyl, R 4 represents hydrogen, R 6 represents hydroxy, R 8 represents hydrogen and R 7 represents benzyl, and the asymmetric carbon atoms to which R 3 and R 5 are attached occur in the S configuration, characterized in that subs -mediated starting materials. A process for the preparation of a compound of formula I as defined in claim 1 and a pharmacologically acceptable salt thereof, wherein R 1 and R 1 each represent a monovalent group bonded via a carboxy group on the amino acid (L) -vinine, R 2 and R 8 on the amino nitrogen. hydrogen, Rg denotes benzyl, R4 denotes hydrogen, R5 denotes hydroxy, R7 denotes hydrogen and R7 denotes isobutyl and the asymmetric carbon atoms to which R3 and R5 are attached appear in the S configuration, characterized in that the corresponding substituted substituents are used. 198 1 1 4634