DD260500A5 - METHOD FOR THE PRODUCTION OF 5-AMINO-4-HYDROXY-VALERYL DERIVATIVES SUBSTITUTED BY SULFUR-BASED GROUPS - Google Patents

Abstract

Sulfur-containing groups substituted 5-amino-4-hydroxy-valeryl derivatives Compounds of formula (I) wherein R 1 is acyl substituted by a thio, sulfinyl or sulfonyl group, A is an optionally N-alkylated α-amino acid residue N-terminally attached to R 1 and C-terminal to the group -NR2-, R2 is hydrogen or lower alkyl, R3 is hydrogen, lower alkyl, optionally etherified or esterified hydroxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl, bicycloalkyl lower alkyl, tricycloalkyl lower alkyl, aryl or aryl lower alkyl, R4 hydroxy, etherified or esterified hydroxy, R5 Lower alkyl, optionally etherified or esterified hydroxy lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, tricycloalkyl, tricycloalkyl-lower alkyl, aryl, aryl-lower alkyl, optionally substituted carbomyl, optionally substituted amino, optionally substituted hydroxy or optionally substituted mercapto, sulfinyl or su Lfonyl and R6 are substituted amino, and salts of such compounds with salt-forming groups inhibit the hypertensive effect of the enzyme renin and can be used as antihypertensives. Formula (I)

Description

Field of application of the invention

The invention relates to a process for the preparation of sulfur-substituted groups substituted 5-amino-4-hydroxyvalerylderivaten with valuable pharmacological properties. The compounds of the invention inhibit the action of the enzyme renin and can be used as an antihypertensives and for the treatment of heart failure.

Characteristic of the known technical solutions

In the exclusion patent of the German Democratic Republic DD 239210 processes for the preparation of 5-amino-4-hydroxyvalerylderivaten are described which inhibit the action of the enzyme renin. These compounds are substituted at the amino group by an acyl-α-aminoacyl radical but contain no sulfur.

There is a further need for compounds that inhibit the action of the enzyme Ren and can be used as antihypertensives. In particular, there is a need for orally effective antihypertensives.

Object of the invention

The object of the invention is to provide a process for the preparation of sulfur-substituted groups substituted 5-amino-4-hydroxyvaierylderivaten which inhibit the action of the enzyme renin.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the property to inhibit the action of the enzyme renin, and to find methods for their preparation.

According to the invention are substituted by sulfur-containing groups 5-amino-4-hydroxyvalerylderivate of the formula

Ra Ru Rs Q

-AN-CH-CH-CH ₂ -CH-C

R ₁ -AK-CH-CH-CH ₂ -CH-CR ₆ (D,

wherein R ₁ is acyl substituted with a thio, sulfinyl or sulfonyl group, with the exception of an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated α-amino acid residue which is N-terminal with R ₁ and C-terminal with the group -connected -NR _2, R ₂ is hydrogen or lower alkyl, R ₃ is hydrogen, lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, cycloalkyl, cycloalkyl, bicycloalkyl, Tricycloalkylniederalkyl, aryl or aryl-lower alkyl, R ₄ is hydroxy, etherified or esterified hydroxy, R ₅ is lower alkyl, optionally etherified or esterified hydroxy lower alkyl, cycloalkyl, Cycloalkylnieoeralkyl, bicycloalkyl, Bicycloalkylniederalkyl, tricycloalkyl, Tricycloalkylniederalkyl, aryl, Arylniederalkyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted hydroxy or optionally substituted mercapto, sulfinyl or sulfonyl and R _{6 represent} substituted amino except for an amino group derived from an α-amino acid, and salts of such compounds having salt-forming groups are also prepared.

In the description of the present invention, in the definition of groups or radicals, e.g. Lower alkyl, lower alkoxy, lower alkanoyl, etc., used the term "lower" to indicate that the groups or groups so defined, unless expressly otherwise defined, contain up to and including 7, and preferably up to and including 4C atoms.

The C atoms substituted by R ₃ , R ₄ and R ₅ may have the R, S or R, S configuration. Preference is given to compounds of the formula I in which the C atoms substituted by R ₃ and R _{4 have} the S configuration.

The general terms and terms used in the description of the present invention preferably have the following meanings:

ACyIR ₁ has z. B. up to 25 carbon atoms and is primarily one by a thio, sulfinyl or sulfonyl group and optionally further. Heteroatom-containing groups substituted acyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heteroaromatic or

heteroaromatic-aliphatic carboxylic acid with the exception of the optionally N-substituted natural amino acids methionine.

Preferred substituents R ₁ are acyl groups of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) - C -

(O). ' ^Ö

^m (CH ₂ ) da),

wherein R ^{a is} unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tricycloalkyl, cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, aryl-lower alkenyl, unsubstituted or substituted heteroaryl, heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or unsubstituted or substituted amino, R ^b Is hydrogen, mono-, bi- or tricycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, mO, 1 or 2, nO, 1 or 2, pO, 1 or 2 and qO, 1, 2, 3 or 4.

The methine carbon atom in the partial formula Ia and, if ml, also the sulfur atom may be in the R, S or R, S configuration.

Lower alkyl R ^a preferably has 1-7 C atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl or tert-butyl, which by one or more functional groups, for example hydroxy, etherified hydroxy, ζ. B. lower alkoxy, such as methoxy or ethoxy, or phenoxy, esterified hydroxy, ζ. B. lower alkanoyloxy, such as acetoxy, halogen, z. As chlorine or bromine, hydroxysulfonyloxy, carboxy, esterified carboxy, ζ. B. lower alkoxycarbonyl, such as methoxy or ethoxycarbonyl, amidated carboxy, ζ. Carbamoyl or mono- or di-lower alkylcarbamoyl, such as methyl or dimethylcarbamoyl, cyano, amino, substituted amino, ζ. B. Mono-lower alkylamino, di-lower alkylamino, acylamino or substituted amino wherein the amino group may be part of a five- or six-membered heterocycle containing one to two nitrogen atoms and, if desired, an oxygen or sulfur atom, or may be substituted by oxo.

Substituted lower alkyl R ^a is, for example, hydroxy-lower alkyl, e.g. B. 2-hydroxyethyl, Niederalkoxyniederalkyl, z. B.

Lower alkoxyethyl, such as 2-methoxyethyl, Phenoxyniederalkyl, z. 2-phenoxyethyl, lower alkanoyloxy-lower alkyl, e.g. B.

Lower alkanoyloxyethyl, such as 2-acetoxyethyl, halo-lower alkyl, e.g. B. Halogenäthyl, such as 2-chloro or 2-bromoethyl, Hydroxysulfonyloxyniederalkyl, z. B. 2-hydroxysulfonyloxyethyl, carboxy-lower alkyl, e.g. Carboxymethyl or 2-carboxyethyl, lower alkoxycarbonyl-lower alkyl, e.g. B. lower alkoxy.carbonylmethyl or lower alkoxycarbonylethyl, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl-lower alkyl,

z. Carbamoylmethyl or 2-carbamoylethyl, lower alkylcarbamoyl-lower alkyl, e.g. Methylcarbamoylmethyl, di-lower alkylcarbamoyl-lower alkyl, e.g. Dimethylcarbamoylmethyl, cyano-lower alkyl, e.g. B. 2-cyanoethyl, amino-lower alkyl,

z. For example, 2-aminoethyl, Niederalkylaminoniederalkyl, z. B. 2-Methylaminoäthyl, Diniederalkylaminoloweralkyl, z. 2-dimethylaminoethyl, morpholinoloweralkyl, e.g. B. 2-Morpholinoäthyl, Piperidinoniederalkyl, z. 2-piperidinoethyl, acylaminoloweralkyl, e.g. Lower alkanoylamino lower alkyl such as 2-acetylaminoethyl, benzyloxycarbonylamino lower alkyl such as 2-benzyloxycarbonylaminoethyl, lower alkoxycarbonylamino lower alkyl such as 2-tert-butoxycarbonylaminoethyl, or oxo-lower alkyl, e.g. For example, 2-oxopropyl or 2-oxobutyl.

Lower alkenyl R ^a contains z. B. 2-7, in particular 2-4, C atoms and z. As vinyl, allyl or 2- or 3-butenyl, lower alkenyl R ^a may be substituted by the same substituents as lower alkyl, for example by hydroxy, etherified hydroxy, for example methoxy, esterified hydroxy, ζ. For example, acetoxy, halogen, z. As chlorine or bromine, carboxy, esterified carboxy, ζ. Methoxycarbonyl or ethoxycarbonyl, or amidated carboxy, e.g. Carbamoyl.

Lower alkynyl R ^a contains, for example, 2-7, in particular 2-A, C atoms and is, for example, ethynyl, 1-propynyl or 2-propynyl.

Cycloalkyl R ^a or R ^b contains z. B. 3-8, in particular 3-6, C atoms and z. As cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Bicycloalkyl R ^a or R ^b contains z. B. 5-10, in particular 6-9, C atoms and z. Bicyclohexyl, heptyl, octyl, nonyl or decyl, for example bicyclo [3 _v 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 [3.3.1] non-9-yl, also alpha or beta -Decahydronaphthyl.

Tricycloalkyl R ^a or R ^b contains z. B. 8-1 OC atoms and is z. Tricyclo [5.2.1.0 ² ' ⁶ ] dec-8-yl or amidamyl, such as 1-adamantyl.

Cycloalkyl-lower alkyl R ^a contains z. B. 4-10, in particular 4-7, C atoms and is for example cyclopropylmethyl, cyciobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

The stated cycloaliphatic or cycloaliphatic-aliphatic radicals may be substituted by the same substituents as lower alkyl R ^a .

Aryl R ^a or R ^b contains z. 6 to 14C atoms and is, for example, phenyl, indenyl, e.g. For example, 2- or 4-indenyl, 1- or 2-naphthyl, anthryl ^1, for example 1- or 2-anthryl, phenanthryl, for example, 9-phenanthryl, or acenaphthenyl, for example, 1-acenaphthenyl. Aryl R ^a or R ^b is exemplified by lower alkyl, e.g. For example, methyl, hydroxy, lower alkoxy, z. For example, methoxy, acyloxy, z. Lower alkanoyloxy such as acetoxy, amino, lower alkylamino, e.g. For example, methylamines, Diniederalkylamino, z. Dimethylamino, acylamino, ζ. B. tert-butoxycarbonylamino, or halo, ζ. As chlorine, bromine or iodine, wherein the substituent in any position of the aryl radical, for example in o-, m- or p-position of the phenyl radical, may be and the aryl radical may also be substituted several times with identical or different substituents.

Aryl-lower alkyl R ^a has, for example 7 to 15 carbon atoms and includes, for example a mentioned lower alkyl R ^a unsubstituted or substituted, optionally branched residue and an under aryl R ^a or R ^b mentioned unsubstituted or substituted radical. Such aryl-lower alkyl is for example benzyl, Niederalkylbenzyl such as 4-methylbenzyl, lower alkoxybenzyl, such as 4-methoxybenzyl, 2-phenylethyl, 2- (p-hydroxyphenyl) ethyl, diphenylmethyl, di (4-methoxyphenyl) methyl, trityl or α- or β-naphthylmethyl.

Arylniederalkenyl R ^a has, for example 8 to 16 carbon atoms and includes, for example, a ^{1-unsubstituted} or substituted radical mentioned under lower alkenyl and R ^{a is} an aryl with R ^a or R ^b mentioned unsubstituted or substituted radical.

Such an aryl-lower alkenyl is, for example, styryl, 3-phenylallyl, 2- (a-naphthyl) -vinyl or 2- (β-naphthyl) -vinyl.

Unsubstituted or substituted heteroaryl R ^a or R ^b is mono-, bi- or tricyclic and contains one to two nitrogen atoms and / or one oxygen or sulfur atom. R ^a or R ^b is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,

Oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, ß-Carboliiiyl or a benzannelliertes, cyclopenta-cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocycle may be attached to a nitrogen atom by oxido, lower alkyl, e.g. Methyl or ethyl, phenyl or phenyl-lower alkyl, e.g. Benzyl, and / or at one or more carbon atoms by lower alkyl, e.g. Methyl, phenyl, phenyl-lower alkyl, e.g. Benzyl, halogen, e.g. As chlorine, hydroxy, lower alkoxy, ζ. For example, methoxy, phenyl-lower alkoxy, e.g. B. benzyloxy, or oxo substituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, z. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, e.g. 1-methyl-2-, 4- or 5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridinio, 2-pyrazinyl , 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, e.g. 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or 3-indolyl, 4.5 , 6,7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolinyl, 1-0x0 1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzthiazolyl, benz [e] indol-2-yl or β-carbolin-3-yl.

Heteroaryl-lower alkyl R ^a contains z. B. a lower alkyl R ^a mentioned unsubstituted or substituted radical and unsubstituted or substituted under heteroaryl R ^a or R ^b unsubstituted or substituted radical and is for example 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylmethyl, 2- (2 -, 3- or 4-pyridyl) -ethyl, 4-imidazolylmethyl, 2- (4-imidazolyl) -ethyl, 2- or 3-indolylmethyl, 2- (3-indolyl) -ethyl or 2-quinolylmethyl.

Hydroxy R ^a is unsubstituted or substituted for example by lower alkyl or aryl and is z. Hydroxy, methoxy, ethoxy, n-butoxy, phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy.

Amino R ^a is unsubstituted, substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or part of a five- or six-membered heterocycle containing one to two nitrogen atoms and, if desired, an oxygen or sulfur atom and is e.g. Amino, methylamino, ethylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, pivaloylamino, methoxy, ethoxy or tert-butoxycarbonylamino, benzyloxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-methyl-4- Pyridazinyl, 4-morpholinyl or 4-thiomorpholinyl.

A is a bivalent residue of an α-amino acid, for example a natural α-amino acid of the L-configuration normally found in proteins, a homologue of such an amino acid, e.g. Wherein the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted aromatic α-amino acid, eg. A substituted phenylalanine or phenylglycine, wherein the substituent is lower alkyl, e.g. Methyl, halogen, e.g. As fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, z. Methoxy, lower alkanoyloxy, e.g., acetoxy, amino, lower alkylamino, e.g. Methylamino, Diniederaikylamino, e.g. Dimethylamino, lower alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamine. B. tert-Butoxycarbonylamino, Arylmethoxycarbonylamino, z. B. benzyloxycarbonylamino, and / or nitro can be and occurs one or more times, a benzannellierten phenylalanine or phenylglycine, such as a-naphthylalanine, or a hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine, a five- or six-membered cyclic, benzannellierten α- Amino acid, e.g. B. lndoline-2-carboxylic acid or "! ^, S ^ -Tetrahydroisochinolin-S-carboxylic acid, a natural or homologous α-amino acid in which ^ is a carboxy group of the side chain in esterified or amidated form, eg., As a lower alkyl group, such as methoxycarbonyl or tert-butoxycarbonyl, or as carbamoyl, as lower alkylcarbamoyl, such as methylcarbamoyl, or as di-lower alkylcarbamoyl group, such as dimethylcarbamoyl, in.der amino group of the side chain in acylated form, for example as Niederalkanoylamino-, such as acetylamino or pivaloylamino , lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, or arylmethoxycarbonylamino, such as benzyloxycarbonylamino, or in which a side chain hydroxy group is in etherified or esterified form, e.g., lower alkoxy, such as methoxy, aryl-lower alkoxy, such as benzyloxy or lower alkanoyloxy , such as acetoxy, or an epimer of such an amino acid, ie with the unnatural DK onfiguration.

Such amino acids are, for example, glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), Norvalih (a-aminovaleric acid), leucine, (H-Leu-OH), isoleucine ( H-Me-OH), norleucine (α-aminobhexanoic acid, H-NIe-OH), serine (H-Ser-OH), homoserine (α-amino-y-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-nitrophenylalanine, (4-aminophenylalanine, 4-chlorophenylalanine, β-phenylserine (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine, cyclohexylalanine (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), glutamic acid mono-tert-butyl ester, glutamine (H-GIn-OH), N ⁵ -dimethylglutamine, histidine (H-His-OH), arginine (H-Arg-OH), lysine (H- Lys-OH), N, tert-butoxycarbonyl Lysine, δ-hydroxylysine, ornithine (α, δ-diaminovaleric acid), N ^ä pivaloyl-ornithine, α, γ-diaminobutyric acid or α, β-diamino-propionsäüre.

The amino acid residue A can be N-terminal to increase the stability of the compound of formula I against enzymatic degradation by lower alkyl, for. Methyl or ethyl.

A is preferably the bivalent radical of alanine, valine, norvaline, L · · · jcin, norleucine, serine, etherified serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, I ^^^ -Tetrahydroisochinolin S'carbonsäure. Aspartic acid, esterified aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, esterified glutamic acid, glutamine, di-lower alkyl glutamine, histidine, lysine, acylated lysine, ornithine or acylated ornithine, N-terminal, if desired, lower alkyl, e.g. As methyl substituted. Most preferred group A is the bivalent residue of histidine, and also of serine and alanine.

Lower alkyl R ₂ or R ₃ has the meanings mentioned above for lower alkyl R ^a . Lower alkyl R ₂ is preferably methyl or ethyl. Lower alkyl R ₃ is preferably isopropyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl or 2-ethylbutyl. Hydroxy-lower alkyl R ₃ or R ₅ is preferably hydroxymethyl or hydroxyethyl and is optionally etherified or esterified by one of the groups given below for etherified or esterified hydroxy R ₄ .

Cycloalkyl R ₃ or R ₅ has the meanings mentioned above for cycloalkyl R ^a or R ^b and is preferably cyclopentyl or cyclohexyl.

Cycloalkyl-lower alkyl R ₃ and R ₅ has the meanings mentioned above for cycloalkyl-lower alkyl R ^a and is preferably cyclohexylmethyl.

Bicycloalkyl-lower alkyl R ₃ or R ₅ contains z. B. 6-14, in particular 7-12, carbon atoms and is, for example, by the above for bicycloalkyl R ^a or R ^b mentioned radicals substituted methyl or ethyl, for example bicyclo [2.2.1] hept-2-ylmethyl.

Tricycloalkyl-lower alkyl R ₃ or R ₅ contains, for example, 9-14, in particular 10-12, C atoms and is, for example, substituted methyl or ethyl, preferably 1-adamantylmethyl, by the radicals mentioned further above for tricycloalkyl R ^a or R ^b .

Aryl R ₃ or Rs has the meanings given for aryl R ^a or R ^b and is preferably phenyl.

Aryl-lower alkyl R ₃ or R ₅ has the meanings mentioned above for Arylniederalkyl R ^a and is preferably benzyl.

An etherified hydroxy group R ₄ is preferably etherified by such organic radicals which are cleavable under physiological conditions and after cleavage in the concentration in question provide pharmacologically acceptable cleavage products.

Etherified hydroxy R ₄ is z. B. Acyloxyniederaikoxy, wherein acyl represents the acyl group of an optionally branched lower alkanecarboxylic acid or the monoesterified by optionally branched lower alkyl carbonic acid, for. B.

Lower alkanoyloxy-lower alkoxy such as acetoxymethoxy, 1-acetoxyethoxy, pivaloyloxymethoxy or 1-pivaloyloxyethoxy, or lower alkoxycarbonyloxy-lower alkoxy such as ethoxycarbonyloxymethoxy, 1-ethoxycarbonyloxyethoxy, tert -butoxycarbonyloxymethoxy or 1-tert-butoxycarbonyloxyethoxy.

Etherified hydroxy R ₄ is also lower alkoxy, e.g. Methoxy or ethoxy, aryloxy, ζ. Phenoxy, or aryl-lower alkoxy, ζ. Β.

Benzyloxy.

Esterified hydroxy R ₄ is z. For example, aliphatic acyloxy, z. B. lower alkanoyloxy, such as acetoxy or pivaloyloxy, cycloaliphatic acyloxy, z. B. Cycioalkylcarbonyloxy, such as cyclohexylcarbonyloxy, or aromatic acyloxy, z. B. benzoyloxy.

Lower alkyl R ₅ has 1-7 C atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl or isopentyl.

Particularly preferred are methyl, isopropyl, isobutyl and tert-butyl.

Bicycloalkyl R ₅ has the meanings given above for bicycloalkyl R ^a or R ^b and is preferably a-decahydronaphthyl.

Tricycloalkyl R ₅ has the meanings given above for tricycloalkyl R ^a or R ^b and is preferably 1-adamantyl.

Optionally substituted carbamoyl R ₅ is unsubstituted or substituted by one or two lower alkyl or hydroxy lower alkyl groups and is e.g. Carbamoyl, methylcarbamoyl, ethylcarbamoyl, n -propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, 2-hydroxyethylcarbamoyl or di- (2-hydroxyethyl) -carbamoyl.

Optionally substituted amino R ₅ is unsubstituted, substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or arylmethoxycarbonyl or part of a five- or six-membered heterocycle containing one to two nitrogen atoms and, if desired, an oxygen or sulfur atom and is e.g. B.

Amino, methylamino, ethylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, benzylamino, acetylamino, pivaloylamino, methoxy, ethoxy or tert-butoxycarbonylamino, O-benzyloxycarbonylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-methyl-4-pyridazinyl, 4 Morpholinyl or 4-thiomorpholinyl, preferably dimethylamino.

Optionally substituted hydroxy R 5 is unsubstituted or etherified or esterified by one of the groups further advocated for etherified or esterified hydroxy R ₄ and is, for example, hydroxy, methoxy, ethoxy, acetoxymethyl, phenoxy, benzyloxy, acetoxy, pivaloyloxy or benzoyloxy.

Optionally substituted mercapto R ₅ is unsubstituted or substituted by lower alkyl, e.g. Methyl or ethyl, aryl, e.g. As phenyl, aryl-lower alkyl, ζ. Benzyl, lower alkanoyl, ζ. Acetyl, or arylcarbonyl, ζ. As benzoyl, and is, for example, mercapto, methylthio, ethylthio, phenylthio, benzylthio, acetylthio or benzoylthio.

Sulfinyl R ₅ carries a lower alkyl group, e.g. Methyl or ethyl, an aryl group, eg phenyl, or an aryl-lower alkyl group,

z. Benzyl, and is, for example, methylsulfinyl, ethylsulfinyl, phenylsulfinyl or benzylsulfinyl.

Sulfonyl R ₅ carries a lower alkyl group, e.g. Methyl or ethyl, an aryl group, e.g. Phenyl, or an aryl-lower alkyl group,

z. B. benzyl, and is for example methylsulfonyl, ethylsulfonyl, phenylsulfonyl or benzylsulfonyl, preferably methylsulfonyl.

Substituted amino R ₆ is, for example, an amino group which is substituted by one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals having up to and including 18, preferably up to and including 10, C atoms or an unsubstituted or substituted, aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical having up to 18, preferably up to and including 10, carbon atoms substituted.

Excluded as a substituted amino R ₆ is the residue of an α-amino acid or its N-substituted, esterified or amidated derivatives.

An unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radical which substitutes the amino group R ₆ is, for example, optionally substituted alkyl having up to 10C atoms, lower alkenyl or lower alkynyl having bjs including 7C atoms, or cycloalkyl-lower alkyl having 4 to 40C atoms. These radicals, like lower alkyl R ^a , can be substituted by one or more of the functional groups mentioned above, as well as by sulfo.

As substituents are hydroxy, lower alkoxy, z. Methoxy, lower alkanoyloxy, e.g. Acetoxy, substituted or uh-substituted phenyloxy, e.g. Carbamoylphenyloxy or carbamoyl-hydroxy-phenyloxy, carboxy, esterified carboxy, ζ. Β.

Lower alkoxycarbonyl such as methoxycarbonyl or tert-butoxycarbonyl, or a physiologically cleavable esterified carboxy, e.g. 1- (lower alkanoyloxy) lower alkoxycarbonyl, such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or 1-propionyloxyethoxycarbonyl, i-f lower alkoxycarbonyloxyJ-lower alkoxycarbonyl, such as 1- (ethoxycarbonyloxy) -ethoxycarbonyl, or a-amino-lower alkanoyloxymethoxycarbonyl, such as a-aminoacetoxymethylcarbonyl or (S) -a-amino- ßmethylbutyryloxymethoxycarbonyl, carbamoyl, substituted or unsubstituted lower alkylcarbamoyl, z. B.

Hydroxy lower alkylcarbamoyl such as 2-hydroxyethylcarbamoyl or tris (hydroxymethyl) methylcarbamoyl, amino, loweralkylamino, e.g. Methylamino, di-lower alkylamino, e.g. Dimethylamino, lower alkoxycarbonylamino, e.g. B. tert-butoxycarbonylamino, guanidino, bonded via a nitrogen atom, saturated five- or six-membered, optionally substituted by oxo heterocyclyl, z. For example, 1-piperidinyl, 4-morpholinyl or 2-oxo-1-pyrrolidinyl, or sulfo preferred.

An aromatic or aromatic-aliphatic hydrocarbon radical in a group R ₆ preferably has the same meanings as mentioned under aryl R ^a or R ^b or aryl-lower alkyl R ^a and is, for example, phenyl or phenyl-lower alkyl.

These radicals may be present in the aromatic e.g. by lower alkyl, e.g. B, methyl or ethyl, hydroxy, etherified hydroxy, e.g.

Lower alkoxy, such as methoxy or tert-butoxy, esterified hydroxy, e.g. Lower alkanoyloxy, such as acetoxy, or halo, e.g. Fluorine or chlorine, carboxy, esterified carboxy, ζ. B. lower alkoxycarbonyl, such as tert-butoxycarbonyl, carbamoyl, amino,

Lower alkylamino, ζ. Methylamine), di-lower alkylamino, ζ. Dimethylamino, acylated amino, ζ. Β. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, and be substituted by nitro.

Lower alkyl in a radical phenyl lower alkyl may be substituted by the same substituents as alkyl in a radical R ₆ . A heteroaromatic or heteroaromatic-aliphatic hydrocarbon radical in a group R ₆ preferably has the same meanings as mentioned under heteroaryl R ^a and R ^b or heteroaryl-lower alkyl R ^a and is, for example, pyridyl-lower alkyl, for. 2-, 3- or 4-pyridylmethyl, imidazolyl-lower alkyl, e.g. B. 2- (4-imidazolyl) -ethyl or 2- (2- [4-imidazolyl] ethylamino) -ethyl, or indolyl-lower alkyl, z. 3-indolylmethyl or 2- (3-indolyl) ethyl.

Substituted amino R ₆ is preferably alkylamino, e.g. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl or n-decylamino , Di-lower alkylamino, e.g. For example, dimethylamino or diethylamino, Hydroxyniederalkylamino, z. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamine or tris (hydroxymethyl) -methylamino, di- (hydroxy-lower alkyl) -amino, e.g. Di- (2-hydroxyethyl) amino, lower alkoxy-lower alkylamino, e.g. B. 2-Methoxyäthylamino, Niederalkanoyloxyniederalkylamino, z. B. 2-Acetoxyäthylamino, Phenoxyniederaikylamino or phenoxy-hydroxy-lower alkylamino, wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, z. For example, 2-phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamino or 3- (3-carbamoylphenoxy) -2-hydroxy-propylamino, carboxyalkylamino or amino-carboxy-alkylamino wherein the carboxy radical is not in the 1-position the alkyl group is, for. 4-carboxy-n-butylamino, 5-carboxy-n-pentylamino, S-amino-S-carboxy-n-pentylamino, 6-carboxy-n-hexylamino, 7-carboxy-n-heptylamino or 8-carboxy- n -octylamino, further dicarboxymethylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonylalkylamino wherein the carbonyl radical is not in the 1-position of the alkyl radical, e.g. 4-tert-butoxycarbonyl-n-butylamino, 5-tert-butoxycarbonylamino-B-methoxycarbonyl-n-pentylamino-T-tert-butoxycarbonyl-n-heptylamino or S-tert-butoxycarbonyl-octylamino, further di-lower alkoxycarbonyl-methylamino, e.g. , B. Di-methoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino, wherein the ester function is not in the 1-position of the alkyl, z. B.4-Pivaloyloxymethoxycarbonyl-n-butylamino, y-fi-Äthoxycarbonyloxyäthoxycarbonyö-n-heptylaminoodery-pivaloyloxymethoxycarbonyl-n-heptylamino, carbamoylalkylamino or Hydroxyniederalkylcarbamoylalkylamino, wherein the carbamoyl radical is not in the 1-position of the alkyl radical, z. 4-carbamoyl-n-butylamino, 7-carbamoyl-n-heptylamino or 4- (tris [hydroxymethyl] -ethyl) -carbamoyl-n-butyl-amino, furthermore dicarbamoyl-methylamino, di (lower alkylcarbamoyl) -methylamino, e.g. Di-methylcarbamoyl-methylamino, DMhydroxy-lower alkylcarbamoyl-O-methylamino, e.g. B. Di- (2-hydroxyäthylcarbamoyO-methylamino, or bis-idiniederalkylcarbamoyO-methylamino, z. B. Bis- (dimethylaminocarbamoyl) methylamino, Aminoniederalkylamino, z. B. 2-Aminoäthylamino or 4-aminobutylamino, Niederalkylaminoniederalkylamino, z. B. 2-methylaminoethylamino, di-lower alkylaminoloweralkylamino, for example 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, eg 2- (tert-butoxycarbonylamino) ethylamino, guanidinoloweralkylamino, eg 2-guanidinoethylamino, bonded via a nitrogen atom saturated five- or six-membered heterocyclyl-lower alkylamino, for example 2- (4-morpholinyl) -ethylamino, 3- (4-morpholinyl) -propylamino or 3- (2-oxo-1-pyrrolidinyl) -propylamino, lower alkenylamino, e.g. Allylamino or 2- or 3-butenylamino, lower alkynylamino, e.g., propargylamino, cycloalkyl-lower alkylamino, e.g., cyclopropylmethylamino or cyclohexylmethylamino, phenylamino or phenyl-lower alkylamino wherein phenyl is added optionally by lower alkyl, e.g. For example, methyl, hydroxy, lower alkoxy, z. Methoxy or tert-butoxy, lower alkanoyloxy, e.g. For example, acetoxy, halogen, z. For example, fluorine or chlorine, carboxy, lower alkoxycarbonyl, z. B. tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino, ζ. Methylamino, di-lower alkylamino, ζ. Β. Dimethylamino, acylamino, ζ. B. tert-butoxycarbonylamino and / or mono- or poly-substituted by nitro, z. Phenylamino, 2-, 3- or 4-methylphenylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,3-, 2,4- or 2,5-dimethoxyphenylamino, 4-chloro-phenylamino, 2-, 3- or 4- Carboxyphenylamino, 2-, 3- or 4-methoxy- or tert-butoxycarbonylphenylamino, 2-, 3- or 4-carbamoylphenylamino, 4-aminophenylamino, 4-tert-butoxycarbonylaminophenylamino or 4-nitrophenylamino, also e.g. Benzylamino, 4-methylbenzylamino, 4-methoxybenzylamino, 2-, 3- or 4-carboxybenzylamino, 2-, 3- or 4-tert-butoxycarbonylbenzylamino, 2-, 3- or 4-carbamoylbenzylamino, 2-phenylethylamino or 3- Phenylpropylamino, Pyridylniederalkylamino, z. 2-, 3- or 4-pyridylmethylamino, 2- (2-, 3- or 4-pyridyl) ethylamino or 3- {2-, 3- or 4-pyridyl) -propylamino, imidazolyl-lower alkylamino, e.g. 4-imidazolylmethylamino, 2- (4-imidazolyl) ethylamino or 2- {2- [4-imidazolyl] ethylaminolethylamino, indolyl-lower alkylamino, e.g. 3-indolylmethylamino or 2- (3-indolyl) ethylamino, or sulfo-lower alkylamino, e.g. B. 2-sulfoethylamino.

Salts are primarily the pharmaceutically acceptable, non-toxic salts of compounds of formula I. Such salts are exemplified by compounds of formula I having an acidic group, e.g. A carboxy group and are primarily suitable alkali metal, e.g. For example, sodium or potassium, or alkaline earth metal salts, z. As magnesium or calcium salts, also zinc salts or ammonium salts, and those salts which are formed with organic amines, such as optionally substituted by hydroxy mono-, di- or trialkylamines, z. Example, with diethylamine, di (2-hydroxyethyl) amine, triethylamine, N, N-dimethyl-N- (2-hydroxyethyl) amine, tri- (2-hydroxyethyl) amine or N-methyl-D-glucamine , The compounds of formula I with a basic group, e.g. As an amino group, can form acid addition salts, eg. As with inorganic acids, eg. As hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic or sulfonic acids, eg. Acetic, propionic, glycolic, succinic, maleic, hydroxymaleic, methylmaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, embonic, nicotinic or isonicotinic acids, further with amino acids, such as. As the aforementioned α-amino acids, and with methanesulfonic acid, Äthansulfonsäure, 2-Hydroxyäthansulfonsäure, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic compounds such as ascorbic acid. Compounds of the formula I with acidic and basic groups can also form internal salts.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. The compounds of the present invention have enzyme-inhibiting effects; In particular, they inhibit the action of the natural enzyme renin. The latter enters the blood from the kidneys and causes there the cleavage of angiotensinogen to form the decapeptide angiotensin I, which is then cleaved in the lungs, kidneys and other organs to the octapeptide angiotensin II. The latter raises the blood pressure both directly by arterial constriction, and indirectly by the release of the sodium ion-retaining hormone aldosterone from the adrenals, which is associated with an increase in extracellular fluid volume. This increase is due to the effect of angiotensin II itself or the

heptapeptide angiotensin II formed from this as a cleavage product! due. Inhibitors of the enzymatic activity of renin cause a reduction in the formation of angiotensin I. As a result, less angiotensin II is produced. The reduced concentration of this active peptide hormone is the immediate cause of the hypotensive effect of renin inhibitors.

The effect of renin inhibitors is demonstrated, inter alia, experimentally by means of in vitro tests, wherein the reduction in the formation of angiotensin I in various systems (human plasma, purified human renin together with synthetic or natural renin substrate) is measured. Among others, the following is used in vitro test: An extract of human renin from the kidney (0,5mGU [milli-Goldblatt units] / ml) for one hour at 37 ⁰ C and pH 7.2 in 1-molar aqueous 2 N- (tris-hydroxymethylmethyl) -amino-ethanesulfonic acid buffer solution containing 23 μg / ml synthetic renin substrate, the tetradecapeptide H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val -Tyr-Ser-OH, incubated. The amount of angiotenside I formed is determined in a radioimmunoassay. The inhibitors according to the invention are added to the incubation mixture in each case in various concentrations. ICgo is the concentration of the respective inhibitor which reduces the formation of angiotenside I by 50%. The compounds of the present invention show the inhibitory effects in vitro systems at minimal concentrations of about 10 ^-7 to about 10 ^-10 mol / l.

In salt-depleted animals, renin inhibitors cause a fall in blood pressure. The human renin is different from the renin of other species. For testing inhibitors of human renin primates (Marmosets, Callithrix jacchus) are used because human renin and primate renin are largely homologous in the enzymatically active region. Among others, the following in vivo test is used: The test compounds are tested on normotensive mantos of both sexes with a body weight of about 300 g that are conscious. Blood pressure and heart rate are measured with a catheter in the femoral artery. The endogenous release of renin is stimulated by the intravenous injection of furosemide (5 mg / kg). Thirty minutes after the injection of furosemide, the test substances are administered either via a catheter in the lateral tail vein by a single injection or by continuous infusion or perorally directly into the stomach as a solution or suspension, and their effect on blood pressure and heart rate is evaluated. The compounds of the present invention are described in the described in vivo assay at doses of about 0.1 to about 1.0 mg / kg i.v. and at doses of about 1.0 to about 10 mg / kg p.o. effective.

The compounds of the present invention may be used as antihypertensive agents, further for the treatment of heart failure.

More particularly, the invention relates to compounds of the formula I in which R _{1 is} an aoyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic radical which is substituted by a thio, sulfinyl or sulfonyl group and optionally by further heteroatoms , heteraromatic or heteroaromatic-aliphatic carboxylic acid except for the optionally N-substituted natural amino acid methionine, A is an optionally N-alkylated a-amino acid residue N-terminal to R ₁ and C-terminal to the group NR ₂ -linked, R ₂ Hydrogen or lower alkyl, R _{3 is} hydrogen, lower alkyl, hydroxynolower I, cycloalkyl, cycloalkyl-lower alkyl, bicycloalkyl-lower alkyl, tricycloalkyl-lower alkyl, aryl or aryl-lower alkyl, R _{4 is} hydroxy, R _{5 is} lower alkyl having 2 or more C atoms, hydroxy-lower alkyl, cycloalkyl, Cycloalkylniederalkyi, Bicycloalkyl, Bicycloalkylniederalkyl, Tricycloalk yl, tricycloalkyl-lower alkyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylamino, aryl or aryl-lower alkyl and R _{6 is} an amino group containing one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals having up to and including 18, preferably up to and including 10, carbon atoms or a unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical having up to and including 18, preferably up to and including 10, carbon atoms substituted, with the exception of one derived from an α-amino acid amino radical, further pharmaceutically acceptable salts thereof Compounds with salt-forming groups

The invention relates mainly to compounds of the formula I in which R _{1 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -

(ό) ⁿ 1 ^p

(CH ₂ ) _q ' ^(ia) '

wherein R ^{a is} unsubstituted or substituted lower alkyl, e.g. Methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-phenoxyethyl, 2-acetoxyethyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, carbamoylmethyl, 2- Carbamoylethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-Mc pholinoäthyl, 2-Piperidinoäthyl, 2-Benzyloxycarbonylaminoäthyl, 2-tert-Butoxycarbonylaminoäthyl, 2-oxopropyl or 2-Oxobutyi, lower alkenyl, z. Vinyl, allyl, 2- or 3-butenyl, lower alkynyl, e.g. For example, ethynyl, 1-propynyl, or 2-propynyl, cycloalkyl, z. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, bicycloalkyl, e.g. Bicyclo [2,2,1] hept-2-yl, tricycloalkyl, eg 1-adamantyl, cycloalkyl-lower alkyl, eg cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, unsubstituted or substituted aryl, eg phenyl, 1- or 2-naphthyl, o-, m- or p-methylphenyl, o-, m- or p-hydroxyphenyl or o-, m- or p-aminophenyl, aryl-lower alkyl, eg. Benzyl, 2-phenylethyl or a-or-naphthylmethyl-aryl-lower alkenyl, e.g. Styryl or 3-phenylallyl, unsubstituted or substituted heteroaryl, e.g. 2-or 3-pyrrolyl, 2-furyl, 2-thienyl, 2- or 4-imidazolyl, 1-methyl-2-, 4- or 5-imidazolyl, 1,3-thiazol-2-yl, 2, 3 or4-pyridyl, i-oxido-2-, 3- or 4-pyridinio, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4- isoquinolyl or 2-benzoxazolyl, heteroaryl-lower alkyl, e.g. B. 2-, 3- or 4-pyridylmethyl, 2- (2-, 3- or 4-pyridyl) -ethyl, 4-imidazolylmethyl or 2- (4-imidazolyl) -ethyl, hydroxy, substituted hydroxy, ζ. B. lower alkoxy, ζ. Methoxy, ethoxy or n-butoxy, or aryloxy, ζ. Phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy, amino or substituted amino, ζ. B. lower alkylamino, ζ. Methylamino, ethylamino, isopropylamino, n- or tert-butylamino, di-lower alkylamino, e.g. As dimethylamine or diethylamino, or amino as part of a five- or six-membered ring containing a nitrogen atom and optionally an oxygen atom, for example 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, R ^{b is} hydrogen, cycloalkyl, for example cyclopentyl or cyclohexyl, bicycloalkyl, ζ , B. bicyclo [2,2,1] hept-2-yl, tricycloalkyl, ζ. 1-adamantyl, unsubstituted or substituted aryl,

ζ. Phenyl, 1- or 2-naphthyl, o, m or p-methylphenyl, o-, m- or p-hydroxyphenyl or o-, m- or p-aminophenyl, or unsubstituted or substituted heteroaryl, e.g. B. 2- or 4-imidazolyl, 2-, 3- or 4-pyridyl, i-oxido-2-, 3- or 4-pyridini or 2-, 4- or 5-pyrimidinyl, m, 0, 1 or 2, preferably 2, η 0, 1 or 2, preferably 1, ρ is 0.1 or 2, preferably 0, and q is 0, 1.2, 3 or 4, preferably 1 or 2,

A is a bivalent radical of an α-amino acid, for example a natural α-amino acid of the L-configuration as normally found in proteins, a homologue of such an amino acid, e.g. Wherein the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted aromatic α-amino acid, for. A substituted phenylalanine or phenylglycine, wherein the substituent is lower alkyl, e.g. Methyl, halogen, e.g. As fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, z. Methoxy, lower alkanoyloxy, e.g. Acetoxy, amino, lower alkylamino, e.g. B. Methylamine di-lower alkylamino, z. Dimethylamino, lower alkanoylamino, e.g. Acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. B. tert-ButoxycarbonylaminOjArylmethoxycarbonylamino, z. B. benzyloxycarbonylamino, and / or nitro may be and occurs one or more times, a benzannellierten phenylalanines or phenylglycine, such as a-naphthylalanine, or a hydrogenated phenylalanines or phenylglycine, such as cyclohexylalanine or cyclohexylglycine, a five- or six-membered cyclic, benzannelierten α- Amino acid, ζ. Β. indoline-2-carboxylic acid or iso-S-tetrahydroisoquinoline-S-carboxylic acid, a natural or homologous α-amino acid in which a carboxy group of the side chain is in esterified or amidated form, for example as lower alkyl ester group, such as methoxycarbonyl or tert-butoxycarbonyl, or as Carbamoyl, as Niederalkylcarbamoyl-, such as methylcarbamoyl, or as Diniederalkylcarbamoylgruppe, such as dimethylcarbamoyl, in which an amino group of the side chain in aeylierter form, for. B. as Niederalkanoylamino-, such as acetylamino or pivaloylamino, as Niederalkoxycarbonylamino-, such as tert-butoxycarbonylamino, or as Arylmethoxycarbonylaminogruppe, such as Benzyloxycarbonylamino, or in which a hydroxy group of the side chain in etherified or esterified form, for. B. as lower alkoxy, such as methoxy, as Arylniederalkoxygruppe, such as benzyloxy, or as Niederalkanoyloxygruppe, such as acetoxy, or an epimer of such an amino acid, ie with the unnatural D configuration, optionally at the N atom by lower alkyl, z. Methyl, substituted, R _{2 is} hydrogen or lower alkyl, e.g. Methyl, R _{3 is} lower alkyl, e.g. For example, isopropyl or isobutyl, cycloalkyl, z. B. cyclohexyl, Cycloalkylniederalkyl, ζ. Cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl, tricycloalkyl-lower alkyl, e.g. 1-adamantylmethyl, phenyl-lower alkyl, e.g. Benzyl, or phenyl, R _{4 is} hydroxy, R _{5 is} lower alkyl, ζ. Β. Methyl, isopropyl, isobutyl or tert-butyl, cycloalkyl, ζ. Cyclopentyl or cyclohexyl, cycloalkyi-lower alkyl, e.g. Cyclohexylmethyl, bicycloalkyl, e.g. For example, a-decahydronaphthyl, tricycloalkyl, e.g. 1-adamantyl, phenyl, phenyl-lower alkyl, e.g. Benzyl, carbamoyl or lower alkylcarbamoyl, e.g. Methylcarbamoyl, di-lower alkylamino, e.g. For example, dimethylamino, hydroxy, lower alkoxy, z. Methoxy, lower alkylthio, e.g. Methylthio, or lower alkylsulfonyl, e.g. Methylsulfonyl, and R _{6 is} alkylamino having 1 to 10C atoms, e.g. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl or n-decylamino, Diniederalkylamino , z. For example, dimethylamino or diethylamino, Hydroxyniederalkylamino, z. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamine or tris (hydroxymethyl) methylamino, di (hydroxyloweralkyl) amino, e.g. Di- (2-hydroxyethyl) amino, lower alkoxy-lower alkylamino, e.g. B. 2-Methoxyäthylamino, Niederalkanoyloxyniederalkylamino, z. 2-acetoxyethylamino, phenoxy-loweralkylamino or phenoxy-hydroxy-loweralkylamino wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, eg 2-phenoxyethylamino, 2- (3-carbamoyl-4-hydroxyphenoxy) ethylamin or 3 - (3-carbamoylphenoxy) -2-hydroxy-propylamino, carboxyalkylamino or amino-carboxy-alkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, for. 4-carboxy-n-butyl, 5-carboxy-n-pentyl, 6-carboxy-n-hexyl, 7-carboxy-n-heptyl or 8-carboxy-n-octylamino or B-amino B-carboxy-n-pentylamino, furthermore dicarboxy-methylamino, Niederalkoxycarbonylalkylaminoder acylamino-lower alkoxycarbonyl-alkylamino, wherein the carbonyl radical is not in the 1-position of the alkyl radical, z. B. 4-tert-butoxycarbonyl-n-butyl, 7-tert-butoxycarbonyl-n-heptyl or 8-tert-butoxycarbonyl-noctylamino or S-tert-butoxycarbonylamino-B-methoxycarbonyl-n-pentylamino, furthermore Diniederalkoxy carbonyl -methylamino, z. B. Di-methoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino, wherein the ester function is not in the 1-position of the alkyl group, for example 4-Pivaloyloxymethoxycarbonyl-n-butylamino, 7- (1-Äthoxycarbonylqxyäthoxycarbonyl) -n-heptylamino or 7-Pivaloyloxymethoxycarbonyl- n-heptylamino, carbamoyl or hydroxy-lower alkylcarbamoylalkylamino wherein the carbamoyl radical is not in the 1-position of the alkyl radical. 4-carbamoyl-n-butylamino, 7-carbamoyl-n-heptylamino or 4- (tris [hydroxymethyl] -methyl) -carbarnoyl-n-butylamino, furthermore dicarbamoyl-methylamino, di (lower alkylcarbamoyl) -methylamino, e.g. , Di- (methylcarbamoyl) -methylamino, di- (hydroxyniederaikylcarbamoyl) -methylamino, e.g. Di- (2-hydroxyethylcarbamoyl-o-methylamino, or bis- (di-lower alkylcarbamoyl) -methylamino, e.g., bis (dimethylcarbamoyl) -methylamino, aminoloweralkylamino, e.g., 2-aminoethylamino or 4-aminobutylamino, lower-alkylaminoloweralkylamino, e.g. 2-methylaminoethylamino, di-lower alkylaminoloweralkylamino, e.g., 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, e.g., 2- (tert-butoxycarbonylamino) ethylamino, guanidinoloweralkylamino, e.g., 2-guanidinoethylamino Nitrogen atom-bonded, saturated five- or six-membered heterocyclyl-lower alkylamino, for example 2- (4-morpholinyl) -ethylamino, 3- (4-morpholinyl) -propylamino or 3- (2-oxcr) -rolidin-1-yl) -propylamino, Lower alkenylamino, e.g. B. allylamino or 2- or 3-butenylamino, lower alkynylamino, z. B. Propargylamino, Cycloalkylniederalkylamino, z. Cyclopropylmethylamino or cyclohexylmethylamino, phenylamino or phenyl-lower alkylamino wherein phenyl is optionally substituted by lower alkyl, e.g. For example, methyl, hydroxy, lower alkoxy, z. B. methoxy or tert-butoxy, lower alkanoyloxy, for example acetoxy, halogen, for example fluorine or chlorine, carboxy, lower alkoxycarbonyl, ζ. For example, tert-butoxycarbonyl, carbamoyl, amino, lower alkylamino, for example MethylaminofDiniederalkylamino, z. Dimethylamino, acylamino, ζ. B. tert-butoxycarbonylamino and / or mono- and polysubstituted by nitro, z. Phenyl, 2-, 3- or 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 2,3-, 2,4- or 2,5-dimethoxyphenyl, 4-chlorophenyl, 2- , 3- or 4-methoxy- or tert-butoxycarbonylphenyl, 2-, 3- or 4-carbamoylphenyl, 4-aminophenyl, 4-tert-butoxycarbonylaminophenyl or 4-nitrophenylamino, furthermore e.g. Benzylamino, 4-methylbenzylamino, 4-methoxybenzylamino, 2-, 3- or 4-carboxybenzylamino, 2-, 3- or 4-tert-butoxycarbonylbenzylamino, 2-, 3- or 4-carbamoylbenzylamino, 2-phenylethylamino or 3- Phenylpropylamino, Pyridylniederalkylamino, z. B. 2-, 3- or 4-pyridylmethyl, 2- (2-, 3- or 4-pyridyl) -ethyl or 3- (2-, 3- or 4-pyridyl) -propyl-amino, imidazolyl-lower alkylamino, z. 4-imidazolylmethylamino, 2- (4-imidazolyl) ethylamino or 2- (2- [4- (midazolyl) ethylamino) ethylamino, indolyl-lower alkylamino, e.g. 3-indolylmethylamino or 2- (3-indolyl) ethylamino, or sulfo-lower alkylamino, e.g. For example, 2-sulfoethylamino, and pharmaceutically acceptable salts of these compounds with salt-forming groups. The invention more particularly relates to compounds of the formula I in which R _{1 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -

(ό) ^η ι ^p

^m (CH ₂ ) '(la),

wherein R ^{a is} unsubstituted or hydroxy, lower alkoxy, phenoxy, lower acyloxy, carboxy, lower alkoxycarbonyl or carbamoyl substituted lower alkyl, e.g. Methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-phenoxyethyl, 2-acetoxyethyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, carbamoylmethyl or 2- Carbamoylethyl, cycloalkyl, ζ. Cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, e.g. Cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, unsubstituted or lower alkyl, hydroxy or amino substituted aryl, eg phenyl, 1- or 2-naphthyl, o-, m- or p-methylphenyl, m- or p-hydroxyphenyl or m- or p- Aminophenyl, aryl-lower alkyl, e.g. Benzyl, 2-phenylethyl or α- or β-naphthylmethyl, unsubstituted or substituted by oxido, lower alkyl or phenyl heteroaryl, e.g. B. 2- or 4-imidazolyl, 1-methyl-2-, 4- or 5-imidazolyl, 1, S-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3 - or 4-pyridinio, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl or 2-benzoxazolyl, heteroaryl-lower alkyl, e.g. B. 2-, 3- or 4-pyridylmethyl or 4-imidazolylmethyl, hydroxy, substituted hydroxy, ζ. B. lower alkoxy, ζ. Methoxy, ethoxy or n-butoxy, or aryloxy, ζ. Phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy, amino or substituted amino, ζ. B. lower alkylamino, ζ. Methylamido, ethylamino, isopropylamino, n-or tert-butylamino, di-lower alkylamino, e.g. Dimethylamino or diethylamino, or amino as part of a five- or six-membered ring containing a nitrogen atom and, if desired, an oxygen atom, e.g. As 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, R ^{b is} hydrogen, cycloalkyl, ζ. Cyclohexyl, aryl, ζ. Phenyl or 1- or 2-naphthyl, or heteroaryl, e.g. B.4-imidazolyl or 2-, 3- or 4-pyridyl, m is 0.1 or 2, η is 0.1 or 2, p0.1 or 2 and q is 0.1.2 or 3. A is the bivalent radical of the amino acids alanine, valine, norvaline, leucine, norleucine, serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, 1 ^, S-tetrahydroisoquinoline-S-carboxylic acid, Aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, di-lower alkylglutamine, histidine, lysine or ornithine, wherein the carboxy group in the side chain of aspartic acid or glutamic acid with a Niederalkanoi, z. As methanol or tert-butanol, esterified, the hydroxy group in serine with lower alkyl, z. Methyl, or etherified with benzyl, the amino group in the side chain of lysine or ornithine by lower alkanoyl, e.g. B. pivaloyl, by lower alkoxycarbonyl, z. For example, tert-butoxycarbonyl, or by arylmethoxycarbonyl, z. B. benzyloxycarbonyl, acylated and / or the a-nitrogen atom of the amino acids by lower alkyl, z. Methyl, may be substituted,

R _{2 is} hydrogen or lower alkyl, e.g. Methyl, R _{3 is} lower alkyl, e.g. Isopropyl or isobutyl, cycloalkyl-lower alkyl, e.g. B. cyclopentylmethyl, cyclohexylmethyl, 2-Cycloriexyläthyl or cycloheptylmethyl, or Tricycloalkylniederalkyl, z. B. 1-adamantylmethyl, R _{4 is} hydroxy and R _{5 is} lower alkyl, for example methyl, isopropyl or tert-butyl, cycloalkyl, for example cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, for. Cyclohexylmethyl, 1-adamantyl, benzyl, carbamoyl or lower alkylcarbamoyl, e.g. Methylcarbamoyl, di-lower alkylamino, e.g. For example, dimethylamino, hydroxy, lower alkoxy, z. B. methoxy, lower alkylthio, z. Methylthio, or lower alkylsulfonyl, e.g. Methylsulfonyl, and

R _{6 is} alkylamino having 1 to 1OC atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl , n-octyl or n-decylamino, di-lower alkylamino, e.g. B. dimethylamino, Hydroxyniederalkylamino, z. B: 2-hydroxyethylamino, 1-hydroxybut-2-ylamino or tris (hydroxymethyl) methylamino, carboxyalkylamino or aminocarboxyalkylamino wherein the carboxy radical is not in the 1-position of the alkyl radical, e.g. For example, 4-carboxy-n-butyl, 5-carboxy-n-pentyl, 6-carboxy-n-hexyl, 7-carboxy-n-heptyl or 8-carboxy-n-octylamino or ö-amino S-carboxy-n-pentylamino, also dicarboxy-methylamino, Niederalkoxycarbonylalkylamino or acylamino-lower alkoxycarbonyl-alkylamino, wherein the carbonyl radical is not in the 1-position of the alkyl radical, z. For example, 4-tert-butoxycarbonyl-n-butyl, 7-tert-butoxycarbonyl-n-heptyl or 8-tert-butoxycarbonyl-n-octylamino or S-tert-Butoxycarbonyiamino-B-methoxycarbonyl-n-pentylamino, also Diniederalkoxycarbonyl -methylamino, z. B. Di-methoxycarbonyl-methylamino, physiologically cleavable esterified Carboxylalkylamino wherein the ester function is not in the 1-position of the alkyl group, for example 4-Pivaloyloxymethoxycarbo'nyl-nbutylamino, 7- (1 -ethoxycarbonyloxyäthoxycarbonyll-n-heptylamino or 7-Pivaloyloxymethoxycarbonyl-n -heptylamino, carbamoyl or hydroxy-lower alkylcarbamoylalkylamino wherein the carbamoyl radical is not in the 1-position of the alkyl radical, for example 4-carbamoyl-n-butylamino, 7-carbamoyl-n-heptylamino or 4- (tris [hydroxymethyl] methyl ) -carbamoyl-n-butylamino, furthermore dicarbamoyl-methylamino, di- (lower alkylcarbamoyl) -methylamino, eg di- (methylcarbamoyl) -methylamino, di- (hydroxy-lower alkylcarbamoyl) -methylamino, eg di (2-hydroxyethylcarbamoyl) -methylamino, or Bis- (lower alkylcarbamoyl) -methylamino, for example bis (dimethylcarbamoyl) -methylamino, aminoloweralkylamino, for example 2-aminoethylamino or 4-aminobutylamino, lower-alkylaminoloweralkylamino, for example 2-methylaminoethylamino, di-lower alkylaminolowera alkylamino, e.g. B. 2-Dimethylaminoäthylamino, Niederalkoxycarbonylaminoniederalkylamino, z. E .. (2-tert-Butoxycarbonylamino) ethylamino, Guanidinoniederalkylamino, z. For example, 2-guanidinoethylamino, Cycloalkylniederalkylamino, z. Cyclopropylmethylamino, benzylamino, pyridylloweralkylamino, e.g. 2-, 3- or 4-pyridylmethylamino, 2- (2-, 3- or 4-pyridyl) ethylamin or 3- (2-, 3- or 4-pyridyl) -propylamino, imidazolyl-lower alkylamino, eg 4-imidazolylmethylamsio or 2- (2- 4-imidazolyl) -ethylamino, indolyl-lower alkylamino, eg 3-indolylmethylamino or 2- (3-indolyl) -ethylamino, or sulfo-lower alkylamino, eg 2-sulfoethylamino, as well as pharmaceutically acceptable salts of these compounds with salt-forming groups

 Very particular preference is given to compounds of the formula I in which R 1 is a radical of the formula

_R ^a - S - (CH ₂ ) - CH - (CH ₂ ) - C-

(O) I. ° (la),

wherein R ^{a is} unsubstituted or substituted by hydroxy, lower alkoxy, phenoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl or carbamoyl lower alkyl, e.g. For example, methyl, ethyl, isopropyl, tert-butyl ^ -hydroxyethyl ^ -Methoxyäthyl ^ -Phenoxyäthyl, 2-Acetoxya'thyl, carboxymethyl, 2-carboxyethyl, methoxycarbonylmethyl, 2-Methoxycarbonyläthyl, Äthoxycarbonylmethyl, 2-Äthoxycarbonyläthyl, carbamoylmethyl or 2-carbamoylethyl , Cycloalkyl, ζ. Cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, e.g. As cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl, unsubstituted or substituted by lower alkyl, hydroxy or amino aryl, for example phenyl, 1- or 2-naphthyl, o-, m- or p-methylphenyl, m- or p-hydroxyphenyl or m- or p Aminophenyl, aryl-lower alkyl, e.g. B. benzyl, 2-phenylethyl or α- or ß-naphthylmethyl, unsubstituted or substituted by oxido, lower alkyl or phenyl heteroaryl, z. 2-or 4-imidazolyl, 1-methyl-2-, 4- or 5-imidazolyl, 1, S-thiazol-2-yl, 2-, 3- or 4-pyridyl, i-oxido-2, 3 or 4 pyridinio, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl or 2-benzoxazolyl, or heteroaryl-lower alkyl, e.g. B. 2-, 3- or 4-pyridylmethyl or 4-imidazolylmethyl, hydroxy, substituted hydroxy, ζ. B. lower alkoxy, ζ. Methoxy or ethoxy, amino or substituted amino, ζ. B. lower alkylamino, ζ. Β. Methylamino, ethylamino, isopropylamino, n- or tert-butylamino, di-lower alkylamino, e.g. Dimethylamino or diethylamino, or amino as part of a five- or six-membered ring containing a nitrogen atom and, if desired, an oxygen atom, e.g. As 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl, R ^{b is} hydrogen, cycloalkyl, ζ. Cyclohexyl, aryl, e.g. Phenyl or 1- or 2-naphthyl, or heteroaryl, eg 4-imidazolyl or 2-, 3- or 4-pyridyl, m is 0.1 or 2, η is O or 1, pO and q is 1 or 2,

A is the bivalent radical of the amino acids alanine, serine, phenylalanine, N-methyl-phenylalanine, cyclohexylalanine, histidine or N-methylhistidine, R _{2 is} hydrogen, R _{3 is} lower alkyl, e.g. For example, isobutyl, or cycloalkyl-lower alkyl, e.g. Cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl, R _{4 is} hydroxy, R _{5 is} lower alkyl, e.g. B. isopropyl, hydroxy, lower alkoxy, ζ. Methoxy, lower alkylthio, e.g. Methylthio, or lower alkylsulfonyl, eg methylsulfonyl, and R ₆ lower alkylamino with 1-7 C-atoms, e.g. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or Isopentylamino, Diniederalkylamino, z. B. dimethylamino, Hydroxyniederalkylamino, z. B. 2-hydroxyethylamino, 1-hydroxybut-2-ylamino or 5-hydroxypentylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, ζ. For example, 4-carboxy-n-butylamino, 7-carboxy-n-heptylamino or 8-carboxy-n-octylamino or S-amino-S-carboxy-n-pentylamino, Niederalkoxycarbonylalkylamino or acylamino-lower alkoxycarbonyl-alkyiamino, wherein the carbonyl radical not in the 1-position of the alkyl group, for example 4-tert-butoxycarbonyl-n-butylamino or 7-tert-butoxycarbonyl-n-heptylamino or B-tert-butoxycarbonylamino-B-methoxycarbonyl-n-pentylamino, amino-lower alkylamino, e.g. B. 2-Aminoäthylamino or 4-Aminobutylamino, Diniederalkylaminoliederalkylamino, z. For example, 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylaminoloweralkylamino, e.g. B. 2-tert-Butoxycarbonylamino-ethylamino, Morpholinoliederalkylamino, z. B. 2-Morpholinoäthylamino, Pyridylniederalkylamino, z. 2-pyridylmethylamino, imidazolyl-lower alkylamino, e.g. B. 2- (4-imidazolyl) ethylamino, or sulfo-lower alkylamino, e.g. 2-sulfoethylamino, and pharmaceutically acceptable salts of these compounds with salt-forming groups. In the first place, the invention relates to compounds of the formula I in which R 1 is a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -

(ό) ^η ι ^p

(CH ₂ ) ^(la) '

wherein R ^{a is} unsubstituted or hydroxy or lower alkoxy substituted lower alkyl, e.g. As methyl, ethyl, isopropyl, tert-butyl, 2-hydroxyethyl or 2-methoxyethyl, phenyl, benzyl or unsubstituted or substituted by oxido or lower alkyl heteroaryl having 1 or 2 nitrogen atoms, for example 2- or 4-imidazolyl, 1-methyl 2-imidazolyl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridini or 2-pyrimidinyl, R ^{b is} cyclohexyl or phenyl, m is 0.1 or 2, η 1, p0 and q is 1 or 2, A is the bivalent radical of the amino acid histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} lower alkylamino having 1-7 C atoms, eg. For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, n-pentyl or Isopentylamino, dimethylamino or 2-hydroxyethylamino, and pharmaceutically acceptable salts of these compounds

More particularly, the invention relates to compounds of the formula I, wherein R _{1 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) - C-

(J) "ι ^ö

wherein R ^{a is} lower alkyl, for example methyl, ethyl, isopropyl or tert-butyl, phenyl, 2-pyridyl, hydroxy, lower alkylamino, ζ.Β. Methylamino or isopropylamino, di-lower alkylamino, e.g. B. dimethylamino or diethylamino, or pyrrolidino, R ^b phenyl, m 2, η 1, p0 and q 1, Aden bivalent radical of the amino acid alanine, serine or histidine, R _{2 is} hydrogen, R ₃ cycloalkyl, eg. Cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl or cycloheptylmethyl, R _{4 is} hydroxy, R _{5 is} methyl, isopropyl, hydroxy, methoxy, methylthio or methylsulfonyl and R _{6 is} lower alkylamino having 1-4 C atoms, e.g. As methylamino, ethylamino, n-propylamino or n-butylamino, S-amino-S-carboxy-n-pentylamino, 4-aminobutylamino, 2- (4-ImidazolyO-ethylamino or 2-Sulfoäthylamino represent and the radicals R ₃ and R ₄ bearing C-atoms have the S-configuration, further pharmaceutically acceptable salts of these compounds.

The invention relates, first of all, to the compounds mentioned in the examples and their pharmaceutically acceptable salts, in particular

the compound of the formula I in which R _{1 is} a radical of the partial formula Ia, where R ^{a is} tert-butyl, R ^{b is} phenyl, m 2, η 1, ρ O and q is 1, A is the bivalent radical of the amino acid L-histidine, R ₂ R _{3 is} cyclohexylmethyl, R _{4 is} hydroxyl, R _{5 is} isopropyl and R _{6 is} n-butylamino, and the C atoms carrying the radicals R ₃ , R ₄ and R ₅ and the methine C atom of the sub-formula I a are the Configuration, and their pharmaceutically acceptable salts,

the compound of the formula I in which R _{1 is} a radical of the partial formula Ia, where R ^{a is} tert-butyl, R ^{b is} phenyl, m 2, η 1, pO and q 1, Aden is bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen , R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} methyl and R _{6 is} methylamino and the C atoms carrying the radicals R ₃ and R ₄ and the methine C atom of the partial formula I a carry the S configuration and the radical R ₅ carries C atom have the R configuration, and their pharmaceutically acceptable

Salts,.

the compound of the formula I in which R _{1 is} a radical of the partial formula Ia, where R ^{a is} tert-butyl, R ^{b is} phenyl, m 2, η 1, pO and q 1, A is the bivalent radical of the amino acid L-alanine, R ₂ R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} n-butylamino, and the C atoms carrying the radicals R ₃ , R ₄ and R ₅ and the methine C atom of the partial formula I a have the S configuration and their pharmaceutically acceptable salts, the compound of formula I, wherein R 1 is a radical of the sub-formula I a, wherein R ^a tert-butyl, R ^{b is} phenyl, m 2, η 1, ρ 0 and q 1, Aden bivalent radical the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cycloheptylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} n-butylamino, and the C atoms carrying the radicals R ₃ , R ₄ and R ₅ and the methine C Atom of the partial formula la having the S-configuration, and their pharmaceutically acceptable salts, and the compound of the formula I, wherein R _{1 is} a radical of the partial formula Ia, wherein R ^a tert-butyl, R ^{b is} Phe nyl, m 2, η 1, pO and q 1, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} methylamino and the radicals R ₃ , R ₄ and R ₅ carrying carbon atoms and the methine C atom of the partial formula I a have the S configuration, and their pharmaceutically acceptable salts.

Method:

The compounds of the formula I according to the invention and salts of such compounds having at least one acid-forming group are obtained by processes known per se, for. B. by

a) a fragment of a compound of formula I having a terminal carboxy group or a reactive acid derivative of this fragment with a compound of the formula I complementary fragment having a free amino group or a reactive derivative thereof with activated amino group, wherein existing in the reaction components free functional groups Optionally in protected form, condensed to form an amide bond, or

b) for the preparation of compounds of formula I, wherein R _{4 is} hydroxy, the keto group in a compound of formula

OR ₅ O

C-CH ₂ -CH-C-

Ri-AN-CH-C-CH ₂ -CH-C-R (II),

R ₃

in which the substituents have the meanings mentioned and free functional groups, with the exception of the keto group participating in the reaction, are optionally in protected form, reduced by reaction with a suitable reducing agent to a hydroxy group, or c) for the preparation of compounds of formula I, wherein R ₄ Hydroxy is an aldehyde compound of the formula

Ri-AN-CH-CH (IH) ₁

wherein the substituents have the meanings given and free functional groups, with the exception of the aldehyde group optionally present in protected form, with an organometallic compound of the formula

M - CH ₂ - Ie - I - Rs .. ^(1V) '

in which the substituents have the meanings mentioned and M is a metal radical, reacting and hydrolyzing the resulting addition product, or

d) in a compound of the formula

l ^z Λ ?⁵ ß

Ri-AN-CH-CH-CH ₂ -CH-CR ₆ (V),

R3

wherein X is a nucleofugic leaving group, the other substituents have the meanings given above and free functional groups are optionally present in protected form, the substituent X is replaced by a substituent R ₄ in nucleophilic form introducing reagent to R ₄ , or

e) in a compound of the formula

R ₁ -AN-CH-CH-CH ₂ -CH-CN ( _V |),

wherein the substituents have the meanings given and existing functional groups are optionally in protected form, the cyano group is converted into an N-substituted carboxamido group (C = O) R ₅ , or f) for preparing a compound of formula I, wherein R _{4 is} free Hydroxy is an epoxide of the formula

I ² / \ ! ⁵ S "

Ri-AN-CH-CH-CH-CH-C-R ₆

(VII)

in which the substituents have the meanings mentioned and free-functional groups are optionally present in protected form, with a regio-selective reducing agent reduced to the corresponding alcohol, or. g) for the preparation of a compound of the formula I, wherein R _{1 is} a radical of the formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C-

(O) ⁿ ι PI ^(la)

and m is 0 or 2, η 1 and ρ 0, a compound of the formula R ^a -S (O) _m H or a salt thereof to a compound of the formula

R- (CH ₂ ) -C-C-A-N-CH-CH-CH ₂ -CH-C-R ₆ (VIII),

^q OH ₂ L

in which the substituents have the meanings mentioned and free-functional groups are optionally present in protected form, added, or

h) for the preparation of a compound of formula I, wherein Ri is a radical of formula

R ^a - S - (CH ₂ ) - CH - (CH ₂ ) -C- (5) ⁿ I ^P ö

^m (CH ₂ ) there)

and pO represents a compound of the formula

a ^R 2? ^ s 9

RS- (CHz) - CH ₂ -CAN-CH-CH-CH ₂ -CH-CR ₆ (IX),

(Ö) _m ö R ₃

in which the substituents have the meanings mentioned and free-functional groups are optionally present in protected form, with a compound introducing the radical R ^b - (CH ₂ ) q - alkylated, and if desired

i) splitting off any protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -h) or any other process for the preparation of a compound of the formula I, an obtainable compound of the formula I having a salt-forming group in its salt or converting an available salt into the free compound or into another salt and / or separating off any isomer mixtures obtainable and / or reversing the configuration of a chiral carbon atom in an available compound of the formula I and / or converting a compound of the formula I into another inventive compound Compound of formula I converts. The invention also relates to the compounds obtainable by any of the above-mentioned processes as compounds of the formula I (by-product), and to compounds of the formula I and their salts, which are prepared by a process other than those mentioned above.

Process a) (Preparation of an amide bond):

Fragments of a compound of the formula I having a terminal carboxy group which can be condensed with a fragment complementary to the compound of the formula I to form an amide bond are, for example, compounds of the formulas R ₁ -OH, R ₁ -A-OH or

J2 IjU R.5

R 1 -A-N-CH-CH-CH ₂ -CH-C-OH,

the activated esters or reactive anhydrides derived from these compounds, and also reactive cyclic amides. The reactive acid derivatives can also be formed in situ.

Activated esters are especially at the linking carbon atom of the esterifying radical unsaturated esters, eg. Vinyl ester type such as vinyl ester (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl vinyl diester (available, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or the Woodward method) or 1-lower alkoxyvinyl ester (obtainable, for example, by treating the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or amidino-type esters such as Ν, Ν'-disubstituted amidinoesters (obtainable, for example, by treating the corresponding acid with a suitable N, N'-disubstituted carbodiimide, for example Ν, Ν'-disubstituted carbodiimide, for example!, N'-dicyclohexylcarbodiimide, carbodiimide method) or N, N-disubstituted amidinoesters (obtainable for example, by treating the corresponding acid with an N, N-disubstituted cyanamide, cyanamide method), suitable aryl esters, in particular by electron-withdrawing substituents substituted phenyl (erhäl eg by treating the corresponding acid with a suitably substituted phenol,

ζ. 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-p-n-tachlorophenol or 4-phenyldiazophenol, in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide; Activated aryl ester method), cyanomethyl esters (obtainable, for example, by treating the corresponding acid with chloroacetonitrile in the presence of a Basel cyanomethyl ester method), thioesters, especially optionally, e.g. For example, by nitro, substituted phenylthioesters (obtainable, for example, by treating the corresponding acid with optionally substituted, for example by nitro, substituted thiophenols, inter alia by means of the anhydride or carbodiimide method of activated thiolesters) or in particular amino or Amido esters (obtainable, for example, by treating the corresponding acid with an n-hydroxyamino or N-hydroxyamido compound, for example N-hydroxy-5-norbornene or norbornane-2,3-dicarboximide, 1-hydroxybenzotriazole or Hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one, ζB according to the anhydride or carbodiimide method, activated N-hydroxy ester method).

Anhydrides of acids may be unsymmetrical or preferably mixed anhydrides of these acids, e.g. Anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treating the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride, acid chloride method), azides (obtainable eg from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid; Azide), anhydrides with carbonic monoesters, eg by treating the corresponding acid with lower alkyl chloroformates or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, e.g. B. 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; Mixed O-alkylcarbonic acid anhydrides), anhydrides with dihalogenated, in particular dichlorinated, phosphoric acid (obtainable, for example, by treating the corresponding acid with phosphorus oxychloride, phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those which are obtained with phenyl-N- phenylphosphorous amido chloridate) or with phosphonic acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treating the corresponding acid with an optionally substituted lower alkane or phenyl-lower alkane carboxylic acid halide, e.g. Mixed phenyl carboxylic anhydrides) or with organic sulfonic acids (obtainable, for example, by treating a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic Su Lfonsäurehalogenid, such as lower alkane or aryl, ζ. For example, methane or p-toluenesulfonyl chloride; Mixed sulfonic acid anhydride method), as well as symmetrical anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylamine propyne; symmetrical anhydride method).

Suitable cyclic amides are in particular amides with five-membered diazacycles of aromatic character, such as amides with imidazoles, z. Imidazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method). Depending on the meaning of R _6, fragments complementary to the compound of formula I having a free amino group are, for example, a primary or secondary amine, furthermore compounds of the formulas

HAN-CH-CH-CH ₂ -CH-CR ₆

R ₂ iU R ₅ Ο

or HN-CH-CH-CH ₂ -CH-C-R ₆

The amido group participating in the reaction in a fragment complementary to a compound of the formula I is preferably present in free form, in particular if the carboxy group reacting therewith is in a reactive form; but it can also be derivatized itself, e.g. by reaction with a phosphite such as diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyldichlorophosphite, ethylene chloride phosphite or tetraethyl pyrophosphite. A derivative of such a complementary fragment with an amino group is e.g. also a carbamic acid halide or an isocyanate, wherein the amino group participating in the reaction by halogencarbonyl, z. As chlorocarbonyl, substituted or modified as an isocyanate group, in the latter case, only compounds of formula I are accessible, which carry a hydrogen atom on the nitrogen atom of the amide group formed by the reaction.

When the complementary fragment having an amino group is a mono- or di-substituted amine by lower alkyl or aryl-lower alkyl, a corresponding urea compound is also a reactive derivative. For example, when equimolar amounts of this urea compound and the free carboxy group component are heated, corresponding compounds of the formula I are obtained. If the complementary fragment is dimethylamine, dimethylformamide is also a reactive derivative.

Functional groups in starting materials whose conversion is to be avoided, in particular carboxy, amino, hydroxyl, mercapto and sulfo groups, may be protected by suitable protective groups, such as those usually used in the synthesis of peptide compounds, but also of cephalosporins and penicillins be used. These protective groups may already be present in the precursors and are intended to protect the relevant functional groups against undesirable side reactions such as acylations, reamings, esterifications, oxidations, solvolysis, etc. However, protecting groups can also be present in the end products. Compounds of formula I having protected functional groups may have higher metabolic stability than the corresponding compounds having free functional groups. The protection of functional groups by such protecting groups, the protecting groups themselves, as well as their cleavage reactions, are described, for example, in standard works such as in 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 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981, and - "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974, described. A carboxy group is e.g. protected as an ester group which is selectively cleavable under mild conditions. A carboxy group protected in esterified form is esterified primarily by a lower alkyl group 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. A protected carboxy group which is esterified by a Niederalkygruppe, in the 1-position of the lower alkyl group

is branched, for example, tert-lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, or arylmethoxycarbonyl having one or two aryl radicals, wherein aryl is unsubstituted or e.g. by lower alkyl, e.g. tert-lower alkyl such as tert-butyl, lower alkoxy, e.g.

Methoxy, hydroxy, halogen, e.g. As chlorine, and / or nitro mono-, di- or trisubstituted phenyl, for example benzyloxycarbonyl, substituted by said substituents benzyloxycarbonyl, z. For example, 4-nitrobenzyloxycarbonyl or t-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by said substituents, e.g. B. di (4-methoxyphenyl) methoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group which is substituted at the 1 or 2 position of the lower alkyl group by suitable substituents is, for example, 1-lower alkoxy-lower alkoxycarbonyl, e.g. B.

Methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, i-lower alkylthio-lower alkoxycarbonyl,

z. For example, 1-methylthiomethoxycarbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl, e.g. Phenacyloxy-carbonyl, 2-halo-lower alkoxycarbonyl, e.g. B. 2,2,2-Trichloräthoxycarbonyl, 2-Bromäthoxycarbonyl or 2-Jodäthoxycarbonyl, and 2-Triniederalkylsilylniederalkoxycarbonyl, z. B. 2-trimethylsilylethoxycarbonyl.

A carboxy group may also be protected as an organic silyloxycarbyl group. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group _/ z. B. trimethyisilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group may also be represented by two lower alkyl groups, e.g. As methyl groups, and the amino group or the carboxy group of a second molecule of the formula I be substituted. Compounds with such protective groups can be, for example

with dimethyichlorosilane as the silylating agent.

A protected carboxy group is preferably tert-lower alkoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl.

An amino group may, for. In the form of an acylamino, arylmethylamino, etherified mercaptoamino or silylamino group or as an azido group.

In a corresponding acylamino group, for example, acyl is the acyl radical of an organic carboxylic acid with ζ. B. up to 18 carbon atoms, in particular an optionally, for. B. by halogen or aryl, substituted lower alkanecarboxylic acid or optionally, for. B. by halogen, lower alkoxy or nitro, substituted benzoic acid, or preferably a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower-alkanoyl, e.g. B. 2-haloacetyl, such as 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally z. B. substituted by halogen, lower alkoxy or nitro substituted benzoyl, z. B. benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or in the 1-position of the lower alkyl radical branched or in 1- or 2-StelIung suitably substituted lower alkoxycarbonyl, z. B. tert-Niederalkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl with one or two aryl radicals, which may be, for. By lower alkyl, e.g. tert-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and / or nitro, mono- or polysubstituted phenyl, for. Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, aroylmethoxycarbonyl, e.g. B.

Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-tri-lower alkylsilyl-lower alkoxycarbonyl, e.g. B. 2-Trimethylsilyläthoxycarbonyl, or 2-Triarylsilylniederalkoxycarbonyl, z. B. 2-Triphenylsilyläthoxycarbonyl.

An arylmethylamino group is z. As mono-, di- or in particular triphenylmethylamino, z. B. benzyl, diphenylmethyl or tritylamino.

In an etherified mercaptoamino group, the etherified mercapto group is primarily substituted arylthio, e.g. B. 4-Nitrophenylthio.

A silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. B. trimethylsilylamino. The silicon atom of the silylamino group may also be replaced only by two lower alkyl groups, e.g. As methyl groups, and the amino group or carboxyl group of a second molecule of the formula I be substituted. Compounds with such protective groups can be z. B.

with dimethyichlorosilane as the silylating agent.

Preferred amino protecting groups are acyl radicals of carbonic monoesters, especially tert-butoxycarbonyl, optionally substituted benzyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. B. 2,2,2-Trichloräthoxycarbonyl, also trityl and formyl.

A hydroxy group may be exemplified by a halogen, e.g. Chlorine, substituted lower alkanoyl group, e.g. B. 2,2-dichloroacetyl, or in particular be protected by an acyl radical of a carbonic monoester mentioned for protected amino groups. A preferred hydroxy-protecting group is, for example, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl. A hydroxy group can also be replaced by tri-lower alkylsilyl, e.g.

Trimethylsilyl or preferably dimethyltert-butylsilyl, an easily cleavable alkyl group, such as tert-lower alkyl, z. For example, tert-butyl, an oxa or a thiaaliphatic or cycloaliphatic hydrocarbon radical, for example 1-Niederalkoxyniederalkyl or i-NiederalkylthioniederalkyLz. Methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa or 2-thiacycloalkyl having 5-7 ring atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analog, and by 1-phenyl-lower alkyl, e.g. B.

Benzyl, diphenylmethyl or trityl, wherein the phenyl radicals, for example by halogen, z. As chlorine, lower alkoxy, z. As methoxy, and / or nitro may be protected.

Two adjacent hydroxyl groups may be protected, for example, by a preferably substituted methylene group, e.g. By lower alkylidene, e.g. Isopropylidene, cycloalkylidene, e.g. As Cyctohexyiiden, or benzylidene.

A mercapto group, such As in cysteine, in particular by S-alkylation with optionally substituted alkyl radicals, silylation, thioacetal, S-acylation or be protected by the formation of asymmetric disulfide groups. ,

Preferred mercapto protecting groups are, for. B. optionally in the phenyl radical, for. Substituted by methoxy or nitro, substituted benzyl, such as 4-methoxybenzyl, optionally on the phenyl radical, e.g. by methoxy, substituted diphenylmethyl, such as 4,4'-dimethoxydiphenylmethyl, triphenylmethyl, trimethylsilyl, benzylthiomethyl, 2-tetrahydropyranyl, acylaminomethyl, benzoyl, benzyloxycarbonyl or lower alkylaminocarbonyl, such as ethylaminocarbonyl, further lower alkylthio, e.g. B. methylthio.

A sulfo group may be exemplified by lower alkyl, e.g. As methyl or ethyl, be protected by phenyl or sulfonamide, for example as imidazolide.

The condensation for the preparation of the amide bond can be carried out in a manner known per se, for example as in standard works, such as "Houbon-Weyl, Methods of Organic Chemistry", 4th edition, volume 15/11, Georg Thieme Verlag,

Stuttgart 1974, "The Peptides" (Ed. E. Gross and J. Meienhofer), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M.Bodanszky, "Principles of Peptide Synthesis", Springer Verlag, Berlin 1984.

The condensation can be carried out in the presence of one of the conventional condensing agents. Usual condensing agents are z. Carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide or, in particular, dicyclohexylcarbodiimide, furthermore suitable carbonyl compounds, for example carbonyldiimidazole, 1,2-oxazolium compounds, eg. 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g. Diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoramidochloridate, bis (2-oxo-3-oxazolidinyl) -phosphinic acid chloride or 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluoro phosphate.

If desired, an organic base is added, e.g. B. a Triniederalkylamin with bulky radicals, eg. B.

Ethyldiisopropylamine, or a heterocyclic base, e.g. For example, pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of acid anhydrides with amines can, for. B. in the presence of inorganic carbonates, eg. B.

Alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate).

The condensation is preferably in an inert, polar, aprotic, preferably anhydrous. Solvent or solvent mixture carried out, for example in a carboxylic acid amides z. Formamide or dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g.

Acetone, cyclic ether, e.g. For example, tetrahydrofuran, an ester, for. As ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, for. B. in a temperature range from about -40 ⁰ C to about + 100 ⁰ C, preferably from about -1O ⁰ C to about + 5O ⁰ C, and optionally under inert gas, for example

Nitrogen atmosphere.

Reactive acid derivatives can also be formed in situ. So you can z. B. forming N, N'-disubstituted amidinoesters in situ by reacting the mixture of the free carboxy group fragment and the complementary fragment with an amino group in the presence of a suitable disubstituted carbodiimide, e.g. B. dicyclohexylcarbodiimide reacted. Further, one may form amino or amido esters of such acids in the presence of the amino component to be acylated by reacting the mixture of the corresponding acid and amino precursors in the presence of a disubstituted carbodiimide,

z. Dicyclohexylcarbodiimide, and an N-hydroxylamine or N-hydroxyamide, e.g. B. N-hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxy-norbornane-2,3-dicarboximide, optionally in the presence of a suitable base,

z. As 4-dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamiri, is reacted.

The condensation of a carboxylic acid R ₁ -A-OH with the corresponding complementary to the compound of formula I fragment having a free amino group can also be achieved in a conventional manner with the aid of enzymes, for example as described by H.-D. Jakubke et al. in Angewandte Chemie 97, 79 (T985). As enzymes, for example, thermolysin, carboxypeptidase Y, papain, chymotrypsin, trypsin or pepsin are suitable. The reaction is preferably carried out in water or in mixtures of water with organic solvents, e.g. B. with lower alkanols such as ethanol, dimethylformamide, dimethyl sulfoxide, ethers such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, acetone, acetonitrile or polyalcohols, for. B.

Ethylene glycol, di-, tri- or poly-ethylene glycol, but also with immiscible organic solvents, eg. B.

Methylene chloride or ethyl acetate, at a pH of 5 to 8, preferably at the Netralpunkt, carried out at temperatures between ^{0 0} C and 50 ⁰ C. The solvents and the reaction conditions are preferably chosen so that the desired compound precipitates or is extracted into the immiscible organic phase and thus removed from the reaction equilibrium. It is also possible to carry out the condensation with enzymes immobilized on a suitable support, as mentioned above, in said organic solvents in a mixture with a little water.

Method b) {Reproduction of a keto group):

In a starting material of the formula II, functional groups, with the exception of the keto group to be reduced, are optionally protected by one of the protective groups mentioned under process a).

For the reduction of the keto group in a compound of formula II, those reducing agents are suitable which, under the reaction conditions of the process, reduce an isolated keto group selectively or faster than the amide groups present in compounds of the formula I.

First of all, suitable borohydrides, such as alkali metal borohydrides, in particular sodium borohydride, lithium borohydride or sodium cyanoborohydride, furthermore zinc borohydride, or suitable aluminum hydrides, such as aluminum quaternary alkoxyaluminum hydride with voluminous radicals, for example lithium tris-tert-butoxyaluminum hydride. The reduction can also be carried out with hydrogen in the presence of suitable heavy metal catalysts, eg Raney nickel or platinum or palladium catalysts, eg platinum or palladium activated carbon, or according to Meerwein-Ponndorf-Verley with HiHe of aluminum alkoxides, preferably aluminum 2-propoxide or ethanolate become. The reduction may preferably be carried out with stoichiometric amounts or a sensibly measured excess of the reducing agent in an inert solvent at temperatures between -8O ⁰ C and the boiling point of the solvent, preferably between -20 ° Ciind +100 ⁰ C, if necessary under inert gas, for example nitrogen or Argon, to be performed. An excess of the reducing agent is particularly necessary if this also with the solvent, for. As the protons of a protic solvent reacts.

When using sodium borohydride are polar, protic solvents, eg. Methanol, ethanol or isopropanol; when using the other reducing agents mentioned under process a) polar, - aprotic solvent, eg. B. tetrahydrofuran.

Process c) (addition of an organometallic compound):

In a starting material of the formula III, functional groups, with the exception of the aldehyde group, are optionally protected by the protective groups mentioned under process a). Likewise, existing functional groups are protected in a compound of formula IV.

In a compound of formula IV is a metal radical M, for example, or -Li-MgHaI, for example _1-MgCl -MgBr or-MgI. The reaction of a compound of the formula III with a compound of the formula IV is carried out in a customary manner in an anhydrous, inert, aprotic solvent. In an ether, such as diethyl ether or tetrahydrofuran, or a hydrocarbon, such as benzene or toluene, or mixtures thereof, optionally uhter cooling, especially after the beginning of the reaction, for. B. to about -30 ° C, or with heating, for. B. up to the boiling point of the reaction mixture, optionally in an inert gas, for. B. nitrogen atmosphere. A preferred embodiment of the process is the reaction of the aldehyde of the formula III with an excess of the lithium compound of the formula IV.

The hydrolysis of the addition product is carried out with H ⁺ -leaching solvents, eg. As water (ice-water mixture) or dilute, aqueous acids, eg. As dilute mineral acids, such as dilute, aqueous sulfuric acid, or dilute organic acids, eg. B. dilute, aqueous acetic acid.

The reaction of a compound of formula III can also be carried out with a compound of formula IV prepared in situ, which z. B. from the corresponding halide, for. As chloride, by reaction with a metallating agent, for. As magnesium, lithium or tert-butyllithium receives.

Method d) (nucleophilic substitution):

In a starting material of the formula V, functional groups are optionally protected by the protective groups mentioned under process a).

In a compound of formula V, the nucleofugic leaving group X is in particular hydroxy esterified with a strong inorganic or organic acid, such as with a mineral acid, e.g. As hydrohalic acid, such as hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or halogenated sulfuric acid, eg. For example, fluorosulfuric acid, with a strong organic Sülfonsäure, such as an optionally, for. Example by halogen, such as fluorine, substituted lower alkanesulfonic acid or an aromatic Sülfonsäure, z. Example, an optionally substituted by lower alkyl, such as methyl, halogen, such as bromine and / or nitro substituted benzenesulfonic acid, eg. As a methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid, or esterified with hydrazoic acid hydroxy.

A substituent R ₄ in nucleophilic form introducing reagent depends on the meaning of R _4, a hydroxide-containing base, for. For example, sodium or potassium hydroxide (R ₄ = OH), an alcohol, eg. As methanol or ethanol (R ₄ = etherified hydroxy).

Preferably, the reaction conditions are chosen so that the reaction proceeds essentially as second order nucleophilic substitution (S _N 2). For example, a compound of formula V, wherein X is a leaving group with high polarizability of the electron shell, z. As for iodine, is, in a polar aprotic solvent, for. For example, acetone, acetonitrile, nitromethane, dimethyl sulfide or dimethylformamide, with the silver salt of a carboxylic acid, eg. B. silver acetate, implement. The reaction with a hydroxide-containing base is preferably carried out in water, optionally as a solubilizer an organic solvent, for. For example, ethanol, tetrahydrofuran or acetone, is added, and the reaction with an alcohol in an excess of this alcohol, optionally in the presence of one of the above polar aprotic solvent performed. The substitution reaction is optionally carried out at reduced or elevated temperature, for. Example in a temperature range of about -40 ⁰ C to about +100 ⁰ C, preferably from about-1O ⁰ C to about +50 ⁰ C, and optionally under an inert gas, such. B. nitrogen atmosphere performed.

Process e) (conversion of a cyano group into an amide group):

In a starting material of the formula VI, functional groups are optionally protected by the protective groups mentioned under a).

The conversion of a compound of the formula VI into a compound of the formula I can be effected by a Ritter reaction or via carboxylic ester salts.

In the Ritter reaction, the nitriles are reacted in the presence of a strong acid, for example 85-90% sulfuric acid, or else polyphosphoric acid, hydrogen fluoride, formic acid, boron trifluoride or other Lewis acids, but not aluminum chloride, with compounds which are acidic Medium can form carbenium ions, eg with olefins, such as propylene, or alcohols, such as benzyl alcohol, usually without a solvent or, for example, in glacial acetic acid.

In a variant of the Ritter reaction, a nitrile of the formula VI is reacted with an olefin and mercury (II) nitrate and the organomercury compound is subsequently reduced with sodium borohydride to an N-substituted compound of the formula I.

Acid-catalyzed, preferably hydrogen chloride-catalyzed, addition of alcohols onto the nitriles of the formula VI gives carboxylic acid ester imides which give amides of the formula I by thermal rearrangement at temperatures above about 80 ° C.

Method f) (reduction of the epoxide):

In a starting material of the formula VII, functional groups are optionally protected by the protective groups mentioned under process a).

It is possible to use those reducing agents which, under the reaction conditions of the process, reduce the epoxy group selectively or more rapidly than the amide groups present and open the epoxide so that a sufficiently large and largest proportion of the reaction products carry the newly formed hydroxy group in the position corresponding to formula I. Examples of such selective reducing agents are lithium borohydride or sodium cyanoborohydride / boron trifluoride etherate. With the latter reagent, the reaction z. B. so that one to 1 mole of the compound of formula VII and an excess, for. 1.4-3 mol, sodium cyanoborohydride in tetrahydrofuran at elevated temperature, e.g. B. under reflux, a solution of Bortrifluoridätherat, BF ₃ · O (C ₂ H ₅ ) ₂ , in tetrahydrofuran so admits that the pH of the reaction solution in the vicinity of the Umschlagspunktes also added indicator bromocresol green is maintained. The reduction with lithium borohydride is preferably carried out in an ether, for example tetrahydrofuran, 1,2-dimethoxyethane or diethylene glycol dimethyl ether, at temperatures between room temperature and reflux temperature.

Method g) (addition to an acrylamide)

A compound of the formula R ^a -S (O) _m H is either a thiol of the formula R ^a -SH or a sulfinic acid of the formula R ^a -SO ₂ H. In a starting material of the formula VIII are functional groups, if appropriate, by the under process a ) mentioned

Protected by protective groups. Likewise, existing functional groups in the compound of the formula R ^a -S (O) _m H are optionally protected.

Suitable salts of the compound of the formula R ^a -S (O) _m H are, for example, alkali metal salts, for. For example, sodium or potassium salts. The addition of a compound of formula R ^a -S (O) _m H or a suitable salt thereof to a compound of formula VIII is carried out in the usual manner in an inert, polar solvent, for. B. in a polar ether, z. For example, tetrahydrofuran, dioxane or dimethoxyethane, a lower alcohol, for. As methanol, ethanol or isopropanol, or a dipolar aprotic solvent, for example dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-methylpyrrolidone or acetonitrile, optionally also in mixtures of said solvents with each other or with water, at temperatures between about -3O ⁰ C. and the boiling point of the particular solvent, e.g. For example, between ⁰ ° C and + 8O ⁰ C, for example at 5O ⁰ C. Instead of a sulfinic acid R ^a -SO ₂ H their salts are preferably used, for example the sodium or potassium salt. A salt of a thiol of the formula R ^a -SH can also be formed in situ, for example by addition of a suitable base, e.g. Example, alkali metal hydroxide, such as sodium or potassium hydroxide, or alkali metal hydride, for. As sodium hydride, although only anhydrous solvents can be used. It is also possible to carry out the addition reaction with a free thiol. Formula R ^a -SH in the presence of an organic base, e.g. B. a tertiary amine, z. Triethylamine, N-methylmorpholine, dimethylaniline, diazabicyclo [5.4.0] undec-7-ene or diazabicyclo [4.3.0] non-5-ene.

Process h) (alkylation in the acyl radical)

In a starting material of the formula IX, functional groups are optionally protected by the protective groups mentioned under process a).

An example of the radical R ^b - (CH ₂ ) q- introducing compound is the corresponding halide, for. As chloride, bromide or iodide, or a relative ester of the corresponding alcohol, for. For example, a sulfonic acid ester, such as the methanesulfonic or p-toluenesulfonic.

For alkylation, the compound of formula IX is preferably converted by the usual methods with a strong, non-nucleophilic base in the corresponding anion, for example with the lithium or potassium salt of a sterically hindered secondary amine, eg. With lithium diisopropylamide, lithium cyclohexyl isopropylamide, lithium 2,2,6,6-tetramethylpiperidide, lithium or potassium bis (trimethylsilyl) amide or the like. The deprotonation with the base is preferably at low temperatures, for example between -100 ⁰ C and -5O ⁰ C in an inert polar solvent, for example in a polar ether, z. For example, tetrahydrofuran, dioxane or dimethoxyethane, optionally mixed with a hydrocarbon, eg. B, hexane or toluene, and / or hexamethylphosphoric triamide or ^ N'-dimethyl- ^ N'-propyleneurea. Contains the compound of formula IX further, more easily deprotonatable methylene or methine groups, eg. For example, in addition to the sulfinyl or sulfonyl group, two or more equivalents of the base are preferably used to obtain the corresponding di- or polyanion.

The thus deprotonated compound of formula IX with the R ^b - (CH ₂ ) q- introducing alkylating agent preferably in situ at low temperatures, for. B. at -78 ⁰ C to -30 ⁰ C, and then warming to room temperature or slightly elevated temperature, for. B. at 50 ⁰ C, reacted in the same solvent or solvent mixture. If η = 0 in a compound of the formula IX, the alkylation can be carried out under much milder conditions, for example in one of the abovementioned solvents or other polar solvents, eg. As dimethyl sulfoxide, dimethylformamide or acetonitrile, with the radical R ^b (-CH ₂ ) q-introducing alkylating agent at temperatures between -30 ⁰ C and about room temperature and a tertiary amine, for. Triethylamine, N-methylmorpholine, diazabicyclo [5.4.0] undec-7-ene or diazabicyclo [4.3.0] non-5-ene, or an insoluble inorganic base, eg potassium carbonate or sodium hydride, or an alkoxide, e.g. For example, potassium tert-butoxide. Also suitable is the alkylation under phase transfer conditions, ie. In a two-phase mixture of aqueous base, eg. As sodium hydroxide solution, and a non-miscible organic solvent, eg. As methylene chloride or toluene, and a phase transfer catalyst, for. As an ammonium or phosphonium salt.

Procedure i) (postoperations):

In an available compound of the formula I in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Rg have the meanings mentioned, it is possible to substitute a carboxamide group, to esterify a carboxy group present in free or reactive form or to give a esterified carboxy group into a carboxy or carboxamide group.

The substitution of a carboxamide group or another amino group takes place for. B. by alkylation.

Suitable means for alkylating a carboxamide group in a compound of formula I are, for. B. diazo compounds, for. B.

Diazomethane. Diazomethane may be decomposed in an inert solvent, the resulting free methylene reacting with a carboxamide group in the compound of formula I. The decomposition of diazomethane is preferably carried out catalytically,

z. B. in the presence of a noble metal in finely divided form, for. As copper, or a noble metal salt, for. As copper (I) chloride or copper (II) sulfate.

Further alkylating agents are the alkylating agents mentioned in German Offenlegungsschrift 2331133, eg. B.

Alkyl halides, sulfonic acid esters, sea wine salts or 1-substituted 3-Aryltriazene, which can be reacted under the reaction conditions mentioned there with a compound of formula I with a carboxamide group.

For esterification of a carboxy group in a compound of the formula I, the free acid can be used or the free acid can be converted into one of the reactive derivatives mentioned under process a) and reacted with an alcohol, or the free acid or a reactive salt, z. As the cesium salt, react with a reactive derivative of an alcohol. For example, one can react the cesium salt of a carboxylic acid with the halide of an alcohol.

The esterification of a carboxy group can be carried out with the above for the substitution of the carboxamide group alkylating agents and under the same reaction conditions, for. With diazomethane, alkyl halides, sulfonic acid esters, seaweed salts, 1-substituted 3-aryl triazenes, etc.

For converting an esterified carboxy group in a compound of formula I into a free carboxy group, one of the methods described under process a), cleavage of the carboxy groups, or optionally an alkaline saponification according to the Organikum, 15th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1976, mentioned

Reaction conditions are applied. · ·

In a compound of the formula I, an esterified carboxy group can be converted by aminolysis with ammonia or a primary or secondary amine into an optionally substituted carboxamide group. The aminolysis can be carried out according to the reaction conditions mentioned in Organikum, 15th edition, VEB German Publishers of Sciences, Berlin (East) 1976, for such reactions.

In an available compound of the formula I in which the substituents have the meanings mentioned and at least one free hydroxy group is present and the remaining functional groups are optionally present in protected form, the free hydroxy group, for example the hydroxy group R ₄ , can be etherified or esterified.

The etherification of this hydroxy group can be carried out with the abovementioned alkylating agents and under the same reaction conditions, for. With diazomethane, alkyl halides, sulfonic acid esters, seaweed salts, 1-substituted 3-aryl triazenes, etc.

The esterification of the free hydroxy group can be carried out with the usual acylating agents and the usual reaction conditions specified in the organic, z. B. with acetic anhydride.

The said alkylation reactions, etherifications, esterifications, etc. can be carried out in place of the end product in a starting material accordingly.

In an available compound of formula I, one can oxidize a thio group to a sulfinyl or sulfonyl group or a sulfinyl group to a sulfonyl group.

The oxidation to the sulfonyl group can be carried out with most of the usual oxidizing agents. Preference is given to using those oxidizing agents which selectively contain the thio group or sulfinyl group in the presence of other functional groups of the compound of the formula I, for. As the amide function and the hydroxy group, oxidize, for example, aromatic or aliphatic peroxycarboxylic acids, ζ. As perbenzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid, performic acid or trifluoroperacetic acid. The oxidation with peroxycarboxylic acids takes place in the usual suitable solvents, for example chlorinated hydrocarbons, ζ. As methylene chloride or chloroform, ether, ethyl acetate or the like, at temperatures between -78 ° C and room temperature, for. B. between -20 ° C and +10 ⁰ C, preferably to O ⁰ C. The peroxycarboxylic acid can also be formed in situ, for. B. with hydrogen peroxide in acetic acid or formic acid, which optionally contains acetic anhydride, for example with 30% or 90% hydrogen peroxide in acetic acid / acetic anhydride. Also suitable are other peroxo compounds, for example Kaliumperoxomonosuifat in lower alkanol / water mixtures, eg. As methanol-water or ethanol-water, or in aqueous acetic acid at temperatures between -70 ° C and +30 ⁰ C, z. B. between -20 ⁰ C and room temperature, further sodium metaperiodate in methanol or methanol-water mixtures at temperatures between ^{0 0} C and 50 ⁰ C, z. B. at room temperature.

For the oxidation of the thio group to the sulfinyl group, selective oxidants are used in equimolar amounts or only slight excess under controlled reaction conditions to avoid overoxidation to the sulfonyl group. Suitable examples are sodium metaperiodatin methanol or methanol-water mixtures at temperatures between -15 ° C and room temperature, for example to 0 ⁰ C, m-chloroperbenzoic acid in methylene chloride, chloroform or ethyl acetate at temperatures between-78 ⁰ C and 1O ⁰ C, preferably between -30 ° C ^and 0 ° C, tert-butyl hypochlorite lower alkanols, eg. As methanol, or hydrogen peroxide in acetone or acetic acid at temperatures around OX, or the above-mentioned Kaliumperoxomonosuifat at low temperatures.

In an available compound of the formula I having a sulfinyl group, this group can be reduced to a thio group. Preference is given to selective reducing agents which leave other functional groups of the compound of the formula I, for example the amide function, unchanged. Examples of such selective reducing agents are dichloroborane, which is preferably used in tetrahydrofuran or dimethoxyethane at temperatures between -30 ⁰ C and + 1O ⁰ C, TriphenyIphosphin in boiling carbon tetrachloride, trichlorosilane or hexachlorodisilane, iron pentacarbonyl, further sodium bisulfite in aqueous alcoholic solvents, eg. As water-methanol, water-ethanol or water-tetrahydrofuran, at temperatures between -10 ⁰ C and + 50 ⁰ C, further sodium borohydride in the presence of cobalt (II) chloride or hydrogen in the presence of catalytic amounts of palladium, eg. B. palladium / carbon in boiling ethanol.

If desired, in an available compound of the formula I, a sulfonyl group can be reduced to a thio group, for example with diisobutylaluminum hydride in ether or tetrahydrofuran. ,

In an available compound of the formula I having a sulfonamide group, this can be alkylated in the manner described for carboxamide groups or hydrolyzed with acid or alkali to a sulfo group. For example, a sulfenamide group may be reacted with one of the reagents mentioned under the oxidation of thio group to sulfonyl group, e.g. As potassium peroxomonosulfate, oxidized to the sulfonamide and be hydrolyzed same in situ. A sulfonic acid ester group can also be converted to a sulfo group by acid or base, for example as described above for the hydrolysis of a carboxylic acid ester group.

In an available compound of the formula I having a sulfo group, these can be converted in a known manner into a sulfonic acid ester or sulfonamide group, for example by conversion into a sulfonic acid halide group and reaction with an alcohol, phenol or amine. A sulfonic acid ester group is converted analogously to the carboxylic acid ester group with an amine into the corresponding sulfonamide group.

In an available compound of formula I wherein one or more functional groups are protected, these groups, e.g. As carboxy, amino, hydroxy, mercapto and / or sulfo groups, in a conventional manner, by solvolysis, in particular hydrolysis, optionally enzymatic hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis, or chemical reduction, optionally gradually or simultaneously released. The deprotection is described in the standard works referred to earlier in the "protecting groups" section.

For example, one can use protected carboxy, ζ. B. tert-lower alkoxycarbonyl ,. lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio, by treatment with a suitable acid, e.g. For example, formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, for. As phenol or anisole, convert into free carboxy. Optionally substituted benzyloxycarbonyl may e.g. B. by means of hydrogenolysis, d. H. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Furthermore, suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, may also be obtained by reduction, e.g. B. by treatment with an alkali metal dithionite, z. For example, sodium dithionite, with a reducing metal, for. As zinc, or a

reducing metal salt, such as a chromium-ll-salt, e.g. Chromium II chloride, usually in the presence of a hydrogen donating agent which is capable of producing nascent hydrogen with the metal, such as an acid, primarily a suitable carboxylic acid such as an optional, e.g. B. substituted by hydroxy, lower alkanecarboxylic, z. As acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water, convert into free carboxy. By treating with a reducing metal or metal salt as described above, one can also convert 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group to a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl into free carboxy. Aroylmethoxycarbonyl may also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 2-tri-lower alkylsilyl-lower alkoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride. For example, sodium or potassium fluoride, optionally in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as Tetraniederalkylammoniumfluorid or Tyriederalkylarylammoniumfluorid ^., B. Tetraäthylammoniumfluorid or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or With an organic silyl group, such as tri-lower alkylsilyl, eg trimethylsilyl, esterified carboxy can be solvolytically in the usual way, for example by treatment with water, an alcohol or acid, or also Esterified carboxy can also be enzymatically cleaved, for example, esterified arginine or lysine, such as lysine methyl ester, by means of trypsin A protected amino group is added in a manner known per se and, depending on the nature of the protecting groups, in a variety of forms Way, preferably By way of solvolysis or reduction, free. 2-halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyioxycarbonylamino can be e.g. By cleavage with a suitable reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonylamino may also be obtained by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. Sodium dithionite, are split. Optionally substituted diphenylmethoxycarbonylamino, tert-loweralkoxycarbonylamino or 2-tri-lower alkylsilyl-lower alkoxycarbonylamino may be prepared by treatment with a suitable acid, e.g. B. formic or trifluoroacetic acid, optionally substituted Benzyloxycarbonylamino z. B. by means of hydrogenolysis, d. H. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino or formylamino z. B. by treatment with an acid such as mineral acid, eg. Hydrochloric acid, or an organic acid, e.g. Example, formic, acetic or trifluoroacetic acid, optionally in the presence of water, and a protected with an organic silyl group amino group z. B. be released by hydrolysis or alcoholysis. A by 2-haloacetyl, z. For example, 2-chloroacetyl, protected amino group may be released by treatment with thiourea in the presence of a base, or with a thiolate salt such as an alkali metal thiolate of the thioureas, followed by solvolysis such as alcoholysis or hydrolysis of the resulting substitution product. An amino group protected by 2-tri-lower alkylsilyl-lower alkoxycarbonyl may also be converted to the free amino group by treatment with a hydrofluoric acid salt yielding fluoride anions as indicated above in connection with the release of a suitably protected carboxy group. It is likewise possible to cleave SiIyI bound directly to a heteroatom, such as nitrogen, such as trimethylsilyl, by means of fluoride ions.

Amino protected in the form of an azido group is converted, for example, by reduction into free amino, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or by treatment with zinc in the presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. As methylene chloride, or in water or a mixture of water and an organic solvent such as an alcohol or dioxane, at about 20 ⁰ C to 30 ⁰ C, or under cooling or heating performed.

A hydroxy or mercapto group protected by a suitable acyl group, an organic silyl group or by optionally substituted 1-phenyl-lower alkyl is liberated analogously to a correspondingly protected amino group. A protected by 2,2-dichloroacetyl hydroxy or. Mercapto group is e.g. by basic hydrolysis, a group protected by tert-lower alkyl or by a 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical by acidolysis, e.g. B. by treatment with a mineral acid or a strong carboxylic acid, for. As trifluoroacetic acid, released. A silyl group, e.g. As a trimethylsilyl or tert-Butyldimethylsilylgruppe is also by acidolysis, z. B. by mineral acid, preferably hydrofluoric acid, ader a strong carboxylic acid cleaved. 2-halo-lower alkoxycarbonyl is replaced by the abovementioned reducing agents, e.g. As reducing metal, such as zinc, reducing metal salts, such as chromium-ll salts, or by sulfur compounds, such as sodium dithionite or preferably sodium sulfide and carbon disulfide removed.

Two hydroxy groups which together through a preferably substituted methylene group, such as by lower alkylidene, z. B. isopropylidene, cycloalkylidene, z. As cyclohexylidene, or benzylidene, can be protected by acid hydrolysis, for. In the presence of a mineral acid or a strong organic acid.

A sulfo group protected as sulfonic acid ester or sulfonamide is obtained, for example, by acid hydrolysis, e.g. In the presence of mineral acid, or preferably by basic hydrolysis, e.g. B. with alkali metal hydroxide or alkali metal carbonate, for example, sodium carbonate released.

Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se. Thus, salts of compounds of formula I with acidic groups z. By treating with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. As the sodium salt of 2-ethylhexanoic acid, or with inorganic alkali or alkaline earth metal salts, eg. Sodium bicarbonate, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a slight excess of the salt-forming agent. Acid addition salts of compounds of formula I are conveniently prepared, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formula I, which z. B. contain a free carboxy group and a free amino group, z. B. by neutralizing salts, such as

Acid addition salts, to the isoelectric point, e.g. With weak bases, or by treatment with ion exchangers.

Salts can usually be converted into the free compounds: metal and ammonium salts z. B. by treatment with suitable acids, acid addition salts z. By treating with a suitable basic agent.

Stereoisomer mixtures, in particular diastereomer mixtures, in a conventional manner, for. B. by fractional crystallization, chromatography, etc., are separated into the individual isomers.

Racemates can in a conventional manner, for. B. after conversion of the optical antipodes into diastereomers, for example by reaction with optically active acids or bases are cleaved.

At individual chiral centers in a compound of the formula I, for example the CH-R ₄ -C-AtOm, the configuration can be specifically reversed. For example, the configuration at the CH-R ₄ -C-AtOm can be reversed by nucleophilic second order substitution according to method d) after conversion of the group R ₄ into a nucleofuge leaving group X and reaction with a reagent introducing the same substituent R ₄ .

The invention also relates to those embodiments of the process starting from a compound obtainable as an intermediate at any stage and carrying out the missing steps or stopping the process at any stage or producing a compound obtainable by the process according to the invention under the process conditions and further processed in situ.

Pharmaceutical preparations:

The pharmacologically useful compounds of the present invention may e.g. Example, be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable excipients.

The pharmaceutical compositions of this invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals) containing an effective dose of the pharmacologically active agent alone or together with a significant Amount of a pharmaceutically acceptable carrier material included. The dosage of the active substance depends on the species of warm-blooded animals, body weight, age and individual condition, the disease to be treated and the mode of administration. The on warm-blooded animals, z. For example, humans of about 70 kg body weight, dosage levels to be administered are between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, e.g. B. at about 300 mg per person per day, preferably divided into 1 to 3 individual doses, z. B. can be the same size. Usually, children receive half the dose of adults.

The new pharmaceutical compositions contain from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. Inventive pharmaceutical preparations may, for. In unit dosage form such as ampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, e.g. by means of conventional solution, lyophilization, mixing, granulation or coating methods.

It is preferable to use solutions of the active ingredient, as well as suspensions, in particular isotonic aqueous solutions or suspensions, these z. As in lyophilized preparations containing the active substance alone or together with a carrier material, for. As mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffer and are in a conventional manner, for. Example by means of conventional solution or lyophilization process. The solutions or suspensions mentioned may contain viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain, as an oily component, the vegetable, synthetic or semisynthetic oils which are customary for injection purposes. As such, particular mention may be made of liquid fatty acid esters containing as acid component a long-chain fatty acid having 8-22, especially 12-22, carbon atoms, such as, for example, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid; Stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids such. As oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a monovalent or polyvalent, z. B. mono-, di- or trihydric, alcohol, eg. As methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol or glycerol. Examples of fatty acid esters include: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M2735" (polyoxyethylene glycerol trioleate from Gattefosse, Paris), "myglyol 812" (triglyceride of saturated fatty acids of chain length C ₈ to C 12 from Chemische Werke Witten / Ruhr, Federal Republic of Germany Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.

The preparation of the injection preparations is usually carried out under sterile conditions, as well as the filling in ampoules or vials and closing the container.

Pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained and processing the mixture or granules, if desired or necessary after addition of suitable auxiliaries, into tablets or dragee cores. They can also be incorporated into plastic carriers, which deliver the active ingredients dosed or diffused. Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, eg. B. tricalcium phosphate or calcium. Hydrogen phosphate, further binders such as starch pastes using z. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrating agents such as the abovementioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, Alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, eg. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee kernels are provided with suitable, optionally enteric coatings, which include i.a. concentrated

Sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Starting materials:

Novel starting materials and / or intermediates as well as processes for their preparation are likewise the subject matter of the present invention. Preferably, such starting materials are used and the reaction conditions chosen so that one arrives at the compounds listed as preferred.

The starting materials for carrying out the process a) can be prepared by processes known per se, for. B. from the relevant amino acids by condensation analogous to the method described above a). For example, one can use a compound of the formula

f ϊ ⁵ 8

-CH-CH-CH ₂ -CH-C-

for 8

H ₂ N-CH-CH-CH ₂ -CH-CR ₆ (X)

produce analogously to the method described in European Patent Application EP 143746. Compounds of formula II are prepared, for example, by reacting a carboxylic acid of formula

Ri-A-R-CH-C-OH. (XI)

Rs

or a suitable functional derivative thereof, wherein the substituents have the meanings given and free functional groups except the optionally modified carboxy group optionally present in protected form, with an organometallic compound of the formula IV, wherein R ₅ and R _{6 have} the meanings mentioned and M a Meta 11 radical, for example, Li or MgHaI, such as -MgCI, -Mg Br or MgJ means, and solvolyzed the resulting addition product.

Suitable functional derivatives of a carboxylic acid of the formula XI are, for example, the corresponding lithium salt of the carboxylic acid, a carboxylic acid halide, for. As carboxylic acid chloride, an anhydride, for. As the symmetrical carboxylic anhydride or a mixed carboxylic acid anhydride with a sterically hindered carboxylic acid, for. With pivalic acid, or a thioester,

z. B. 2-pyridylthioester. , -

The reaction of a carboxylic acid of the formula XI or a suitable functional derivative thereof with a compound of the formula IV is carried out in the usual manner, for. B. according to the reaction conditions specified in process c), but if necessary under cooling, for. B. at temperatures of about -50 ⁰ C to about 0 ° C. In a preferred embodiment of the process, a 2-pyridylthioester of the carboxylic acid of the formula XI is reacted with a bromine magnesium compound of the formula IV. Compounds of the formula III can be prepared by processes known per se, for example by reacting in a compound of the formula XI, wherein the substituents have the meanings mentioned and free functional groups optionally in protected form, the carboxy group according to known methods, for example the corresponding methyl or ethyl ester, via an imidazolide or via an N-methoxy-N-methylamide, reduced to the aldehyde function.

Compounds of the formula IV can be prepared, for example, by reacting a halide of the formula ## STR1 ## which can be prepared by known methods or methods known per se

R ₅ Hal -CH ₂ -CH-OR ₆ ' ^(XII) '

e.g. of the chloride, with a metalating agent, e.g. As magnesium, lithium or tert-butyllithium, are produced. Compounds of formula V are prepared, for example, by reacting an aldehyde of formula III with an organometallic compound of formula IV according to process c) and the resulting hydroxy compound of formula I, optionally after separation of the isomers, having a definition corresponding to X strong esterified organic or inorganic acid.

Nitriles of the formula VI are prepared, for example, by reacting a compound of the formula

R2 Ru R ₅

R ₁ -Ati-CH-CH-CH ₂ -OH-Hal (XIII),

wherein the substituents have the meanings mentioned, with a salt of hydrocyanic acid. Suitable salts of hydrocyanic acid should be sufficiently soluble in the selected inert solvent for reaction to occur. Such salts are for. For example, ammonium cyanide, alkali metal or alkaline earth metal cyanides, z. For example, sodium or potassium cyanide, or transition metal cyanides, e.g. B. copper cyanide. The latter are suitable because of their lower basicity compared to the alkali metal cyanides.

Depending on the nature of the cyanide used and the solvent, a balance between the isomeric nitrile and isonitrile forms. The nitrile form is preferably formed when z. B. the reaction takes place with such metal cyanides whose metal cations have a lower atomic weight than that of copper.

Suitable inert solvents are, in particular, polar, aprotic solvents, for example carboxylic acid amides, eg. For example, dimethylformamide or dimethylacetamide, nitriles, z. For example, acetonitrile or propionitrile, or Diniederalkylsulfoxide, z. For example, dimethyl sulfoxide.

The reaction takes place at room temperature, at reduced or elevated temperature, for. Example, in a temperature range of about -40 ⁰ C to about + 100 ⁰ C, preferably from about - 10 ⁰ C to about +50 ⁰ C and, if desired, in an inert gas, eg nitrogen atmosphere

 Epoxides of formula VII are z. B. prepared by reacting a compound of formula

Z ₁ HN - CH - CHO. (XIV)

wherein Z _{1 is} an amino-protecting group, with a phosphoranylidene compound of the formula

¹ W JM ff

R 1 P = CH - CH - ti - Z ₂ (XV),

wherein R _{0 represents} an optionally substituted hydrocarbon radical, R 5 has the meaning given and Z _{2 is} a carboxy protecting group, and an obtainable compound of the formula

Z ₁ HN - CH - CH = CH - CH - ti - Z ₂ (XVD

with an oxidant containing the peroxy group converted into an epoxide and in an available compound in any order of the reaction steps, the protective groups Zi and Z ₂ split off and replaced by the groups R ₁ -A- and R ₆ .

R ₀ is preferably phenyl. The reaction of a compound of the formula XIV with a phosphoranylidene compound of the formula XV is carried out under those known for Wittig reactions and z. B. in the organic reaction conditions described. The case obtainable olefin of the formula XVI is optionally in situ with the oxidizing agent, for. As peracetic acid or m-chloroperbenzoic acid reacted. The cleavage of the protective groups Zi and Z ₂ and the introduction of the groups R ₁ -A- or R ₆ is described above under process a).

Compounds of the formula VIII are prepared, for example, by reacting an acrylic acid of the formula

(XVII) H 2

or a suitable functional derivative thereof with a compound of the formula

-Ina-

t ²

HAN CH - CH - CH ₂ - OH - ti - R ₆ (XVIII)

according to method a). The compound of the formula XVIII is likewise prepared according to process a) from an amino acid protected amino acid of the formula HA-OH and a compound of the formula X and subsequent removal of the protective group, if appropriate. Before or after introduction of the radicals R ₂ and R ₄ .

embodiments

The following examples serve to illustrate the invention, but do not limit its scope in any way. Temperatures are given in degrees centigrade. The R _r values are determined on silica gel thin-layer plates in the following solvent systems:

A vinegar-n-hexane. 1: 1

B ethyl acetate-n-hexane 1: 2

C ethyl acetate-n-hexane 1: 4

D ethyl acetate-n-hexane 1: 5

E ethyl acetate-n-hexane. 1: 6

F ethyl acetate-n-hexane _ 1: 9

G Vinegar n-hexane 1:19

H methylene chloride-methanol 19: 1

I methylene chloride-methanol '9: 1

J methylene chloride-methanol 4: 1

K methylene chloride-methanol-water 300: 10: 1

L methylene chloride ether · 4: 1

M methylene chloride-methanol-ammonia conc. 400: 10: 1

N methylene chloride-methanol-ammonia conc. 200: 10: 1

O methylene chloride-methanol-ammonia conc. 100: 10: 1

P methylene chloride-methanol-ammonia conc. 90: 10: 1

Q methylene chloride-methanol-ammonia conc. .80: 10: 1

R methylene chloride-methanol-ammonia conc. 40: 10: 1

S methylene chloride-methanol-ammonia conc. 1000: 50: 1

T methylene chloride-methanol-ammonia conc. 850: 50: 1

U methylene chloride-methanol-ammonia conc. - 700: 50: 1

V methylene chloride-methanol-ammonia conc. 500: 50: 1 W methylene chloride-methanol-ammonia conc. 350: 50: 1 X methylene chloride-methanol-ammonia conc. 300: 50: 1 ι

Y methylene chloride-methanol-water-glacial acetic acid 150: 54: 10: 1 Z methylene chloride-methanol-ammonia conc. 300: 10: 1 AA methylene chloride-methanol-ammonia conc. 65: 10: 1 BB methylene chloride-methanol-ammonia conc. '60: 10: 1 CC methylene chloride-methanol-ammonia conc. 50: 10: 1 DD methylene chloride-methanol-water 5: 3: 1 EA methylene chloride-methanol-water. 14: 6: 1

For example, the abbreviation "R _f (A)" means that the R _r value was determined in the system A. The proportion of the solvents to each other is expressed in parts by volume.

The same abbreviations are used for the designation of the flux systems in flash chromatography and medium pressure chromatography.

Abbreviations for amino acids and amino acid derivatives:

H-Ala-OH L-Alanine

H-Cha-OH L-cyclohexylalanine

H-Gly-OH glycine

H-His-OH L-histidine

H-Ser-OH L-serine

H-VaI-OH L-VaIi η

The values for proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) are in ppm (parts per million) based on tetramethylsilane as

internal standard, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dxd = double doublet. m / e: Molecular ion of the designated mass in mass spectrometry.

The fragment named -Cha-Val- represents the divalent radical of (2S, 4S, 5S) -5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid and has the formula

The fragment named -Cha- ^ Val-derived from the fragment -Cha-Val- by bridging NH and OH by an isopropylidene group and has the formula

4 1 ί ^υ

• «

II "

The fragment named GIy (Ra) -Gy (Rs) represents the divalent radical of 2-R ₅ -4 (S) -hydroxy-5-amino-5-R ₃ -pentanoic acid with (R) - or (S) -Configuration at C-atom 2 or 5 and has the formula

Cj) H

"r

The fragment named GIy (R ₃ J- ¹²¹ GIy (R ₅ )) is derived from the fragment Gly (R ₃ ) -Gly (R ₅ ) by bridging NH and OH through an isopropylidene group.

The fragment named - (S) -Gly (R ₃ ) -Val- thus means the divalent radical of 2 (S) -isopropyl-4 (S) -hydroxy-5 (S) -amino-5-R3-pentanoic acid ,

Further abbreviations:

Section. = absolute (anhydrous) ac = Acetyl BOC = tert-butoxycarbonyl DCCI = Dicyclohexylcarbodiimide DCH = Dicyclohexylurea DMF = Dimethylformamide DMSO = Dimethyl sulfoxide. HOBt = 1-hydroxybenzotriazole Minute = Minute (s) Bp. = Boiling point Mp. = Melting point Hours. = Hour (s) THF = Tetrahydrofuran Z = Benzyloxycarbonyl

Example 1: N-iatR.Sl-benzyl-S-tert-butylsulfonyl-propionyl-O-His-Cha-Val-methyl-amide

A mixture of 50 mg of H-His-Cha-Val-methylamide, 37 mg of 2-benzyl-3-tert-butylsulfonyl-propionic acid, 20 mg of HOBt, 32 mg of DCCI and 3 ml of DMF is stirred for 50 hours at room temperature. The crystallized DCH is filtered off and the filtrate is evaporated.

The crude product is purified by medium pressure chromatography (1 Lobar® column size B, eluent N). The fractions containing the title compound are combined and lyophilized from tert-butanol. R _f (Q) = 0.26 and 0.30 (2 diastereomers).

The starting materials are prepared as follows:

a) bisk) H-His-Cha-Val-methylamide

a) 2 (S) -benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester:

243 g of 2 (S) -benzyloxycarbonylamino-3-cyclohexyl-propionic acid (preparation: Helvetica Chimica Acta 57, 2131 (1974) are initially charged in 600 ml of toluene and 900 ml of ethanol, the reaction mixture is cooled to ⁰ ° C. and 88.3 g of thionyl chloride The cooling is removed and the mixture is stirred for 18 hours, the reaction mixture is filtered and the filtrate is concentrated The residue is separated by flash chromatography (2 kg of silica gel 60.40-63 μm, solvent F) The product-containing fractions are combined, evaporated and dried under high vacuum to give the title compound as a light yellowish oil: R _f (F) = 0.2, R _f (B) = 0.52.

b) 2 (S) -benzyloxycarbonylamino-3-cyclohexyl-propanal: 116.1 g

2 (S) -Benzyloxycarbonylamino-3-cyclohexyl-propionsäure¬ be submitted in 2.21 toluene and cooled to -65 ⁰ C. 836 ml Diisobutylaluminiumhydrid be within 30 min. Dropwise at -65 ⁰ C was added and the mixture stirred for 20 min. Then 84.2 ml of methanol within 10 min. Dropwise at -65 ° C, then 825 ml of aqueous potassium-sodium tartrate solution without cooling. The reaction mixture is discharged onto 3 l potassium sodium tartrate solution / ice and extracted with 5 l ether. The ether phase is washed with 21 water, then immediately poured into a solution consisting of 106g semicarbazide hydrochloride and 156.5g sodium acetate in 620ml water and 620ml ethanol. The reaction mixture is stirred for 1 hr. At room temperature, then separated in a separating funnel and extracted the water phase with 2 x 1.51 ether. The organic phase is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography (2 kg of silica gel 60, 40-63μΐτι, mobile phase A). Evaporation of the combined, product-containing fractions gives the semicarbazone of the title compound, Rf (I) = 0.51.13Og of this semicarbazone are dissolved in 11THF, mixed with 282 ml of 37% formaldehyde solution and then at 10 ⁰ C with 143 ml of 0.5 N HCl. The reaction mixture is 2h. stirred at room temperature, filtered and the filtrate washed with 0.51 water, 0.51 NaHCO ₃ and 0.51 water. The water phases are extracted with 600 ml of ether. The ether phases are dried over magnesium sulfate and evaporated. The residue is treated with 100 ml of toluene and evaporated to give the title compound is obtained. This will be processed immediately.

c) (HS1-benzyloxycarbonylamino) -cyclohexyl-ethoxy-oxirane: 18.9 g

Sodium hydride (55% in oil) are dissolved in a dry sulfonating flask under argon by stirring three times in 50 ml of petroleum ether (bp 40-60 ⁰ C) and then decanting the solvent from the oil. After drying in a high vacuum, a gray powder is obtained which is initially charged in 500 ml of THF and admixed with 55.6 g of trimethylsulfoxonium iodide, the temperature rising to about 40 ° C. The gray suspension is boiled at reflux for 1 h and then within 50 min. at -70 ⁰ C with a solution of 108.6g 2 (S) -Benzyloxycarbonylamino-3-cyclohexyl-propanal in 250ml THF added. The yellow suspension is 2h. stirred at 0 ⁰ C. The yellowish cloudy solution is poured onto 500g of ice. The aqueous solution is extracted with 2.51 ether, the organic phase washed with water and evaporated after drying over sodium sulfate. The oily residue is separated by flash chromatography (2.5 kg silica gel 60.40-63 / xm, eluent C). The product-containing fractions are combined, evaporated and dried under high vacuum. The title compound (diastereomer mixture, about 4: 1) is obtained as a slightly yellowish oil. Rf (K) = 0.71; Rf (C) = 0.16.

d) SiSJ-benzyloxycarbonylamino ^ -cyclohexyl-i-iodo-butane ^ tR ^ J-ol:

42.3 g of (1 (S) -benzyloxycarbonylamino-2-cyclohexyl-ethyl) -oxirane are taken up in 200 ml of acetonitrile and the resulting solution is cooled to ⁰ ° C. After addition of 20.9 g of sodium iodide during 30min. added dropwise at ^{0 0} C 17,7ml trimethylchlorosilane. The mixture is stirred for 40 min. At 0-3 ⁰ C and then poured onto 700 ml of ice-cold water. The aqueous mixture is extracted with ether and the organic phase washed with 750 ml of 5% aqueous sodium thiosulfate solution and 750 ml of saturated aqueous sodium chloride solution. After drying over sodium sulfate and evaporation, an oily mixture of the title compound is obtained, which is processed further directly.

e) 3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-5 (R) -iodo-methyl-1,3-oxazolidine: 49.3 g of the compound Example

1 d) and 1.07 g of p-toluenesulfonic acid monohydrate are dissolved in 140 ml of 2,2-dimethoxypropane and 450 ml of methylene chloride for 3 h. stirred long at room temperature. The mixture is partitioned between 11% methylene chloride and 500 ml of saturated, aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and evaporated. The crude product is purified by flash chromatography (3 kg silica gel 60.40-63 / xm, run medium E). Evaporation of the combined, product-containing fractions gives the title compound as a slightly yellowish oil. Rf (C) = 0.55; R, (E) = 0.46.

f) 2 (R, S) - (3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidinyl-5 (S) -ethyl) -3-methyl-butyric acid methyl ester:

14,3ml of diisopropylamine are dissolved in 200 ml of absolute tetrahydrofuran under argon and cooled to 0 ⁰ C. The mixture is then treated dropwise at 0-5 ⁰ C for 20 min. With 65.8ml of a 1.6 M solution of n-butyllithium in hexane and stirred for 20 min. Then, at -70 ⁰ C 13.3 ml Isovaleriansäuremethylester are stirred to -75 ⁰ C were added dropwise and the mixture 1.5 h. At -75 ⁰ C. At -6O ⁰ C to -75 ⁰ C 320 ml of hexamethylphosphoric triamide are added dropwise with stirring. The resulting suspension is stirred for 10 min. Last and finally at -70 ⁰ C to -75 ° C in 5 min. Dropwise with a solution of 43.4 g of the compound Example 1 e) in 110 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 2.5 hours and finally poured onto a mixture of 11% saturated aqueous ammonium chloride solution and 500 g of ice. The aqueous phase is extracted with 21 ethyl acetate, the organic phase washed with water and dried over sodium sulfate. After evaporation, the diastereomeric mixture of the title compound is obtained as a yellow oil. Rf (C) = 0.36; Rf (F) = 0.21 (values for the less polar component).

g) 2 (R, S) - (3-Benzyloxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidinyl-5 (S) -methyl) -3-methyl-butyric acid: 16.5 g Potassium tert-butoxide is added in 250 ml of ether at about 5 ° C with 1.77 ml of water. The white suspension is stirred for 10 min. In an ice bath and then treated with 35.8 g of the compound Example 1 f) (diastereomer mixture) in 250 ml of ether, the temperature is kept below 10 ⁰ C. The reaction mixture is then kept for 18h. Stirred at room temperature and finally poured onto 500 ml of saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate and the organic phase washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The oily crude product is separated by fiash chromatography (2.5 kg of silica gel 60.40-63 μ, ιτι, mobile phase C). Z-Cha-VaI-OH, the less polar component of the title compound having the desired configuration of the isopropyl-bonded C atom (S-configuration), is obtained as a yellow oil. Rf (K) = 0.20; Rf (L) = 0.35. ,

h) Z-Cha-Val-methylamide: A mixture of 311.9 mg of Z-Cha-VaI-OH, 6.4 ml of DMF, 138.2 mg of HOBt and 186.1 mg of DCCI is allowed to stand at ⁰ ° C. for 24 hours , The mixture is treated with an excess of methylamine and 2 hours at ⁰ ° C. and 2 hours.

stirred at room temperature. The crystallized DCH is filtered off, the filtrate is concentrated and dried under high vacuum. From the residue, the title compound is obtained as a colorless oil by flash chromatography (solvent system A):

R _f (A) = 0.45. -.

i) H-Cha-Val-methylamide: 243 mg of Z-cha-Val-methylamide are hydrogenated in 10 ml of methanol-water 9: 1 in the presence of 50 mg of palladium-carbon (10% Pd) at normal pressure and room temperature to saturation. The reaction mixture is filtered and the filtrate is stirred with 10 ml of water at room temperature. After evaporation of the solvent, the title compound is obtained as a colorless oil. R _f (W) = 0.11; Rf (Y) = 0.31.

j) Z-His-Cha-S-Val-methylamide: A mixture of 150.8 mg H-Cha-Val-methylamide, 6 ml DMF, 81.1 mg HOBt, 153.3 mg Z-His-OH and 144.2 mg DCCI is stirred for 48 hours at room temperature. The DCH is filtered off, the filtrate is concentrated and dried under high vacuum. The residue is separated by flash chromatography (145 g of silica gel 60.40-63 μΐπ, mobile phase U). Evaporation of the combined, product-containing fractions gives the title compound. Rf (W) = 0.35; R _f (Y) = 0.65.

k) H-His-Cha-Val-methylamide: 130mg of Z-His-Cha-Val-methylamide are hydrogenated in 5ml methanol-water 9: 1 in the presence of 20mg palladium-carbon (10% Pd) at normal pressure and room temperature to saturation , The reaction mixture is filtered and the filtrate is stirred with 5 ml of water at room temperature. After evaporation of the solvent, the title compound is obtained as a colorless oil. R _f (R) = 0.38.

I) to o) 2-Benzyl-3-tert-butylsulfonyl-propionic acid

I) α-Benzylacrylsäure-ethyl ester: 20g Benzylmalonsäurediäthylester in 40ml of ethanol at room temperature with 4.0g KOH in 50ml ethanol, overnight at room temperature with 4.0g KOH in 50ml ethanol, stirred overnight at room temperature, evaporated, with 7 , 1 ml of water and in an ice bath with 6.3 ml of conc. Hydrochloric acid acidified. It is partitioned between water and ether, the organic phase is dried and the ether distilled off. The residue is treated with 12.9 ml of pyridine, 0.61 g of piperidine and 1.78 g of paraformaldehyde. The mixture is heated in an oil bath (130 ^° C.) for 90 minutes.

cooled, treated with 220 ml of water and extracted three times with 75 ml of η-hexane. The combined organic phases are washed with water, 1 N HCl, water, sat. NaHCO ₃ solution and brine. The title compound is recovered by distillation.

¹ H-NMR (DMSO-d ₆ ): 1.2 ppm (t, 3H); 3.6 (d, 2H); 4.1 (q, 2H); 5.6 (m, 1H); 6.15 (m, 1H); 7.25 (m, 5H).

m) α-Benzyl-S-tert-butylthio-propionic acid ethyl ester: 4.0 g of a-benzylacrylic acid ethyl ester are dissolved in 40 ml of THF and at room temperature with 2.39 ml of tert-butyl mercaptan and 459 mg sodium hydride dispersion (55% in oil ) implemented. The mixture is stirred for 5 hrs. At room temperature, poured onto 1 N hydrochloric acid and extracted with ethyl acetate. The extracts are dried and evaporated. The residue is purified by flash chromatography on 200 g silica gel 60 (eluent G).

Colorless oil, ¹ H-NMR (DMSO-d ₅ ): 1.1 ppm (t, 3H); 1,2 (s, 9H); 2.4-3.0 (m, 5H); 4.05 (q, 2H); 7.2 (s, 5H).

n) 2-Benzyl-3-tert-butylsulfonyl-propionic acid ethyl ester:

0.5 g of 2-benzyl-3-tert-butylthio-propionic acid ethyl ester are dissolved in 8 ml of methanol, with ice cooling with 1.63 g Oxone® (potassium peroxomonosulfate, 50% KHSO ₅ , Ventron GmbH, Karlsruhe) in 7 ml of water and over Stirred at room temperature overnight. The solution is diluted with water and extracted with methylene chloride, the extracts are dried and evaporated.

¹ H-NMR (DMSOd ₆ ): 1.0 ppm (t, 3H); 1,3 (s, 9H); 2.8-3.5 (m, 5H); 3.95 (q, 2H); 7.15-7.3 (m, 5H).

o) 2-Benzyl-3-tert-butylsulfonyl-propionic acid: 550 mg of 2-benzyl-3-tert-butylsulfonyl-propionic acid ethyl ester are reacted in 8 ml of 2 N potassium hydroxide solution. The mixture is stirred overnight at room temperature, neutralized with 0.88 ml of 2 N hydrochloric acid and evaporated. The residue is purified by flash chromatography on 30 g silica gel 60 (eluent H). Yellow oil; m / e 284; ¹ H-NMR (DMSO-d ₆ ): 1.27 ppm (s, 9H); 2.73-3.1 (m, 4H); 3.2-3.5 (m, 1H); 7.2-7.4 (m, 5H); 12.5 (s, 1H).

Example 2: N- {2 (R, S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound starting from 50 mg of H-His-Cha-Val-n-butylamide, 34mg of 2-benzyl-3 ^l tert-.

butylsulfonyl-propionic acid, 18 mg HOBt and 29 mg DCCI and purified by flash chromatography on 30 g of silica gel 60 (mobile phase M). R ₉ (O) = 0.30 and 0.35 (2 diastereomers).

The starting material is prepared as follows:

a) H-His-Cha-Val-n-butylamide is obtained by hydrogenation of 1.6 g of Z-His-Cha-Val-n-butylamide in the presence of 200 mg of palladium-carbon (10%) analogously to Example 1 k) , R, (W) = 0.05; R _f (Y) = 0.16.

b) Z-His-Cha-Val-n-butylamide is prepared starting from 1.75 g of Z-His-OH, 1.97 g of H-Cha-Val-n-butylamide, 930 mg of HOBt and 1.62 g of DCCI analogously to Example 1 j) and purified by flash chromatography with solvent system W. Mp 208-210 ⁰ C. R, (W) = 0.49;. Rf (Y) = 0.62.

c) H-Cha-Vai-n-butylamide is obtained by hydrogenation of 4.2 g of Z-cha-val-n-butylamide in the presence of 500 mg of palladium-carbon (10%) analogously to Example 1 i). R _f (W) = 0.25.

d) Z-Cha-Val-n-butylamide is prepared from 4.01 g of Z-Cha-VaI-OH, 2.68 g of n-butylamine, 1.80 g of HOBt and 2.41 g of DCC! obtained as in Example 1 h) and purified by flash chromatography with solvent system C. Rf (A) = 0.61.

Example 3: N- (2 {R, S) -Benzyl-3-tert-butylsulfinyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound is prepared starting from 50 mg of H-His-Cha-Val-n-butylamide, 32 mg of 2-benzyl-3-tert-butylsulfinyl-propionic acid, 18 mg of HOBt and 29 mg of DCCI and by medium pressure chromatography (1 Lobar® column size B, eluent N). Rf (Q) = 0.35 and 0.425 (at least 2 out of 4 possible diastereomers).

The starting material is prepared as follows:

a) 2-Benzyl-3-tert-butylsulfinyl-propionic acid: 3.2 g of 2-benzyl-3-tert-butylsulfinyl-propionic acid ethyl ester are dissolved in 30 ml of methanol and treated with 30 ml of water and 10.8 ml of 1 N sodium hydroxide solution. The mixture is stirred for 16 hours at room temperature, neutralized with 10.8 ml of 1 N hydrochloric acid and concentrated in vacuo. The residue is purified by flash chromatography on 150 g silica gel 60 (eluent J). R _f (J) = 0.38.

b) 2-Benzyl-3-tert-butylsulfinyl-propionic acid ethyl ester: 4.48 g of ethyl 2-benzyl-3-tert-butylthio-propionate are dissolved at -78 ° C. with a solution of 3.67 g of m-chloroperbenzoic acid in 40 ml Methylene chloride added. The reaction solution is stirred for 2 hours at -78 ⁰ C and 17 hours at room temperature, then washed with aqueous NaHCO ₃ solution and water, dried and concentrated in vacuo. The residue is purified by flash chromatography on 150 g silica gel 60 (eluent A). ¹ H-NMR (DMSO-d _e ): 1.0-1.2 ppm (m, 15H); 2.6-3.2 (m, 5H); 4.0 (m, 2H); 7.2-7.4 (m, 5H) (2 diastereomers).

Example 4: N- (2 (R, S) -Benzyl-3-tert-butylthio-propionyl) -His-Cha-Val-n-butylamide

The title compound is prepared analogously to Example 1, starting from 50 mg of H-His-Cha-Val-n-butylamide, 30 mg of 2-benzyl-3-tert-butylthiopropionic acid, 18 mg of HOBt and 29 mg of DCCI and by flash chromatography on 30 g of silica gel 60 (Mobile phase M), R _f (O) = 0.36.

The starting material is prepared as follows:

a) 2-Benzyl-3-tert-butylthio-propionic acid: 0.5 g of ethyl 2-benzyl-3-tert-butylthio-propionate are dissolved in 5 ml of THF and treated with 3.2 ml of water and 0.9 ml of 2N potassium hydroxide added. The mixture is stirred overnight at room temperature, neutralized with 0.9 ml of 2 N hydrochloric acid and evaporated. The residue is purified by flash chromatography on 30 g of silica gel 60 (eluent H). Yellow oil, ¹ H-NMR (DMSO-d ₆ ): 1.23 ppm (s, 9H); 2.55-2.9 (m, 5H); 7.15-7.3 (m, 5H); 12.4 (s, 1H).

Example 5: N- (2 (R, S) -Benzyl-3-methylsulfonyl-propionyl) -His-Cha-Val-methylamide

The title compound is prepared analogously to Example 1 starting from 50 mg of H-His-Cha-Val-methylamide, 32 mg of 2-benzyl-3-methylsulfonylpropionic acid, 20 mg of HOBt and 32 mg of DCCI and by medium-pressure chromatography (1 Lobar® column size B, Mobile phase P). R _f (Q) = 0.14 and 0.23 (2 diastereomers).

The starting material is prepared as follows:

a) 2-Benzyl-3-methylsulfonyl-propionic acid: 1.74 g of ethyl 2-benzyl-3-methylsulfonyl-propionate are refluxed in 35 ml of 4N hydrochloric acid for 2 hours. The cooled solution is extracted with ethyl acetate, the extracts dried and concentrated and the residue purified by medium pressure chromatography (1 Lobar® column size B, eluent A). ¹ H-NMR (DMSO-d ₆ ): 2.95 ppm (s, 3H); 2.8-3.8 (m, 5H); 7.2 (s, 5H).

b) 2-Benzyl-3-methylsulfonyl-propionic acid ethyl ester: 2,198 g of ethyl 2-benzyl-3-methylthio-propionate are dissolved in 20 ml of methanol, in an ice bath with 8.4 g Oxone® (potassium peroxomonosulfate, 50% KHSO ₅ , ventron ) in 35 ml of water and stirred at room temperature overnight. The mixture is diluted with water and extracted with ethyl acetate, the extracts dried and evaporated and the residue purified by medium pressure chromatography (1 Lobar® column size B, eluent C). ¹ H-NMR (DMSO-d _e ): 1.0 ppm (t, 3H); 3.0 (s, 3H); 3.05-3.6 (m, 5H); 4.0 (q, 2H); 7.2 (s, 5H).

c) 2-Benzyl-3-methylthio-propionic acid ethyl ester: 2.0 g of α-benzylacrylic acid ethyl ester are dissolved in 20 ml of ethanol, treated in an ice bath with 1.474 g of sodium thiomethylate and stirred for 45 minutes at 0 ⁰ C. The reaction mixture is poured into a solution of 18 g of sodium dihydrogenphosphate in water and extracted with ether. The extracts are dried and evaporated to leave the title compound. ¹ H-NMR (DMSO-d ₆ ): 1.65 ppm (t, 3H); 2.1 (s, 3H); 2.4-3.0 (m, 5H); 4.0 (q, 2H); 7.2 (s, 5H) /

Example 6: N- ^ fR 1 -benzyl-S-methylsulfonyl-propionyl-O-His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound is prepared from 50 mg of H-His-Cha-Val-n-butylamide, 29mg2-benzyl-3-methylsulfonylpropionic acid, 18 mg HOBt and 29 mg DCCI and purified by medium pressure chromatography (1 Lobar® column size B, eluent N ) cleaned. R _f (Q) = 0.37 and 0.44 (2 diastereomers).

Example 7: N- (2 (R) - and 2 (S) -methylsulfonyl-4-phenyl-butyryl-His-Cha-Val-n-butylamide

The title compounds starting from 46 mg of H-His-Cha-Val-n-butylamide, 46 mg of 2-methylsulfonyl-4-phenylbutyric acid dicyclohexylammonium salt, 17 mg of HOBt and 27 mg of DCCI are prepared analogously to Example 1 and purified by flash chromatography on 110 g of silica gel 60 (cf. Eluent T) separated. Diastereomer I: R _f (V) = 0.23. Diastereomer II: R _f (V) = 0.125. The starting material is prepared as follows:

a) 2-Methylsulfonyl-4-phenylbutyric acid dicyclohexylammonium salt:

2.09 g of 2-methylsulfonyl-4-phenylbutyric acid ethyl ester are dissolved at room temperature in 11.59 ml of 1 N sodium hydroxide solution and 11.59 ml of ethanol and stirred overnight. The solution is neutralized with 11.59 ml of 1 N hydrochloric acid, evaporated, taken up in a little acetonitrile and boiled, then filtered. The filtrate is mixed with 1.54 ml of dicyclohexylamine, the crystals are filtered off and recrystallized from acetonitrile / diisopropyl ether. Mp 184-185 ° C.

b) 2-methylsulfonyl-4-phenylbutyric acid ethyl ester: (To 1,745g of sodium hydride dispersion 55% in oil) in 40 ml DMF 6,648g methylsulfonyl-ethyl acetate at -30 ⁰ C over 30 minutes dropwise.. The solution is stirred for 15 min, then heated and added dropwise under reflux within 150 min. 7.4g 2-Phenyläthylbromid in 10 ml of DMF. The reaction mixture is stirred for 20 min, acidified with 12 ml of glacial acetic acid and evaporated. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate, evaporated and purified by flash chromatography on 700 g of silica gel 60 (mobile phase D). ¹ H-NMR (DMSO-d _e ): 1.35 ppm (t, 3H); 2.6-2.9 (m, 2H); 3.75 (dxd, 1H); 4.25 (q, 2H).

Example 8: IM- (2 (R, S) -methylsulfonyl-3-phenylpropionyl) -His-Cha-Val-n-butylamide

The title compound is prepared analogously to Example 1 starting from 46 mg of H-His-Cha-Val-n-butylamide, 45 mg of 2-methylsulfonyl-3-phenylpropionic acid-dieyclohexlammonium salt, 17 mg of HOBt and 27 mg of DCCI and purified by flash chromatography on 50 g of silica gel 60 (cf. Mobile solvent U). R _f (X) = 0.46

 The starting material is prepared as follows:

a) 2-Methylsulfonyl-3-phenylpropionic acid dicyclohexylammonium salt:

3.6 g of 2-methylsulfonyl-3-phenylpropionic acid ethyl ester are stirred in 21 ml of ethanol and 21 ml of 1 N sodium hydroxide solution overnight at room temperature. The solidified reaction mixture is neutralized with 21 ml of 1 N hydrochloric acid, evaporated, boiled in acetonitrile and filtered. The filtrate is mixed with 2.8 ml of dicyclohexylamine, the crystals are filtered off and recrystallized from acetonitrile / diisopropyl ether. Mp 187-188 ° C.

b) 2-Methylsulfonyl-3-phenylpropionic acid ethyl ester: To 1.754 g of sodium hydride dispersion (55% in oil) in 40 ml of DMF are added dropwise at -25 ° C within 25 min. 6.648g Methylsulfonyl-acetic acid ethyl ester in 20ml DMF. The solution is stirred for 30 min. At -25 ° C, then added dropwise 6.84 g of benzyl bromide in 40 ml of DMF. The reaction mixture is stirred for 1 hour at room temperature, acidified with 12 ml of glacial acetic acid, left to stand overnight and evaporated. The residue is taken up in ethyl acetate, washed with water, dried, evaporated and purified by flash chromatography on 700 g of silica gel 60 (eluent E). ¹ H-NMR (DMSO-d ₆ ): 1.1 ppm (t, 3H); 3.05 (s, 3H); 3.1-3.6 (m, 2H); 3.9-4.3 (m, 3H); 7.25 (m, 5H).

Example 9: N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 2, the title compound is prepared starting from 50 mg of H-His-Cha-Val-n-butylamide, 34 mg of (2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid, 18 mg of HOBt and 29 mg of DCCI and by flash chromatography on 30 g Silica gel 60 (mobile phase M) was purified, R _f (N) = 0.09, R _f (Y) = 0.57, R _f (O) = 0.35

 The starting material is prepared as follows:

a) 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid: 5.00 g of 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid 1 '(S) -benzyl-2'-hydroxyethylamide are dissolved in 25 ml Glacial acetic acid and 75 ml of 6N HCI kept at 90 ° C for 5 hrs. The reaction mixture is concentrated and extracted with methylene chloride. The organic phase is washed with 1N HCl, concentrated and chromatographed on silica gel with running medium M. The pure title compound is recrystallized / hexane Essigester, mp 99-101 ⁰ C. Rf (A) = 0.16. [α] ² , ² = 10.9 ⁰ C (c = 0.91 in CH ₂ Cl ₂ ); ¹ H NMR and DC run behavior identical to compound Example 1 o).

The pure title compound can also be obtained by fractional crystallization of the (+) - dehydroabietylammonium salts of the racemic acid in isopropanol and cleavage of the diastereomerically pure crystals.

b) 2 (R) -ünd2 (S) -benzyl-3-tert-butylsulfonyl-1-propenoic acid-1'{S) -benzyl-2'-hydroxy-ethyl-amide: Starting from 12.5 g of racemic 2-benzyl 3-tert-butylsulfonyl-propionic acid (Example 10), 7.32 g of 2 (S) -amino-3-phenylpropanol (L-phenylalaninol), 7.41 g of HOBt and 11.80 g of DCCI in 400 ml of DMF. The crystallized DCH is filtered off, the filtrate is concentrated and the residue is separated by flash chromatography on silica gel with mobile phase A. Non-polar 2 (S) -amide: R _f (C) = 0.21; [α] ² , ² = +0,4 ⁰ C (c = 1,0 in CH ₃ OH). ¹ H-NMR (DMSO-d ₆ ): 1.22 (s, 9H); 2.58-2.67 (m, 1H); 2.75-2.95 (m, 4H); 3.05-3.17 (m, 2H); 3.17-3.35 (m, 2H); 3.85-4.63 (t, 1H, OH); 7.11-7.32 (m, 10H); 7.95 (d, 1H, NH).

Polar 2 (R) -amide: R, (C) = 0.11; [a] g ² = -47.4 ⁰ C (c = 1.0 in CH ₃ OH). ¹ H-NMR (DMSO-d ₆ ): 1.20 (s, 9H); 2.45-2.58 (m, 2H); 2.62-2.97 (m, 3H); 3.03-3.13 (m, 1H); 3.20-3.31 (m, 1H); 3.35-3.48 (m, 2H); 3.88 (m, 1H); 4.66 (t, 1H, OH); 7.05-7.28 (m, 10H); 8.05 (d, IH, NH).

Example 10: N- (2- (R) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide

The title compound is prepared analogously to Example 2 starting from 50 mg of H-His-Cha-Val-n-butylamide, 34 mg of (R) -benzyl-3-tert-butylsulfonylpropionic acid, 18 mg of HOBt and 29 mg of DCCI and by flash chromatography on 30 g of silica gel (mobile phase M ) cleaned. R, '(N) = 0.11; R, (Y) = 0.61; R, (O) = 0.30.

The starting material is prepared as follows:

a) 2 (R) -Benzyl-3-tert-butylsulfonyl-propionic acid is obtained analogously to Example 9a) by hydrolysis of the corresponding (polar) 1 '(S) -benzyl-2'-hydroxy-ethylamide (Example 9b). [a] g ² = -8.6 ° C (c = 1.01 in CH ₃ OH); ¹ H NMR and DC run behavior identical to compounds Example 9a) and 10).

Example 11: N- (2 (R, S) -Benzyl-3-isopropylsulphonyl-propionyl) -His-Cha-Val-methylamide Analogously to Example 1, 56mg of 2 (R, S) -benzyl-3-isopropylsulfonylpropionic acid, Obtained 80 mg H-His-Cha-Val-methyl I am id, 32 mg HOBt and 51 mg DCCI the title compound and purified by flash chromatography with eluent N. R f (Q) = 0.4 and 0.35 (2 diastereomers).

The starting material 2-benzyl-3-isopropylsulfonyl-propionic acid is prepared analogously to Example 1 m), n) and o) from a-Benzylacrylsäureäthylester and Isopropylmercaptan.

Example 12: N-IS-ethylsulfonyl-fR.Si-benzyl-propionyl-D-His-Cha-Val-methylamide

The title compound is obtained analogously to Example 1 from 67 mg of 3-ethylsulfonyl-2 (R, S) -benzylpropionic acid, 100 mg of H-His-Cha-Val-methylamide, 40 mg of HOBt and 63 mg of DCCI and purified by flash chromatography with eluent N. R f (Q) = 0.26 and 0.20 (2 diastereomers).

The starting material 3-ethylsulfonyl-2-benzyl-propionic acid is prepared analogously to Example 1 m), n) and o) from a-Benzylacrylsäureäthylester and Äthylmercaptan.

Example 13: N-tefR.SJ-benzyl-a-te-pyridylsulfonyl-propionyl-O-His-Cha-Val-methylamine

41.8 mg of 2 (R, S) -benzyl-3- (2-pyridyl) sulfonyl-propionic acid, 50 mg of H-His-Cha-Val-methylamide, 19.9 mg of HOBt and 31.8 mg of DCCl are obtained analogously to Example 1, the title compound and purified by flash chromatography with eluent O. R _f (R). = 0.56. '

The starting material is prepared as follows:

a) 2-Benzyl-3- {2-pyridyl) sulfonyl-propionic acid: 233 mg of ethyl 2-benzyl-3- (2-pyridyl) -sulfonyl-propionate are dissolved in 4 ml

4 N HCI 2 hrs. Boiled at reflux. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phases are washed with water, dried and evaporated. The residue is chromatographed on silica gel with eluent H and gives white crystals of the title compound with Rf (I) = 0.3.

b) 2-Benzyl-3- (2-pyridyl) sulfonyl-propionic acid ethyl ester: A solution of 239 mg of 2-benzyl-3- (2-pyridyl) thio-propionsäureäthylester in 2 ml of methanol at room temperature with a solution of 724 mg Oxone® (Potassium peroxomonosulfate, 50% KHSO ₅ , ventron) in 3.5 ml of water and stirred for 20 hrs. At this temperature. Thereafter, the reaction mixture is extracted twice with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with eluent A gives the title compound as a colorless oil. R _f (A) = 0.57. ,

c) 2-Benzyl-3- (2-pyridyl) thio-propionic acid ethyl ester: A solution of 1 g of ethyl α-benzylacrylate and 643 mg of 2-mercaptopyridine in 5 ml of abs. Ethanol is added at 0 ° C while stirring with 106mg of triethylamine. The reaction mixture is

Stirred for 5 days at room temperature and then evaporated in vacuo. Flash chromatography of the residue on silica gel with eluent G gives the title compound as a colorless oil. Rf (C) = 0.44.

Example 14: N- (2 (R, S) -Benzyl-3-dimethylaminosulfonyl-propionyl) -His-Cha-Val-methylamide

Analogously to Example 1, the title compound is obtained from 21.8 mg of 2 (R, S) -benzyl-3-dimethylaminosulfonyl-propionic acid, 36.3 mg of H-His-Cha-val-methylamide, 13.1 mg of HOBt and 21 mg of DCCI Flash chromatography with eluent Z purified. R _f (Q) = 0.42

 The starting material is prepared as follows:

a) 2-Benzyl-3-dimethylaminosulfonyl-propionic acid: A mixture of 299 mg of 2-benzyl-3-dimethylaminosulfonylpropionsäureäthylester, 1 ml of methanol, 2 ml of water and 0.42 ml of 1 N NaOH is stirred for 16 hrs. At room temperature, then with 0 , 42 ml of 1 N HCl neutralized and extracted with ethyl acetate. The organic extracts are washed with water, dried, evaporated and purified by chromatography on silica gel with mobile phase I. Rf (J) = 0.48.

b) 2-Benzyl-3-dimethylaminophenylsulfonyl-propionic acid ethyl ester: A solution of 359 mg of ethyl 2-benzyl-3-chlorosulfonylpropionate in 2 ml of methylene chloride is cooled to -10 ° C. and treated with 0.464 ml of a 5.6M solution of dimethylamine in ethanol. The solution is stirred for 15 min. At - 15 ° C, mixed with 2 N HCl and extracted with methylene chloride. The extracts are washed with water, dried with magnesium sulfate and evaporated. The residue is chromatographed over silica gel with eluent C. R _f (A) = 0.43.

c) 2-Benzyl-3-chlorosulfonyl-propionsäureäthylester: In a suspension of 333 mg of 3-acetylthio-2-benzylpropionsäureäthylester in 15 ml of water, a chlorine gas stream is introduced at room temperature for 30 min. Thereafter, the reaction mixture is purged with nitrogen and extracted with methylene chloride. The organic phase is washed with brine, dried with magnesium sulfate and evaporated. The raw title compound is processed directly. R _f

d) S-Acetylthio ^ -benzyl-propionsäureäthylester: A mixture of 576 mg of α-Benzylacrylsäureäthylester and 0.259 ml of thioacetic acid is 20h. stirred at 70 ⁰ C and then evaporated in vacuo. The residue is purified by flash chromatography with mobile phase F. R _f (C) = 0.35.

Example 15: N- (2 (R, S) -Benzyl-3-diethylaminosulphonyl-propionyl) -His-Cha-Val-methylamide Analogously to Example 1, 94mg of 2 (R, S) -benzyl-3-diethylaminosulphonyl-propionic acid, 75 mg of H-His-Cha-Vai-methylamide, 49 mg HOBt and 84 mg DCCI, the title compound and purified by flash chromatography in system Z. Rf (Q) = 0.4. The starting material 2-benzyl-3-diethylaminosulfonyl-propionic acid is prepared analogously to Example 14a) and b).

Example 16: N- (2 (R, S) -Benzyl-3-isopropylaminosulphonyl-propionyl) -His-Cha-Val-Methyiamide Analogously to Example 1, 13mg of 2 (R, S) -benzyl-3-isopropylaminosulphonyl-propionic acid, 21.2 mg H-His-Cha-Val-methylamide, 7.7 mg HOBt and 12.2 mg DCCI, the title compound and purified by flash chromatography with eluent O purified. R f (Q) = 0.46 and 0.35 (2 diastereomers)

 The starting material 2-benzyl-3-isopropylaminosulfonyl-propionic acid is prepared analogously to Example 14a) and b).

Example 17: N- (3-phenyl-2 (R, SH 2 -thiaolinylthio) propionyl) -His-Cha-Val-methylamide

Analogously to Example 1, the title compound is obtained from 15 mg 2 (R, S) - (2-thiazolinylthio) -hydrocinnamic acid, 23.6 mg H-His-Cha-Val-methylamide, 8.5 mg HOBt and 15 mg DCCl and by flash chromatography cleaned with eluent W. Rf (Q) = 0.48. The starting material is prepared as follows:

a) 2- (2-Thiazolinylthio) hydrocinnamic acid: A mixture of 250 mg of 2- (2-thiazolinylthio) -hydrocinnamic acid ethyl ester, 36 mg of lithium hydroxide monohydrate and 5 ml of THF / water 9: 1 is stirred for 5 days at room temperature and then evaporated to dryness. The residue is taken up in water, washed with ethyl acetate, adjusted to pH 5 with 0.5 N HCl and extracted with ethyl acetate. The extracts are washed with water, dried with sodium sulfate, evaporated and purified over silica gel with eluent R Chromatography R f (R) = 0.22.

b) 2- (2-Thiazolinylthio) -hydrozimtsä'ure ethyl ester: A solution of 1.8 g of 2-mercapto-1,3-thiazoline and 2.6 g of 2-Bromhydrozimtsäure ethyl ester in 15 ml of THF is added dropwise with 1.4 ml of triethylamine are added and 6h. stirred under reflux. The reaction mixture is filtered, the filtrate evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with water, dried, evaporated and purified by chromatography on silica gel with mobile phase R. R _f (W) = 0.67.

Example 18:! 1 - (2 (R, S) -Benzyl-3-tert-butylsulphonyl-propionyl) -His-Cha-Val-2- (4-imidazolyl) -ethylamide

As in Example 1, 38.6 mg of 2 (R, S) -benzyl-3-tert-butylsulfonyl-propionic acid, 61.9 mg of H-His-Cha-Val-2- (4-imidazolyl) -ethylamide, 20.8 mg of HOBt and 33.1 mg DCCI, the title compound and purified by flash chromatography with eluent O. R _f (CC) = 0.42 and 0.32 (2 diastereomers)

 The starting material is prepared as follows:

a) H-His-Cha-Val-2- (4-imidazolyl) ethylamide: A mixture of N ^a , N ^lm -ditrityl His-Cha-Val-2- (4-imidazolyl) ethyl amide and 2 ml trifluoroacetic acid Stirred for 30 min. At room temperature, concentrated on a water jet vacuum at 40 ° C, with 2ml of a mixture of methylene chloride / methanol / NHa conc. 5: 3: 1 and again evaporated in vacuo. From the residue, the title compound is obtained by chromatography with eluent CC. Rf (R) = 0.155.

b) IM ^G , N ^lm -ditrityl-His-Cha-Val-2- (4-imidazolyl) ethylamide:

Analogously to Example 1 j), the title ^compound of 155 mg N ^a , N ^lrn -Ditrityl-histidine, 63 mg H-Cha-Val-2- (4-imidazolyl) -äthylamid, 37 mg HOBt and 57mg DCCI obtained and by chromatography with Eluent N cleaned. Rf (Q) = 0.82.

c) H-Cha-Val-2- (4-imidazolyl) ethylamide: Analogously to Example 1 i), the title compound is obtained by hydrogenation of 103 mg of Z-cha-Val-2- (4-imidazolyl) ethylamide with 50 mg of Pd / C in 20 ml of methanol / water 19: 1 at atmospheric pressure and room temperature. Colorless oil, Rf (BB) = 0.25.

d) Z-Cha-Val-2- (4-imidazolyl) ethylamide: Analogously to Example 1 h), 100 mg of Z-Cha-VaI-OH, 45.4 mg of histamine dihydrochloride, 60 mg of DCCI, 37.8 mg of HOBt and 63 , 8 mg of diisopropylethylamine, the title compound and purified by chromatography with eluent AA. R _f (BB) = 0.62.

Step Example! 19: N- (2 (R, S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-i'Val - ((S) -5-tert-butoxycar-furfurylamino-5-methoxycarbonyl-pentyl) -amide

Analogously to Example 1, 56.9 mg of 2-benzyl-3-tert-butylsulfonyl-propionic acid, 118.3 mg of H-His-Cha-Val - ((S) -5-tert-butoxycarbonylamino-5-methoxycarbonyl-pentyl) -amide, 30 , 6 mg HOBt and 49.4 mg DCCI in 3.3 ml DMF, the title compound and purified by flash chromatography with solvent system W. R _f (X) = 0.67; Rf (U) = 0.09. The preparation of the starting material H-His-Cha-Val-ilSl-S-tert-butoxycarbonylamino-δ-methoxycarbonyl-pentyO-amide is described in European Patent Application EP 184560.

Example 20: N- {2 (R, S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val- ({S) -5-amino-5-carboxypentyl) -amide

75.6 mg of N- (2 (R, S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val - ((S) -5-tert-butoxycarbonylamino-5-methoxycarbonylpentyl) -amide and 1, 25 ml of 0.1 N NaOH are stirred in 1.25 ml of methanol at room temperature for 16 hrs. The reaction mixture is evaporated, treated with 1.5 ml of trifluoroacetic acid and allowed to stand for 20 min. At room temperature. The trifluoroacetic acid is evaporated off and the crude product is purified by flash chromatography (90 g silica gel 40-63 μηη, mobile phase DD). The residue is lyophilized from tert-butanol leaving the title compound as a white powder. R _f (DD) = 0.70; R, (Y) = 0.24.

Example 21: 1-J- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -Ala-Cha-Val-n-butylamide

Analogously to Example 2, the title compound is prepared starting from 105 mg of H-Ala-Cha-Val-n-butylamide, 98 mg of 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid (Example 9a), 53 mg of HOBt and 82 mg of DCCI and by flash chromatography on 65g silica gel (solvent N) cleaned. R _f (P) = 0.62

 Dk, starting materials are prepared as follows:

a) H-Ala-Cha-Val-n-butylamide is obtained by hydrogenation of 135 mg of Z-Ala-Cha-Val-n-butylamide in the presence of 50 mg of palladium-carbon (10%) analogously to Example 1k). R _f (O) = 0.33.

b) Z-Ala-Cha-Val-n-butylamide is obtained starting from 64 mg Z-Ala-OH, 62 mg H-Cha-Val-n-butylamide (Example 2c), 38 mg HOBt and 59 mg DCCI analogously to Example 1 j) and purified by flash chromatography with solvent system N. Rf (N) = 0.22.

Example 22: N- (2 (S) -Benzyl-3-tert-butylsulphonyl-propionyl) -Ala-Cha-Val-methylamide Analogously to Example 1, the title compound is prepared starting from 90 mg of H-Ala-Cha-Val-methylamide, 93 mg 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid, 46 mg HOBt and 78 mg DCCI and purified by flash chromatography on 30 g silica gel (eluent N). R _f (N) = 0.19; R _f (P) = 0.48

 The starting material is prepared as follows:

a) H-Ala-Cha-Val-methylamide by hydrogenation of 390 mg of Z-Ala-Cha-Val-methylamide in the presence of 40 mg of palladium-carbon (10%) analogously to Example 1 behavior. R _f (P) = 0.38; R _f (N) = 0.15.

b) Z-Ala-Cha-H-Val-methylamide is prepared starting from 326 mg of Z-Ala-OH, 380 mg of H-Cha-Val-methylamide (Example 1 i), 225 mg of HOBt and 358 mg of DCCI analogously to Example 1 j) and purified by flash chromatography with solvent system N.

Example 23: IM- (2 (S) -Benzyi-3-tert-butylsulfonyl-propionyl) -His (S) -gly (2-cyclohexyethyl) val-n-butyl-amide

A mixture of 76mg H-His- (S) -Gly (2-cyclohexylethyl) -val-n-butylamide, 50mg 2- (S) -benzyl-3-tert-butylsulfonyipropionic acid, 27mg HOBt, 43mg DCCI and 2.4ml DMF is stirred for 8 hours at 0 ° C and then for 12 hours at room temperature. The crystalline DCH is filtered off and the filtrate is evaporated. The residue is stirred in a mixture of methanol / water / glacial acetic acid 94: 3: 3 for 60 min. At 6O ⁰ C and then concentrated. The residue is purified by flash chromatography (90 g of silica gel Si 60.40-63 μίτι, System U). The fractions containing the title compound are combined and lyophilized from tert-butanol. R _f (W) = 0.34

 The starting material is prepared as follows:

a) H-His ^ SJ-Glyß-cyclohexyläthyO-Val-n-butylamide is prepared analogously to Example 2 a) to d) and 1 a) to g) from 2 (S) -amino-4-cyclohexylbutyric acid. Rf (R) = 0.58.

b) 2 {S) -Amino-4-cyclohexylbutyric acid: 896 mg of L-homophenylalanine (2 (S) -amino-4-phenylbutyric acid) are dissolved in 25 ml of water and 5.5 ml of 1N HCl in the presence of 18mg Nishimura catalyst (rhodium oxide / platinum oxide) hydrogenated. The reaction mixture is filtered while warm. From the filtrate crystallized after addition of 5.5 ml of 1 N NaOH, the title compound as white crystals. M.p. 265-266 ⁰ C; R _f (R) = 0.09.

Example 24: N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His (S) -gly (cyclopentylmethyl) -val-n-butylamide

A mixture of 72 mg of H-His-isl-glycyclopentylmethyl-Val-n-butylamide, 50 mg of 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid, 27 mg of HOBt, 43 mg of DCCI and 2.4 ml of DMF is added at 0 for 8 hrs ° C and then stirred for 12 hours at room temperature. The crystalline DCH is filtered off and the filtrate is evaporated. The residue is stirred in a mixture of methanol / water / glacial acetic acid 94: 3: 3 for 60 min. At 60 ⁰ C and then concentrated. The residue is separated by flash chromatography (100 g of silica gel Si 60.40-63 μηη, System U). The fractions containing the title compound are combined and lyophilized from tert-butanol. R _f (W) = 0.31; R _f (Y) = 0.64. The starting material is prepared as follows:

a) H-His- (S) -gly (cyclopentylmethyl) val-n-butylamide is prepared analogously to Example 2a) to d) and 1 a) to g) from 2-amino-3-cyclopentylpropionic acid (PRPal, Ch. G. Skinner, RLDennis and W.Shive, J. Am. Chem. Soc., 78, 5116 [1956]). R _f (R) = 0.42.

Example 25: N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His (S) -gly (cycioheptylmethyl) val-n-butyiamide

A mixture of 76mg of H-His-f Si-Glycycloheptylmethyl-Val-n-butylamide, 50mg of 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid, 27mg of HOBt, 43mg of DCCI and 2.4ml of DMF is left at 0 ° C for 8h and then stirred for 12 hours at room temperature. The crystalline DCH is filtered off and the filtrate is evaporated. The residue is stirred in a mixture of methanol / water / glacial acetic acid 94: 3: 3 for 60 min. At 60 ° C and then concentrated. The residue is separated by means of flash chromatography (100 g of silica gel Si60.40-63 μm, system U). The fractions containing the compound are combined and lyophilized from tert-butanol. Rf (W) = 0.58

 The starting material is prepared as follows:

a) H-His-isl-GlylcycloheptylmethyO-Val-n-butylamide is prepared analogously to Example 2a) to d) and 1 a) to g) from 2-amino-3-cycloheptylpropionic acid, R f (R) = 0.60. The amino acid used as starting material can be synthesized analogously to the corresponding cyclopenty! Substituted amino acid and separated into the enantiomers by fractional crystallization of diastereomeric salts or chromatographic separation of diastereomeric amides.

Example 26: N- (2 {R _/ S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Gly {SCH ₃ ) -n-butylamide

The title compound is prepared analogously to Example 1 starting from 140 mg of H-His-Cha-Gly (SCH ₃ ) -n-butylamide, 128 mg of 2-benzyl-3-tert-butylsulfonyl-propionic acid, 72 mg of HOBt and 92 mg of DCCI and by flash chromatography on 30 g of silica gel 60 (solvent N) cleaned. R _f (I) = 0.32 and 0.28 (2 pairs of diastereomers)

 The starting material is prepared as follows:

a) H-His-Cha-Gly (SCH ₃ ) -n-butylamide: A mixture of 132 mg of H-Cha-Gly (SCH ₃ ) -n-butylamide, 260 mg of 1-benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, 384 mg N ^Q , N ^lm -Ditrityl-histidine, 3 ml of DMF and 0.1 ml of triethylamine is stirred for 14 hrs. At room temperature. The reaction mixture is concentrated and the residue is purified by flash chromatography (25 g of silica gel 60, mobile phase A). Subsequently, the N ^a, N ^lm -Ditrityl-His-Cha-Gly (SCH ₃₎ -n-butylamide treated with 3 ml 90% trifluoroacetic acid and stirred for 30 min. At room temperature. The reaction mixture is concentrated and the residue is partitioned between aqueous potassium carbonate solution and methylene chloride. The combined organic extracts are washed with brine and dried over sodium sulfate. Evaporation gives the diastereomeric mixture of the title compound as a white foam. Rf (Y) = 0.18. ,

b) H-Cha-GlyfSChy-n-butylamide: A mixture of 240 mg of Z-Cha-Gly (SCH ₃ ) -n-butylamide, 200 mg of 4-methylmercaptophenol and 4 ml of trifluoroacetic acid is stirred for 30 hours at room temperature. The reaction mixture is concentrated, the R xkstand at 0-5 ⁰ C with 0.2 N aqueous NaOH to pH9.gestellt and anschleißend extracted several times with methylene chloride. The combined extracts are dried and evaporated. The residue is purified by flash chromatography on 25 g of silica gel (eluent O). R _f (P) = 0.08 (2 diastereomers).

c) Z-Cha-Gly (SCH ₃ ) -n-butylamide is prepared starting from 950 mg of Z-Cha-Gly (SCH ₃ ) -OH, 460 mg of HOBt, 440 mg of n-butylamine and 700 mg of DCCI analogously to Example 2d) and purified by flash chromatography with solvent system C, R f (A) = 0.56 and 0.50 (2 diastereomers). '

d) Z-Cha ^ G! y (SCH ₃ ) -OH: A mixture of 790 mg of Z-Cha- ^ Gly (SCH ₃ ) -methylester, 5 ml of 2 N aqueous NaOH and 10 ml of 1,4-dioxane is 3 Std. stirred at room temperature. The reaction mixture is neutralized with 5 ml of 2N aqueous HCl and then lyophilized. From the residue, the title compound is obtained by flash chromatography (solvent system A). R _f (A) 0.15 and 0.10 (2 diastereomers).

e) ^ {R.sil.-iS-benzyloxycarbonyl-.fsl-cyclohexylmethyl) -4-dimethyl-IS-oxazolidinyl-SfSl-methyll-methylthioacetic acid methyl ester, Z-Cha-Gly (SCH3) -methylester: 0.85 ml of diisopropylamine are dissolved in 15 ml abs. Dissolved THF and 10ml hexamethylphosphoric triamide under nitrogen and cooled to -78 ⁰ C. Then the mixture is treated with 4 ml of a 1.5M solution of n-butyllithium in hexane and 30 min. touched. Then, at -7O ⁰ C 0,65ml methylthioacetic acid-methylester are added dropwise and stirred for V2 h. At -75 ⁰ C. The reaction mixture is treated with a solution of 1.3 g of the compound Example 1 e) in 5 ml of tetrahydrofuran and 5 ml of hexamethylphosphoric triamide and within 1 n j »» nor 7 7 7 7 7 wv / rriner Ammoniiimr.hloridlnsiina becomes the product with ether

extracted. The combined organic phases are washed with brine, dried with sodium sulfate and evaporated. The crude product is purified by flash chromatography (60 g of silica gel 60.40-63 μιτι, eluent G). Evaporation of the combined, product-containing fractions gives the two diastereomers of the title compound as slightly yellowish oils. R _f (C) = 0.35 and 0.32.

Example 27: N-telR.Sl-benzyl-S-tert-butylsulfonyl-propionyl-His-Cha-GlytSOaCHsJ-n-butylamide

35 mg of N- (2 (R, -S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Gly (SCH ₃ ) -n-butylamide are dissolved in 2 ml of methanol and 2 ml of 0.1 NH ₂ SO ₄ , with 55 mg oxone® (potassium peroxomonosulfate, 50% KHSO ₅ , ventron) and stirred at room temperature overnight. The mixture is diluted with saturated sodium bicarbonate solution and extracted with methylene chloride, and the extracts are dried with sodium sulfate and concentrated to leave a diastereomeric mixture of the title compound. R _f (I) = 0.18. ,

Example 28: N- (2 (R, S) -Benzyl-3-tert-fautylsulfonyl-propionyl) -His-Cha-Gly (OCH ₃ ) -methylamide

The title compound is prepared analogously to Example 1 starting from 102 mg of H-His-Cha-Gly (OCH ₃ ) -methylamide, 78 mg of 2-benzyl-3-tert-butylsulfony.l-propionic acid, 42 mg of HOBt and 67 mg of DCCI and by flash chromatography on 30 g Silica gel 60 (mobile phase O) cleaned. R (O) = 0.24 and 0.20 (2 pairs of diastereomers).

a) H-His-Cha-Gly (OCH ₃ ) -methylamide is prepared by hydrogenation of 130 mg of Z-His-Cha-Gly (OCH ₃ ) -methylamide in the presence of 50 mg of palladium-carbon (10%) analogously to Example 1 k) receive. R _f (R) = 0.32 (mixture of diastereomers).

b) Z-His-Cha-Gly (OCH ₃ ) -methylamide is obtained starting from 125 mg Z-His-OH, 107 mg H-Cha-Gly (OCH ₃ ) -methylamide, 66 mg HOBt and 106 mg DCCI analogously to Example Ij) and purified by flash chromatography with solvent system O.

R _f (Q). = 0.26.

c) H-Cha-Gly {OCH ₃ ) -methylamide is obtained by hydrogenation of 184 mg of Z-Cha-Gly (OCH ₃ ) -methylamide in the presence of 50 mg of palladium-carbon (10%) analogously to Example 1 i). R _f (R) = 0.35.

d) Z-Cha-Gly (OCH ₃ ) -methylamide: 258 mg of Z-chloro-1-gallyl-ethyl ester are dissolved in 2 ml of methanol and mixed with 2 ml of 33% ethanolic methylamine in solution. The mixture is heated for 20 hrs. In a bomb tube at 120-130 ⁰ C and then concentrated. The residue was purified by flash chromatography on 50g silica gel 60 (Run A). Yellow oil,

R, (A) = 0.16. ".

e) Z-Cha-Gly (OCH ₃ ) ethyl ester is prepared starting from 601 mg of methoxyacetic acid ethyl ester, 0.72 ml of diisopropylamine, 3.2 ml of a 1.6M solution of n-butyllithium in hexane and 2 g of the compound Example 1 e) analogously Example 26e) and purified by flash chromatography with solvent system G. Rf (C) = 0.36 and 0.32 (mixture of diastereomers).

Example 29: N- (2 (R, S) -Benzyl-3- [2-pyridylthio] -propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound is obtained from 85 mg of 2-benzyl-3- (2-pyridylthio) propionic acid, 115 mg of H-His-Cha-Val-n-butylamide, 50 mg of HOBt and 102 mg of DCCI and purified by flash chromatography with mobile phase V. , R _f (X) = 0.30 and 0.20 (2 diastereomers).

The starting material is prepared as follows:

a) 2-Benzyl-3- (2-pyridylthio) -propionic acid: 903 mg of ethyl 2-benzyl-3- (2-pyridylthio) propionate (Example 13c) are refluxed in 10 ml of 4N HCl for 10 hrs. The reaction mixture is extracted with methylene chloride / methanol 10: 1. The extracts are adjusted to pH 6 with NaHCO ₃ solution and then washed with brine, dried with Na ₂ SO ₄ and evaporated. The residue is lyophilised from dioxane / water. R _f (I) = 0.2.

Example 30: IM- (2 (R) - and 2 (S) -Benzyl-3- [1-methyl-2-imidazolylthio] -propionyl) -His-Cha-Val-n-butylamide

The title compound is obtained analogously to Example 1 from 277 mg of 2-benzyl-3- [1-methyl-2-imidazolylthio] -propionic acid, 560 mg of H-His-Cha-Val-n-butylamide, 175 mg of HOBt and 310 mg of DCCI and by flash chromatography with solvent O separated into the two diastereomers. Diastereomer I: R _f (I) = 0.26. Diastereomer II: R _f (l) = 0.19.

The starting material 2-benzyl-3- [1-methyl-2-imidazolylthio] propionic acid is prepared analogously to Example 29a) and 1 m) from ethyl a-benzylacrylic acid and 2-mercapto-1-methylimidazole.

Example 31: N- (2 (R, S) -Benzyl-3-phenylsulfonyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound is obtained from 150 mg of H-His-Cha-Val-n-butylamide, 151 mg of Σ-ΒβηζγΙ ^ -ρηβηγΙβυΙτοηγΙ-ρΓορίοηβθυΓβ, 58 mg HOBt and 103 mg DCCI and purified by flash chromatography (eluent H). R _f (I) = 0.33 and 0.28 (2 diastereomers).

The starting material 2-8enzyl-3-phenylsulfonyl-propionic acid is prepared analogously to Example 1 m), n) and o) from a-Benzylacrylsäureäthylester and thiophenol.

Example 32: N- (2 (R, S) -Benzyl-3-pyrrolidinosulfonylpropionyl) -His-Cha-Val-n-butylamide

The title compound is obtained from 175 mg of 2-benzyl-3-pyrrolidinolsulfonylpropionic acid, 139 mg of H-His-Cha-Val-n-butylamide, 70 mg of HOBt and 120 mg of DCCI, and purified by flash chromatography with eluent N. R _f (I) = 0.24 and 0.19 (2 diastereomers)

 The starting material 2-benzyl-3-pyrrolidinosulfonyl-propionic acid is prepared analogously to Example 14a) and b).

Example 33: N- (3-ethylthio-2 (R, S) -benzyl-propionyl) -His-Cha-Val-n-butylamide

Analogously to Example 1, the title compound is obtained from 134 mg of 3-ethylthio-2-benzyl-propionic acid, 185 mg of H-His-Cha-Val-n-butylamide, 70 mg of HOBt and 132 mg of DCCI and purified by flash chromatography using mobile phase H. Rf (I) = 0.20 and 0.15 (2 diastereomers).

The starting material 3-ethylthio-2-benzyl-propionic acid is prepared analogously to Example 4a) and 1 m) from a-benzylacrylic acid ethyl ester and ethylmercaptan.

Example 34: N- (3-ethylsulfonyl-2 (R) - and 2 (S) -benzyl-propionyl) -His-Cha-Val-n-butylamide

A mixture of 81 mg of N- (3-ethylthio-2 (R, S) -benzyl-propionyl) -His-Cha-Val-n-butylamide (Example 33), 61 mg of 3-chloroperbenzoic acid and 5 ml of chloroform is added 20 h stirred at 25 ° C. The reaction mixture is basified with concentrated NaHCO ₃ solution and then extracted with 50 ml of chloroform. The organic phase is washed with 10 ml of brine, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is separated by flash chromatography (20 g silica gel 60, medium N). The product-containing fractions of the two diastereomers are combined, concentrated and then lyophilized from dioxane / water 9: 1. Diastereomer I: R _f (Q) = 0.38. Diastereomer II: R _f (Q) = 0.43.

Example 35: 1 \ - (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -Ser-Cha-Val-methylamide

The title compound is prepared analogously to Example 1 from 80 mg of 2 (S) -benzyl-3-tert-butylsulfonyl-propionic acid, 80 mg of H-Ser-Cha-Val-methylamide, 40 mg of HOBt and 67 mg of DCCI and purified by flash chromatography on 65 g of silica gel 60 (Mobile phase 0) cleaned. R _f (0) = 0.28. ^:

The starting material is prepared as follows:

a) H-Ser-Cha-Val-methylamide is obtained by hydrogenation of 230 mg of Z-Ser-Cha-Val-methylamide in the presence of 50 mg of palladium-carbon (10%) analogously to Example 1 k). R _f (P) = 0.21.

b) Z-Ser-Cha-Val-methylamide is obtained starting from 213 mg of Z-Ser-OH, 169 mg of H-Cha-Val-methylamide, 109 mg of HOBt and 184 mg DCCI analogously to Example 1 j) and by flash chromatography 80 g silica gel 60 (mobile phase 0) cleaned. R _f (O) = 0.37.

Example 36: N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-methylamide

Analogously to Example 1, the title compound is prepared from 50 mg of H-His-Cha-Val-methylamide, 37 mg of 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid (Example 9a), 20 mg of HOBt and 32 mg of DCCI and purified by medium-pressure chromatography ( 1 Lobar® column size B, mobile phase N). R _f (Q) = 0.30.

Example 37: N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Ala-methylamide

The title compound is prepared analogously to Example 1 starting from 63 mg of H-His-Cha-ala-methylamide, 60 mg of 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid (Example 9a), 32 mg of HOBt and 46 mg of DCCI and by flash chromatography on 50 g of silica gel 60 (solvent P) cleaned. R _f (P) = 0.24

 The starting material is prepared as follows:

a) H-His-Cha-Ala-methylamide, by hydrogenation of 80mg Z-His-Cha-Ala-methylamide in the presence of 30 mg of palladium. Coal (10%) is obtained analogously to Example 1 k), R _f (P) = 0.11; R, (AA) = 0.22.

b) Z-His-Cha-Ala-methylamide is obtained starting from 72 mg of Z-His-OH, 53 mg of H-Cha-Ala-methylamide, 35 mg of HOBt and 60 mg DCCI analogously to Example 1 j) and purified by flash chromatography (mobile phase P) , R _f (P) = 0.16.

c) H-Cha-Ala-methylamide: 220 mg BOC-Cha-Ala-methylamide are dissolved in 5 ml trifluoroacetic acid / water 95: 5. After 30 minutes, the mixture is concentrated on a rotary evaporator and the residue is purified by flash chromatography (mobile phase AA). Evaporation of the product-containing fractions gives the title compound. Rf (AA) = 0.33.

d) BOC-Cha-Ala-methylamide: 185 mg of BOC-Cha-Ala-OH are preactivated for 2 hours at room temperature in a stirred solution in DMF with 111 mg HOBt and 149 mg DCCI and then with 1 ml of a 5 N solution of Methylamine in DMF added. After 2 h at room temperature, the solvent is removed and the title compound is purified by flash chromatography in System A. Rf (A) = 0.25.

e) BOC-Cha-Ala-OH: 340 mg of 3-tert-butoxycarbonyl-4) (S) -cyclohexyl-methyl-2,2-dimethyl-5 (S) - (3-hydroxy-2 (R) -methyl) Propyl) -1,3-oxazolidine are dissolved in DMF and stirred with 1040 mg of pyridinium chromate in DMF16 hrs. The mixture is concentrated on a rotary evaporator and the residue is purified by flash chromatography (mobile phase B). Rf (B) = 0.12.

f) 3-tert-Butoxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-5 (S) - (3-hydroxy-2 (R) -methyl-propyl) -1,3-oxazolidine is obtained by hydrogenation of 1.90g 5 (S) - (3-Benzyloxy-2 (R) -methyl-propyl) -3-tert-butoxycarbonyl-4 (S) -cyclohexylmethyl-2,2-dimethyl-1,3-oxazolidine in methanol in Presence of 200 mg Pd / charcoal (10%). Rf (C) = 0.15.

g) SfSl-fS-benzyloxy-1-methyl-propyl-S-tert-butoxycarbonyl-1S-cyclohexylmethyl ^ -dimethyl-i ^ -oxazolidine is prepared analogously to Example 1 e) from benzyl-5 (S) -tert-butoxycarbonylamino 6-cyclohexyl-4 (S) -hydroxy-2 (R) -methyl-1-hexyl-ether and 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid monohydrate in methylene chloride. R _f (C) = 0.45.

h) Benzyl-5 (S) -tert-butoxycarbonylamino-6-cyclohexyl-4 (S) -hydroxy-2 (R) -methyl-1-hexyl-ether: A from 3.6 g (S) - (+) - 3-Benzyloxy-2-methyl-propyl bromide (A. Fischli et al., HeIv. Chim. Acta 60, 925 [1977]) and 360 mg of magnesium in diethyl ether prepared Grugnard's solution within 15 min. At 0 ⁰ C to 1.50 g 2 (S) -tert-butoxycarbonylamino-3-cyclohexylpropionaldehyde (J. Boger et al., J. Med. Chem. 28, 1779 [1985]) was added dropwise in 15 ml of diethyl ether. After 30 min. At 0 ⁰ C, the reaction solution is poured onto 50 ml of 1 N HCl and the crude product (diastereomer ratio (4S): (4R) = 4: 1) extracted with dichloromethane. The desired diastereomer with the 4 (S) configuration is separated by flash chromatography on 250 g silica gel 60 (eluent dichloromethane / ether 20: 1) in pure form. Rf (L) = 0.10.

Example 38: N- (2 (S) -benzyl-3-sulfopropionyl) -His-Cha-Val-n-butylamide

A mixture of 51 mg of N- (2 (S) -benzyl-3- [1-methyl-2-imidazolylthio] -propionyl) -His-Cha-Val-n-butylamide (Example 30), 64 mg Oxone® (potassium peroxomonosulfate, 50% KHSO ₅ , ventron), 2 ml of 0.1NH ₂ So ₄ and 2 ml of methanol is stirred at 25 ° C for 20 hrs. The reaction mixture is extracted with chloroform, the extracts washed with brine, dried and concentrated. The residue is lyophilised from dioxane / water 3: 1. R _f (EE) = 0.2.

Example 39: 5 (S) - [N- (2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -histidinyl] -amino-6-cyclohexyl-4 (R) - and 4 (S) -hydroxy- 2 (S) -isopropyl-hexanoic acid-n-butylamide

A solution of 37 mg of 5 (S) - [N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -histidinyl] -amino-6-cyclohexyl-2 (S) -isopropyl-4-oxo-hexanoic acid-N- Butylamide and 8 mg sodium borohydride in 3 ml of methanol is stirred for 6 hrs. At 25 ° C. It is then acidified with 2N HCl and partitioned between 50 ml of CH ₂ Cl ₂ and 10 ml of saturated NaHCO ₃ solution. The organic extracts are dried and evaporated. The residue is purified by flash chromatography on 10 g silica gel 60 (mobile phase M).

Rf (O) = 0.35 (mixture of diastereomers). The diastereomeric mixture contains, in addition to 3 parts of the 4 (R) compound 1, part of the 4 (S) compound that is identical to the compound of Example 9.

The starting material is prepared as follows:

a) 5 (S) - [N- (2 (S) -Benzyl-3-tert-butylsulphonyl-propionyl) -histidinyl] -amino-6-cyclohexyl-2 (S) -isopropyl-4-oxo-hexanoic acid-n -butylamide: A mixture of 253 mg of N- (2 (S) -benzyl-tert-butylsulfonyl-propionyl) -His-Cha ⁱ Val-n-butylamide (Example 9), 130 mg of pyridinium chlorochromate and 5 ml of methylene chloride is stirred for 10 hours at room temperature , The reaction mixture is diluted with 100 ml of ethyl acetate and then washed with 20 ml of water. The organic phase is dried and evaporated and the residue is purified by flash chromatography on 40 g of silica gel 60 (eluent H). R _f (O) = 0.43.

Example 40: N- {2 (S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-Butylamide by an Alternative Condensation Reaction

A mixture of 127 mg of N- (2 (S) -benzyl-tert-butylsulfonyl-propionyl) -His-OH, 65 mg of H-Cha-Val-n-butylamide, 55 mg of N-hydroxy-norbornane-endo-2,3-dicarboximide , 62mg DCCI and 2ml DMF will take 70h. stirred at room temperature. The crystallized DCH is filtered off and the filter is evaporated. The residue is stirred in a mixture of methanol / water / glacial acetic acid 94: 3: 3 for 30 min. At 6O ⁰ C and concentrated naschließend. The residue is purified by flash chromatography on 40 g of silica gel 60 (mobile phase M). The fractions containing the title compound are pooled and lyophilized from dioxane / water 9: 1. The product is identical to the compound of Example 9, R _f (O) = 0.35. The starting material is prepared as follows:

a) N- (2 (R) - and 2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-OH: 284 mg of 2-benzyl-3-tert-butylsulfonyl-propionic acid (Example 10), 121 mg N-hydroxysuccinimide and 227 mg DCCI are dissolved in 4 ml DMF and stirred for 1 hour at 25 ° C. The crystallized DCH is filtered off and the filtrate is stirred with a solution of 245 mg of histidine sodium salt in 6 ml of DMF / water for 2: 1 3 h at room temperature. The reaction mixture is diluted with 1 ml of 1N HCl and concentrated. The residue is separated by flash chromatography (30 g of silica gel 60, eluent J). The product-containing fractions of the separated diastereomers are combined and lyophilized from dioxane / water 5: 1. 2 (R) compound: Rf (EE) = 0.27. 2 (S) compound: R _f (EE) = 0.32. , ': Alternative representation:

b) IM-2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-OH Starting with 4.15 g of 2 (S) -benzyl-3-tert-butylsulfonylpropionic acid, 1.77 g of N-hydroxysuccinimide, 3 , 62 g DCCI and 3.55 g histidine sodium salt analogously to Example a). R _f (EE) = 0.32.

Example 41: N- (2 (R, S) -Benzyl-3-tert-butylsulphonyl-propionyl) -His-Cha-Val-n-butylamide by oxidation of the sufinyl compound

A mixture of 142 mg of N- (2 (R, S) -benzyl-3-tert-butylsulfinylpropionyl) -His-Cha-Val-n-butylamide (Example 3), 64 mg of sodium (meta) periodate and TOmI methanol / water 1: 1 will be 20h. stirred at room temperature. The reaction mixture is diluted with 10 ml of NaHCO ₃ solution and then extracted with 100 ml of methylene chloride. The methylene chloride extracts are washed with brine, dried with Na ₂ SO ₄ and concentrated. The residue is purified by flash chromatography (50 g silica gel 60, mobile phase M). The product is identical to the diastereomeric mixture of Example 2, R _f (O) = 0.30 and 0.35 (2 diastereomers).

Example 42: N-tefR.SJ-benzyl-S-tert-butylsulfonyl-propionyl-D-His-Cha-Val-methyl-amide by sulfinate addition

A mixture of 100 mg of N- (a-benzylacryloyl) -His-Cha-Val-methylamide and 80 mg of sodium tert-butylsulfinate are stirred in THF for 20 hrs. At 50 ⁰ C The reaction mixture is then partially concentrated and the title compound is purified by flash chromatography on 80 g of silica gel 60 (Laufmittel O). The product is identical to the diastereomeric mixture of example, R _f (Q) = 0.26 and 0.30 (2 diastereomers).

The starting material is prepared as follows:

a) N- (α-Benzylacryloyl) -His-Cha-Val-methylamide: Analogously to Example 1, the title compound is obtained from 32 mg of α-benzylacrylic acid, 50 mg of H-His-Cha-valmethylamide, 20 mg of HOBt and 32 mg of DCCI and flash Chromatography in the system Q purified.

Rf (Q) = 0.36.

Example 43: N- {2 (R, S) -Benzyl-3-tert-butylsulphonyl-propionyl) -His-Cha-Val-n-butylamide by Removal of a Silyl

Protective group "

840mg of 5 (S) - [N- (2 (R, S) -benzyl-3-tert-butylsulfonyl-propionyl) -histidinyl] -amino-4 (S) -tert-butyldimethylsilyloxy-6-cyclohexyl-2- (S) -isopropyl-hexanoic acid-n-butylamide are in 24 ml acetonitrile gel solder and treated at 25 ⁰ C with 1.25 ml of 48% hydrofluoric acid. After 30 min, 2.0 g of sodium bicarbonate are added and the solvent is evaporated off. The residue is taken up in ethyl acetate, washed with water, dried with sodium sulfate, evaporated again and purified by flash chromatography on 100 g of silica gel (mobile phase M). The product is identical to the diastereomeric mixture of example, R f (O) = 0.30 and 0.35 (2 diastereomers)

 The starting material is prepared as follows:

a) 5 (S) - [N- (2 (R, S) -Benzyl-3-tert-butylsulphonyl-propionyl) -histidinyl] -amino-4 (S) -tert-butyldimethylsilyloxy-6-cyclohexyl-2 (S. ) -isopropylhexanoic acid-n-butylamide is prepared analogously to Example 1 from 2-benzyl-3-tert-butylsulfonyl-propionic acid and the tert-butyldimethylsilyl ether of H-His-Cha-Val-n-butylamide, analogously to Example 2a), b ) and c) is obtained from the corresponding ether of Z-cha-val-n-butylamide (Example 43b).

b) SfSl-benzyloxycarbonylamino-tSJ-tert-butyldimethylsilyloxy-e-cyclohexyl-f-isopropyl-hexanoic acid-n-butylamide is prepared from 4.6 g of Z-cha-val-n-butylamide in the presence of 1.36 g of imidazole and 2, 3g tert-butyldimethylchlorosilane formed in 75 ml of DMF.

Example 44: N- (2 (R, S) -Benzyl-3-tert-butylsulphonyl-propionyl) -His-Cha-Val-n-butylamide by cleavage of the 2-chloroethoxycarbonyl protecting group

830 mg 5 (S) - [N- (2 (R, S) -Benzyl-3-tert-butylsulfonyl-propionyl) -histidinyl] -amino-4 (S) - (2-chloroethoxycarbonyloxy) -6-cyclohexyl-2 ( S) -isopropylhexanoic acid-n-butylamide are added dropwise in 20 ml of DMF in a solution of 0.8 g of carbon disulfide and 2.5 g of sodium sulfide nonahydrate in DMF. The mixture is heated for 10 min. At 40 ⁰ C, then evaporated. The residue

is taken up in ethyl acetate, washed with 20 ml of water, dried with sodium sulfate, evaporated again and purified by flash chromatography on 100 g of silica gel (mobile phase M). The product is identical to the diastereomeric mixture of Example 2, R _f (0) and 0.30 and 0.35 (2 diastereomers).

The starting material is prepared analogously to Example 43a) and b) from Z-cha-val-n-butylamide and 2-Chloräthoxychloroformiat and condensation with histidine and 2-benzyl-3-tert-butylsulfonyl-propionic acid.

Example 45: Alternative reaction conditions for the preparation of N- (2 (R, S) -Benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide by condensation

a) With bis (2-oxo-3-oxazolidinyl) -phosphinic acid chloride: 50 mg of 2-benzyl-3-tert-butylsulfonylpropionic acid, 81 mg of H-His-Cha-Val-n-butylamide and 47 mg of bis (2-oxo) 3-oxazolidinyl) -phosphinic chloride are added during 20h. stirred at room temperature in 4 ml of acetonitrile. The reaction mixture is then concentrated and the residue is purified by flash chromatography on 70 g of silica gel 60 (System Q). R _f (0) = 0.30 and 0.35 (2 diastereomers).

b) With 1-benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluoroborate (Castro's reagent, BOP): 50 mg of 2-benzyl-3-tert-butylsulfonylpropionic acid, 81 mg of H-His-Cha-Val-n-butylamide and 78 mg of the title reagent BOP are incubated for 20h. stirred at room temperature in 5 ml of methylene chloride and worked up as under a).

c) With 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ): 50 mg of 2-benzyl-3-tert-butylsulfonylpropionic acid, 81 mg of H-His-Cha-Val-n-butylamide and 44 mg of title reagent EEDQ are added during 20h. stirred at room temperature in 4 ml of THF and worked up as under a).

Example 46: The following are prepared analogously to the above examples:

a) N- (2 (R, S) -Benzyl-3-sulphamoyl-propionyl) -His-Cha-Val-n-butylamide.

b) N- (2 (R, S) -Benzyl-3-methylaminosulphonyl-propionyl) -His-Cha-Val-n-butylamide.

c) N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Gly (OH) -methylamide.

d) N- (2 (S) -Benzyl-3-tert-butylsulphonyl-propionyl) -His-Cha-Val- (2-sulphoethyl) -amide.

e) N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val- (4-aminobutyl) -amide.

Example 47: Gelatin solution

A sterile filtered aqueous solution of N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide is added under aseptic conditions with heating with a sterile gelatin solution containing phenol as a preservative mixed so that 1.0 ml solution has the following composition:

N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -

His-Cha-Val-n-butylamide 3mg

Gelatin 150.0 mg

Phenol 4.7 mg

least. Water up to 1.0 ml "

The mixture is filled under aseptic conditions in Vialenzu 1.0 ml.

Example 48: Sterile dry substance for injection

Dissolve 5 mg of N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide in 1 ml of an aqueous solution containing 20 mg of mannitol. The solution is sterile filtered and filled under aseptic conditions into a 2 ml ampoule, 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 formulation can also be filled in double-chamber spray ampules.

Example 49: Nasal Spray

In a mixture of 3.5 ml of Myglyol812® and O, 08 g of benzyl alcohol, 500 mg of finely ground (<5.0 μηη) N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val -n-butylamide suspended. This suspension is filled into a container with metering valve. 5.0 g of Freon® 12 are filled under pressure through the valve into the container. By shaking, the Freon® is dissolved in the myglyol benzyl alcohol mixture. This spray container contains about 100 single doses, which can be applied individually.

Example 50: Lacquered tablets

For the preparation of 10000 tablets containing per 100 mg of active ingredient, the following ingredients are processed:

N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyD-

His-Cha-Val-n-butylamide 1 000 g corn starch 680 g Colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl 250 g water q.s.

A mixture of the N- (2 (S) -benzyl-3-tert-butylsulfonyl-propionyl) -His-Cha-Val-n-butylamide, 50g cornstarch and the colloidal silica is made with 250g corn starch starch starch and 2.2kg demineralized Water processed into a moist mass. This is driven through a sieve of 3 mm mesh size and at 45 ° C for 30 min. In the fluidized bed dryer

dried. The dry granules are forced through a 1 mm mesh screen, mixed with a previously sieved blend (1 mm sieve) of 330 g cornstarch, magnesium stearate, stearic acid and sodium carboxymethyl starch and pressed into slightly curved tablets.

The compacts are placed in a 45 cm diameter coating pan with a solution of 20 g shellac and 40 g hydroxypropylmethyl cellulose (low viscosity) in 110 g methanol and 1350 g methylene chloride by uniform spraying for 30 min. overdrawn; it is dried by simultaneous injection of air of 60 ⁰ C. Instead of the above-mentioned active ingredient, it is also possible to use the same amount of another active ingredient of the preceding examples.

Claims (13)

A process for the preparation of sulfur-containing substituted 5-amino-4-hydroxyvaleryl derivatives of the formula R ₂ IU $ 5 0 Ri-AN-CH-CH-CH ₂ -CH-CR ₆ (|), wherein R ₁ is acyl substituted with a thio, sulfinyl or sulfonyl group, with the exception of an optionally N-substituted acyl radical of a natural amino acid, A is an optionally N-alkylated α-amino acid residue which is N-terminal with Ri and C-terminal with the group -NR is -connected _2, R ₂ is hydrogen or Niederälkyl, R ₃ is hydrogen, lower alkyl, optionally etherified or esterified hydroxy-lower alkyl, cycloalkyl, cycloalkyl, bicycloalkyl, Tricycloalkylniederalkyl, aryl or aryl-lower alkyl, R ₄ is hydroxy, etherified or esterified hydroxy, R ₅ is lower alkyl, optionally etherified or esterified hydroxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl, bicycloalkyl, bicycloalkyl lower alkyl, tricycloalkyl, tricycloalkyl-lower alkyl, aryl, aryl-lower alkyl, optionally substituted carbamoyl, optionally substituted amino, optionally substituted hydroxy or optionally substituted mercapto, sulfinyl or sulfonyl and R _{6 represent} substituted amino except for an amino group derived from an α-amino acid, furthermore salts of such compounds having salt-forming groups and of pharmaceutical preparations containing such compounds, characterized in that a) a fragment of a compound of formula I having a terminal carboxy group or a reactive acid derivative of this fragment with a compound of the formula I complementary fragment having a free amino group or a reactive derivative thereof with activated amino group, wherein existing in the reaction components free functional groups Optionally in protected form, condensed to form an amide bond, or b) for the preparation of compounds of formula I, wherein R _{4 is} hydroxy, the keto group in a compound of formula R _{1 is} -AN-CH-C-CH ₂ -CH-CR ₆ . (II) in which the substituents have the meanings given and free functional groups, with the exception of the keto group participating in the reaction, are optionally present in protected form, reduced to a hydroxy group by reaction with a suitable reducing agent, or c) for the preparation of compounds of formula I, wherein R _{4 is} hydroxy, an aldehyde compound of the formula Ri-A- -·* H in which the substituents have the meanings mentioned and free functional groups, with the exception of the aldehyde group, optionally in protected form, with an organometallic compound of the formula M - CH ₂ - wherein the substituents have the meanings mentioned and Μ represents a metal radical, reacting and hydrolyzing the formed addition product, or d) in a compound of the formula Ri-AN-CH-CH-CH ₂ -CH-CR ₆ wherein X is a nucleofugic leaving group, the other substituents have the meanings mentioned but and functional groups optionally in protected form, the substituent X replaced by a substituent R ₄ in nucleophilic form introducing reagent to R ₄ , or e) in a compound of the formula R ₂ R-Rs R ₁ -AN-CH-CH-CH ₂ -CH-CN (VI) R ₃ wherein the substituents have the meanings mentioned and existing functional groups are optionally present in protected form, the cyano group in an N-substituted carboxamido - - transferred (C = O) R ₆ , or f) for the preparation of a compound of the formula I in which R _{4 is} free hydroxy, an epoxide of the formula N-CH- di- ^ H -CH- Ri - A - N - CH - CH - CH - CH - C - R ₆ (VII) wherein the substituents have the meanings given and free functional groups are optionally in protected form, reduced with a regio-selective reducing agent to the corresponding alcohol, or
g) for the preparation of a compound of the formula I in which R 1 is a radical of the formula R ^a -S - (CH ₂ ) - CH - (CH ₂ ) -C- (O) ⁿ ι Ρ β ^m (CH ₂ ) _q '(la) and m is 0 or 2, η is 1 and p is O, a compound of the formula R ^a -S (O) _m H or a salt thereof to a compound of the formula R - (CH ₂ ) - C ₁ --C - A - N - CH - CH - CH ₂ --CH - C - R ₆ (VIII), wherein the substituents have the meanings mentioned and free functional groups are optionally in protected form, added, or h) for the preparation of a compound of the formula I, wherein R _{1 is} a radical of the formula R ^a - S - (CHz) _n - CH - (CH ₂ ) - ^m (CH ₂ ) _q (Ia) and pO represents a compound of the formula _a ^ 2 ^ ψ ~~ ft RS- (CHa) _-CH2 -CAN CH-CH-CH ₂ -CH-CR ₆ l \ y \ (Ό) -ⁿ δI ₃   ⁽ '' wherein the substituents have the meanings given and free functional groups are optionally present in protected form, with a compound introducing the radical R ^b - (CH ₂ ) q- alkylated, and if desired i) splitting off any protecting groups present in an available compound and / or, if desired, after carrying out one of the abovementioned processes a) -h) or any other process for the preparation of a compound of the formula I, an obtainable compound of the formula I having a salt-forming group in its salt or converting an available salt into the free compound or into another salt and / or separating off any isomer mixtures which may be obtained and / or in an available compound of the formula I Configuration of a chiral carbon atom and / or converting a compound of the formula I according to the invention into another compound of the formula I according to the invention, and if desired mixing an available compound or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier. 2. The method according to claim 1 for the preparation of compounds of formula I, characterized in that a fragment of a compound of formula I with a terminal carboxyl group or a reactive acid derivative of this fragment with a compound of the formula I complementary fragment having a free amino group or an reactive amino-functional derivative thereof, wherein free-functional groups present in the reaction components are optionally in protected form except for the reacting groups, to form an amide bond, and optionally protecting groups present in an available compound by treatment with acid, base, by hydrogenolysis or by treatment with a 'reducing agent and / or überf an available compound of formula I with a salt-forming group in its salt or an available salt in the free compound or in another salt and / or optionally obtainable isomer mixtures and / or converts a compound of the formula I according to the invention into another compound of the formula I according to the invention. 3. The method according to claim 1 for the preparation of compounds of formula I, characterized by reacting a fragment of a compound of formula I with a terminal carboxyl group or an activated ester derived therefrom, reactive anhydride or reactive cyclic amide with a compound of formula I. complementary fragment having a free amino group, wherein in the reaction components present free functional groups, except for the groups participating in the reaction optionally in protected form, in the presence of a condensing agent selected from a carbodiimide, carbonyldiimidazole, 1,2-oxazolium compounds, a 1,2 -Dihydrochinolin or an activated phosphoric acid compound, and condensed optionally in the presence of an organic base or of alkali metal carbonates in an inert polar aprotic solvent in a temperature range of -40 ^c C to +100 ⁰ C, said activated ester v amino or amido ester type, if desired, formed in situ by the addition of an N-hydroxyamino or N-hydroxyamino compound and, if desired, protecting groups present in an available compound by treatment with acid, with base, by hydrogenolysis or by treatment with a reducing agent cleaves off and / or converts an obtainable compound of the formula I with a salt-forming group into its salt or an available salt into the free compound or into another salt and / or separates any isomer mixtures obtainable and / or a compound of the formula I according to the invention into another converts the compound of formula I according to the invention. 4. The method according to any one of claims 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein R _{1 is} a by a thio, sulfinyl or sulfonyl group and optionally substituted by further, heteroatom-containing groups acyl group of a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heteroaromatic or heteroaromatic-aliphatic carboxylic acid with the exception of the optionally N-substituted natural amino acid methionine, A is an optionally N-alkylated a-amino acid residue, the N-terminal with R ₁ and C-terminal with the group NR ₂ , R _{2 is} hydrogen or lower alkyl, R _{3 is} hydrogen, lower alkyl, hydroxy lower alkyl, cycloalkyl, cycloalkyl lower alkyl, bicycloalkyl lower alkyl, tricycloalkyl lower alkyl, aryl or aryl lower alkyl, R _{4 is} hydroxy, R _{5 is} lower alkyl 2 and more C atoms, hydroxy lower alkyl, cycloa alkyl, cycloalkyl-lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, tricycloalkyl, tricycloalkyl-lower alkyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylamino, aryl or aryl-lower alkyl; and R _{6 represents} an amino group which contains one or optionally two unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radicals having up to 18C atoms or a unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon radical having up to 18 carbon atoms, with the exception of an amino-acid-derived amino radical, further pharmaceutically acceptable salts of such compounds having salt-forming groups. 5. The method according to any one of claims 1-3, characterized in that one selects such starting materials that compounds of formula I, wherein R-i is a radical of the formula R ^a - S - (CH ₂ ) _n - CH - (CH ₂ ) _p - C - ^m (CH ₂ ) < ^{! a} >' wherein R ^{a is} unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, Bioder-tricycloalkyl, cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl, aryl-lower alkenyl, unsubstituted or substituted heteroaryl, heteroaryl-lower alkyl, hydroxy, substituted hydroxy, amino or substituted amino, R ^{b is} hydrogen, mono -, BioderTricycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, mO, 1 or 2, nO, 1 or 2, ρ0,1 or 2 and qO, 1,2,3 or 4 represent. A is a bivalent radical of a natural α-amino acid of the L-configuration normally present in proteins, a homolog of such an amino acid in which the amino acid side chain is extended or shortened by one or two methylene groups and / or a methyl group is replaced by hydrogen, a substituted phenylalanine or phenylglycine wherein the substituent may be loweralkyl, halo, hydroxy, loweralkoxy, loweralkanoyloxy, amino, loweralkylamino, di-loweralkylamino, loweralkanoylamino, loweralkoxycarbonylamino, arylmethoxycarbonylamino and / or nitro, and one or more times, a benzannellated phenylalanine or phenylglycine, one hydrogenated phenylalanines or phenylglycines, a five- or six-membered cyclic, benzannellated α-amino acid, a natural or homologous α-amino acid in which a carboxy group of the side chain in esterified or amidated form, an amino group of the side chain in acy lierter form or a hydroxy group of the side chain in etherified or esterified form, or an epimer of such an amino acid, ie with the unnatural D-configuration, optionally substituted on the N-atom by lower alkyl, R _{2 is} hydrogen or lower alkyl, R _{3 is} lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, tricycloalkyl-lower alkyl, phenyl-lower alkyl or phenyl, R _{4 is} hydroxy, R _{5 is} lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, bicycloalkyl, tricycloalkyl, phenyl, phenyl-lower alkyl, carbamoyl, lower-alkylcarbamoyl, di-lower alkylamino, hydroxy, lower-alkoxy, Lower alkylthio or lower alkylsulfonyl, and R _{6 is} alkylamino having 1 to IOC atoms, di-lower alkylamino, hydroxy lower alkyl amino, di (hydroxy lower alkyl) amino, lower alkoxy lower alkyl amino, lower alkanoyloxy lower alkyl amino, phenoxy lower alkyl amino or phenoxyhydroxy lower alkyl amino wherein phenoxy is optionally substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or carbamoyl, carboxyalkylamino or amino-carboxy-alkylamino in which the carboxy radical is not in the 1-position of the alkyl radical, furthermore dicarboxymethylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonylalkylamino in which the carbonyl radical is not in the 1-position of the alkyl radical, furthermore di-lower alkoxycarbonyl-methylamino-physiologically cleavable esterified Carboxyalkylamino, wherein the ester function is not in the 1-position of the alkyl, carbamoyl or Hydroxyniederalkylcarbamoylalkylamino, wherein the carbamoyl radical is not in the 1-position of the alkyl radical, further dicarbamoyl-methylamino, di (lower alkylcarbam oyl) -methylamino, di (hydroxynyl-alkylcarbamoyl) -methylamino or bis (dinol-alkylcarbamoyl) -methylamino, amino-lower alkylamino, lower-alkylaminoloweralkylarnino, diniberalkylaminoloweralkylamino, lower-alkoxycarbonyl-amino-lower alkylamino, guanidinol-lower alkylamino, saturated five- or six-membered heterocyclyl-lower alkylamino, lower alkenylamino, lower alkynylamino, cycloalkyl-lower alkylamino bonded through a nitrogen atom Phenyiamino or phenyl-lower alkylamino, wherein phenyl is optionally mono- or polysubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkylamino, di-lower alkylamino, acylamino and / or by nitro, pyridyl-lower alkylamino, imidazolyl-lower alkylamino, indolyl-lower alkylamino or Sulfoniederalkylamino, as well as pharmaceutically acceptable salts of these compounds are formed with salt-forming groups. 6. The method according to any one of claims 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein R _{1 is} a radical of the formula R ^a - S - (CH ₂ ) - CH - (CH ₂ ) - C (ό) ^Ω I ^P (CH ₂ ). R ^{a is} unsubstituted or hydroxy, lower alkoxy, phenoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl or carbamoyl-substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, unsubstituted or lower alkyl, hydroxy or amino-substituted aryl, aryl-lower alkyl, unsubstituted or substituted by oxido, lower alkyl or phenyl heteroaryl, Heteroaryl-lower alkyl, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, di-lower alkylamino or amino as part of a five- or six-membered ring containing a nitrogen atom and, optionally, an oxygen atom, R ^{b is} hydrogen, cycloalkyl, aryl or heteroaryl, mO, 1 or 2, nO, 1 or 2, ρ0,1 or 2 and q0, 1, 2 or 3, A is the bivalent residue of the amino acids alanine, valine, norvaline, leucine, norleucine, serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine, cyclohexylalanine, indoline 2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, Am inomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, di-lower alkylglutamine, histidine, lysine or ornithine, wherein the carboxy group esterified in the side chain of aspartic acid or glutamic acid with a lower alkanol, etherified the hydroxy group in serine with lower alkyl or with benzyl, the amino group in the side chain of lysine or Ornithine may be acylated by lower alkanoyl, by lower alkoxycarbonyl or by arylmethoxycarbonyl and / or the a-nitrogen atom of the amino acids may be substituted by lower alkyl, R _{2 is} hydrogen or lower alkyl, R _{3 is} lower alkyl, cycloalkyl-lower alkyl or tricycloalkyl-lower alkyl, R _{4 is} hydroxy and R _{5 is} lower alkyl, cycloalkyl, cycloalkyl-lower alkyl , 1-adamantyl, benzyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylamino, hydroxy, lower alkoxy, lower alkylthio or lower alkylsulfonyl, and R _{6 is} alkylamino having 1 to 10C atoms, di-lower alkylamino, hydroxy-lower alkylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, furthermore dicarboxy-methylamino, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonyl-alkylamino, wherein the Carbonyl radical is not in the 1-position of the alkyl radical, furthermore Diniederalkoxycarbonyl-methylamino, physiologically cleavable esterified carboxyalkylamino wherein the ester function is not in the 1-position of the alkyl radical, carbamoyl or Hydroxyniederalkylcarbamoylalkylamino, wherein the carbamoyl radical is not in the 1-position of the alkyl radical, further Dicarbamoyl-methylamino, di- (lower alkylcarbamoyl) -methylamino, di (hydroxy-lower alkylcarbamoyl) -methylamino or bis (diniederalkylcarbamoyl) -methylamino, aminoloweralkylamino, lower-alkylaminoloweralkylamino, di-lower alkylaminoloweralkylamino, lower alkoxycarbonylaminoloweralkylamino, guanidinoloweralkylamino, cycloalkylthio eralkylamino, benzylamino, pyridyl-lower alkylamino, imidazolyl-lower alkylamino, indolyl-lower alkylamino or sulfo-lower alkylamino, as well as pharmaceutically acceptable salts of these compounds having salt-forming groups. 7. The method according to one of der'Ansprüche 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein R _{1 is} a radical of the formula R ^a -S - (CHa) _n - CH - (CH ₂ ) _p - C- ^m (CH ₂ ) _q (Ia), R ^{a is} unsubstituted or hydroxy, lower alkoxy, phenoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl or carbamoyl-substituted lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, unsubstituted or lower alkyl, hydroxy or amino-substituted aryl, aryl-lower alkyl, unsubstituted or substituted by oxido, lower alkyl or phenyl heteroaryl, Heteroaryl-lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino or amino as part of a five- or six-membered ring containing a nitrogen atom and, optionally, an oxygen atom, R ^{b is} hydrogen, cycloalkyl, aryl or heteroaryl, mO, 1 or 2, n0 or 1, p0 and q represents 1 or 2, Aden is the bivalent radical of the amino acids alanine, serine, phenylalanine, N-methyl-phenylalanine, cyclohexylalanine, histidine or N-methylhistidine, R _{2 is} hydrogen, R _{3 is} lower alkyl or Cycloalkyl-lower alkyl, R _{4 is} hydroxy, R _{5 is} lower-alkyl, hydroxy, lower-alkoxy, lower-alkylthio or lower-alkylsulfonyl, and R _{6 is} lower alkylamino having 1-7C atoms, di-lower alkylamino, hydroxy-lower alkylamino, carboxyalkylamino or amino-carboxyalkylamino, wherein the carboxy radical is not in the 1-position of the alkyl radical, lower alkoxycarbonylalkylamino or acylamino-lower alkoxycarbonylalkylamino, wherein the carbonyl radical is not in 1-step of the Alkyl radicals, Aminiederiederalkylämino, di-lower alkylaminoloweralkylamino, Niederalkoxycarbonylaminoniederalkylamino, Morpholinoliederalkylamino, Pyridylniederalkylamino, Imidazolylniederalkylamino or Sulfoniederalkylamino represent, and pharmaceutically acceptable salts of these compounds are formed with salt-forming groups. 8. The method according to any one of claims 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein R _{1 is} a radical of the formula _R a _ s - (CH ₂ ) _n - CH - (CH ₂ ) _p - m _(CHa) , there), wherein R ^{a is} unsubstituted or substituted by hydroxy or lower alkoxy Niederaikyl, phenyl, benzyl or unsubstituted or substituted by oxido or Niederaikyl heteroaryl having 1 or 2 nitrogen atoms, R ^b cyclohexyl or phenyl, m is 0.1 or 2, η 1, ρ 0 and q 1 or 2, A is the bivalent radical of the amino acid histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} lower alkylamino, dimethylamino or 2-hydroxyethylamino, and pharmaceutically acceptable salts are formed from these compounds , 9. The method according to any one of claims 1-3, characterized in that one selects such starting materials that compounds of the formula I, wherein R _{1 is} a radical of the formula _R ^a _ c - (CH ₂ ) - CH - (CH ₂ ) - (6). ⁿ ι ^m (CH ₂ ) (La), wherein R ^{a is} lower alkyl, phenyl, 2-pyridyl, hydroxy, lower alkylamino, di-lower alkylamino or pyrrolidino, R ^{b is} phenyl, m 2, n1, p0 and q1, A is the bivalent radical of the amino acid alanine, serine or histidine, R _{2 is} hydrogen, R _{3 is} cycloalkyl-lower alkyl R _{4 is} hydroxy, R _{5 is} methyl, isopropyl, hydroxy, methoxy, methylthio or methylsulfonyl and R _{6 is} lower alkylamino, S-amino-B-carboxyn-pentylamino, 4-aminobutylamino, 2- (4-imidazolyl) -ethylamino or 2-sulfoethylamino and the C atoms carrying the radicals R ₃ and R _{4 have} the S configuration, and furthermore pharmaceutically acceptable salts of these compounds are formed. 10. The method according Anpsruch 9, characterized in that one selects those starting materials that the compound of formula l / wherein R _{1 is} a radical of the partial formula la in which R ^a te rt-butyl, R ^b is phenyl, m2, n1, p0 and q1 is Aden bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} n-butylamino and the radicals R ₃ , R ₄ and R ₅ carry C atoms and the methine C atom of the partial formula Ia have the S configuration, and pharmaceutically acceptable salts thereof are formed. 11. The method according to claim 9, characterized in that one selects such starting materials, that the compound of formula I, wherein R _{1 is} a radical of the partial formula Ia, wherein R ^a tert-butyl, R ^{b is} phenyl, m2, η 1, p0 and q1, A is the bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxyl, R _{5 is} methyl and R _{6 is} methylamino, and the C atoms carrying the radicals R ₃ and R ₄ and the methine C atom of the partial formula Ia, the S configuration and the carbon atom carrying the radical R _{5 have} the R configuration, and their pharmaceutically acceptable salts are formed. A process as claimed in claim 9, characterized in that such starting materials are chosen such that the compound of formula I wherein R 1 is a radical of partial formula Ia wherein R ^{a is} tert-butyl, R ^{b is} phenyl, m 2, n 1, p o and q is a-divalent Rest of the amino acid L-Aianin, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} n-butylamino and the radicals R ₃ , R ₄ and R ₅ carrying C atoms and methine-C Atom of partial formula Ia have the S-configuration and their pharmaceutically acceptable salts are formed. 13. The method according to claim 9, characterized in that one selects such starting materials that the Vebindung of formula I, wherein R _{1 is} a radical of the sub-formula I a, wherein R ^a tert-butyl, R ^{b is} phenyl, m2, n1, pO and Q1 is Aden bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cycloheptylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} n-butylamino and the radicals R ₃ , R ₄ and R ₅ carry C atoms and the methine C atom of the partial formula Ia have the S configuration, and pharmaceutically acceptable salts thereof are formed. 1.4. Process according to Claim 9, characterized in that starting materials are chosen such that the compound of the formula I in which R _{1 is} a radical of the partial formula Ia, in which R ^{a is} tert-butyl, R ^{b is} phenyl, m 2, n 1, PO and q 1, Aden bivalent radical of the amino acid L-histidine, R _{2 is} hydrogen, R _{3 is} cyclohexylmethyl, R _{4 is} hydroxy, R _{5 is} isopropyl and R _{6 is} methylamino and the radicals R ₃ , R ₄ and R ₅ carrying C atoms and methine-C Atom of the partial formula I a have the S configuration, and their pharmaceutically acceptable salts are formed.